To determine whether tapentadol prolonged-release (PR) is effective and tolerable for managing moderate to severe tumor-related pain

Patients whose pain was rated 5 or above on an 11-point scale were randomized (2:1) and titrated to an optimal dose of tapentadol PR (100–250 mg BID) or morphine sulfate CR (40–100 mg BID) over two weeks. Immediate-release morphine sulfate was allowed as needed as a breakthrough medication. During the last three days of titration, patients who achieved an average pain intensity of less than 5 and took less than 20 mg per day of rescue pain medication entered a four-week maintenance period. Patients who received tapentadol were rerandomized (1:1) to either tapentadol BID or a placebo for the maintenance period. Response at the end of titration and response at the end of the maintenance were assessed. Tolerability and side effects were evaluated.

• N = 327
• AGE = 68% < 65 years, 32% ≥ 65 years
• MALES: 53%, FEMALES: 47%
• KEY DISEASE CHARACTERISTICS: The most common neoplasms included were breast and nipple cancers and non-small cell neoplasms of the respiratory tract. Metastases were present in greater than 75% of all patients.   

• SITE: Multi-site    
• SETTING TYPE: Not specified    
• LOCATION: 71 sites in 16 countries

• PHASE OF CARE: Late effects and survivorship
• APPLICATIONS: Palliative care 

Randomized-withdrawal, parallel-group, active- and placebo-controlled, double-blinded study

During the study, pain levels were evaluated with an 11-point Numeric Rating Scale (NRS) twice daily. The proportion of patients classified as responders (patients who completed 28 or more days, had a mean pain intensity score < 5, and had a mean total daily dose of ≤ 20 mg rescue medication during the maintenance period) was evaluated as a primary endpoint during the titration and maintenance periods. Mean pain intensity at the start of the maintenance period was calculated as the mean daily pain intensity scores during the last three days of the titration period. Mean weekly pain intensity during the maintenance period was calculated from the mean daily pain intensity scores during each week of the maintenance period. Adverse events were coded using the Medical Dictionary for Regulatory Activities v15.0. The treatments for emergent adverse events in all groups were collected and compared as were specific gastrointestinal and nervous system effects and general disorders or administration site effects.

Patients receiving tapentadol were twice as likely to respond than the patients who received a placebo. Tapentadol PR was noninferior to morphine CR (p < 0.001). Mean pain intensity scores improved in both the tapentadol PR and morphine CR groups during titration. These reductions were sustained throughout the maintenance period. There were no statistically significant differences between the tapentadol and placebo groups in changes in pain intensity from the start of maintenance to weeks 1–4 (p ≥ 0.0152). A higher percentage of patients in the placebo group (72.1%) took ≥ 20 mg per day of rescue morphine immediate-release compared to the tapentadol (71.4%) or morphine CR (61.5%) groups. During titration, 50% of patients in the tapentadol group and 63.9% of patients in the morphine group reported one or more treatment-emergent adverse effects (TEAEs). A smaller percentage of patients receiving tapentadol PR had any TEAEs (p = 0.0039) than those receiving morphine CR.

Tapentadol PR 100–250 mg BID was effective in the treating tumor-related pain. The analgesic effect of tapentadol PR was not inferior to morphine CR and had better overall and gastrointestinal tolerability than morphine CR. However, more tapentadol users required rescue pain medication than those taking morphine CR.

• Findings not generalizable
• Subject withdrawals ≥ 10%  
• Other limitations/explanation: The comparison of tapentadol PR and morphine CR was limited to two weeks because of the study design.

Tapentadol, one of a new class of centrally acting analgesics, was effective in treating tumor pain and was generally better tolerated than morphine CR. Nurses should be familiar with the common side effects associated with this medication including nausea, vomiting, constipation, dizziness, sleepiness, and fatigue to safely care for patients receiving this drug.

To evaluate the effects of a stepped psychotherapeutic intervention on patients with baseline anxiety

Patients who had completed curative therapy, were referred for follow-up, found to have relevant levels of distress, and consented to participation had a telephone interview at baseline. After the interview, they were randomized to usual care or the stepped program, which included watchful waiting, guided self-help via the Internet or a booklet, face-to-face problem-solving therapy, and psychological interventions and/or medications. Time frames for data collection varied depending upon the duration of the stepped program. General measures were obtained at 3, 6, 9, and 12 months after study entry. Usual care consisted of no psychosocial care in 64% of the group.

• N = 156, 106 at 12-month follow-up   
• MEAN AGE = 62 years (SD = 9.4 years)
• MALES: 60.9%, FEMALES: 39.1%
• CURRENT TREATMENT: Not applicable
• KEY DISEASE CHARACTERISTICS: Patients with head and neck or lung cancer in various stages
• OTHER KEY SAMPLE CHARACTERISTICS: Of the patients, 77.6% had anxiety or a depressive disorder.

• SITE: Single site   
• SETTING TYPE: Multiple settings    
• LOCATION: Netherlands

PHASE OF CARE: Transition phase after active treatment

Single-blind, randomized, controlled trial

• Hospital Anxiety and Depression Scale (HADS)
• European Organization for Research and Treatment of Cancer Core Quality of Life (EORTC QLC-C30)
• EORTC IN-PATSAT32 for inpatient satisfaction with care 
• Composite International Diagnostic Interview (CIDI) for the presence of depression or an anxiety disorder

The course of anxiety (p = 0.046) and depression (p = 0.007) was better for the intervention group than for the controls. When corrected for baseline anxiety and depression, depression was better for the intervention group over time (p < 0.001), but anxiety was not significantly different (p = 0.061). The stepped program had more influence over the course of symptoms among patients with a depression or anxiety disorder compared to those without a psychiatric disorder (p = 0.001). Among those without a psychiatric disorder, no differences in anxiety or depression scores were observed after a six-month measurement.

The stepped psychological intervention approach was shown to be effective to reduce anxiety and depression in the short-term, and had particular effectiveness for individuals with psychiatric disorders.

• Baseline sample/group differences of import
• Risk of bias (no blinding)
• Risk of bias (no appropriate attentional control condition)
• Unintended interventions or applicable interventions not described that would influence results
• Subject withdrawals ≥ 10% 
• About 40% were lost to follow-up at six months.
• Patients were not blinded.  
• No information was provided regarding medication use, etc.
• More patients in the intervention group used alcohol.
• Although all patients had clinically relevant anxiety at study entry, the majority of patients in the usual care group had no interventions.
• Patients had completed initial treatment at highly varied time points prior to the study.

Psychiatric and stepped psychological interventions resulted in relatively short-term improvement in anxiety and depression among patients with cancer and anxiety. Interventions were most helpful for individuals with anxiety or depressive disorders over a longer period of time as well.

To determine the effectiveness of a lay-administered tailored education and coaching intervention on cancer pain severity, pain-related impairment, and quality of life  

Patients with baseline “worst pain” of more than 4 on a 0–10 scale or at least moderate functional impairment were randomized to tailored education coaching (TEC) or enhanced usual care (EUC). TEC was delivered by a health educator in a private room one hour prior to the patients' visit with their healthcare provider. The intervention was a brief, patient-centered, tailored education and coaching intervention designed to enhance skills and self-efficacy for communicating with the oncologist while also correcting common misconceptions. The EUC intervention included review of selected aspects of a National Cancer Institute (NCI) booklet on pain control by a health educator. The TEC patients also received the NCI booklet. Patients completed questionnaires before and after the visit and were interviewed by telephone at 2, 5, and 12 weeks. Oncologists and follow-up assessors were blinded to patient group assignments.

• The study reported on 258 patients (126 in the intervention group and 132 in the usual care group).
• Mean patient age was 58 years.
• The intervention group was 77.8% female and 22.2% male. The usual care group was 79.5% female and 20.5% male. 
• Patients had breast and lung cancers and were predominantly white (71%).

• Mutlisite
• Outpatient setting
• Three healthcare systems and one private practice located in the metropolitan Sacramento, CA, area
• Forty-five medical oncologists and three radiation oncologists participated in the study.

Patients were undergoing multiple phases of care.

The study was a randomized controlled trial.

• Pain severity: two component numeric scales     
• Pain impairment: five of thesix items from the Medical Outcomes Study
• Functional status and well-being: physical and mental health components of the SF-12
• Pain misconceptions: 11 five-point Likert scale items based on the Short Barriers Questionnaire
• Self-efficacy for communicating about pain with the cancer doctor: five items in the Perceived Efficacy in Patient-Physician Interactions Scale
• Pain-control self-efficacy: 2 items from the pain management subscale of the Chronic Pain Self-Efficacy Scale
   

The TEC patients had an improvement in pain-related impairment at two weeks (–0.025 points on a five-point scale, 95% confidence interval –0.43 to –0.06, p = 0.01), but it was not sustained at 6 and 12 weeks (p > 0.20). Pain severity was not improved at two weeks (–0.21 points on an 11-point scale, –0.60 to 0.17, p = 0.27). Pain misconceptions in both the intervention and control group decreased significantly between baseline and the two-week follow-up interview (p < 0.001), but there was no significant effect of the intervention on misconceptions at the two-week follow-up (p = 0.8). Communication self-efficacy increased more among the TEC patients than in the control group (p < 0.001).

TEC provides a temporary improvement in pain impairment but not in pain severity.

The TEC intervention was designed to be brief and easy to deliver, but the health educator needed 30–40 hours of training and regular reinforcement (several hours every three to six months) in order to deliver the intervention appropriately. Physicians were not randomized to the study, so they may have learned from the TEC patients and applied it to the EUC patients. Generalizability of findings is limited due to the fact that the study was conducted in a metropolitan area in California, with no blinding.

Because the TEC provided only temporary relief of pain impairment and no improvement of pain severity, it is not recommended for use in cancer-related pain management.

To estimate the effect of patient-centered tailored education and coaching (TEC) on the likelihood of analgesic treatment adjustment during oncology visits; to estimate the influence of treatment adjustment on subsequent cancer pain control

Patients with at least a moderate baseline pain received TEC or control just prior to a scheduled oncology visit. Just after the visit, they reported on whether the physician recommended a new pain medication or a change in the dose of an existing medication. Pain severity and pain-related impairment were measured 2, 6, and 12 weeks later. TEC included assessing knowledge, attitude, and preferences; correcting misconceptions; teaching about pain control and communication with providers; planning communication; and rehearsing communication with physicians. Sessions occurred one hour before initial clinic visits and were conducted on an individual basis. Sessions were recorded on audiotape. Control patients received the Natiional Cancer Institute booklet on pain control. Patients completed questionnaires immediately after a clinic visit.

• The sample was composed of 258 patients.
• Patients' age range was 18–80 years.
• Of all participants, 21.4% were male and 78.6% were female.
• Diagnoses in the sample included lung, breast, prostate, head and neck, esophageal, colorectal, bladder, and gynecologic cancer.
• Patients reported a score of 4 or higher, on a 0–10 scale, when asked to cite worst pain during the past two weeks or pain during the same period that interfered at least moderately with functioning.
• Potentially eligible patients were identified using computer-generated lists. Consenting patients received an enrollment packet by mail and were promised $80 compensation for completing the trial.

Settings included three health systems—academic medical center, health maintenance organization, and Veterans Affairs hospital—and one private practice, all in Sacramento, California.

• Phase of care: active treatment
• Clinical applications: elder care, palliative care

Randomized controlled trial

• Medical Outcomes Study Pain Impairment Scale
• Postvisit questionnaire regarding pain medication changes

• Patients assigned to TEC were more likely than controls to report a change in the analgesic treatment regimen (60% vs. 36%, p < 0.01).
• Significant effects persisted after adjustment for baseline pain, study site, and physician (adjusted odds ratio 2.61, 95% CI 1.55, 4.40, p < 0.01).
• In a mixed-effects repeated-measures regression, analgesic change was associated with a sustained decrease in pain severity (p < 0.05).

TEC increases the likelihood of self-reported, physician-directed adjustments in analgesic prescribing. Treatment intensification is associated with improved cancer pain outcomes.

• The study had low accrual rates.
• Invesigators obtained data about independent and dependent variables by means of patients' self-reports. The study shows poor concordance between patients' reports and medical record review.
• Authors did not assess appropriateness of physicians' decisions.
• Regression effects that may cause between-group comparisons may appear to be larger than they would be if analgesic change were randomly assigned.
• Time points at which pain severity were measured are unclear.

A routine oncology visit is an opportunity to adjust a patient’s analgesic regimen. Available evidence suggests that clinicians often miss opportunities to intensify analgesic regimens appropriately. Oncologists are often unaware of patients’ pain. Patients may be reluctant to discuss pain because of misconceptions about pain management or fear of distracting the physician. The findings of this study suggest that interventions to counter this reluctance, and to improve pain management, include education, including role-playing, that helps patients plan communication with physicians.

The study design was based on a goal of 120 patients, so that the two-sided, 0.05-level Wilcoxon rank sum would have a power of 97.5% to detect an improvement in diarrhea severity. After stratification, patients were randomly assigned to the experimental group (4 grams of glutamine twice per day for 7 days per week during radiation and for 2 weeks thereafter) or an identically appearing placebo (glycine) for the same time period.

• The study reported on 129 patients from 14 institutions.
• Patients were stratified by
  • History of anterior resection of the rectum versus no prior rectal surgery
  • Total planned cumulative radiation dose
  • Use of fluorouracil (FU)
  • Primary tumor site (rectal versus prostate versus gynecological versus other).

This was a two-arm, placebo-controlled, randomized clinical trial.

The primary measure of treatment efficacy was diarrhea levels, which were evaluated using a bowel function questionnaire that was derived from previous studies on radiation therapy and bowel functioning. Participants completed the questionnaire weekly for 4 weeks, then at 12- and 24-month follow-up intervals. Toxicity was measured using National Cancer Institute (NCI) Common Terminology Toxicity Criteria for Adverse Events: Diarrhea.

No significant differences were found in incidence of diarrhea (p = 0.99), stools per day, maximum stools per day, antidiarrheal agent used, or use of loperamide.

• This study was inconsistent with other studies which found a significant effect (improvement) in diarrhea with glutamine supplementation. Further research is needed to determine whether a lower dose of glutamine was used in this study.
• The authors did not report on the validity or reliability of the bowel function questionnaire.
• No dose-response data was provided to assess whether higher doses or longer pretreatment use of glutamine would have been more effective in treating or preventing diarrhea.

To compare the long-term efficacy of pneumatic compression and low-level laser therapies in the management of postmastectomy lymphoedema

Sixty-four women who had undergone modified radical mastectomy with complete axillary dissection and radiotherapy were recruited for the study. All patients gave informed consent, and the hospital ethics committee had approved the study protocol. Patients who had a history of arm lymphedema of at least three months were recruited to the study. Fourteen patients were excluded from the study (three had current metastases, five had continuing radiotherapy, one had cellulitis, two had a history of receiving a physical therapy program in the previous six months, one was using diuretic agent for hypertension, and two refused the treatment and did not provide informed consent). Patients were randomized to the pneumatic compression therapy group (group I, n = 25) or the low-level laser therapy group (group II, n = 25) by consecutive alternate allocation according to the admittance to the study clinic. The physician who randomized the patients was blind to the treatment groups. Group I received two hours of therapy with an intermittent pneumatic compression therapy device. A pressure of 60 mmHg, which is generally recommended for the treatment of lymphedema, was used. Total treatment period was four weeks and consisted of 20 sessions. Group II received 20 minutes therapy (2800 Hz, 1.5 J/cm2) with a Ga-As 904 nm laser device three times a week. Total treatment period was four weeks and consisted of 12 sessions. Laser therapy was administered at three points on the antecubital fossa and at seven points on the axilla where the lymph nodes accumulated. All patients were advised to perform daily limb exercises (active range of motion, elevation and pumping exercises), hygiene, and skin care. In addition to pre- and post-treatment evaluation, follow-up measurements were performed at 3, 6 and 12 months by the same physician.

• The study sample (N = 50) was comprised of two groups receiving either pneumatic compression therapy (group I, n = 25) or low-level laser therapy (group II, n = 25). 
• Mean age for group I was 51.2 years and group II was 45.4 years. 
• All patients had breast cancer-related lymphedema. 
• Patients were included in the study if they had a history of arm lymphedema of at least three months. 
• Patients were excluded from the study if they
  • Had current metastases, continuing radiotherapy, cellulitis, venous thrombosis, chronic inflammatory diseases, a history of severe trauma, or photosensitivity
  • Were using any medications that affect body fluid and electrolyte balance
  • Had limitation of the upper-extremity joints
  • Had a history of physical therapy other than skin care and home exercises directed to lymphedema within the previous six months.

The study took place at the Department of Physical Medicine and Rehabilitation of Cukurova University in Turkey.

Patients were undergoing long-term follow-up care. The study has clinical applicability for late effects and survivorship. 

The study used a randomized controlled trial design.

• The affected and unaffected upper limbs of the patients were measured by tape at seven anatomic sites, including the axilla, 10 cm proximal and distal to the antecubital fossa, elbow, 5 cm proximal to the wrist, wrist, and mid-palm. Lymphedema was defined as a difference of more than 2 cm at least three of the seven points. The sum of the circumferences of the affected and unaffected limbs was calculated and the difference between these two values was recorded as delta circumference.
• Pain with motion was measured by a visual analog scale of 0–100 mm, ranging from no pain to very severe pain.
• Range of motion of the upper-extremity joints was measured using a conventional goniometer when patients were lying in the supine position.
• Grip strength was measured by portable hydraulic hand dynamometer. The measurements were performed when patients were seated in straight position, with the shoulder adducted, elbow flexed at 90°, and forearm in neutral rotation. A mean of three attempts was calculated, with a 15-second rest in between each of three contractions.

Delta circumference decreased significantly at one, three, and six months within both groups, and the decrease was still significant at month 12 only in group II (p = 0.004). Improvement of group II was greater than that of group I post-treatment (p = 0.04) and at month 12 after 12 months (p = 0.02). Pain was significantly reduced in group I only at post-treatment evaluation, whereas in group II it was significant post-treatment and at follow-up visits. No significant difference was detected in pain scores between the two groups. Grip strength was improved in both groups, but the differences between groups were not significant.

Patients in both groups improved after the interventions. Group II had better long-term results than group I. Low-level laser might be a useful modality in the treatment of post-mastectomy lymphedema.

• The study sample was small, with less than 30 participants for each group and less than 100 participants in total. 
• The study lacked a sham or control group because of ethical issues.
• Patients were not blinded because of the different types of treatment. 

Prospective randomized controlled studies with a larger sample size are needed to better understand the efficacy of low-level laser therapy and pneumatic compression in the treatment of postmastectomy lymphedema. In addition to these suggested treatment modalities, patients are recommended to perform daily limb exercises and follow skin care instructions throughout their lives.

To assess the efficacy and safety of palonosetron versus ondansetron in the prevention of chemotherapy-induced nausea and vomiting (CINV) in pediatric patients receiving moderately (MEC) or highly emetogenic chemotherapy (HEC)

Four cycles of 10 mc/kg palonosetron was compared to three 150 mc/kg doses of ondansetron on day 1 of chemotherapy, and 20 mc/kg palonosetron was compared to three 150 mc/kg doses of ondansetron on day 1 of chemotherapy. The intervention assignment was stratified based on the age of the participant and the emetogenicity of the chemotherapy. The efficacy of antiemetic regimens was evaluated through the proportion of patients who achieved complete response (CR) (no vomiting, retching, or use of rescue drugs) during the acute phase (0–24 hours post chemotherapy) of chemotherapy on day 1. Safety was evaluated through the number of adverse events reported.

• N = 493   
• AGE RANGE = 2.1 months–16.9 years
• MEAN AGE = 8.21 years
• MALES: 53.1%, FEMALES: 46.9%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: No specific type of cancer required for inclusion
• OTHER KEY SAMPLE CHARACTERISTICS: MEC or HEC

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: United States, South America, and Europe

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Pediatrics

• Double-blind, double-dummy, phase-III study

• Episodes of CINV, retching, and rescue medications used were documented in a daily diary kept by the patient/caregiver.  
• Adverse events were measured through physical examination, vital signs, laboratory assessments, and 12-lead electrocardiograms. The severity of all adverse events was rated mild, moderate, or severe based on the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.

Twenty mc/kg palonosetron resulted in a significantly higher proportion of patients who achieved CR (no vomiting, retching, or use of antiemetic rescue medication) on day 1 of chemotherapy compared to those who received ondansetron (p = 0.0022). No difference existed in the proportion of CR on day 1 of chemotherapy for those who received 10 mc/kg palonosetron compared to ondansetron. Adverse events were reported in 80% (n = 134) of patients who received 10 mc/kg palonosetron, 69% (n = 113) of those who received 20 mc/kg palonosetron, and 82% (n = 134) of those who received ondansetron. Adverse events attributed to palonosetron were headache (n = 4), infusion site pain (n = 1), and cardiac issues (n = 5).

Compared to ondansetron, 20 mc/kg palonosetron resulted in significantly greater control of CINV and minimal adverse events in pediatric patients receiving MEC or HEC.

To evaluate the immediate and short-term effects of relaxation training with the Yoga in Daily Life program on anxiety in patients with breast cancer

Patients were randomized to standard physiotherapy or standard physiotherapy plus the relaxation program after surgery for breast cancer. Physiotherapy was provided for one week. The experimental group also had one-hour group sessions daily in groups of three for one week. The program involved relaxation breathing exercises, visualization, and body scan, providing progressive muscle relaxation techniques. Those in the experimental group were given audiocassettes with instructions for home practice and were asked to do this daily for another three weeks.

• N = 32  
• AGE: All patients were over 40; further information was not provided.
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Patients with breast cancer having just undergone initial surgery

• SITE: Single site  
• SETTING TYPE: Multiple settings    
• LOCATION: Slovenia

• PHASE OF CARE: Active antitumor treatment

• Single blind RCT

• State Trait Anxiety Scale
• Patient diary of use of relaxation at home

There was significant reduction in anxiety in the experimental group (p < .01), while mean anxiety level in the control group remained essentially the same. State anxiety levels were significantly lower after physiotherapy and relaxation training in the experimental group compared to controls one hour after physiotherapy (p = .038).

Visualization and progressive muscle relaxation as provided in this program may help reduce anxiety after surgery among patients with breast cancer.

• Small sample (< 100)
• Risk of bias (no blinding)
• Risk of bias (no appropriate attentional control condition)
• Measurement/methods not well described
• Other limitations/explanation: Single blind only. There is no information about how often patients did the program at home after hospital discharge.

Relaxation therapy including visualization and progressive muscle relaxation as accomplished in this program may be helpful for patients to reduce anxiety. This study has limitations and does not provide strong support for effectiveness; however, these are very low-risk types of interventions that may be helpful to some patients.

To determine effectiveness of GM-CSF impregnated gauze in preventing and healing acute radiation-induced dermatitis

The study took place from November 1981 to March 1998. Group A (n = 37) was comprised of patients treated from 1981 to 1993 and received steroid creams (e.g., Betamethasone) as prophylaxis to radiation-induced dermatitis. Group B (n = 24) was comprised of patients treated from 1993 to 1998 and received steroid creams from the start of treatment and, following 20 Gy of radiation, also recieved GM-CSF impregnated gauze. Dressings were applied twice daily, 12 hours apart, for the rest of their treatment, while steroid cream was applied once a day, intermediately. The same doctors and technicians treated all patients during this time interval and were evaluated using a standard protocol. Findings from both groups were analyzed retrospectively.

• The study sample was comprised of 61 female patients.
• Median age of the sample was 74 years, with a range of 38–84 years.
• Patients had a diagnosis of invasive squamous cell carcinoma of the vulva.

The study took place at a university hospital in Greece.

The study used a retrospective design.

• Patients were examined clinically twice a week to estimate the cutaneous reactions to the groin areas, vulva, perineum, and labiocrural folds.
• Radiation dermatitis was classified in four grades using Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer (RTOG/EORTC) toxicity scoring.
• Pain was classified into four grades according to the subjective scale of Subjective Objective Management Analytic grading system.

Group B had overall lower subjective pain results (p = 0.0014). Those who had received the GM-CSF had overall less severe skin toxicity by RTOG/EORTC grading (p = 0.008).

GM-CSF impregnated gauze can be effective in preventing and healing radiation-induced dermatitis and in reducing the interruption intervals in radiation therapy for vulvar carcinomas.

• The sample size is small, with less than 50 patients.
• The study used a nonrandomized, retrospective design. Small non-randomized study, retrospective study, Low accumulation of participants:12 years of study for group A (37 patients)
• Group A had 12 years of study and Group B had 5 years of study.
• The study did not specify the breakdown of stage and grade of cancers in each group, and a wide range of patient characteristics in body mass were included.
• The study did not specify number of patients per group who had surgery before radiation, required a boost dose, required pelvic radiation, or had a treatment break.
• No explanation/validation of the SOMA pain grading system was provided.

To compare effectiveness of pegfilgrastim given as a prophylactic single-fixed dose versus daily filgrastim for incidence of febrile neutropenia (FN), severe neutropenia, treatment delays, and dose reductions in high-risk breast cancer patients receiving adjuvant dose dense chemotherapy. The secondary aim was to evaluate the impact of both granulocyte–colony-stimulating factors (G-CSFs) on patients’ overall survival (OS).

All patients treated with E-T-CMF received G-CSF in each cycle of chemotherapy. Patients randomized to receive ET-CMF received G-CSF only during intensified phase of CMF treatment; patients randomized to receive E-CMF-DOC or E-CMF-PAC received G-CSF during the intensified phase of epirubicin and CMF treatment. G-CSF was arbitrarily chosen by physicians. Patients received either single fixed dose of pegfilgrastim 6 mg on the next day after chemotherapy completion or daily administration of filgrastim 5 mcg/kg per day on days 2-7 of each cycle (compliance for filgrastim was more than 90% of cycles).

• N = 1,058 (529 filgrastim; 529 pegfilgrastim)  
• MEAN AGE = 52.3 years
• AGE RANGE = 22–79 years
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Postoperative high-risk patients with breast cancer receiving sequential chemotherapy with epirubicin, pacitaxel, or docetaxel, and CMF supported by G-CSF.
• OTHER KEY SAMPLE CHARACTERISTICS: No difference in menopausal status, higher % of patients had positive estrogen/progesterone status, no difference in tumor size, number of positive nodes, 92% completed treatment in filgrastim arm/95.3% in pegfilgrastim arm. Eligible patients came from sample of 2,123 participants in randomized trials: ACTR N12609001036202 (HE10/00) (reported in: Fountizilas, G et al. [2008]. Postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel and CMF in patients with high-risk breast cancer: Safety analysis of the Hellenic Cooperative Oncology Group randomized phase III trial HE 10/00. Annals of Oncology, 19(5):853–860). ACTRN12610000151033 (HE 10/05) and 989 participants in an observational study (protocol HE 10/08).
• INCLUSION CRITERIA: Exposure to pegfilgrastim or nonexposure (i.e., filgrastim) during treatment with dose-dense sequential chemotherapy E-T-CMF and E-CMF-DOC or E-CMF-PAC
• EXCLUSION CRITERIA: Patients treated with ET-CMF; patients whose supportive care switched from pegfilgrastim to filgrastim and vice versa throughout the period they received chemotherapy, as well as those who received pegfilgrastim on the same day as chemotherapy

• SITE: Multisite
• SETTING TYPE: Unknown
• LOCATION: Greece

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care

• Retrospective cohort study with matched sampling using data from prior prospective randomized phase III trials and an observational study

Data endpoints were rates of FN, severe (grade 3 or 4) neutropenia, dose reduction, and treatment delay. FN was defined as body temperature > 38.2 °C and neutrophil count < 0.5 × 10⁹/L. Severe (grade 3 or 4) neutropenia was assessed according to standard NCI criteria. Dose reduction was defined as any reduction greater than 10% of the dose planned based on the protocol assigned, and treatment delay was defined as chemotherapy administration with more than a two-day delay from the planned date.

No difference in rates of febrile neutropenia comparing filgrastim and pegfilgrastim arms existed. A significant increase in rates of severe neutropenia, treatment delays, and dose reduction in patients receiving prophylaxis with filgrastim was reported. More than half of the total episodes of febrile neutropenia occurred during the first four cycles of chemotherapy. No difference in overall survival between the two groups existed.

This retrospective study with matched sampling using data taken from a former prospective study of high-risk patients with breast cancer receiving postoperative dose dense sequential epirubicin, paclitaxel, and CMF matched samples found that those patients receiving pegfilgrastim had reduced incidence and risk for FN, dose delay, and dose reduction compared to filgrastim. No difference was found in reducing rates of neutropenia.

• Risk of bias (no random assignment)
• Unintended interventions or applicable interventions not described that would influence results
• Measurement/methods not well described
• Questionable protocol fidelity
• This study was not designed for the purpose of evaluating neutropenia as a secondary analysis with post hoc matching. 
• Unknown sampling technique and methods for patient selection were poorly described. 
• Retrospective data were from two randomized trials evaluating breast cancer treatment regimens ACTR N12609001036202 (HE 10/00) - ACTRN12610000151033 (HE 10/05) and one observational study (protocol HE 10/08). 
• Treatment dose of filgrastim two to seven days compared to pegfilgrastim could be considered unequal dosing/timing support for neutropenia prophylaxis. 
• Selection bias with G-CSF chosen arbitrarily by physician
• Several different chemotherapy regimens had no data for incidence of grades of neutropenia or FN specific to the type of regimen comparing filgrastim versus pegfilgrastim.
• No data existed for sequelae of FN events or infectious events.

Pegfilgrastim 6 mg 24 hours after chemotherapy is more effective in reducing incidence/risk of FN, dose delay, and dose reduction compared to filgrastim 5 mcg/kg/d on days two through seven in high-risk patients with breast cancer receiving postoperative adjuvant sequential chemotherapy regimens with epirubicin, paclitaxel, or docetaxel and CMF. Prospective randomized, controlled trials are needed to validate these results and to determine specific treatment regimens/population where pegfilgrastim or filgrastim dose/timing may be more effective in preventing FN.