To determine if a response to antiemetic APF530 is sustained over multiple cycles of chemotherapy

This study consisted of three treatment arms. During cycle 1, group 1 received 250 mg of subcutaneous APF530, group 2 received 500 mg of subcutaneous APF530, and group 3 received palonosetron at 0.25 mg IV in addition to an subcutaneous placebo before moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC). Patients receiving MEC also received dexamethasone at 8 mg IV 30–90 minutes before chemotherapy. Patients receiving HEC were given 20 mg of IV dexamethasone followed by 8 mg orally twice per day on days 2–4. In cycles 2–4, palonosetron was discontinued, and all patients in the palonosetron group were randomized to receive either 250 mg or 500 mg of APF530 with dexamethasone (dosing as previously stated). Cycles were separated by a range of 3–28 days. Rescue antiemetics were allowed as needed. Local anesthetic was administered to the injection site before the study drugs were administered. Study subjects kept diaries of emetic episodes, the use of rescue medications, and the severity of nausea for each 24-hour period after receiving chemotherapy. Adverse events were documented according to standard toxicity criteria. Complete response (CR) was defined as no rescue medications and no emetic episodes. Complete control (CC) was defined as no more than mild nausea and no rescue medications. Total response was defined as no nausea and no rescue medications.

• N = 580 (four cycles) 
• MEAN AGE = 57 years
• MALES: 25%, FEMALES: 75%
• KEY DISEASE CHARACTERISTICS: Primarily breast, lung, and ovarian cancer; mean time since diagnosis was 0.7 years; scheduled to receive single-day MEC (Hesketh score 3 or 4) or single-day HEC (Hesketh score 5) as defined at the time of study
• OTHER KEY SAMPLE CHARACTERISTICS: The sample size in cycle 1 of the study was 1,389 patients. However, the sample size for subsequent cycles was the number of patients who remained in the study using a modified intent-to-treat population of patients who received the drug and had efficacy data. 

• SITE: Multi-site    
• SETTING TYPE: Not specified    
• LOCATION: United States, India, and Poland

• PHASE OF CARE: Active antitumor treatment

Prospective, multicenter, randomized, double-blinded, placebo-controlled, parallel-group, phase 3 trial with stratification according to the emetogenicity of regimens

• Efficacy measures were assessed from patient diaries which recorded emetic episodes, the use of rescue medication, and the severity of nausea for each 24-hour period after chemotherapy (the specific tool to measure the severity of nausea was not described).
• Adverse events were assessed using standard toxicity criteria.
• Efficacy was measured as the percentage of patients who achieved CR (no emetic episodes and no rescue medication) during the acute and delayed phases of chemotherapy.
• Sustainability over cycles was measured as the proportion of patients with CR during the acute and delayed phases, the time to first emetic episode, the time till the first rescue medication, and the time till the first treatment failure in cycles 2–4.
• Treatment comparisons were based on the Fisher exact test.

In cycle 1, ≥ 75% of both doses of APF530 had acute-phase CR, and ≥ 50% had delayed-phase CR. There was a similar response rate for cycles 2–4 with the HEC group having a slightly better response than the MEC group. Acute phase CR increased over the four cycles of HEC (81%–88%) for APF530 500 mg dose and CR increased from 67% to 83% in the delayed phase for this group. In patients who received palonosetron in cycle 1, ≥ 90% of those who had CR maintained CR in subsequent cycles (with APF530). Half of the of MEC and palonosetron group that did not achieve CR in cycle 1 achieved CR in next cycle (with APF530). No treatment-related serious adverse events were seen. Common adverse events across all cycles included constipation, headache, fatigue, and diarrhea for patients who received APF530. APF530 at 250 or 500 mg caused injection site reactions. Most were mild, and greater than than 3% were moderate.

This study demonstrated sustained responses in the acute and delayed phases of chemotherapy over four cycles in both 250 mg adnd 500 mg oses of APF530. Patients who responded to APF530 in cycle 1 also responded in cycles 2–4. Patients receiving palonosetron for chemotherapy-induced nausea and vomiting had a similar response to APF530 in subsequent cycles. Patients receiving APF530 had mild adverse effects primarily related to injection site reactions.

• Measurement/methods not well described
• Subject withdrawals ≥ 10%  
• Other limitations/explanation: The Hesketh scoring system has changed since the study was conducted. Some regimens considered MEC at the time of the study are now considered HEC, changing the efficacy of MEC versus HEC regimens in the current system. The treatment group size and characteristics varied from cycle to cycle. Patients who no longer received the study drug or who had no data were removed, resulting in a greater than 42% drop in the number of subjects for the final cycle of chemotherapy. It was difficult to read the results of the data in bar graph format. 

APF530 was an effective 5HT3 blocker for the prevention of chemotherapy-induced nausea and vomiting in HEC and MEC regimens, and its efficacy was sustained over multiple cycles. There was no significant benefit in using higher doses over the 250 mg dose. There was a potential for injection site reactions caused by the subcutaneous route of APF530, which may affect patients' quality of life.

To examine the efficacy of three different doses of oral palonosetron compared to IV palonosetron for chemotherapy-induced nausea and vomiting (CINV) management and to explore the contribution of dexamethasone to these regimens

Patients were randomized to one of four different groups: oral palonosetron at 0.25, 0.5, and 0.75 mg or IV palonosetron at 0.25mg. Within each of these groups, patients were randomized to receive a single 8 mg IV dose of dexamethasone or placebo. Patients were stratified by age and by whether they had received previous chemotherapy. All patients were receiving single day chemotherapy. The noninferiority margin for analysis was set at a maximum difference in complete response rate at 24 hour of 15%.

• The study looked at 635 patients with a mean age of 56.7 years.
• The sample was 47% male and 53% female.
• Diagnoses were breast, colon, and lung.  All patients were receiving single-day, moderately emetogenic chemotherapy (MEC).
• Most patients were Caucasian or Hispanic.  Slightly more than half were chemotherapy naïve.

This was a multisite study conducted in outpatient settings in multiple countries.

All patients were in active antitumor treatment.

This was a randomized, double-blind, double-dummy trial.

• Complete response (CR) in the acute, delayed and overall phases was defined as no emesis and no rescue antiemetics.
• Nausea severity was rated on 4-point, Likert-type scale.

• In the acute phase, all of the oral doses were shown to not be inferior to IV palonosetron. In the delayed phase, none of the oral doses reached noninferiority to the IV dose.  In the overall phase, (0-120 hours postchemotherapy), only the 0.5 mg oral dose was found to be noninferior.
• CR was 77%–83% in the acute phase, 68%–75% in the delayed phase, and 61%–70% in the overall phase. 
• No differences were found across palonosetron groups in nausea.
• In general, in both the acute and delayed phases, subgroups that also received dexamethasone showed higher CR rates. 
• Use of rescue antiemetics was similar across study groups.  
• Adverse events were comparable across groups, with no apparent dose-response relationship.

Both oral and IV palonosetron formulations were shown to be effective in CINV prevention, and similar effects were seen at all three oral doses studied.  IV palonosetron may be more effective for reduction in CINV during the delayed phase. The addition of dexamethasone was associated with improved CR rates for both acute and delayed CINV.

• The measurements and methods were not well described.
• The findings are not generalizable.
• Other limitations include that the timing and method of nausea measurement were not well described and the findings are applicable to single-day MEC only.

Findings show that effectiveness of oral and IV palonosetron is similar, though the IV formulation may be slightly more effective for prevention of CINV during the delayed phase.   Findings also show that dexamethasone improves CINV control. Further research with multiday chemotherapy regimens and other emetogenic chemotherapy levels is warranted.  Findings continue to show that nausea is not as well controlled as emesis. High quality assessment of CINV in both acute and delayed phases is essential to ongoing planning for the most effective antiemetic approach for individual patients. A continued need exists to find effective interventions to reduce nausea as well as emesis.

To determine the effects of a specific protocol of prophylactic measures on the development of secondary lymphedema

The preventive protocol included preoperative upper-limb lymphscintigraphy, principles for lymphedema risk minimization, and early management of lymphedema. The positive lymphscintigraphy group underwent a microsurgical operation of lymphatic-venous multiple anastomoses at the same time of axillary nodal dissection. When postoperative lymphscintigraphy revealed disruption of blockage of arm lymphatic drainage before the onset of limb swelling, the preventive protocol group underwent early use of elastic sleeves, manual lymphatic drainage, prophylactic external compression, and remedial exercises. In case of appearance or worsening of lymphedema notwithstanding the physical methods, the patients underwent early microsurgical operation. In the control group, once a volume abnormality was determined, the standardized diagnostic and therapeutic procedures to assess and non-operatively treat lymphedema were carried out. Time points of evaluation were preoperatively and at 1, 3, 6, 12, and 24 months postoperatively.

• The study sample (N = 49) was comprised of a preventive protocol group (n = 25) and control group (n = 24) of female patients diagnosed with breast cancer. 
• Mean age was 53.4 and 54.6 years for the preventive protocol and control groups, respectively.

The study took place at the University of Genoa S. Martino Hospital in Italy.

The study used a prospective randomized controlled design.

• Arm volume was measured using water displacement.
• Lyphatic patterns of the upper limb were displayed using lymphscintigraphy.

Of the 49 women with unilateral breast cancer surgery who were measured at 24 months, 10 (21%) were identified with secondary lymphedema with an incidence of 8% in the preventive protocol group and 33% in the control group. At 12 months and 24 months, the number of patients with arm volume increases was significantly lower in the preventive protocol group ( p = 0.038 and p = 0.012, respectively). There were no differences between groups at six months and no significant differences between groups at baseline in terms of risk factors.

The prophylactic strategies appear to reduce the development of secondary lymphedema and alter its progression in comparison to the control group.

• The sample size was small, with less than 100 participants.
• The study had only one site.

The study indicates that healthcare professionals, including nurses, should inform patients with breast cancer of risk for developing lymphedema and help them understand signs and symptoms for early lymphedema. Healthcare professionals also need to examine whether patients develop lymphedema at every clinic visit. Anytime lymphedema is noted, patients should be referred for lymphedema treatment by certified lymphedema therapists or knowledgeable physical therapists. Strategies for prevention appear to be effective in the longer term.

To assess the efficacy of lymphactic venous anastomosis (LVA) during surgery for prevention of lymphedema in women having surgery for breast cancer

Patients who consented to participation prior to surgery were randomly assigned to the intervention group or usual care.  Those in the intervention group underwent the LVA microsurgical technique. Specifics of the surgery were described. In the treatment group, 16 patients had lymph node metastasis and underwent the LVA during primary surgery and axillary dissection. In those patients assigned to the intervention who did not have lymph node metastasis with intraoperative frozen section, the procedure was planned after finding micrometastasis after immunohistochemical analysis, and the LVA could be done during lymph node dissection at a second surgery. All patients had volume measurement done by the Kuhnke method and by lymphoscintigraphy. Follow-up included these measures at 1, 3, 6, 12, and 18 months after surgery.

• The study reported on 46 patients with breast cancer.
• Mean age was 67.5 years with a range of 52–74 years.
• The sample was 100% female.

The study was conducted in Italy. The site was not specified.

• Patients were undergoing the transition phase after initial treatment.
• The study has clinical applicability for late effects and survivorship.

This was a randomized clinical trial.

• Limb volume was measured.    
• Lymphoscintigraphy (LS) was used.

Beginning at month three, the proportion of patients with lymphedema was higher in the control group (p = 0.047). No significant differences were reported between volume measures at baseline, one, and six months in the intervention group. By comparison, a significantly higher arm volume was reported at one and six months in the control group (p < 0.01). Postoperatively, LS demonstrated a patency rate of 95.6% for LVAs. 

This trial demonstrated that intraoperative LVA microsurgery was effective in reducing arm lymphedema during the first six months after surgery in women with breast cancer.

• The sample size was small with fewer than 100 patients.
• No information was provided regarding any other interventions during the study period to combat development of lymphedema. 
• Although the mean follow-up time for the study was reported to be 18 months, only analysis of 6 months was provided. 
• No information was provided regarding use of adjuvant treatment during the study follow-up period or differences in body mass index (BMI) that could have influenced findings.

Study findings suggested that operative LVA with breast surgery can be effective in reducing development of secondary lymphedema. More research in this area is needed to further strengthen these findings. Nurses can advocate for patients to ask about the availability and potential use of this surgical technique.

To evaluate efficacy of palifermin versus placebo for prevention of oral mucositis (OM), as well as burden of patients with multiple myeloma (MM) who receive autologous stem cell transplant (SCT)

This randomized study compared three groups: (1) placebo, (2) palifermin on days -6, -5, -4, 0, 1, and 2 (pre-/post-SCT), and (3) palifermin on days 0, 1, and 2 (post-SCT). The palifermin dose was 60 µg/kg per day IV. Patients were assessed daily for OM from day 2 until day 32 or discharge.

• The study reported on 257 patients with MM.
• Median age was 57 years old with a range of 32–69 years.
• The placebo group sample was 58% male and 42% female; the group 2 sample was 55% male and 45% female; and the group 3 sample was 54% male and 46% female.
• All patients were receiving autologous SCT and high-dose melphalan.

This was a multisite, inpatient study conducted in the Netherlands.

• Patients were undergoing the active antitumor treatment phase of care. 
• This study has clinical applicability for elder care.

This was a randomized, placebo-controlled, parallel-group study.

• The World Health Organization (WHO) scale for OM, the Oral Mucocitis Daily Questionnaire, and the Quality of Life Utility Scale were used.
• Investigators recorded the use of opioids, non-opioids, days of severe OM, incidence of infections, time to absolute monocyte count (AMC) recovery, and adverse events.

• No statistically significant differences were found in maximum OM severity. Severe OM occurred in 37% of patients in the placebo group, 38% in the pre-/post-group (group 2), and 24% in the pre- group (group 3).
• No significant differences were observed with respect to PRO assessments or medical resource use, but more infections and fever during neutropenia were reported in group 2 versus the placebo group (51% versus 26%).
• No significant differences were found across groups in incidence of ulcerative OM or duration of OM. Those on palifermin pre-transplant had significantly lower incidence of opioid analgesic use compared to placebo (p = 0.03).

Palifermin was unable to reduce OM or OM-related patient burden in patients with MM undergoing transplant.

• A risk of bias exists because no blinding was done.
• Unintended interventions or applicable interventions that could have influenced results were not described.
• Findings are not generalizable.
• The authors indicated that the short period of intervention time or timing of giving palifermin may have had a suboptimal effect with palifermin. The authors also suggested that hyperkeratosis may have been misinterpreted for mucositis, despite observer training in assessment.

Short term of use of palifermin for auto-SCT in patients with MM undergoing transplant was not effective in reducing OM. The fact that authors suggest that hyperkeratosis may have been incorrectly interpreted as OM suggests that correct assessment can be an issue in evaluating this symptom. Findings suggest that the specific timing of use of this agent may be critical. In using palifermin, nurses need to be aware of the appropriate timing in concert with timing of antineoplastic treatment and treatment effects.

Parenteral nutrition supplemented with 0.57 g/kg glutamine-dipeptide was started on day 6 for a median of 19 days for patients in the treatment group.

• The sample consisted of 32 patients receiving allogenic stem cell transplantation.
• Median age in the treatment group was 49 years old with a range of 25–64 years. Median age in the control groupw as 48 years old with a range of 28–57 years.

The study was conducted between July 1999 and July 2002.

This was a randomized, double-blinded, placebo-controlled pilot study.

Oral assessment was conducted daily. Lesions, erythema, edema, pain, bleeding, dryness, and the production of viscous mucous were scored on a 0–3 scale and summed to produce a daily oral mucositis score (DMS).

• DMS was 8.1 (SD = 3.5) in the glutamine group versus 9.3 (SD = 3.1) in the placebo group; results were not significant.
• No difference was found in mean daily dose of morphine to alleviate mucositis-related pain.

• The sample size was small.
• Multiple other measures were used; most were not significant.

To evaluate the efficacy of a topical gel containing lorazepam, diphenhydramine, and haloperidol (ABH), in reducing chemotherapy-induced nausea and vomiting (CINV) among patients with cancer

This article reported on two pilot trials.

Patients in one physician practice were prescribed prophylactic antiemetics according to standard guidelines. They were given a prescription for six prefilled, capped tuberculin syringes of ABH gel when they received emetogenic chemotherapy. The patients were instructed to use the ABH gel when they developed significant nausea or vomiting in the days that followed chemotherapy, with the option to repeat use at six-hour intervals. Patients were instructed to place 0.5 ml of the gel on the palmar aspects of their wrists using the prefilled syringe. After applying the gel, the participants were instructed to rub their wrists together gently for one to three minutes to facilitate transdermal absorption.

In the first trial, an investigator contacted patients by telephone within one month. Patients provided verbal informed consent at this time. The investigator asked patients questions about their progress with ABH gels using a standard questionnaire, developed for the pilot. Patients were asked to rate their CINV and if they believed the gel to cause sedation, skin irritation, or muscle spasms.

In the second trial, after patients provided verbal consent, an investigator used a structured interview by telephone or in person to rate the severity of CINV on a combined scale at 30 minutes and fours hours after applying the ABH gel.

• Trial 1 consisted of 23 adult patients with solid tumor or hematology cancer diagnosis receiving chemotherapy.
• Trial 2 consisted of 10 adult patients with a cancer diagnosis.
• No control for diagnosis or chemotherapy treatment was included.

The trials were conducted at the outpatient clinic of a university in the midwestern United States.

• Trial 1 incorporated the use of a standardized questionnaire developed for the study.
• Trial 2 involved the use of a numeric rating scale, ranging from 0 (no nausea or vomiting) to 10 (worst imaginable nausea or vomiting).

• In trial 1, 74% of patients believed the gel decreased their nausea and 70% of patients experienced relief from vomiting. The majority of patients (70%) reported relief within 30 minutes of applying the gel. Some of the patients (13%) reported fatigue after using the gel. No patients reported skin irritation or muscle spasms.
• In trial 2, nausea scores significantly decreased at 30 minutes. No significant side effects were reported.

Transdermal ABH gel decreased the severity of CINV with only slight sedation reported.

• The sample size was small and heterogeneous.
• No control for disease, chemotherapy agents, cycle, or antiemetic agents was included.
• Trial 1 was retrospective, asking participants to recall symptom experience.

Use of transdermal ABH is convenient and easily taught to patients; however, availability of this combination topical agent may be a challenge in community settings because hospital pharmacies are less likely to compound products.

To evaluate the use of palonosetron compared to ondansetron for the complete control of chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic oxaliplatin or irinotecan plus a fluoropyrimidine regimen

Patient charts were reviewed for time periods before the use of palonosetron and after use of palonosetron. Prior to use of palonosetron, ondaansetron was given in combination with 12 mg oral dexamethasone 30 minutes prior to chemotherapy on day 1 of each regimen.  In the post palonosetron group, palonosetron was used instead of ondansetron.  In the setting of grade 1 or more vomiting or grade 2 nausea, aprepitant was added to the regimen. Nurses graded nausea and vomiting during chemotherapy administration.

• The study consisted of 305 participants.
• The majority of patients (73%) were more than 50 years old.
• The sample was 53% male and 47% female.
• Patients had been diagnosed with gastrointestinal cancers.
• In early-stage disease, more patients had received oxaliplatin. The highest percentage of patients in this study had metastatic colorectal cancer.

This was a single-site study conducted in both the inpatient and outpatient settings of a Midwest (Ohio) Academic medical center.

• All patients were in active treatment.
• This study has application to palliative care.

This study was a retrospective review of patients’ medical records.

• Failure of the prophylactic antiemetic was considered the primary endpoint in both groups. Failure was defined as vomiting at grade 1 or more or nausea at grade 2 or more. 
• The Common Terminology Criteria for Adverse Events, version 3, was used for grading.

With the use of palononsetron, the incidence of CINV failure was 28.4% versus 50.3% with the use of ondansetron (p < 0.001) regardless of the agent used (oxaliplatin or irinotecan).

The findings of this study support the use of palonosetron in regimens that include oxaliplatin or irinotecan plus either 5-FU or capecitabine. The study reported that the use of palononsetron resulted in a statistically significant reduction in the risk of CINV.

• A risk of bias exists because assignment was not random.
• Unintended interventions or applicable interventions that would influence results were not described.
• Measurement and methods were not well described.
• Antiemetic failure in the acute setting versus the delayed setting was not distinguished.

Although the National Comprehensive Cancer Network (NCCN) Guidelines for Antiemesis state that, for moderately emetogenic chemotherapy, a 5-HT₃ antagonist and dexamethasone should be used to prevent CINV, this study showed that, for regimens with oxaliplatin or irinotecan and either 5-FU or capecitabine, the 5-HT₃ of choice may be palononsetron. What is unknown is whether the use of palononsetron is equally as effective in reducing CINV using other moderately emetogenic chemotherapeutic regimens.

• DATABASES USED: Not stated
• KEYWORDS: Not stated
• INCLUSION CRITERIA: Not stated (based on each reviewer’s experience)
• EXCLUSION CRITERIA: Not stated

PHASE OF CARE: Active antitumor treatment

Many systematic reviews were used as references such as the Cochrane Library, but no number articles reviewed or how these were chosen were mentioned. Selection was based on each reviewer’s experience. 

• Assess and eradicate dental infection sites ahead of radiation therapy and transmit irradiated volumes to the dentist
• Use a soft toothbrush and replace it regularly
• Apply fluoride to dental splints
• Perform regular mouth rinses with nonalcoholic saline solution
• Ensure the early diagnosis and treatment of bacterial, fungal, and viral super infections (grade B).

• No clear statement of review process
• No stated inclusion or exclusion criteria
• Number of articles retrieved and reviewed for these guidelines was not provided

The categorization using the ANAES guides to determine level of evidence and grades was appropriate. However, the search methods used in these guidelines were not clearly stated and need reconfirmation because there was no way to know whether the search was comprehensive. The recommendations were grade B and expert opinions.

To evaluate the maintenance of efficacy and safety during long-term treatment with combined oxycodone/naloxone prolonged-release tablets (OXN PR) in adults with moderate-to-severe chronic pain.

474 patients received open-labeled OXN PR during 52 weeks of extension phases of two studies, having completed 12 weeks of double-blinded, randomized treatment with oxycodone prolonged-release tablets (Oxy PR) (n = 160) or OXN PR (n = 162). The starting dose was the effective analgesic dose of OXY or OXN that the patient received at the end of the double-blind phase. Dose titration was to a maximum of 80 mg per day (OXN3001S) or 120 mg per day (OXN3006S) at the discretion of the investigator. Use of laxatives and analgesic rescue therapy was recorded in patient diaries. Oxycodone immediate-release (IR) and bisacodyl were provided for the first seven days of the extension phase. Protocols for rescue medicines and laxatives were prescribed according to standard protocols of the investigational sites. There were seven mandated office visits.

• N = 474  
• AGE = 362 aded 65 and younger; 112 older than age 65
• MALES: 36.9%, FEMALES: 63.1%

• SITE: Multi-site    
• SETTING TYPE: Not specified

• PHASE OF CARE: Mutliple phases of care

• Pooled analysis of two Phase III double-blind, randomized studies

• Analgesia and bowel function were assessed at each study visit using average pain over last 24 hours scale and Bowel Function Index (BFI).
• Treatment Satisfaction Questionnaire for Medication (TSQM) was assessed at end of study only.

Improvement in bowel function was seen when patients switched from Oxy PR in the double-blinded phase to OXN PR in the extension phase, resulting in a clinical reduction (greater points) in BFI score: At the start of the extension phases, mean BFI score was 44.3 (SD = 28.13) and was 29.8 (SD = 2.36) for patients who had received OXN PR in the double-blinded phase. One week later, BFI scores were similar for the two groups (26.5 [SD = 24.4] and 27.5 [SD = 25.6], respectively), as was observed throughout the following months. Fewer than 10% of patients received laxatives regularly. Mean 24-hour pain scores were low and stable throughout the extension phases. No unexpected adverse events were observed.

Pooled data demonstrated OXN PR in patients with moderate-to-severe chronic pain is an effective long-term therapy for patient opioid-induced pain. Improvement in bowel function was seen during the double-blinded studies and was continued throughout the 52 weeks of OXN PR versus Oxy PR in this pooled analysis. No new or unexpected safety issues were observed, and patient satisfaction was high and maintained throughout the 52 weeks.

• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)

Prolonged-release oxycodone/naloxone (OXN PR) is a good option for patients with opioid-induced constipation.