STUDY PURPOSE: To discuss the usefulness and safety of axillary reverse mapping (ARM) of the arm and breast during surgery on the development of breast cancer-related lymphedema

TYPE OF STUDY: Systematic review

PHASE OF CARE: Late effects and survivorship

This review showed that the ARM technique is feasible and can result in low rates of lymphedema, and identification of ARM lymphatics and nodes was higher with ANC than SNB. The rate of lymphedema during SNB was 0%–6% and 5.9%–24% during lymphatic preservation at ANC, both of which are still lower than previously stated rates. Ochoa et al. reported a lymphedema rate of 2.5% for SNB alone and 2% with ARM. Casabona et al. reported no cases of lymphedema. Crossover nodes were identified in four studies assessing ARM in SNB, two of which were metastases. Kuusk et al. identified 1/ 5 nodes, and Ochoa et al. identified 2/14 nodes, thereby suggesting that crossover nodes are not common during ARM and however many metastases are present (0%–20%). Metastases were detected at the same rate (0%–19%) in patients where ARM nodes were not preserved when identified. Ochoa et al. reported 5/27 ARM positive nodes and Han et al. reported 2/17 positive ARM nodes during SNB, while Tausch et al. identified 13/58 metastases ARM nodes during ANC.

• Limited search
• Low sample sizes
• Short follow-up intervals did not allow a long enough interval to establish the oncologic safety of ARM
• Standard SNB technique was not used in all studies.
• Different definitions of lymphedema
• Clinical diagnoses of lymphedema were made occasionally.
• Inconsistent knowledge of number of nodes excised and if patients were undergoing adjuvant

The implications for nursing would be in the area of low-level laser therapy (LLLT) patient education, understanding of the ARM technique, and evidence related to lymphedema rate. For the present, nurses need to be knowledgeable of clinical trials involving the ARM technique and stay current with lymphedema management.

To determine whether oxycodone/naloxone prolonged-release tablets (OXN PR), as compared with oxycodone prolonged-release tablets (OxyPR), can improve constipation and maintain analgesia in patients with moderate or severe chronic cancer pain.  

Stopping their prestudy opioid and laxative medication, eligible patients were randomized to receive one of two treatments, OXN PR or OxyPR, for a four-week double-blind treatment phase. After beginning the study, patients attended three additional clinic visits, once weekly. Oxycodone immediate-release capsules were available as pain rescue medication and bisacodyl tablets were available as laxative rescue medication. Evaluations of bowel function, pain control, use of rescue medication, and use of laxative medication during the prior seven days were performed at each clinic visit. Quality-of-life (QOL) assessments were conducted at screening and study end.

• In this sample, 133 of 184 patients (72.3%) completed the study.
• Patients were aged 18 years or older. Mean patient age was 61.86 years (SD = 10.93, median = 62, range 36-84) in the OXN PR group and 64.3 years (SD = 9.63, median = 66, range 42-82) in the OxyPR group. 
• The OXN PR group was 52% male and 48% female, whereas the OxyPR group was 50% male and 50% female.
• Key disease characteristics were having a diagnosis of cancer and moderate or severe, chronic pain requiring around-the-clock opioid therapy, with constipation induced or worsened by the opioid medication.
• Patients were excluded if they had clinically unstable disease; significant cardiovascular, renal, hepatic, or psychiatric disease; clinically significant gastrointestinal (GI) disease; significant structural abnormality of the GI tract; cyclic chemotherapy within two weeks before the screening visit; planned chemotherapy during the study; or radiotherapy that would influence bowel function or pain.

• Multi-site
• Outpatient
• International  (64 study sites in Australia, Czech Republic, France, Germany, Hungary, Israel, Netherlands, Poland, and United Kingdom)

Patients were undergoing the active treatment phase of care.

This was a randomized, double-blind, active-controlled, double-dummy, parallel-group, phase II trial.

• Bowel Function Index (BFI)
• Brief Pain Inventory (Short Form) (BPI-SF)
• EuroQol EQ-5D
• European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30)
• Patient Assessment of Constipation Symptoms (PAC-SYM)
• Modified Subjective Opiate Withdrawal Scale (SOWS)
   

• Mean BFI score was significantly lower in the OXN PR group (p ˂ 0.01) after four weeks of treatment.
• Mean total laxative intake was 20% lower in the OXN PR group, but the difference was not statistically significant (p = 0.17).
• Mean BPI-SF scores and analgesic rescue medication use were similar for both groups.
• The OXN PR group had greater improvements in constipation-specific QOL assessments in terms of total symptom score (p = 0.014) and frequency of symptoms (p ˂ 0.01).
• Adverse events were similar and low in both groups.

OXN PR, as compared with OxyPR, seems to provide comparable analgesia for patients with moderate or severe cancer pain while significantly improving bowel function and reducing symptoms of constipation.

Demographic characteristics were generally well balanced between treatment groups, with the exception of a slightly higher percentage of patients aged 65 years or younger in the OXN PR group. 

OXN PR seems superior to OxyPR with respect to bowel function by reducing constipation without compromising pain relief. In addition, patients receiving OXN PR had improved QOL with decreased opioid-induced constipation complications.

To answer the following questions: What are the effects of oral laxatives, rectal preparations, and opioid antagonists for constipation in people prescribed opioids?

Databases searched were MEDLINE, Embase, Cochrane Central Register of Controlled Trials and Library, NHS Centre for Reviews and Dissemination (CRD), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment, TRIP, and the National Institute for Health and Clinical Excellence (NICE) up to August 2009. Alerts from the U.S. Food and Drug Administration and the U.K. Medicines and Healthcare Products Regulatory Agency were included to identify any adverse effects.

Search keyword were constipation and opioids, Lactulose, macrogols, senna, bisacodyl, co-danthrusate/co-danthramer, docusate, ispaghula husk, liquid paraffin, magnesium salts, methylcellulose, arachis oil enema, glycerol suppository, phosphate enema, sodium citrate enema, and opioid antagonists.

Studies were included in the review if they

• Were randomized controlled trials (RCTs), observational studies, or systematic reviews
• Had a study sample of at least 20 participants
• Had a maximum loss to follow-up of 30% per year in longitudinal studies.

The GRADE System was used to evaluate study quality. Full information is available online with a subscription.

The final sample comprised 23 systematic reviews, RCTs, or observational studies. This was an update of a previous review that added 1 systematic review and 5 RCTs, with no change in overall recommendations provided.

Oral Laxatives

• Lactulose, polyethylene glycols (PEGs) plus electrolytes, and senna were identified as beneficial in this systematic review. Evidence in this area was graded as low-to-moderate quality. Lactulose appears to be as effective as PEG in reducing the number of hard stools, and as effective as senna in reducing the number of days without defecation.
• Preparations identified as unknown effectiveness included bisacodyl, co-danthrusate and co-danthramer, docusate, ispaghula husk, liquid paraffin, magnesium salts, and methylcellulose.
• Some oral laxatives such as bisacodyl often are prescribed in combination with other agents or rectal suppositories, but no evidence supports this use, particularly in people taking opioids.
• Liquid paraffin may be harmful in patients who have difficulty swallowing.

Rectal Preparations

• All of the rectal preparations studied were categorized as unknown effectiveness. The preparations included arachis oil enema, glycerol suppository, phosphate enema, and sodium citrate micro-enema.

Opioid Antagonists

• Opioid antagonists, including alvimopan, methylnaltrexone, and naloxone, were categorized as beneficial.  Categorization was based on studies comparing those agents to no treatment or placebo.  The most common side effects reported were abdominal pain, nausea, and diarrhea, particularly with higher doses. 
• A concern with these agents is the potential for use to reverse the therapeutic action of opioids.  Alvimopan and methylnaltrexone are considered safer than naloxone in this regard, as neither of those agents can cross the blood-brain barrier and a few small studies of acute pain have shown success in blocking the constipating effect of opioids without compromising pain relief.

• Although various combinations of oral laxatives and rectal agents may be used clinically, their effectiveness for constipation in people taking opioids has not been evaluated. This area can benefit from continued well-designed study.
• Opioid antagonists are considered effective for reducing constipation in people prescribed opioids. However, only a few studies with small groups of patients have examined the effect of these agents on pain relief with opioids. Use of opioid antagonists may also have implications for which type of opioid should be used for pain control.  Long-term use with chronic pain managed by opioids is not well researched.

Nurses should be aware of potential implications related to the use of opioid antagonists in controlling constipation for opioid interactions and changes in pain control. In addition, nurses should routinely assess for pain relief, as well as symptoms of constipation, in this patient population.

To determine whether oxycodone/naloxone prolonged-release tablets (OXN PR) can improve constipation and maintain analgesia, compared with oxycodone prolonged-release tablets (OxyPR) in patients with moderate to severe cancer pain

This was a randomized, double-blind, active-controlled, double-dummy, parallel-group study in which 185 patients were randomized to receive up to 120 mg per day of OXN PR or OxyPR over four weeks. Efficacy assessments included Bowel Function Index (BFI), Brief Pain Inventory Short-Form (BPI-SF), and laxative and rescue medication use. Quality-of-life and safety assessments also were conducted.

• N = 184
• AGE = In the OXN PR group, 65.2% of the patients were aged 65 years or younger and 34.8% were older than 65 years. In the OxyPR group, 48.9% of the patients were aged 65 years or younger and 51.1% were older than 65 years.
• MALES: 51%, FEMALES: 49%
• KEY DISEASE CHARACTERISTICS: Eligible patients aged 18 years or older with a diagnosis of cancer and a documented history of moderate to severe, chronic cancer pain requiring around-the-clock opioid therapy equivalent to OxyPR 20–80 mg per day at the initiation of the trial
• OTHER KEY SAMPLE CHARACTERISTICS: Willing and able to participate in the use of medication, complete subjective evaluations, attend scheduled clinic visits, complete telephone contacts, and comply with protocol requirements as evidenced by providing written, informed consent

• SITE: International
• SETTING TYPE: Multi-center
• LOCATION: Australia, Czech Republic, France, Germany, Hungary, Israel, Netherlands, Poland, and United Kingdom

• PHASE OF CARE: Active treatment
• CLINICAL APPLICABILITY: Palliative care

• Randomized, double-blind, active-controlled, double-dummy, parallel-group study

• Evaluations of BFI, pain control (BPI-SF), use of rescue medication, and use of laxative medication during the last seven days were performed at each clinic visit.
• Quality-of-life assessments, including the European Quality of life (EuroQo) EQ-5D instrument and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) were conducted at screening and at study end.
• Patient Assessment of Constipation Symptoms (PAC-SYM) was conducted at screening, randomization, and four weeks.
• Adverse events were noted at each assessment post-randomization.
• Patients were followed up regarding adverse events and adverse drug reactions after study completion.

Overall, 133 of 184 patients (72.3%) completed the study. Rates of discontinuation were similar for OXN PR (28.3%) and OxyPR (27.2%). In both groups, the primary reason for discontinuation was adverse events. At randomization, mean BFI values were high and comparable in the OXN PR and OxyPR groups (63.97 [SD = 17.42] versus 62.40 [SD = 23.56], respectively), and similar to baseline assessments in previous phase III trials. The difference in change from baseline in BFI score between groups was statistically significant. A statistically significant difference between treatments in favor of OXN PR was observed at week 1.

At randomization, mean BPI-SF scores were comparable for OXN PR and OxyPR treatment groups (4.16 [SD = 1.87] versus 4.18 [SD = 1.87]). After four weeks of treatment, mean BPI-SF scores remained comparable between the two groups (3.50 [SD = 1.88] and 3.52 [SD = 1.80]). Results of the primary analysis confirmed non-inferiority of OXN PR to OxyPR.

Patients who were switched directly from other opioids to OXN PR experienced a similar analgesic effect as well as a statistically significant and clinically relevant improvement in bowel function, compared with those switched to OxyPR.

Opioid-induced bowel dysfunction is common and adds to the burden of living with chronic pain. Current oral and rectal laxatives often are ineffective and do not have a good evidence base. The new targeted approach of administering peripherally acting opioid antagonists is effective and supported by extensive clinical trial data. The present trial demonstrates that oral OXN PR tablets are well tolerated and can effectively and conveniently provide targeted treatment of opioid-induced constipation.

The study is a double-blind, randomized, controlled phase ll trial of heliox 28 gas mixture in patients with lung cancer with dyspnea on exertion.

The study compared the effects of heliox 28 (72% helium and 28% oxygen) to oxygen-enriched air (72% nitrogen and 28% oxygen) or medical air (78.9% nitrogen and 21.1% oxygen) on dyspnea and exercise capacity in patients with lung cancer.

The study reported on a sample of 12 patients with lung cancer; patients had to be able to do a six-minute walk prior to screening evaluation and at defined time points throughout the study.

The study was a double-blind, randomized, controlled phase ll trial.

Patients’ symptoms were evaluated with a VAS and modified Borg scale (0–10). Pulse oximetry (SaO₂) monitoring was done continuously before, after, and then for five minutes after patients breathed the gas mixture.

Dyspnea assessments and VAS scores indicated a significant decrease in breathlessness following heliox 28 compared to medical air. No significant difference was found between heliox and oxygen-enriched air. Borg assessments showed no significant differences across treatments. Patients receiving heliox 28 walked farther than patients receiving oxygen-enriched air or medical air (p < 0.001). No significant difference was found in oxygen saturation percentage measured before the walk. Oxygen saturation was significantly higher during the walk and at rest after breathing heliox 28 than with the other two gas mixtures (p < 0.0001). No significant difference was found between oxygen-enriched air and medical air. No adverse events were reported.

The study had a small sample size of 12.

A promising beneficial role may exist for heliox therapy to improve exercise tolerance in dyspneic patients with cancer.

To compare transdermal fentanyl and sustained-released morphine in palliative care patients with cancer by measuring efficacy, tolerance, and quality of life (QOL).

Patients received one treatment for 15 days, then the other for 15 days to compare which provided the greatest efficacy and QOL, and the fewest side effects. The null hypothesis was 50% of patients would prefer fentanyl and 50% would prefer morphine.

• The study reported on a sample of 202 adult palliative care patients with cancer; 110 completed the study.
• Mean patient age was 61.5 years.
• The sample was 55% male.
• Patients had a life expectancy greater than a month and were receiving a strong, stable dose of opioids.

38 different palliative care centers in the United Kingdom

This was a randomized, open, two-period, crossover study.

• QOL was assessed with World Health Organization (WHO) performance status (measured prestudy, post-study, and daily during the study) and the European Organization for Research and Treatment of Cancer (EORTC) QOL questionnaire, which measures side effects, convenience, and effects on activities of daily living (ADLs) or careers (measured after each arm of the study). These tools have been validated for patients with advanced cancer. 
• Constipation and diarrhea were assessed with the EORTC scale prestudy and on days 8, 16, 23, and 31. 
• Daily diaries were used to record estimated sleep length, night awakening, daytime drowsiness, and use of rescue medications.
• Memorial Pain Assessment Card was used BID for assessment of pain and mood.
• Skin assessment was performed when removing patches.

• The top reason patients withdrew from the study was because of adverse events.
• Fentanyl was associated with significantly less constipation than morphine (p <  0.001). This was confirmed through multiple assessment mechanisms.
• The remaining results did not pertain to constipation.

• Patients were allowed short-acting morphine for breakthrough pain, which could alter the results for fentanyl; however, the results were still significant.
• Having a \"washout\" period is unethical.
• Some patients may have dropped out because of morphine withdrawal.
• The study was not blinded; therefore, bias may exist according to delivery mechanism preference.
• Fentanyl and morphine doses varied among individuals and were titrated, as needed, throughout the study.

To examine associations between exercise and lymphedema in breast cancer survivors

The study and all protocols were approved by the University of Minnesota.

• The study sample (N = 85) was comprised of female breast cancer survivors who were recruited from October 2001–June 2002.
• Forty-two women were randomly selected for the intervention group, 23 of which had undergone axillary dissection.
• Forty-three women were randomly selected to the control group, 23 of which had also had axillary dissection.
• All participants gave signed informed consent.

The study took place in the Minneapolis-Saint Paul greater metropolitan area in Minnesota.

The study used a randomized controlled trial design.

• Arm circumference measurements were taken on both arms at the level of the metacarpophalangeal joints, just distal to the ulnar styloid process, 10 cm distal to the midpoint of the lateral epicondyle, and 10 cm proximal to the midpoint of the lateral epicondyle. During measurements, participants lay prone with their arms at their sides and elbows straight. A cloth measuring tape was placed around the arm so that there was no slack and no indentation of the tissue. Participants who wore compression sleeves removed them one hour before measurements were taken. The mean of two measurements was used. The outcome measure was the calculated difference in each circumference measure between the ipsilateral and contralateral arms.
• A validated survey measured self-report of lymphedema diagnosis, symptoms, and treatment over the past three months. The survey had a specificity of 0.90 and sensitivity of 0.86–0.92 for diagnosing lymphedema (difference in arm circumferences of 2 cm), compared with clinical assessment by a physical therapist with training in lymphedema. Symptoms of lymphedema included whether or not a patient had noticed that her hand or lower or upper arm on the side of the cancer was larger than the side of the opposite arm and if the difference was mild, moderate, or severe. Additionally, other symptoms included altered fine motor function, puffiness, swelling, or pain of the hand or arm.
• A patient was a self-reported “incident” case of lymphedema if she self-reported a clinician diagnosis of lymphedema at six months but not at baseline. A patient was a self-reported “prevalent” case if she self-reported a clinician diagnosis of lymphedema. A participant was considered to have lymphedema symptoms if she reported any lymphedema symptoms in the survey.

After dropouts and loss to follow-up, 78 women completed baseline and six-month measurements of arm circumference. A twice-a-week weight training for a period of six months did not increase arm-circumference measurements or exacerbate symptoms of lymphedema in survivors of breast cancer compared with nonintervention controls.

• Six months may not have adequately captured acute or transient changes in circumferences or symptoms that may result from exercise.
• They did not measure change in volume, which is correlated with circumference measures but may be more sensitive to change.
• Few of the women randomly selected at baseline had lymphedema.

To examine associations between exercise and lymphedema in breast cancer survivors

The study and all protocols were approved by the University of Minnesota.

• The sample was comprised of (N = 85) breast cancer survivors recruited from October 2001 to June 2002.
• The randomized intervention group (n = 42) included 23 patients who underwent axillary dissection.
• The randomized control group (n = 43) included 23 patients who underwent axillary dissection.
• All participants gave signed informed consent.

The study was conducted in the great Minneapolis-St. Paul, MN, metropolitan area.

A randomized controlled trial

Lymphedema was measured three ways: arm circumference measurements, self-reported symptoms, and symptoms of lymphedema.

Arm circumference

• Arm circumference measurements were taken on both arms at the level of the metacarpophalangeal joints, just distal to the ulnar styloid process, 10 cm distal to the midpoint of the lateral epicondyle, and 10 cm proximal to the midpoint of the lateral epicondyle.
• During arm circumference measurements, participants lay prone with their arms at their sides and elbows straight. A cloth measuring tape was placed around the arm so that there was no slack and no indentation of the tissue. Participants who wore compression sleeves removed them one hour before measurements were taken. The mean of two measurements was used. The outcome measure was the calculated difference in each circumference measure between the ipsilateral and contralateral arms.

Self-reported symptoms

• A validated survey measured self-report of lymphedema diagnosis, symptoms, and treatment over the past three months.The survey had a specificity of 0.90 and sensitivity of 0.86–0.92 for diagnosing lymphedema (difference in arm circumferences 2 cm), compared with clinical assessment by a physical therapist with training in lymphedema.
• Symptoms of lymphedema included whether or not a participant had noticed that her hand, lower or upper arm on the side of the cancer was larger than the side of the opposite arm and if the difference was mild, moderate, or severe.
• Other symptoms included altered fine motor function, puffiness, swelling, and/or pain of the hand or arm.

Symptoms of lymphedema

• A participant was a self-reported “incident” case of lymphedema if she self-reported a clinician diagnosis of lymphedema at six months but not at baseline.
• A patient was a self-reported “prevalent” case if she self-reported a clinician diagnosis of lymphedema.
• A participant was considered to have lymphedema symptoms if she reported any lymphedema symptoms in the survey.

• After dropouts and loss to follow-up, 78 women completed baseline and six-month measurements of arm circumference.
• A twice-a-week weight training for a period of six months did not increase arm circumference measurements or exacerbate symptoms of lymphedema in survivors of breast cancer compared with nonintervention controls.

• Six months may not have adequately captured acute or transient changes in circumferences or symptoms that may result from exercise.
• Researchers did not measure change in volume, which is correlated with circumference measures but may be more sensitive to change.
• Few of the women randomly selected at baseline had lymphedema.

To evaluate the effect of low-level laser therapy (LLLT) on limb volume, shoulder mobility, and grip strength

Patients were randomized to treatment and placebo control groups. The treatment group received LLLT at an average dose of 1.5 J/cm² for 20 minutes three times per week for 36 sessions. In the placebo group, the patients were set up with the same parameters of therapy but the machine was not turned on. All patients were advised to perform the same arm and shoulder exercises daily. Patients were evaluated every 4 weeks for 12 weeks.

• The study sample (N = 50) was comprised of female patients with breast cancer.
• Mean age of the sample was 54.06 years.
• All patients had axillary node dissection and unilateral arm lymphedema.
• Patients had arm circumference increases in the affected arm of 2–8 cm.
• Patients with severe lymphedema were excluded.
• Seventy-two percent of patients had modified radical mastectomy.
• Lymphedema was in the dominant arm in 78% of patients.
• Mean duration of lymphedema was 14 months and average time since surgery was 40 months.

The study took place in an outpatient setting in Egypt.

The study has clinical applicability for late effects and survivorship.

The study used a randomized double-blind placebo-controlled design.

• Arm circumference was measured.
• Grip strength was measured with a dynamometer.
• Goniometer measured shoulder range of motion.

The laser group had greater reduction in limb volume than controls. The difference was significant at 8 and 12 weeks (p < 0.01).  At 16 weeks, total limb circumference was 31 in the laser group and 23 in the control group. Shoulder mobility was better in the laser group and significantly better than controls at 12 weeks (p < 0.01).  Grip strength improved in both groups. At 8 and 12 weeks, grip strength improvement was significantly higher in the laser treatment group (p < 0.01).

 LLLT reduces lymphedema arm volume and increased shoulder mobility and grip strength in women after mastectomy.

• The study sample was small, with less than 100 participants.
• Subject withdrawals were greater than or equal to 10%.
• The study was of short duration, so long-term efficacy is not clear.

Low-level laser therapy can reduce lymphedema volume and improve extremity strength and mobility. The study showed that 14% of patients did not adhere to receiving all treatments, which has also been shown in other studies of LLLT. The need for patients to make multiple visits for treatments may limit the practicality of the approach. Effects over the longer term are unclear.

The intervention was a Swedish/Esalen massage of shoulders, neck, and scalp lasting 20 minutes up to three times per week. Prior to hospitalization, patients were randomly assigned to massage or standard medical care conditions.

• Thirty-five adult patients with varying diagnoses admitted for autologous bone marrow transplantation were included.
• Mean age was 41 years, and the sample was predominantly female.
• Race and ethnicity were not reported.

All participants were inpatients in the bone marrow transplantation unit of a cancer center.

Patients were undergoing the active treatment phase of care. 

The study was a randomized trial comparing massage (n = 16) with a quiet time control condition (n = 18).

Fatigue was measured by a zero to 10 Numerical Rating Scale.

• Borderline significant decreases were observed in fatigue (p = 0.06) over time, although significant decreases were seen during week 1 (pretreatment) and prior to discharge.
• The most robust effects were found during the first week of treatment.

• The study had a small sample size and a lack of control for covariates.
• The analysis of time by group interaction was confusing.
• Effects may not be as great during the posttreatment phase when patients are most ill.
• Massage was performed by a trained healing arts specialist.