Adult patients with cancer receiving cyclic chemotherapy for solid tumors or lymphoma who were at risk for temporary, severe neutropenia (absolute neutrophil count [ANC] < 500/mm³) were treated with oral levofloxacin 500 mg or matching placebo daily for seven days during the expected neutropenic period. Treatment began on day 5 for regimens associated with early onset of neutropenia (e.g., docetaxel), day 8 for 14-day and 21-day cycles, and day 15 for 28-day cycles.

Patients were on study for a mean of 4.4 cycles of chemotherapy, with 45% of patients completing six cycles.

784 patients were randomly assigned to the placebo arm and received 3,459 cycles of chemotherapy (mean = 4.4 cycles per patient).

Random assignment of patients in the SIGNIFICANT trial was stratified by age (younger than age 40, 40–59, and 60 years of age and older) and cancer type (breast, testicular, small cell lung, Hodgkin disease, non-Hodgkin lymphoma [NHL], and others).

1,565 adults starting chemotherapy for solid tumors or lymphomas; eligible regimens were known to be associated with a risk of neutropenia (ANC <  500/mm³), but were not routinely given with granulocyte–colony-stimulating factor (G-CSF) support. Many different types of cancer were included.

60 oncology centers in the United Kingdom.

The study was a prospective, multicenter, randomized, double-blind, placebo-controlled trial with secondary univariate and multivariate analysis.

• The primary outcome measure was the incidence of clinically-documented febrile episodes (FEs), defined as a core temperature exceeding 38°C and attributed to infection.
• The original results demonstrated a reduction in FEs in patients receiving levofloxacin. However, the use of prophylactic antibiotics may increase the rate of antibiotic resistance, so the data from a 2005 study by the authors were analyzed to determine which patients benefit most from prophylactic antibiotics. The analysis measured rates of FEs across all cycles, calculated as the proportion of randomly assigned patients experiencing the event at least once during the chemotherapy program (per patient FE rate). The analysis separates events in cycle 1 because chemotherapy dose reductions and possibly antibiotic resistance may affect later cycles. Per cycle FE rates are calculated as the proportion of observed cycles in which an event occurs.
• Rates of hospitalization for the treatment of suspected infection (HTSI) also were analyzed. HTSI occurred in a subset of patients with FEs and also in some patients not meeting the trial criteria for an FE.
   

119 of 784 (15.2%) control group participants had at least one FE during chemotherapy.

Treatment benefit of quinolone prophylaxis was present across all cycles.

As reported in a 2005 article by the authors, the per-patient FE rate was 10.8% (84 of 781) for patients receiving levofloxacin compared with 15.2% for patients receiving placebo (119 of 784), giving a statistically significant reduction in the risk of FE (odds ratio = 0.67; 95% confidence interval [0.5, 0.91]; p =0.009).

For the first cycle only, the per-patient FE rate was 3.5% in patients receiving levofloxacin compared with 7.9%  in controls (odds ratio = 0.42; 95% confidence interval [0.26, 0.66]; p =0.0001),  whereas for non–first cycles, the per-patient FE rate was 7.8% (61 of 781) and 9.8%  (77 of 784), respectively (odds ratio = 0.78; 95% confidence interval [0.55, 1.11]; p = 0.16).

Per-cycle FE rates in cycle 2 and cycles 2–6 indicate that prophylactic benefit is gained in the small number of patients who experience an FE in cycle 1, but not in the much larger group of patients who do not experience an FE in cycle 1.

The data suggest that the benefit of antibiotics is greatest in those who experience an FE in cycle 1 because they are at higher risk of developing an FE in subsequent cycles compared with patients who do not develop an FE in cycle 1.
 

• Secondary analysis
• The primary outcome is the incidence of FEs rather than documented infections, and a reduction in documented infections may be a more meaningful endpoint.
• The sample is at low risk for febrile neutropenia. An important consideration for low-risk patients with short durations of neutropenia is whether quinolone prophylaxis is of greater benefit than the option of outpatient quinolone treatment for fever and neutropenia, should it occur. Both the National Comprehensive Cancer Network and the Infectious Diseases Society of America recommend oral quinolone-based regimens as outpatient empirical therapy for neutropenic fever in adults meeting criteria for low risk for complications.
• Use of quinolone prophylaxis may preclude later use of the regimens as empirical therapy for neutropenic fever in the same patient. Guidelines on outpatient management of adults with neutropenic fever assume that quinolones were not used as prophylaxis and the use of quinolones for prophylaxis precludes their use for treatment.
   

To evaluate the effect of olive oil on radiodermatitis

Patients were randomly assigned to the olive oil group or the control group. Patients treated with olive oil used it three times daily beginning on the first day of radiation therapy (RT) and continued for two weeks after completion of RT. The control group used water in place of the olive oil. Both groups were instructed to gently wash with water alone or mild soap and water. Side effects were recorded by a dermatologist and radiologist who were blinded to the study group assignment.

• N = 94
• MEAN AGE = 55.9 years
• MALES: 93.6%, FEMALES: 6.4%
• KEY DISEASE CHARACTERISTICS: All had nasopharyngeal cancer, and most were stage III.
• OTHER KEY SAMPLE CHARACTERISTICS: All were receiving high-dose RT (total dose = 70 Gy) with weekly cisplatin and docetaxel. Intensity-modulated radiation therapy (IMRT) was used in two Gy daily fractions for seven weeks.

• SITE: Single site  
• SETTING TYPE: Outpatient  
• LOCATION: China

PHASE OF CARE: Active antitumor treatment

Single-blind, randomized, controlled trial

• Radiation Therapy Oncology Group (RTOG) skin scoring
• Visual analog scales (VASs) for itching, pain, and burning (0–10)

Grade I and II skin reactions occurred in 93.6% of those using olive oil and 72.3% of those using water. Grade III reactions were seen in 6.4% of those in the experimental group and 27.7% of those in the control group (p < 0.01). Symptoms from VAS scores were also lower in the experimental group (p < 0.01). No patients developed grade IV skin toxicity.

Olive oil appeared to provide some protection against the development of severe radiodermatitis compared to cleansing and water alone.

• Small sample (< 100)
• Measurement/methods not well described
• Whether all symptoms were on a single VAS score and the frequency of that scoring were unclear. 
• Whether patients were instructed not to use any other skin treatments was not stated.

Prophylactic use of topical olive oil may provide protection from the development of more severe radiodermatitis. Results of this study provide promising results. Further research to confirm these findings would be beneficial.

To assess feasibility and effectiveness of aquatic-based exercise in the form of deep water running as part of a multimodal physiotherapy program for breast cancer survivors in an effort to decrease cancer-related fatigue

Eight week program of one hour sessions, three times per week, of multimodal physiotherapy program combined with deep water running delivered by physiotherapists in groups of 8–10 participants. Each session included 30 minutes of land-based exercise, followed by 20 minutes of deep water running.

• N = 42  
• MEAN AGE = 47.27 years for the intervention group and 48.67 years for the control group
• FEMALES:100%
• KEY DISEASE CHARACTERISTICS: Patients were within one year of breast cancer diagnosis, were aged 25–65 years, and post-cancer treatment within past six months.
• OTHER KEY SAMPLE CHARACTERISTICS: Patients were excluded if they had a fear of aquatic exercise.

• SITE: Multi-site  
• SETTING TYPE: Outpatient  
• LOCATION: Two primary care centers in Andalusia, Spain

• PHASE OF CARE: Transition phase after active treatment

• Non-randomized study with a wait-list control group 
• Outcomes were measured/evaluated by one assessor who was blinded to participant group allocation.

• Piper Fatigue Scale–Revised
• SF-12 Health Survey
• European Quality of Life (five dimensions)
• European Visual Analog Scale

Statistically significant differences in fatigue were found between groups after eight weeks, with the intervention group reporting greater improvement in behavioral severity, affective/meaning, and sensory fatigue.

Demonstrated positive effects of exercise on cancer-related fatigue. Supports prior studies that demonstrated greater improvement combining educational and exercise programs

• Small sample (< 100)
• Risk of bias (no random assignment)
• Intervention expensive, impractical, or training needs existed
• No long-term follow-up

This is a difficult program to replicate, but it appears that it is likely to be effective in reducing cancer-related fatigue.

To evaluate the efficacy of methadone as a substitute for morphine, and to investigate whether the addition of acetaminophen improves pain control in switching to methadone

Patients using morphine for oncologic pain who were on a stable dose for at least one week were recruited. Patients were rapidly switched to oral methadone without a transition period and randomized to receive acetaminophen or placebo with methadone for seven days. The daily morphine dose was converted to methadone in ratios according to the total daily morphine dose. In case of additional pain, patients were instructed to use extra methadone no more than every two hours using a dose equal to 25% of the total daily dose. Use of coanalgesics such as anti-inflammatory drugs, antidepressants, and neuroleptics was allowed. Pain intensity was evaluated daily and recorded by patients in a diary along with all analgesic medications used. Patients were followed for seven days.

• The study reported on 49 patients.
• Median patient age was 58.5 years (range = 19–81 years).
• The sample was 53% male and 47% female.
• Various tumor types were cited, with the most frequent being colorectal, breast, and lung.
• Eighty-eight percent of patients had non-neuropathic pain.
• Median pain intensity at baseline was 5 in the acetaminophen group and 3.5 in the placebo group. Median morphine daily dose at baseline was 60 mg, with a range of 40–540 mg.

• Single site
• Outpatient setting
• Brazil

The study design was double-blind, randomized, placebo-controlled for use of acetaminophen, and open label for switch to methadone.

• Numeric rating scale (0–10)
• Faces pain rating scale
• Four-point rating scale for side effects
• European Organization for Research and Treatment Cancer Core Quality of Life questionnaire (EORTC QLQ-C30)

Of the original study sample, 16% ended participation early due to treatment failure with intense pain, somnolence, or vomiting. Most patients who completed the study had a significant improvement in pain by the faces (p = 0.05) and numeric (p = 0.03) rating scales. There were no differences between patients who did and did not receive acetaminophen.

Study findings show that most patients can be switched from morphine to methadone with no transition period, with some improvement in side effects of constipation and xerostomia and adequate pain control. The addition of acetaminophen in this process was of no benefit.

• The study had a small sample, with less than 100 participants.
• No data were provided on total opioid consumption or use of rescue doses during the study.
• The study period was very short, and even within this time frame, 16% experienced treatment failure with methadone.
• No information was provided on actual use of adjuvant medications for pain control.

This study shows that patients can be rapidly switched from morphine to methadone; however, this approach failed in 16% of patients. Methadone may be associated with less constipation and dry mouth, and may be a good pain control option for patients with these problems. Acetaminophen did not improve pain control with this switching process.

To evaluate the efficacy and safety of gabapentin for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) during the first cycle of moderately or highly emetogenic chemotherapy

Chemotherapy naïve patients with cancer who were scheduled to begin moderately or highly emetogenic chemotherapy were randomized to either receive 300 mg gabapentin or a placebo, in addition to a standard regimen of antiemetic prophylaxis (8 mg IV ondansetron, 10 mg IV dexamethasone, and 50 mg IV ranitidine before chemotherapy on day 1 and 4 mg oral dexamethasone twice a day on days 2 and 3).

Patients received either the gabapentin or the placebo five and four days before chemotherapy, once per day; three and two days before chemotherapy, twice per day; and one day before through five days after chemotherapy, three times per day. After chemotherapy was administered until the morning of day 5, patients kept diaries to record episodes of emesis or retching and severity of nausea over the previous 24 hours.

The primary outcome of this study was an evaluation of the number of patients reporting a complete response (CR), defined as the absence of nausea and vomiting and no use of rescue medications, during three timeframes.

• Acute phase of treatment (starting after chemotherapy was administered and ending 24 hours later)
• Delayed phase (starting 24 hours after chemotherapy was administered and ending on day 5 of treatment)
• Overall

• The study consisted of 80 patients.
• The mean age of patients was 53.95 years (SD = 10.15 years).
• The majority of the sample was female (93.75%).
• Cancer diagnoses were lung, breast, and head and neck cancer.
• Patients were chemotherapy-naive and scheduled to receive moderately or highly emetogenic chemotherapy (cisplatin greater than 60 mg/m² or doxorubicin greater than 50 mg/m²).

The study was conducted at a single site at a large medical institution in Brazil.

All patients were in active treatment.

This was a randomized, double-blind, placebo-controlled trial.

• Patients recorded episodes of vomiting or retching using diaries. Patients were asked to record each episode of emesis or retching from the morning of chemotherapy administration until the morning of the sixth day after.
• Nausea was recorded using diaries. Patients were asked to record the intensity of their nausea over the last 24 hours on a 100-mm visual analog scale (VAS) ranging from ”no nausea” to ”nausea as bad as it could be” from the morning of chemotherapy administration until the morning of the sixth day after.
• Patients recorded the impact of CINV on daily life via the Functional of Living Index-Emesis (FLIE).
• Use of rescue medication was recorded in diaries. Patients were asked to record each instance a medication was taken to control nausea or emesis from the morning of chemotherapy administration until the morning of the sixth day after.
• Adverse events were recorded at the post-study visit on day 6 using the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0.

• Patients who received gabapentin in addition to the standard regimen of antiemetic prophylaxis were significantly more likely to experience CR compared to those who received a placebo and standard antiemetic prophylaxis (p = 0.04).
• Patients taking gabapentin also were significantly more likely to experience CR during the acute phase of treatment (the first 24 hours after chemotherapy administration) compared to the placebo group.
• No difference was found between groups for episodes of CR during the delayed phase of treatment (24 hours after chemotherapy administration up to day 5).
• No adverse events were reported.

Gabapentin may be a low-cost, nausea prophylaxis medication that can be used as an alternative to more expensive antiemetic medications. Although the authors described gabapentin as a low-risk medication, recent reports have linked gabapentin to increased rates of depression and suicide. It also has been commonly associated with the side-effects of drowsiness and dizziness.

• This study involved a small sample of fewer than 100 participants.
• The study sample was predominantly women with breast cancer. Generalizing to other cancers and men is difficult.
• The comparative standard regimen did not include an NK1, which is recommended as of this writing.

For patients who are uninsured or underinsured and those living in developing countries where obtaining high-cost medications may be difficult, gabapentin may prove useful as a less-expensive alternative antiemetic prophylactic medication. Research should attempt to compare less expensive alternatives with current best practices.

780 nm 60 mW 4 J/cm² was applied uniformly to five areas of the oral cavity for five consecutive days from initiation of chemotherapy.

The sample was pediatric patients (some with HSCT) receiving a variety of chemotherapies.

Laser group: n = 29
Control group: n = 31
 

The study ran from May 2003-February 2005.

RCT was the study design.

CTC-NCI
Nutritional Status Assessment
Day 8,15
 

Day 8 results: 13 patients in the laser group and 7 patients in the control group with mucositis; median grade of mucositis was 2 for the laser group and 1 for the control group (p = 0.234)

Day 15 results: 13 patients in the laser group and 11 patients in the control group with mucositis; median grade of mucositis was 1 in both groups; prevalence and severity were similar (p = 0.208)
 

Almost identical prevalence of mucositis and other findings; no evidence to support laser for prevention

Rigorous oral care may have masked results.

Optimal timing of laser treatment is unknown.

Small sample
 

To compare prophylaxis with a fluoroquinolone (ciprofloxacin, ofloxacin, perfloxacin, or norfloxacin) in combination with an antibiotic against gram-positive bacteria (penicillins, macrolide, rifampin, or vancomycin) compared to fluoroquinolone alone in neutropenic patients with cancer

DATABASES USED: MEDLINE, CANCERLIT, Database of Abstracts of Reviews of Effects, and Cochrane Library (1984–2002); the bibliographies of retrieved studies also were reviewed.

• FINAL NUMBER STUDIES INCLUDED = 9 RCTs
• TOTAL PATIENTS INCLUDED IN REVIEW: 1,202
• KEY SAMPLE CHARACTERISTICS: Neutropenic patients with cancer

The addition of gram-positive prophylaxis to fluoroquinolones reduced

• Total episodes of bacteremia by 11.1%
• Staphylococcal and streptococcal infections
• Febrile morbidity by 6.7%.

No difference was found between gram-positive prophylaxis and a fluoroquinolone compared with a fluoroquinolone alone with regard to

• Clinically documented infections
• Gram-negative infections
• Unexplained episodes of fever
• Infectious mortality.

However, adding gram-positive prophylaxis significantly increased the occurrence of side effects, primarily gastrointestinal intolerance and liver function test abnormalities seen with rifampin and roxithromycin.

The authors concluded that the evidence does not support routine use of gram-positive coverage in combination with a fluoroquinolone for antibacterial prophylaxis in neutropenic patients with cancer.

DATABASES USED: MEDLINE was searched for literature published from January 1984–October 1994. Current Contents also was used, as were the bibliographies from MEDLINE articles.

KEYWORDS: Key words used in the search were neutropenia/agranulocytosis and bacterial infections.

INCLUSION CRITERIA: Eligible studies were randomized, controlled trials with fluoroquinolones alone or in combination with gram-positive prophylaxis in granulocytopenic patients receiving chemotherapy for cancer.

• FINAL NUMBER STUDIES INCLUDED = 19
• KEY SAMPLE CHARACTERISTICS: The majority of patients had hematologic malignancies. Patients with solid tumor were included in six of the studies.

Prophylaxis with fluoroquinolones alone was shown to significantly reduce the frequency of gram-negative bacteremia. No significant difference was found in terms of gram-positive bacteremia or infection-related mortality. Fluoroquinolone with gram-positive prophylaxis significantly reduced the frequency of gram-positive bacteremia. Fever-related morbidity and infection-related mortality were not affected. Of note, the majority of the studies (four of six) used fluoroquinolone alone in the control group.

Carnitine deficiency is among the many metabolic disturbances that may contribute to fatigue in patients with cancer. Administration of exogenous L-carnitine may hold promise as a treatment for this symptom. Carnitine was prepared by the institutional pharmacy at a concentration of 1 g/mL. The drug was administered in two daily doses for seven days. After the intervention period, patients were allowed to continue L-carnitine supplementation if desired. Patient outcomes were evaluated at baseline and on day seven.

• In total, 27 patients (37% female) with advanced cancer were included.
• Mean age was 59.7 years.
• The majority of patients were Caucasian (59%).
• The most common diagnosis was breast cancer (22%).
• Most patients reported severe fatigue (70%), and all were carnitine-deficient.
• Patients were excluded from the study if they had hemoglobin levels less than 9 g/dL, had increased risk of seizure or heart failure, were receiving current treatment (chemotherapy, radiotherapy, or recombinant erythropoietin), or had renal insufficiency.

Beth Israel Medical Center Continuum Hospice Care, Jacob Perlow Hospice, or the Cancer Center

Patients were undergoing the active treatment phase of care.

The study was an open-label, phase I/II clinical trial.

Brief Fatigue Inventory (BFI)

Patients who received the L-carnitine intervention experienced a significant decline in fatigue (p < 0.001) as BFI scores decreased from baseline (66.1 [standard deviation (SD) = 12]) to one week after treatment to (39.7 [SD = 26]).

• Of the 85 patients who were eligible for study, 47 elected not to participate, the most common reason being that patients were interested in trials that aimed to treat their condition and were less interested in symptom management studies.
• The study lacked a neutral comparison group.
• The assessment of side effects did not rely on validated measures, and a range of potential safety measurements, such as repeated liver function tests, were not performed.

Carnitine is hypothesized to be key in the energy metabolism and regulation of adenosine triphosphate (ATP) promotion and a protective effect of mitochondrial metabolism. Carnitine deficits are common in cancer patients and other chronically ill persons.
 

L-carnitine supplementation was given in dose levels of 250 mg/day. Dose levels were planned to increase by 500 mg until the target dose of 3000 mg/day was reached.

Of 645 adult patients, 13% met following inclusion criteria:

• Age of at least 18 years
• Greater than 3 month life expectancy
• Self-reported fatigue was moderate to severe for at least one week
• Carnitine deficiency
• Karnofsky Performance Status (KPS) of 50% or greater.

Patients were excluded from the study if they had severe disease, brain tumor, or stroke; were unable to complete the assessment tools; had started erythropoietin within less than 3 months; had received radiotherapy or chemotherapy within one week prior to the study; or were unable to consent.

Hospice and Cancer Center

The study used an open-label, dose-finding, safety design, with dose cohorts of three.

• Brief Fatigue Inventory (BFI)
• Center for Epidemiological Studies Depression Scale (CESD)
• Quality of sleep
• Epworth Sleepiness Scale (ESS)
• KPS

• Of the patients, 83% reported fatigue with a significant decrease in BFI score after one week (p = .009).
• CESD decreased (p = 0.028).
• ESS decreased (p = 0.015).
• No significant change occurred in KPS.
• Dose was safely escalated to 1750 mg/d.

• The study had a small sample size.
• Hospice patients often have multiple medical problems. 
• Three higher dose levels were not reached.
• Treatment length was short (one week). 
• The effect of prolonged use is unknown.
• No monitoring of dietary carnitine was performed.
• It is unknown if L-carnitine supplementation accelerates cancer or interferes with the effects of certain agents.

Cost of supplements and monitoring levels of L-carnitine is unknown.