PURPOSE: To evaluate the use of granulocyte-colony stimulating factor (G-CSF) in adult patients receiving chemotherapy for cancer

TYPES OF PATIENTS ADDRESSED: Adult patients receiving chemotherapy for cancer

PROCESS OF DEVELOPMENT:

The following questions were applied by the European Organisation for Research and Treatment of Cancer (EORTC) G-CSF Guidelines Working Party.

In adult patients with cancer receiving chemotherapy:

1. Is there evidence that patient-related factors increase the risk of febrile neutropenia (FN)?
2. Is there evidence that certain chemotherapy regimens increase the risk of FN?
3. Is there evidence that some patients are more at risk for severe morbidity as a result of an FN episode?
4. Is there evidence to support the use of G-CSF when there is a 20% risk level for FN?
5. Is there evidence to support the use of G-CSF to
   1. Maintain the correct dose of chemotherapy and relative dose intensity and density?
   2. Improve overall and progression-free survival?
6. Is there evidence to support the use of G-CSF to enable the delivery of dose-dense and -intense chemotherapy
   1. By increasing the dose?
   2. By withdrawing one drug and increasing the dose of the remaining drugs?
   3. By increasing the dose frequency?
7. Is there evidence to support the use of G-CSF to reduce the risk of infection-related mortality?
8. Is there evidence to support the use of G-CSF to reduce the incidence of FN?
9. Is there evidence to support the use of G-CSF for the treatment of ongoing FN?
10. Is there evidence to support the use of different G-CSFs?

The article describes guidelines prepared by the G-CSF Guidelines Working Party of the EORTC to systematically review available published data and derive evidence-based recommendations on the appropriate use of G-CSF in adult patients receiving chemotherapy for cancer.

The following are levels of evidence applied by the EORTC G-CSF Guidelines Working Party.

• Level I: Evidence obtained from meta-analysis of multiple, well-designed, controlled studies or from high-power randomized, controlled clinical trial
• Level II: Evidence obtained from at least one well-designed experimental study or low-power randomized, controlled clinical trial
• Level III: Evidence obtained from well-designed, quasi-experimental studies such as nonrandomized, controlled single-group, pre-post, cohort, time, or matched case-control series
• Level IV: Evidence obtained from well-designed, non-experimental studies such as comparative and correlational descriptive and case studies
• Level V: Evidence obtained from case reports and clinical examples

The following grades of recommendations were applied by the EORTC G-CSF Guidelines Working Party.

• Grade A: There is evidence of type I or consistent findings from multiple studies of types II, III, or IV.
• Grade B: There is evidence of types II, III, or IV, and findings are generally consistent.
• Grade C: There is evidence of types II, III, or IV, but findings are inconsistent.
• Grade D: There is little or no systematic empirical evidence.

DATABASES USED: MEDLINE, PreMEDLINE, EMBASE, and the Cochrane Library.

INCLUSION CRITERIA: Articles selected were published in English from December 31, 1994–September 16, 2005. Reference lists of the identified meta-analyses were interrogated manually, and any primary papers considered relevant were included. Abstract books from key international congresses were searched manually to identify relevant evidence presented at meetings from 2003–2005.

EXCLUSION CRITERIA: Studies involving children younger than 18 years of age or patients with leukemia were excluded, as were cost analyses, as these lack international applicability. Relevant articles “in press” and additional papers identified by members of the working party were included in limited instances.

Recommendation 1: Patient-related risk factors for increased incidence of FN

• Patient-related risk factors should be evaluated in the overall assessment of FN risk prior to each cycle of chemotherapy. Particular consideration should be given to the elevated risk of FN for patients aged 65 years or older. Other adverse risk factors that may influence FN risk based on level I and II evidence included advanced stage of disease, experience of previous episode(s) of FN, and lack of G-CSF use and antibiotic prophylaxis. However, please note that the indiscriminate use of antibiotic prophylaxis is not recommended by either the Working Party or the EORTC Infectious Disease Group. Risk factors that may influence FN risk based on level III and IV evidence included poor performance and/or nutritional status, female gender, hemoglobin less than 12 g/dl, and liver, renal, or cardiovascular disease.
• Recommendation grade B

Recommendation 2: Chemotherapy regimens associated with increased risk of FN

• Consideration should be given to the elevated risk of FN with certain chemotherapy regimens. The risk of FN for certain chemotherapy regimens is summarized in Table 4 of the original paper.
• Recommendation grade A/B (depending on the evidence for each chemotherapy regimen)

Recommendation 3: G-CSF to support chemotherapy

• In situations in which dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF should be used as a supportive treatment. If reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis, primary G-CSF prophylaxis should be used to maintain chemotherapy. Examples of this could be when the patient is receiving adjuvant or potentially curative treatment, or when the treatment intent is to prolong survival. When this is not crucial, use of less myelosuppressive chemotherapy or dose and schedule modifications should be considered.
• Recommendation grade A

Recommendation 4: Impact of the overall FN risk on G-CSF use

• The risk of complications related to FN should be assessed individually for each patient. When assessing FN risk, the clinician should take into account patient-related risk factors, the chemotherapy regimen and associated complications, and treatment intent. If the patient is at more than 20% overall risk of FN, prophylactic G-CSF is recommended. With chemotherapy regimens associated with an FN risk of 10%–20%, particular attention should be given to the assessment of patient characteristics that may increase the overall risk of FN.
• Recommendation grade A

Recommendation 5: G-CSF in patients with existing FN

• Treatment with G-CSF for patients with solid tumors and ongoing FN is indicated only in special situations. These are limited to those patients who are not responding to appropriate antibiotic management and who are developing life-threatening infections (e.g., severe sepsis, septic shock).
• Recommendation grade B

Recommendation 6: Choice of formulation

• Filgrastim, lenograstim, and pegfilgrastim have clinical efficacy, and the authors recommend the use of any of these agents to prevent FN and FN-related complications, where indicated.
• Recommendation grade A

To characterize the antiemetic treatment response of aprepitant when combined with ondansetron and dexamethasone compared to ondansetron and dexamethasone alone, in multiple patient populations receiving highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC)

Study participants had been diagnosed with lung, breast, gastrointestinal (GI), and genitourinary (GU) tumor types and were included in four previously completed randomized control trials. Authors selected the articles for review. Inclusion and exclusion criteria were outlined for each study.

All patients were in active antitumor treatment.

The results of the post hoc analysis of the pooled data demonstrated that complete antiemetic responses were observed in a higher proportion of both HEC and MEC treated patients for all tumor types. For HEC treated patients, significant differences were found in GU (61% versus 44.7%, p = 0.001), GI (68% versus 45%, p = 0.013), and lung cancers (73% versus 53%, p = 0.001). In MEC-treated patients, a significant difference was found in breast cancer (54.9% versus 43.9%, p = 0.0001). Complete response (no vomiting and no rescue medications) following MEC ranged from 54.9% in the breast cancer group to 76% in the lung cancer group.

This analysis demonstrates the consistent efficacy of aprepitant as part of an antiemetic regimen across different tumor types and chemotherapy regimens. The authors recommend the use of an antiemetic regimen that includes aprepitant prior to the first cycle, noting that it will prevent anticipatory chemotherapy-induced nausea and vomiting (CINV) in those patients who respond to the preventative measures.

• This was not a systematic review but, rather, a report of four pooled studies examined by post hoc analysis. 
• The sample size for some of the tumor types was small. 
• This article did not address nausea but, instead, focused on vomiting and use of rescue antiemetic medications.
• The studies were believed to be from randomized trials sponsored by Merck to test efficacy of Amend.

Evidence supports the use of aprepitant in combination with other antiemetic medications for patients receiving MEC and HEC. This supports current understanding of multiple pathways leading to CINV.

To describe commonly used therapies that National Comprehensive Cancer Network (NCCN) Task Force members agreed are appropriate standards of care to manage dermatologic and ocular toxicities that occur in patients with cancer being treated with epidermal growth factor receptor (EGFR) inhibitors.

NCCN Task Force members reviewed available published data on treating toxicities associated with EGFR inhibitors, reviewed data from the treatment of clinically similar toxicities from different etiologies, and shared their expert opinions. Through this process, they developed recommendations for managing dermatologic and ocular toxicities associated with EGFR inhibition in patients with cancer. 

The databases searched were not identified specifically. The authors stated their recommendations were supported only by anecdotal evidence.

Search keywords, inclusion criteria, and exclusion criteria were not provided.

• Patients were undergoing the active treatment phase of care.
• The study has clinical applicability to late effects.

Modifying EGFR Inhibitor Therapy

• Brief dosing interruptions can be helpful in managing high-grade EGFR-inhibitor–associated skin and ocular toxicities. These toxicities may lessen over the course of one to two weeks, and then reintroduction of the EGFR inhibitor often is feasible.
• The role of dose reduction remains uncertain. The reproducible relationship between rash and survival for all EGFR antagonists suggests, but does not prove, that maintaining full dose in patients with rash may be beneficial.

Topical Therapies for Rash

Prophylactic/Mitigating Treatments:

• Long-term prophylactic topical mupirocin ointment can be used in the nose to prevent Staphylococcus aureus colonization, especially for patients with recurrent infection.

Reactive Treatments: 

• Topical steroids (low-strength on the face; medium strength on the body) and topical antibiotics (e.g., clindamycin, erythromycin) are based on expert reference and clinical experience, rather than data from randomized clinical trials.
• Petroleum jelly, ammonium lactate, or dilute hydrogen peroxide soaks with gentle debridement may remove excessive formation of yellow crusts and debris in severe skin rash.
• If superinfection is suspected (because of excessive induration and erythema, the presence of a dominant lesion that appears larger and more inflamed than the remainder of the lesions, or purulent drainage), then the site should be cultured to determine the organism and sensitivity. Positive cultures may be evidence of infection or colonization, and clinical judgment is needed to evaluate culture results.
• Pulsed dye laser and intense pulsed light may effectively decrease the erythema and prominence of telangiectatic vessels (dilated blood vessels).
• Postinflammatory hyperpigmentation may fade through the use of hydroquinone, azelaic acid, topical retinoids, or laser-based therapies.

Systemic Therapies for Rash

Prophylactic/Mitigating Treatments:

• These treatments are used to decrease the severity of rash.
• Oral antibiotics include tetracycline (500 mg BID), minocycline (100 mg daily), and doxycycline (100 mg BID).
• Multiagent prophylactic skin treatment (Skin Toxicity Evaluation Protocol With Panitumumab [STEPP] study—randomized trial) includes oral doxycycline (100 mg BID), topical corticosteroids (1% hydrocortisone), skin moisturizer, and sunscreen.
• Sunscreens that are non–alcohol based and physical sunblocks (e.g., zinc oxide, titanium dioxide) with 30 sun protection factor (SPF) that block ultraviolet A (UVA) and ultraviolet B (UBV) light should be applied thickly. 
• A topical vitamin K3 analog, menadione, is being investigated in a phase 1 trial for use in reducing the skin rash associated with EGFR inhibitors.

Reactive Treatments:

• The following treatments are based on anecdotal reports or nonrandomized studies.
  • Oral antibiotics:  tetracycline, minocycline, and doxycycline
  • Retinoids:  isotretinoin (problem with paronychia) and low-dose acitretin (oral 10 mg per day)
  • Systemic steroids: May be appropriate in some settings (usually in the inpatient setting) with careful supervision.

Paronychia:

• For bacterial and fungal cultures, treat infection with appropriate oral antibiotics.
• Apply Monsel’s (ferric subsulfate) solution or silver nitrate to bleeding, overgrown tissue.
• Soaks for symptomatic relief include 4% thymol in alcohol, aluminum acetate (Burow's solution), white vinegar (1:10), and bleach (1/4 cup bleach: 3 gallons water).
• Use topical corticosteroid cream (e.g., methylprednisolone) for inflammatory, noninfected paronychia.
• Clip nails, remove embedded nails or possibly the nail plate, and pack the area with cellulose sponge (Surgifoam^®).
• Wear well-fitted shoes or sandals.
• Cushion nail beds for symptomatic comfort.
• Use topical corticosteroid cream (e.g., methylprednisolone) for inflammatory paronychia.

Pruritus:

• Apply cool compresses, sedating antihistamines (diphenhydramine) at evening or bedtime, topical steroids, and topical menthol lotions.
• Give oral gabapentin or pregabalin (100 mg BID).
• For dry skin, minimize the use of soap, increase use of emollients, avoid alcohol-based agents and topical antipruritics (e.g., Aveeno^® Anti-Itch, Sarna^® Ultra).
• Topical agents for the scalp include fluocinonide 0.05%, clobetasol foam, or steroid shampoo.

Xerosis:

• Frequently apply zinc oxide (30%), petroleum jelly, and other thick emollients (e.g., Aquaphor^®, Aveeno, Bag Balm^®, Cetaphil^®, Cutemol^®, Eucerin^®, Vanicream^®).
• Avoid alcohol-based lotions, antibacterial soaps, long baths or frequent water immersion, and contact with harsh chemicals.

Fissuring on the heels or fingertips:

• Do not use Monsel’s solution (ferric subsulfate) on the face. Some NCCN Task Force members believed this solution may increase the size of the fissures and stain tissue.
• Silver nitrate
• Aluminum chloride solution
• Zinc oxide cream (20%–30%)
• Bleach soaks (10 minutes per day) to prevent infection (1/4 cup bleach: 3 gallons water)
• Protective coverings
• Apply cyanoacrylate glue (e.g., Krazy Glue^®, Super Glue^®) to fissures to relieve pain and promote healing. Some patients and healthcare providers prefer cyanoacrylate glue because liquid cyanoacrylate coverings may increase the sensation of burning and delay healing.
• Antibiotics (e.g., doxycycline) for infected fissures

Desquamation:

• Petroleum jelly or other thick emollients (e.g., Bag Balm)
• Mild (neutral pH) soap
• 12% ammonium lactate, 6% salicylic acid, and 20% urea

The NCCN Task Force report described the management of dermatologic and ocular toxicities that occur in patients receiving EGFR inhibitors. Few recommendations were evidence based; however, some commonly used therapies have data supporting their use. 

Implications for nursing practice include integrating the recommendations of the NCCN Task Force into facility algorithms for preventing or managing several types of EGFR-induced skin reactions. Well-designed research is needed in this area.