To assess the effect of gender on treatment response for aprepitant plus a 5-HT₃ antagonist and corticosteroid for the prevention of chemotherapy-induced nausea and vomiting (CINV) 

The data from two phase III studies of aprepitant plus a 5-HT₃ antagonist and corticosteroid for the prevention of CINV were pooled. The two trials were of patients receiving more than 70 mg/m² of cisplatin randomly assigned to control regimen or aprepitant regimen. Patients were randomized to one of the treatment groups and stratified by gender. Patients used a diary to document emetic episodes, severity ratings of nausea (on a 100-mm horizontal visual analogue scale), and any use of rescue medications.

The study reported on 1,044 patients older than 18 years with a Karnofsky score greater than 60 and who were scheduled for first their cycle of chemotherapy, including cisplatin.

The studies were conducted in the United States and the Netherlands, predominately in university cancer centers.

Two identically designed, randomized, double-blind parallel group, placebo-controlled trials were reviewed.

Visual analogue scales (VASs) and patient diaries were used.

• In the control group, 41% of women had an overall complete response (CR) compared with 53% of men.
• In the aprepitant group, 66% of women had an overall CR compared with 69% of men.
• The enhanced efficacy of aprepitant regimen in women occurred during acute and delayed phases and resulted in similar rates of antiemetic control for men and women.
• The aprepitant regimen partly maintained improvement over multiple cycles for men and women.

The addition of aprepitant may reverse the risk of gender for CINV in women receiving highly emetogenic chemotherapy.

Details of design, primary efficacy, and tolerability are not included, but the results of the studies are published elsewhere.

To examine the efficacy of acupuncture in women with breast cancer experiencing hot flashes as a result of anti-estrogen medication

Patients were randomized to either 10 weeks of traditional Chinese acupuncture or sham acupuncture.

The trial reported on a sample of 59 women with breast cancer.

A prospective, controlled trial design was used.

• Mean number of hot flashes at day and night were recorded prior to treatment, during the treatment period, and during the 12 weeks following treatment.
• Kupperman Index was completed at baseline, at the end of the treatment period, and at 12 weeks following treatment.

During the treatment period, the mean number of hot flashes at day and night was significantly reduced by 50% and almost 60%, respectively, from baseline in the acupuncture group, and was further reduced by 30% both at day and night during the next 12 weeks. In the sham acupuncture group, a significant reduction of 25% in hot flashes at day was seen during treatment, but was reversed during the following 12 weeks. No reduction was seen in hot flashes at night. Kupperman Index was reduced by 44% from baseline to the end of the treatment period in the acupuncture group, and largely maintained 12 weeks after treatment ended. No corresponding changes were seen in the sham acupuncture group.

• A placebo effect may have occurred.
• The study had a small sample size.

Longer studies are needed to see if effect continues.

To evaluate the prophylactic use of a Safetac product, Mepitel Film, on moist desquamation rates

At the start of radiation treatment, the breast or chest wall was divided into medial and lateral halves, and sections were randomly assigned to treatment with either Mepitel Film or aqueous cream. Mepitel Film was applied at the start of radiation treatment by the research radiation therapist on either the entire lateral or the entire medial part of the breast or chest wall to be irradiated as randomly assigned, and aqueous cream was applied twice daily to the control area by the patients.

The date of onset and location of moist desquamation were recorded for each patient. Moist desquamation was treated according to the standard departmental protocol consisting of Mepilex Lite dressings. Mepitel Film was left on during radiation because it had been determined that the Film has a clinically insignificant bolus effect of 0.12 mm. Follow-up assessment was done up to four weeks after the completion of treatment.

• N = 78 included for analysis
• MEAN AGE = 59.9 years
• AGE RANGE = 30–94 years
• MALES: 2.56% (2 men), FEMALES: 97.44% (76 women)
• KEY DISEASE CHARACTERISTICS: Breast cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Most were of European ethnicity. Patients did not have concurrent chemotherapy. Most patients had 40–50 Gy in 15–25 fractions.

• SITE: Single center—University of Otago  
• SETTING TYPE: Clinic    
• LOCATION: New Zealand

• Phase-III, randomized trial
• Intrapatient, controlled, single-center trial

Skin reaction severity was assessed using the radiation-induced skin reaction assessment scale (RISRAS) and Radiation Therapy Oncology Group (RTOG) scales.

Overall skin reaction severity was reduced by 92% (p < 0.0001) in favor of Mepitel Film (RISRAS). All patients developed some form of reaction on cream-treated skin, which progressed to moist desquamation in 26% of patients (RTOG grades I: 28%, IIA: 46%, IIB: 18%, III: 8%). Only 44% of patients had a skin reaction under the Film, which did not progress to moist desquamation in any of the patients (RTOG grades I: 36%, IIA: 8%). No patients had moist desquamation with the Mepitel Film. No relationship existed between smoking, skin type, or other patient variables and skin toxicity results. Patients who received hypofractionation were less likely to develop moist desquamation than others (p = 0.012).

Mepilex Film was effective in preventing severe skin reactions.

• Small sample (< 100)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• The Mepilex Film was in situ for days at a time
• Neither the research radiation therapist nor the patients were blinded to which skin area had been randomized to Mepilex Film and which to cream.

Mepital Film use may be an effective approach to prevent severe radiodermatitis in patients treated for breast cancer. Further research to confirm these findings in other patient groups is warranted.

To determine if acetyl-L-carnitine (ALC) prevents chemotherapy-induced peripheral neuropathy (CIPN) in women with early stage breast cancer receiving taxane-based treatment

Patients were randomly assigned to receive either placebo or ALC 3,000 mg (6 capsules) daily for 24 weeks.

• N = 409 (final sample); 208 received ALC and 201 received placebo
• MEDIAN AGE = 51 years
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Women with stage I-II breast cancer who were to receive adjuvant taxane therapy

• SITE: Multi-site 
• SETTING TYPE: Outpatient

PHASE OF CARE: Active antitumor treatment

Randomized, double-blind, placebo-controlled

• Neurotoxicity component of the Functional Assessment of Cancer Therapy–Taxane scale (FACT-NTX)
• Functional Assessment of Cancer Therapy–Taxane Trial Outcome Index (FACT-TOI)
• Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-Fatigue)

At week 12,  patients taking ALC had lower FACT-NTX scores (0.9), indicating more CIPN than those taking placebo (P = .17). After 24 weeks, patients taking ALC had a greater than 5-point decrease in FACT-NTX scores (P = .05). The FACT-TOI scores were lower with ALC (P = .03 ). There was no difference in the FACIT-Fatigue score between arms. Patients reported grade 3-4 neuropathy in the ALC arm versus grade 1 reported in the placebo arm resulting from taxane (P = .46).

At the end of 24 weeks, patients who had been taking ALC reported an increase in CIPN and a decrease in function, compared to those taking placebo.

• Subject withdrawals were ≥ 10%.
• Since this study was done with a taxane-based chemotherapy, it is unknown how other neurotoxic drugs given with ALC would influence CIPN.
• The scores at 24 weeks represented the main secondary endpoint and not the primary endpoint; however, since not all patients had completed the taxane treatment at 12 weeks from when they were registered, 24 weeks may have been the most appropriate endpoint after all.
• Since this trial indicated a detrimental effect with ALC and a taxane, it is recommended that a taxane-based chemotherapy and ALC trial not be repeated.

It has been reported in the literature that many patients take supplements without any evidence of efficacy. Patients often have discussions with nurses and ask questions about the use of supplements. To give patients correct information, including the risks, nurses need to be knowledgeable about the efficacy of nutritional supplements. It is recommended, from the results of this study, that nurses discourage patients from taking ALC since it may be harmful.

STUDY PURPOSE: To provide evidence-based guidance on optimum prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathy in adult cancer survivors

TYPE OF STUDY: Systematic review

DATABASES USED: Ovid Medline (1946–April, week 2, 2013); EMBASE (1980–2013, week 16); AMED Allied and Complementary Medicine (1985–April 2013)

KEYWORDS: chemotherapy-induced peripheral neuropathy; adult cancer survivors; randomized clinical trials

INCLUSION CRITERIA: Adult cancer survivors with chemotherapy-induced peripheral neuropathy; randomized trials

EXCLUSION CRITERIA: Phase 1 trials; published in a language other than English; less than 10 patients; focused on radiation or stem cell transplant neuropathy; animal studies

TOTAL REFERENCES RETRIEVED = 1,252

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: An expert panel representing neurology, nursing, medical oncology, community oncology, pain research, and genetics met through teleconference and emails to review and develop the American Society of Clinical Oncology guidelines.

• FINAL NUMBER STUDIES INCLUDED = 48
• TOTAL PATIENTS INCLUDED IN REVIEW: Treatment studies: 780; prevention studies: 3,741

PHASE OF CARE: Active antitumor treatment

Forty-two randomized clinical trials involved 19 various interventions for prevention of chemotherapy-induced peripheral neuropathy. These agents included anticonvulsants, antidepressants, vitamins, minerals, and other chemoprotectant drugs. Only six randomized clinical trials discovered six different drugs, such as antidepressants, anticonvulsants, and a topical gel, for the prevention of chemotherapy-induced peripheral neuropathy. The following are not recommended for use: acetyl-l-carnitine, amifostine, amitriptyline, calcium and magnesium, glutathione, nimodipine, ORG 2766, trans retinoic acid, rhuLIF, and vitamin E. Venlafaxine is not recommended for routine use in clinical practice. Although data support potential utility, evidence is not strong enough to suggest use. For treatment of chemotherapy-induced peripheral neuropathy, clinicians can offer duloxetine. No recommendation is made regarding ALC. Tricyclic antidepressants or gabapentin through trial use may be reasonable.  The panel felt that trying topical gel containing baclofen, amitriptyline, and ketamine would be reasonable. 

No agents were recommended for the prevention of chemotherapy-induced peripheral neuropathy, but duloxetine is moderately recommended for the treatment of chemotherapy-induce peripheral neuropathy. Even though conclusive evidence is lacking to recommend tricyclic antidepressants such as nortriptyline, gabapentin, and a topical gel containing baclofen,amitriptyline, and ketamine for treatment of chemotherapy-induced peripheral neuropathy, the expert panel agreed that offering these agents based on treatment for neuropathic pain is reasonable. The panel also recommended that patients be counseled regarding the lack of evidence in treating chemotherapy-induced peripheral neuropathy with these agents.

• Small, insufficient sample
• Inability to compare studies because of different outcomes
• Measurements and instruments used at different points in treatment

Nurses are at the frontline in assessing patients who are receiving agents with the potential for chemotherapy-induced peripheral neuropathy. Nurses should be aware of the standard of care in treating this population. Many drugs prescribed have no evidence in preventing or treating these patients. However, with these American Society of Clinical Oncology guidelines, a role for duloxetine is clear and a role for tricyclic antidepressants is possible. Nurses need to be knowledgeable about this information to better inform patients.

To determine if omega 3 fatty acids can be effective in decreasing arthralgia resulting from aromatase inhibitor (AI) treatment

Patients were randomized to receive either a placebo or 3.3 g of omega 3 fatty acids daily for 24 weeks. Random assignment was stratified by prior history of arthritis and prior taxane use. Study assessments were done at baseline and at six, 12, and 24 weeks.

• N = 209  
• MEDIAN AGE = 59.2 years
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Patients with stage 1 and 2 hormone-sensitive breast cancer receiving adjuvant AI therapy 
• OTHER KEY SAMPLE CHARACTERISTICS: Pain score greater than 5 out of 10 associated with AI use; median of 1.2 years of AI treatment

• SITE: Multi-site  
• SETTING TYPE: Outpatient    
• LOCATION: United States

• PHASE OF CARE: Active antitumor treatment

Double-blinded, placebo-controlled, randomized trial

• Brief Pain Inventory Short Form (BPI-SF)
• Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)
• Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hand (M-SACRAH)
• Functional Assessment of Cancer Therapy (FACT) Endocrine Symptoms
• Serum lipids and C reactive protein

There were no significant differences between the groups in worst pain scores or stiffness at any study time point. The mean observed changes in other study measures showed somewhat reduced symptoms in the omega 3 arm, but these changes were not statistically significant. There were no significant changes in serum measures over time other than decreased triglycerides in those receiving the fatty acids. Over time, symptoms improved in both study groups.

This study did not show any improvements in arthralgia symptoms induced by AIs with the use of omega 3 fatty acids compared to a placebo.

There are no effective therapies for the prevention or treatment of AI-associated arthralgia. Ongoing research to determine optimal approaches to prevent or manage this symptom is necessary. These symptoms' mechanism of development is not clear, but they may have inflammatory and autoimmune components.

To examine the effects of generic psychotherapeutic interventions on dysfunctional fear of progression (FoP)

Randomization was stratified by diagnosis, and participants were blinded with regard to group assignment. The intervention group received four sessions of group psychotherapy, each 90 minutes. The first group received cognitive behavioral group therapy (CBT) and a manual that was structured with content, topics, and interventions. The supportive experiential group therapy (SET) had a manual with regard to structure, but it was less prescriptive in content than was the CBT manual. The groups were led by psychotherapists who had had three years or more of clinical experience or were in the final phase of training. Sessions were recorded, to monitor integrity. Measures were taken at the initial session, before discharge, at three months, at 12 months, and after discharge. The control group provided data at the initial, before-discharge, and after-discharge points only. The intervention groups received booster telephone calls at six and nine months after discharge. The control group was sampled in the same clinics as were other patients and at one year after the completion of the intervention, using the same eligibility criteria.

• The sample was composed of 872 participants total; 174 had chronic arthritis (CA)  and 174 had cancer.
• All participants were at least 18 years old.
• Mean age of CA patients was 46.7 years (SD = 9.5 years); mean age patients with cancer, 53.7 years (SD = 10.2 years).
• The number of female patients in the CA group was 194; in the cancer group, 220. The number of male patients in the CA group was 64; in the cancer group, 45.
• Of participants with cancer, 58.8% had breast cancer, 8% had colon cancer, 9.5% had bladder or prostate cancer, 9.1% had gynecologic cancer, and 14.4% had some other kind of cancer.

• Multisite.
• Inpatient.
• Patients with chronic arthritis were from one rehabilitation clinic. Patients with cancer were from two rehabilitation clinics.

Active treatment and transition phase

Single-blind partially longitudinal randomized controlled study

• Fear of Progression Questionnaire (FoP-Q), consisting of 43 items relating to five dimensions
• German version of the Hospital Anxiety and Depression Scale (HADS)
• German version of the SF-12
• Questions on Life Satisfaction Modules (FLZM)

Both interventions were associated with a decrease in FoP over time, but only among cancer patients. The two interventions did not differ in reducing FoP. A significant interaction between time and illness group emerged for anxiety, depression, and the mental component of health-related quality of life, indicating an improvement in cancer patients. The intervention had no effect  on any of the secondary outcomes.

Dysfunctional FoP can be identified and targeted with brief group interactions. These interventions may reduce FoP, especially in populations with cancer. The intervention used here did not appear to have a long term benefit related to symptoms of depression.

• Randomization was incomplete.
• Participants in the rehabilitation setting may have had issues other than CA or cancer, and these issues may have affected outcomes.
• Authors did not specify the stage of disease. Stage would affect a patient’s perception of progression.
• Because of the settings involved, results may not be generalizable.

Dealing with FoP is important in the care of cancer survivors. Findings of this study suggest that dysfunctional fear can be identified and that interventions can be appropriately targeted. While the intervention in this study did not show a lasting benefit related to depression, the study does provide potential approaches to identifying patients who may benefit from interventions to address fear.

To review the pathophysiology of cancer-related nausea and vomiting and the research regarding various medications for management of this symptom, as well as similarities and differences among guidelines of various professional groups

Multinational Association of Supportive Care in Cancer (MASCC) guidelines are based on consensus via surveys and a consensus conference.

High emetic risk (e.g., cisplatin, dacarbazine, high-dose cyclophosphamide)

• Acute: Serotonin antagonist plus dexamethasone plus aprepitant
• Delayed: Aprepitant days 2–3 plus dexamethasone day 2–3 or 2–4

Moderate emetic risk (e.g., cyclophosphamide at more than 100 mg/m², anthracyclines, oxaliplatin, carboplatin)

• Acute: Serotonin antagonist plus dexamethasone
• Delayed: Dexamethasone days 2–3
• Patients receiving cyclophosphamide plus an anthracycline should receive acute protection for high emetic risk and delayed emesis protection with aprepitant or dexamethasone days 2–3.

Low emetic risk (e.g., topotecan, gemcitabine, taxanes, capecitabine, trastuzumab)

• Acute: Low-dose dexamethasone
• Delayed: No routine prophylaxis

Minimal emetic risk (e.g., bleomycin, vinca-alkaloids, bevacizumab): No routine prophylaxis

No approach to anticipatory nausea was provided.

New medications are highly effective in prophylaxis of emesis, but prevention of nausea remains challenging.

To provide guidance to clinicians for the prevention and management of chemotherapy-induced nausea and vomiting in patients receiving cancer chemotherapy of varying emetogenic potential

The evidence-based process was not fully described. Specific research was not stated. Literature cited were the antiemetic resource center at www.mascc.org and the Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer 2004 consensus conference, cited in Annals of Oncology 2006, 17, 20–28.

Levels of evidence and grades of recommendation as used by the American Society of Clinical Oncology (ASCO) were applied to specific recommendations and considered by the authors and European Society for Medical Oncology (ESMO) faculty. This was approved by the ESMO guidelines working group.

This reference provides definitions of nausea and vomiting; relative emetogenic potential of oral and IV drugs; recommended drugs, dosing, and schedules for antiemetic drugs; and recommendations for management of nausea and vomiting based on emetogenic potential.

Specific regimens are outlined below. Stated level (I–V) and grade of evidence assessed are shown in parentheses.

• Acute nausea and vomiting
  • High-emetogenic potential: Serotonin antagonists + corticosteroid + aprepitant (I, A)
  • Anthracycline + cyclophosphamide: Serotonin antagonist + dexamethasone + aprepitant (II, A)
  • Moderate potential: Serotonin antagonist + corticosteroid (I, A)
  • Low potential: Single agent such as corticosteroid (III, IV, D)
  • Minimal potential: No prophylaxis (V, D)

• Delayed nausea and vomiting
  • High-emetogenic potential: Corticosteroid + aprepitant (II, A)
  • Anthracycline +cyclophosphamide: Dexamethasone or aprepitant (II, A)
  • Moderate potential: Corticosteroid (I, A) or serotonin antagonist (II, B)
  • Low potential: No routine prophylaxis
  • Minimal potential: No routine prophylaxis

• Specific issue recommendations
  • Multiple-day chemotherapy: As for acute on chemotherapy days and as delayed 1–2 days after chemotherapy
  • Refractory nausea and vomiting: Consider aprepitant if not already used or add dopamine antagonists to serotonin antagonists and corticosteroids (V, D)
  • Anticipatory nausea and vomiting: Lorazepam or similar drugs, behavioral techniques (V, D)
  • High-dose chemotherapy: Corticosteroids, serotonin and dopamine antagonists in full doses (III, C)

• The principal author performed ad hoc advisory board activity for multiple pharmaceutical companies and was conducting research sponsored by Merck.
• The secondary author was a member of advisory boards on palonosetron and aprepitant, had been a sponsored speaker, and had conducted research on casopitant and fosaprepitant.
• Recommended timing of interventions for delayed nausea and vomiting prophylaxis was unclear.
• The authors were not clear if the recommendation was to use these medications prophylactically interventionally for delayed symptoms.
• No discussion was provided regarding dosage titration approaches to individualize management.

• This guideline provides a good reference for classification of chemotherapeutic agents according to emetogenic potential and a good reference for initial dosing of medications used.
• The recommendations are based on patients who are chemotherapy-naïve.
• The recommendations focus on pharmaceutical management, except for consideration of behavioral techniques for anticipatory nausea and vomiting.

To compare tropisetron plus metopimazine versus tropisetron plus placebo for the prevention of chemotherapy-induced nausea and vomiting (CINV)

This study reported on 82 patients with germ cell tumors scheduled to receive four cycles of cisplatin, given as a five-day treatment every three weeks.

This was a randomized, double-blind trial.

Patients used diaries to record the number of vomiting and retching episodes, nausea severity (on a four-point Likert-type scale), and appetite evaluation (on a four-point Likert-type scale).

Satisfaction with antiemetic treatment was collected via a categorical question (satisfied versus not satisfied). Those who were not satisfied with the antiemetic treatment were withdrawn from the study, as they were requesting additional or other treatments.

Tropisetron plus metopimazine was reported to be superior to tropisetron plus placebo in the overall period (days 1-9) in terms of complete protection from vomiting as well as decreased nausea. The treatment arm also was superior over multiple cycles, providing cumulative emetic protection.

This study addressed an appropriate and effective antiemetic prophylaxis for multiple-day chemotherapy regimens (usually cisplatin-based). However, antiemetic control in both treatment arms was poor.

Since this study was conducted, newer agents (i.e., palonosetron and aprepitant) have been proven to have greater efficacy than the treatments used in this study. Furthermore, the treatments described in this study are known to be inferior to treatments that include a corticosteroid. Finally, the rates of protection from CINV associated with the agents studied are not good.