To examine the difference in incidence of specific grade 2 or higher skin toxicities of interest between patients with metastatic colorectal cancer in preemptive and reactive skin treatment groups during a six-week treatment period that included epidermal growth factor receptor inhibitors (EGFR-Is).

Eligible patients were randomly assigned to preemptive or reactive skin treatment arms. The chemotherapy regimen schedule was a random assignment stratification factor.

The preemptive skin treatment regimen was administered beginning on day –1 (one day before the administration of the first panitumumab dose) and continued through weeks 1 to 6.

Clinical and experimental data suggest that four major alterations occur in the skin of patients treated with EGFR-Is: follicular and interfollicular inflammation, bacterial superinfection, dry skin, and sensitivity to ultraviolet (UV) radiation. The rationale for selection of the preemptive skin regimen was based on those four alterations. The preemptive skin treatment regimen comprised the following.

• Skin moisturizer applied to the face, hands, feet, neck, back, and chest daily in the morning on rising (rationale: restore the permeability barrier and treat dry skin)
• Sunscreen (para-aminobenzoic acid [PABA] free, sun protection factor [SPF] ≥ 15, UVA and UVB protection) applied to exposed skin areas before going outdoors (rationale: prevent UV radiation–induced skin toxicity)
• topical corticosteroid (1% hydrocortisone cream) applied to face, hands, feet, neck, back, and chest at bedtime (rationale: instituted against cutaneous inflammation and pruritus)
• Semisynthetic tetracycline (doxycycline 100 mg BID) (rationale: anti-inflammatory and antibacterial properties)

The reactive skin treatment regimen comprised any treatments the investigator deemed necessary for the management of emergent skin toxicity and could be administered anytime during weeks 1 to 6. Patients randomly assigned to the reactive skin treatment group were not prohibited from using skin moisturizer or sunscreen at any time during the treatment if they chose to do so.

All patients were monitored weekly from weeks 1 to 7 for compliance with the randomized skin treatment regimen and for skin toxicity assessment.

• The study reported on a sample of 95 patients.
• The sample was 67% male and 33% female in the preemptive skin treatment group, and 55% male and 45% female in the reactive skin treatment group.

• Multi-site
• Outpatient
• United States

Patients were undergoing the active treatment phase of care.

This was a phase 2, multicenter, open-label, randomized clinical trial.

• Protocol-defined skin toxicities of interest included pruritus, acneform dermatitis, skin desquamation, exfoliative dermatitis, paronychia, nail disorder, skin fissures, skin laceration, pruritic rash, pustular rash, skin infection, skin ulceration, and local infection.
• Dermatology Life Quality Index (DLQI): Assessed patient-reported quality of life (QOL) at screening, weeks 2 to 7, and the week 13 or 14 visit, depending on the skin treatment schedule. The DLQI comprises 10 simple questions to assess QOL in patients with skin disorders. The DLQI is scored on a scale from 0 to 30, where higher scores indicate more QOL impairment.
• Patient diary: Throughout the skin treatment period, patients completed a daily diary of symptoms and treatment compliance. The diary was shared with study personnel at each weekly clinic visit and was used for case report data entry.
   

• The incidence of protocol-specific grade 2 or higher skin toxicities during the six-week skin treatment period was 29% for the preemptive skin treatment group (23% grade 2 and 6% grade 3) and 62% for the reactive skin treatment group (40.4% grade 2 and 21.3% grade 3) (odds ratio, 0.3; 95% confidence interval [0.1, 0.6]).
• Acneform dermatitis at any grade occurred in 77% of patients in the preemptive skin treatment group and 85% in the reactive skin treatment group.
• Incidence of pruritus was similar in both groups.
• Seventeen percent of patients in the preemptive skin treatment group developed paronychia, compared to 36% in the reactive skin treatment group.

The preemptive skin treatment regimen was well tolerated. The incidence of specific grade 2 or higher skin toxicities during the six-week skin treatment period was lower in the preemptive skin treatment group compared with the reactive skin treatment group.

• The sample size was small (fewer than 100 patients enrolled).
• The only EGFR-I used to treat patients was panitumumab. Patients who were receiving cetuximab were not included in the study.
• The study was not blinded.
• Information was not provided on reactive treatments used for comparison of effectiveness or the stage at which reactive treatments were instituted.
• Patient compliance results were not reported.

The findings supported the importance of establishing a preemptive, comprehensive skin treatment regimen in patients treated with panitumumab to decrease skin toxicities and improve QOL. The skin toxicities are considered a class-based effect; therefore, these results may be generalized to other EGFR-Is.  

To develop first-generation, evidence-based recommendations for eight epidermal growth factor receptor inhibitor (EGFRI)-associated dermatologic toxicities: papulopustular (acneform) rash, hair changes, radiation dermatitis, pruritus, mucositis, xerosis, fissures, and paronychia.

The type of patients addressed was those receiving EGFRIs.

In this guideline, topic review committees were formed according to expertise to review the literature and develop guidelines for each dermatologic toxicity. Each review committee comprised three members, with a primary reviewer to present the findings of the committee to the Skin Toxicity Study Group. Each committee reviewed from 17 to 35 articles to formulate the recommended guidelines. Randomized clinical trials were considered the best source. The level of evidence and grade of the recommendation were considered. In the absence of experimental evidence, pertinent studies and case reports were presented in conjunction with expert opinion derived from clinical practice. When available, data were extrapolated from other dermatologic conditions with similar clinical or pathologic characteristics (e.g., xerosis, alopecia, hirsutism, pruritus, paronychia, radiation dermatitis).

Databases searched were Ovid, MEDLINE, and Embase.

Search keywords were rash, hair changes, radiation dermatitis, pruritus, mucositis, xerosis, fissures, paronychia, EGFR inhibitors, and recommendations (this information was not stated directly in the article).

Studies were included in the review if they were published before December 2010. 

Studies were excluded if they were published during or after December 2010.

• Patients were undergoing the active treatment phase of care.
• The study has clinical applicability for late effects.

Eight tables outlining prophylactic and reactive recommendations were included for papulopustular (acneform) rash, hair changes, radiation dermatitis, pruritus, oral complications, xerosis, fissures, and paronychia.

Papulopustular (Acneform) Rash

Preventive (Weeks 1–6 and 8 of EGFRI Initiation): 

• Systemic: minocycline 100 mg daily (less photosensitizing) and doxycycline 100 mg BID (preferred in patients with renal impairment)
• Topical: hydrocortisone 1% cream with moisturizer and sunscreen BID 

Treatment:

• Systemic: minocycline 100 mg daily (less photosensitizing), doxycycline 100 mg BID (preferred in patients with renal impairment), and isotretinoin at low doses (20–30 mg per day).
• Topical: alclometasone 0.05% cream, fluocinonide 0.05% cream BID, and clindamycin 1% cream

Hair Changes (Hair Loss)

Preventive:

• Topical and Systemic: Follow rash recommendations for scarring alopecia.

Treatment:

• Topical: minoxidil 2% or 5% BID (nonscarring alopecia); class 1 steroid lotion, shampoo, or foam, or antibiotic lotion (scarring alopecia)

Hair Changes (Increased Hair)

Preventive:

• Support interventions (e.g., patient education)
• Treatment: eflornithine and lasers (facial hypertrichosis) and eyelash trimming (eyelash trichomegaly)

 Radiation Dermatitis

Preventive:

• Topical: maintenance of appropriate skin hygiene with gentle cleansing in radiated areas prior to radiation treatment; high-potency topical steroids

 Treatment:

• Topical: maintenance of appropriate skin hygiene with gentle cleansing in radiated areas prior to radiation treatment, moisturizers, antibacterial moisturizers, drying gel or antiseptics (chlorhexidine), hydrophilic dressings, and antibiotics if infected
• Systemic: doxycycline
• Other: blood cultures for fever or signs of sepsis

Pruritus

Preventive:

• Topical: gentle skin instructions

Treatment:

• Systemic: antihistamines (first generation, sedating: hydroxyzine and diphenhydramine; second generation, nonsedating: loratadine), anti-epileptic agents (gabapentin or pregabalin), and doxepin
• Topical: menthol (0.5%–3%), cooling, pramoxine 1%, doxepin, and medium-to-high–potency steroids (triamcinolone acetonide 0.025%, desonide 0.05%, fluticasone propionate 0.05%, and alclometasone 0.05%)

Mucositis

Preventive:

• Topical: benzydamine, steroids, cryotherapy or ice chips, and low-level laser therapy
• Systemic: patient-controlled analgesia
• Other: radiation blocks and intensity-modulated radiation therapy

Treatment:

• Topical: No topical treatments are recommended.
• Systemic: doxycycline

Xerosis

Preventive:

• Topical: bathing techniques: using bath oils or mild moisturizing soaps and bathing in tepid water; regular moisturizing creams
• Other: Avoid extreme temperatures and direct sunlight.

Treatment:

• Topical (mild to moderate): emollient creams packaged in a jar or tub that lacks fragrance or potential irritants; occlusive emollients containing urea, colloidal oatmeal, and petroleum-based creams; exfoliants for scaly areas: ammonium lactate 12% or lactic acid cream 12%; urea creams (10%–40%); salicylic acid 6%; zinc oxide (13%–40%)
• Topical (severe): Use medium-to-high–potency steroid creams (triamcinolone acetonide 0.025%, desonide 0.05%, fluticasone propionate 0.05%, and alclometasone 0.05%).

Fissures

Preventive:

• Topical: Wear protective footwear and avoid friction with fingertips, toes, and heels.

Treatment:

• Topical: thick moisturizers or zinc oxide (12%–40%) creams; liquid glues or cyanoacrylate to seal cracks, steroids or steroid tape, hydrocolloid dressings, and topical antibiotics; bleach soaks to prevent infection; and zinc oxide

Paronychia

Preventive:

• Topical: Diluted bleach soaks; avoid irritants.

Treatment:

• Systemic: tetracyclines, antimicrobials (reserved for culture-proven infection), and biotin for brittle nails
• Topical: corticosteroids and calcineurin inhibitors
• Other: silver nitrate chemical cauterization weekly; nail avulsion

Recommendations were based on randomized clinical trials with control groups when possible. However, because of the lack of high-quality studies investigating EGFRI-associated dermatologic changes, many recommendations were based on expert opinion and consensus.

The authors developed first-generation, evidence-based recommendations for eight EGFRI-associated dermatologic toxicities: papulopustular (acneform) rash, hair changes, radiation dermatitis, pruritus, mucositis, xerosis, fissures, and paronychia. In addition, the authors rated each intervention according to the level of evidence (I–V) and the recommendation grade (A–D). 

The authors proposed that multidisciplinary teams, including radiation and medical oncologists, nurses, dermatologists, pharmacists, oral healthcare providers, and wound care specialists, should assess the occurrence and management of EGFRI-associated dermatologic toxicities. In addition, the Multinational Association for Supportive Care in Cancer (MASCC) EGFRI Skin Toxicity Tool (MESTT) should be used in clinical trials and practice.

Nurses should provide patient education prior to EGFRI therapy to ensure patients can expect, prepare for, and use preventive and treatment approaches to manage the eight toxicities described. In addition, nurses should encourage the multidisciplinary team to collaborate on management of EGFRI-associated dermatologic toxicities.

From pooled analysis, 64.2% of patients experienced an IRAEs of any grade, and 17.8% were severe (grade 3 or 4). Dermatologic IRAEs were the most common (44.9% any grade). Most IRAEs develop within the first 12 weeks (five to nine weeks depending on the dose). Ipilimumab rash differs from that of targeted therapies, with ipilimumab rash more closely resembling maculopapular rash. Pruritus with or without rash and can have major impact on quality of life. Ipilimumab appearance, histology, time to onset of IRAEs, grading, and management of skin IRAEs were reviewed.

Guidelines are developed to aid providers to manage IRAEs by early intervention and vigilance. First, determine the severity of the rash or pruritis. For grade 1 or 2 rash, topical corticosteroids and oral antihistamines may be useful. Resume ipilimumab with resolution of rash or with improvement if systemic steroid dose is 7.5 mg of prednisone or less. If grade 3 rash is present, hold ipilimumab and give oral corticosteroids at 1–2 mg/kg/day of prednisone or equivalent. If symptoms improve, healthcare professionals can re-challenge. If symptoms worsen or are evaluated as grade 4, permanently discontinue ipilimumab. Administer corticosteroids at a grade 3 dose and taper for one month if rash improves. For mild or localized pruritus, use topical corticosteroids and antipruritics. For intermittent intense or widespread pruritus, topical corticosteroids and oral antihistamines are indicated. If pruritus is constant, limiting self-care or sleep, use oral antihistamines and corticosteroids and consider gabapentin, pregabalin, mirtazapine, and aprepitant.

These are expert opinion guidelines developed from pooled trial data of patients with metastatic melanoma and from evaluating other clinical trial results of ipilimumab. Interventions are not developed from randomized, controlled clinical trials. These guidelines do not differentiate disease type or dose-related IRAEs.

Quality of life and optimal therapy for patients receiving these new therapies are dependent on vigilance and early detection for interventions. Patient and healthcare providers need to be instructed to recognize findings for improved outcomes early. Mechanisms for patients to report their experiences should be outlined early.

PubMed was searched to identify English or French language reports of randomized or controlled studies and meta-analyses concerning the benefits of physical activity in patients receiving cancer treatment. The dates encompassed by the search process were not specified.

Eleven randomized or controlled studies that had evaluated the effects of physical exercise on cancer-related fatigue as one of their primary or secondary objectives were identified for analysis. Varied patient-reported outcome measures were used to evaluate fatigue, including the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), Piper Fatigue Scale, Functional Assessment of Cancer Therapy-Fatigue (FACT-F), or the Profile of Mood States (POMS) Fatigue-Inertia subscale. Studies evaluated aerobic exercise, strength training, or a combination of both. Supervised and home-based exercise interventions were studied, and the duration of exercise treatment ranged from only the duration of hospitalization to several months.

• The groups represented in these studies included survivors of breast cancer and individuals with prostate cancer, multiple myeloma, mixed solid tumors, lymphomas, breast cancer, and colon cancer.
• In total, 718 patients were represented across these studies, most without metastases.
• Age ranged from 18 to 77 years.
• Participants were either undergoing active cancer therapy or had completed therapy.
• Most study samples were small, with less than 50 participants.

Of the seven studies of exercise during active cancer therapy, five studies (all with less than 25 patients) found no significant differences in fatigue across the treatment period. A sixth study in a highly selected population of patients hospitalized for stem cell transplant noted that fatigue increased significantly in the control group but remained steady in the exercise group. The seventh study of men with prostate adenocarcinoma on hormone therapy and receiving strength training noted a statistically significant improvement in fatigue in patients receiving the strength training intervention.

In the posttreatment setting, three studies with small samples suggested that exercise (aerobic exercise of low or moderate intensity) or a motivational counseling intervention to increase home-based exercise and a small study in patients with breast and colon cancer who were three to 15 months posttreatment showed significant improvement in fatigue as a result of either low- or moderate-intensity exercise, compared to controls. An additional study in patients who had completed chemotherapy or surgery within the past month showed an improvement in aerobic fitness in the intervention group but a statistically significant increase in fatigue.

Taken together, these results suggested that there is no clear evidence that exercise during active treatment improves fatigue outcomes, although it may have a favorable effect on cardiorespiratory conditioning. The results of this review point to the possibility that a minimum of rest or mild activity is needed to promote some initial recovery from treatment-related fatigue before residual fatigue is addressed, but current studies provide no guidance on how long the interval should be between the end of chemotherapy and the start of exercise for therapeutic purposes.

Database searched was MEDLINE (1993–2003) for randomized, controlled trials evaluating mucositis interventions.

A total of 50 randomized controlled trials were presented. Other trials and papers were referenced.

• Sample sizes ranged from 10–222.
• Patients were treated with chemotherapy, radiotherapy, and bone marrow transplantation.

The author concluded that most agents require more study.

• Evidence for cryotherapy and bolus 5-fluorouracil was strong.
• Sucralfate studies produced conflicting results and included varying doses and administration frequencies, making comparisons difficult. Most studies indicated no difference in severity or duration. The validity and reliability of the data were questioned because of the measurement scales used.
• Similarly, studies of cytokine-like agents used different doses, making comparisons difficult.
• Moderate evidence suggested that benzydamine is effective in relieving mouth pain caused by radiation-induced mucositis in patients with head and neck cancer. The agent requires additional investigation and study for chemotherapy-induced mucositis.
• Large studies of chlorhexidine mouthwashes have failed to show significant findings; however, the studies may have had inadequate sample sizes, as power analyses were not performed.
• Povidone-iodine showed significant reduction in onset, incidence, total duration, and worst grade of mucositis for patients with head and neck cancer undergoing radiation with carboplatin in two studies. Both studies had sample sizes of 40. Given these sample sizes and specific populations, generalizability of the findings was restricted.
• Oral hygiene protocols were shown to reduce the duration and severity of mucositis; however, the content of the protocols was not proven.

The author noted the problem of variation in study protocols, insufficient sample sizes, and a lack of consensus regarding the scoring system for mucositis.

The author noted the need to include psychotherapeutic interventions and management and pointed out the lack of a quality-of-life tool for mucositis.

Determine the effectiveness of an intensive intervention (i.e., two weeks at a SPA centre involving exercise, physiotherapy, and dietary education) on overall quality of life, weight, nutrition, and physical activity in women who recently had completed treatment for non-metastatic breast cancer

The intervention included a two-week stay at a SPA centre with a daily routine of physical training (i.e., two hours daily under the supervision of a physiotherapist, which included walking, strength training, and aquaexercise), dietary education with cooking lessons and provision of healthy meals, and aesthetic care, massage, etc. Dietary consultations every six months for three years also were incorporated into standard follow-up care.

• N = 222
• MEAN AGE: Intervention group: 51.8 years (SD = 8.7 years), control group: 52.3 years (SD = 10.1 years)
• MALES: 0%, FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: The stage of cancer is not reported; it's described only as invasive and non-metastatic. A description of disease characteristics is not reported. Subjects had completed treatment (chemo and/or radiation) for breast cancer less than nine months prior to study enrollment. The majority of patients received chemotherapy and radiation therapy, and more than two-thirds of the sample were on hormonal therapy; a minority (less than 15%) were on trastuzumab as well.
• OTHER KEY SAMPLE CHARACTERISTICS: No significant differences were seen between the treatment and control group, except for a statistically significant difference in smoking history, in that a greater percentage of the treatment group reported a history of smoking.

• SITE: Not stated/unknown 
• SETTING TYPE: Other 
• LOCATION: This is a French study. The intervention occurred at three different SPA centres, also mentioned as “thermal centres.” From where the sample was recruited is not reported.

PHASE OF CARE: Transition phase after active treatment

Prospective, randomized, repeated measures (baseline, 6, 12, 18, and 24 months after intervention) two-group clinical trial

• Short Form 36 Health Survey (SF-36) as quality-of-life measure
• Hospital Anxiety and Depression Scale (HADS)
• Adapted Leeds Sleep Evaluation Questionnaire
• Ricci & Gagnon questionnaire for physical activity
• Questionnaire for sitting time and impedancemetry for body composition

Statistically significant differences were seen between groups on the SF-36 measure at six months, but these differences did not persist in any dimension at year one except for a difference in vitality at one year between groups. Although data were collected on weight/body mass index, diet, and sleep, results for these variables are not reported (except to note no significant differences in sleep between the groups). The plots/trends in quality of life over time (at 6, 12, 18, and 24 months) look very similar for both groups, except for a significant upward trend at six months for the intervention group. The correlation was stronger between HADS depression and SF-36 quality of life. In the SPA group, an overall decrease was seen in anxiety compared to baseline scores (p = 0.0005). No significant difference was seen in the anxiety scores between the SPA and control groups at six months. Depression decreased in both groups but to a greater degree in the SPA group. A significant difference was seen between the SPA group and control group in terms of depression scores. What the “control” or comparison group was or what care was given to them is not clear.

As reported, patients with non-metastatic breast cancer did not appear to derive significant benefit (improved quality of life as measured by the SF-36) from a two-week SPA intervention in terms of improving quality of life and reducing anxiety and depression.

This unrealistic intervention (two-week SPA stay) does not seem sustainable. Furthermore, if this “intensive” intervention did not demonstrate significant impact on quality of life or anxiety, except for depression, then the “cost” of such an intensive intervention is not worth the benefit. When exactly the intervention occurred is not reported relative to timing of completion of breast cancer treatment except to say “within nine months,” but this is an important variable/covariate because time since treatment completion (and intervention) might impact study results. Importantly, unclear is how subjects were screened or that only a “distressed” group was enrolled. The report that global SF-36 scores at study inclusion were 56 and 54 respectively (treatment and control groups) indicates that this is not a very “stressed” group, as evidenced by SF-36. The higher the scores on the SF-36, the better the quality of life. These scores at study inclusion are right at the midpoint range of 0%–100%; thus, a possible floor effect is at play. Overall, this is not a very well developed or reported study.

No real meaningful nursing implications are drawn from this study. The intervention seems unrealistic and unsustainable and did not impact outcome measures as predicted, except for depression.

To identify and synthesize the evidence for mind-body interventions for which the evidence suggests benefit for at least two of the three cluster symptoms of pain, fatigue, and sleep disturbance.

Databases searched were CINAHL, MEDLINE, and PsycINFO through March 2009.

Search keywords were guided imagery, hypnosis, relaxation, biofeedback, cognitive behavioral therapy, coping skills training, meditation, virtual reality, music AND cancer AND fatigue, sleep disturbance, sleep difficulty, insomnia, and pain.

Studies were included in the review if they

• Were limited to research
• Included adults aged 18 years and older
• Included mind-body activities that involved primarily mental activity that could be performed by almost all patients
• Included pain, fatigue, or sleep among study dependent variables.

Studies were excluded if they

• Involved the use of yoga
• Involved patients in whom a diagnosis of cancer was not yet established
• Had a sample that included people without cancer.

A total of 47 studies were identified. In four of those, all testing virtual reality, only the symptom of fatigue was measured, so these were eliminated.

The final sample included 43 studies. Study sample sizes and total patients involved across studies were not reported.

Relaxation

Six studies examined relaxation interventions in hospitalized patients, outpatients with chronic pain, and women with early-stage breast cancer.

• Significantly greater pain relief was obtained with progressive muscle relaxation compared to massage, usual treatment, mood manipulation, distraction, and controls.
• One study found no difference in pain between a daily relaxation exercise and distraction.
• Training in muscle relaxation did not improve fatigue in one study compared to provision of information.
• In one study, muscle relaxation improved sleep compared to usual treatment controls.

Imagery and Hypnosis

Six studies examined imagery and hypnosis.

• In four studies, imagery was used in hospitalized patients with cancer pain, and beneficial effects were reported.
• One study found no differences in pain or fatigue between patients with an imagery intervention and those receiving standard care.
• Four studies used imagery in comparison to cognitive-behavioral therapy (CBT) and combined imagery with relaxation. Of those, one study reported no significant effect, two reported significant pain reduction, and one reported significant reduction in fatigue and sleep disturbance.

Cognitive Behavioral Therapy (CBT)/Coping Skills Training (CST)

Twenty-one studies tested CBT/CST.

• In three studies, fatigue was the primary focus. Significantly more improvement in fatigue was reported with a six- to 12-week CBT/CST intervention compared to usual treatment and controls.
• Three studies evaluated CST effects on the combination of pain and fatigue. In all of these, a one-session CST intervention resulted in no difference in symptoms compared to controls.
• Seven studies evaluated the effects of CBT/CST on fatigue and sleep disturbance. One study reported a decreased incidence of fatigue and sleep disturbance using an audio recording for coping skills training prior to chemotherapy. Two studies reported improvement in sleep with a four- to eight-week CBT intervention, but only one of these also reported improvement in fatigue. One study reported improvement in sleep and fatigue with a five-session CBT intervention, two other studies showed improvement in sleep but no change in fatigue, and one study reported no improvement in either of these two symptoms.
• Four studies reported effects of CBT/CST on all three symptoms concurrently. One showed improvement in fatigue and sleep but no impact on pain. One study reported less sleep disturbance but no difference in pain or fatigue. One reported lower ratings of worst pain immediately after the CBT program and greater reduction in pain and fatigue six months after the intervention compared to controls. One study found no differences in any of the three symptoms with a CST intervention.

Meditation

Four studies were included.

• Three of these studies used mindfulness-based interventions. One study reported significant improvements in both fatigue and sleep among outpatients who participated in an eight-week intervention.

Music

• Four studies looked at the effect of music on pain. Two studies found significant improvements in a pre-/posttest design using 30 minutes of preferred music among hospitalized patients. Two other studies found no difference in pain with listening to music compared to control groups.
• Two studies tested a music intervention on fatigue. One found a significant effect, and one found no difference in fatigue between intervention and control groups.

Findings of this review were equivocal.

• Although the authors stated a criterion for inclusion of examination of at least two of the three symptoms of interest, the review appeared to include studies in which only one of these symptoms was reported.
• Few investigators used multisymptom interventions and evaluations.
• Measures of symptom clusters were not been well identified.
• Some instruments were stated to potentially be more sensitive; however, the scales and individual items that were most useful to measure this symptom cluster were not determined.
• Timing, dosage, and frequency of interventions varied among studies, making it difficult to draw systematic conclusions. Most music interventions were very brief.
• This review did not provide study details, such as clear sample descriptions, sample sizes, or actual statistical results, and no effect sizes were calculated, although some studies used the same outcome measures.

Although the findings did not clearly demonstrate the effects of these interventions across studies, the authors concluded that these interventions hold promise. Although such interventions carry minimal risk to patients, some interventions would require substantial time and resource commitment to provide.

To assess, among hospitalized patients with cancer-related pain, responses to progressive muscle relaxation (PMR) and analgesic imagery, including the impact of these interventions on pain-related distress and perceived control over pain

To examine the influence of ability, outcome expectancy, previous experience, and concurrent symptoms on the effectiveness of the interventions

Scripts relating to \"control conditions,\" PMR, and guided imagery interventions were recorded on a CD. The recorded voice was male, and the recording did not include music. The day 1 control recording consisted of identification of health team members, explanation of patient rights, and a description of various hospital services. The second control recording described exercise and other activities to maintain strength while hospitalized and presented issues for consideration in discharge planning. The PMR recording guided listeners in tensing and relaxing muscles in a series of 12 major muscle groups from head to feet. The analgesic, or guided imagery, recording asked listeners to scan their bodies to identify areas of pain and to imagine replacing pain with comforting sensations. Then the recording asked listeners to imagine putting their hand in an anesthetic fluid, feeling it go numb, and then transfer the numbness to painful areas of the body. All recordings were of similar length. Trials were done when current pain was rated 2–8 on a 10-point scale. Trials were delayed if patients had received an oral analgesic within one hour or an IV analgesic within 30 minutes. Patients with the option of patient-controlled analgesia were asked to refrain from increasing doses during the 15-minute trial and were maintained on basal continuous infusion. A control trial was the first trial done each day. If pain persisted at the end of the control trial, the research nurse continued with whichever experimental trial was assigned for that day. Two intervention trials were done each day, at least one hour apart. Patients completed pre- and post-trial ratings of pain intensity and related distress. For each outcome measured, scores were averaged across two control, two PMR, and two analgesic imagery trials. In cases where only one trial was completed, this score was used in analysis. Patients were randomly assigned to two different groups. In one group, PMR preceded imagery interventions; in the other, the sequence was reversed. All patients received the same control trials.

• The study reported on a sample of 32 patients.
• Mean patient age was 48.9 years (SD = 16.29 years).
• The sample was 55% female and 45% male.
• Of all patients, 55% had hematologic malignancy.
• All patients were Caucasian.
• The average number of months since diagnosis was 18.36 (SD = 33.32 months). Of all patients, 33% were receiving chemotherapy, 13% were undergoing radiotherapy, and 20% were undergoing combined therapy; 78% were being treated with a combination that included a strong opioid, a weak opioid, and nonopioid medications for pain management.

• Single site
• Inpatient setting
• Academic medical center in the Midwest, United States

The study used a crossover design with control.

• Scale of pain intensity (0 = no pain, 10 = worst pain imaginable)
• Scale of pain distress (0–10)
• Control Subscale of the Survey of Pain Attitudes
• Imaging Ability Questionnaire
• Outcome Expectancy Scale
• Edmonton Symptom Assessment Scale

• Compared to the control conditions, PMR resulted in greater change in pain intensity (Z = –2.15, p < 0.05) and pain-related distress (Z = –1.82, p < 0.05) and greater perceived control over pain (Z = –3.02, p < 0.01).
• Compared to the control conditions, guided imagery resulted in greater change in pain intensity (Z = –2.7, p < 0.01), change in pain-related distress (Z = –2.11, p < 0.05), and greater perceived control over pain (Z = –2.4, p < 0.01).
• PMR was associated with meaningful reduction in pain for 41% of participants. Imagery was associated with meaningful improvement in pain for 52% of patients. Authors defined meaningful improvement as an improvement greater than or equal to 30% reduction in pain intensity along with improvement in pain-related distress or perceived control.
• Compared to other patients in the study, those who experienced meaningful improvement with imagery had greater imaging ability (p < 0.05), more positive outcome expectancy (p < 0.05), and fewer concurrent symptoms (p < 0.05).
• The control condition was associated with some reduction in pain intensity and pain-related distress.

In only 50% of patients did PMR and guided imagery appear to have a more positive short-term effect on pain intensity, pain-related distress, and perceived control of pain than did simple distraction. Variables examined did not appear to influence the effects of PMR, but expectations and number of concurrent symptoms appeared to influence the effects of guided imagery.

• The study had a small sample size, with fewer than 100 participants.
• Interventions had very short-term effects on the outcomes examined. Authors did not state how long patients had been experiencing pain; whether patients were suffering acute, chronic, or episodic pain was unclear.
• Of all patients approached for participation, 41% declined to enter the study.
• Despite the crossover design, the study had risk of bias due to several factors.
  • Pain intensity measures were self-reported by patients.
  • Patients certainly knew the difference between the control and intervention recordings.
  • Analysis was limited to comparisons between responders and nonresponders; therefore, the capacity of the investigators to identify influencing variables was limited.
  • While changes in pain intensity showed differences that were statistically significant, whether the changes were clinically significant is unclear.
  • Many factors can affect the results evaluated (e.g., time of day, nature of hospital care, activities of the day). Investigators could not have accounted for or controlled for these factors.
  • The trial was extremely brief, only two days.

PMR and analgesic imagery, facilitated by a recording on CD, might be helpful to some patients to reduce short-term pain intensity, decrease pain-related distress, and increase sense of control over pain. However, much more evidence is needed before investigators can draw firm conclusions. These interventions could be implemented easily in a hospital setting and do not appear to harm patients. They appear to be more effective for individuals with greater ability to imagine, greater expectations of effectiveness, and fewer additional symptoms. This fact might lead clinicians to identify that group of patients most likely to benefit from such interventions.

To evaluate the feasibility of a patient-controlled, cognitive-behavioral intervention for pain, fatigue, and sleep disturbance during treatment for advanced cancer and to assess the initial efficacy of the intervention.

Patients provided baseline measures, such as measures relating to demographics and a symptom inventory, received education, and underwent training to use an mp3 player loaded with 12 cognitive-behavioral strategies (relaxation exercises, guided imagery, nature sounds). Patients used the strategies as needed for symptom management for two weeks and kept a log of symptom ratings with each use. Following the two-week intervention, patients completed a second symptom inventory and an evaluation of the intervention. Clinic staff identified patients who met the eligibility criteria based on diagnosis and treatment and then were briefly introduced to the study and asked if a research nurse could visit to provide additional information. The research nurse met with interested patients, assessed symptoms, and completed eligibility screening. Study purpose and procedures were explained, and written informed consent was obtained.

• The sample was comprised of 30 patients (20% male, 80% female).
• Mean age was 56.27 years (range 36–79).
• All patients had advanced (recurrent or metastatic) cancer and were receiving chemotherapy or radiotherapy. Half of the patients had a diagnosis of gynecologic cancer. Patients had been diagnosed with lung cancer (n = 8), colorectal cancer (n = 6), and prostate cancer (n = 1).
• Most patients were Caucasian, women, and had earned a bachelor’s degree or higher.
• Almost all patients (n = 27) were taking two or more prescribed supportive medications to treat symptoms.
• Studies were included if they included at least two of the following three symptoms:  pain rated 3 or higher on a 0-to-10 scale in the previous 48 hours, fatigue in the previous week, and sleep disturbance in the previous week. 
• Studies were excluded if they involved postoperative or neuropathic pain.

• Multisite
• Outpatient
• Midwestern United States
   

• Patients were undergoing multiple phases of care.
• The study has clinical applicability for late effects and survivorship, end of life care, and palliative care.

The study used a one-group, pre- and postintervention design.

• Demographic questionnaire and chart review form to record age, gender, education, race, ethnicity, cancer diagnosis, current treatments, and supportive medications prescribed, such as analgesics, steroids, psychostimulants, hypnotics, or sedatives
• Symptom inventory, to measure
  • Pain severity, by means of four, 0-to-10 numeric rating scales for pain now, worst pain, least pain, and average pain in the last 24 hours
  • Fatigue severity, by means of four, 0-to-10 scales for fatigue now, worst fatigue, least fatigue, and average fatigue in the last 24 hours
  • Sleep disturbance, by means of a 0-to-10 scale rating sleep disturbance in the last 24 hours and, from the Pittsburgh Sleep Quality Index (PSQI), a verbal rating of sleep quality
• Additional symptoms and their effects on daily functioning, as assessed by the MD Anderson Symptom Inventory (MDASI), which includes items measuring 13 common cancer-related symptoms and their effect on general activity, mood, work, relations with others, walking, and enjoyment of life
• Treatment log book, in which patients tracked each time they used a cognitive-behavioral strategy. Data tracked were time of day; strategy used; and immediate pre- and posttreatment scores, on a 0-to-10 scale, regarding severity of pain, fatigue, and sleep disturbance
• Poststudy evaluation, a 12-item survey created, for the current study, to assess patients’ perceptions of the acceptability of the study procedures. Among the items evaluated were time commitment; equipment; and questionnaires and factors relating to the patient-controlled, cognitive-behavioral intervention, such as length, variety, and usefulness.
   

• Symptom scores at two weeks did not differ significantly from baseline scores; however, significant reductions in pain, fatigue, and sleep disturbance severity were found in ratings made immediately before and after the use of a cognitive-behavioral strategy.
• Mean pain scores decreased from 4.54 pretreatment to 2.77 posttreatment.
• Mean fatigue scores decreased from 4.9 pretreatment to 3.44 posttreatment.
• Average sleep disturbance scores decreased from 5.05 pretreatment to 2.81 posttreatment.

The patient-controlled, cognitive-behavioral intervention is feasible and may reduce the day-to-day severity of co-occurring pain, fatigue, and sleep disturbance.

• The study had a small sample size, with less than 100 patients.
• The study had a risk of bias due to no control group.
• The study used a convenience sample comprised of well-educated, primarily female patients—a sample that may not be representative of all populations.
• Uncontrolled extraneous variables, such as supportive medication use, could have influenced symptom outcomes.

The findings support nurse education and the recommendation of the specified patient-controlled, cognitive-behavioral interventions for the management of pain, fatigue, and sleep disturbance. In regard to patient care and symptom management at all stages of cancer, nurses are the front-line educators of patients. This intervention supports the principle of autonomy for patients able to participate actively in care. Further study—a randomized, controlled trial to test the efficacy of the intervention for co-occurring pain, fatigue, and sleep disturbance—was under way at the time this study was published.

To test the effects of a psychoeducational intervention on pain, fatigue, and sleep disturbance.

Patients were randomly assigned to the intervention group or the wait-list control group. The intervention consisted of a single one-on-one training session with a research nurse, which was followed by recorded guidance that provided imagery, relaxation exercises, and nature sounds. Most exercises lasted 20 minutes and were delivered via an mp3 player. The study lasted two weeks.

• The sample was comprised of 78 patients (41% male, 59% female).
• Mean age was 60.29 years (standard deviation = 11.09 years).
• Patients had lung, prostate, colorectal, or gynecologic cancer.
• Patients were receiving chemotherapy or radiation therapy and had multiple concurrent symptoms at baseline.
• At study entry, all patients had to have fatigue, sleep disturbance, and pain scores of at least 3 on an 11-point numeric scale.
• Of the patients, 71% were taking steroids, 59% were taking opioids, and 86% were taking antiemetics.
   

• Multisite
• Outpatient
• Midwestern United States

Patients were undergoing the active antitumor treatment phase of care.

The study used a randomized, controlled trial, pre- and postintervention design.

• Selected items from various instruments, including the Brief Fatigue Inventory (BFI), Brief Pain Inventory (BPI), and Pittsburgh Sleep Quality Index (PSQI)
• Eleven-point numeric scales, to measure symptoms
• Patient diaries, which recorded use of cognitive-behavioral therapy (CBT) exercises
• Symptom cluster score, calculated by averaging the pain, fatigue, and sleep disturbance scores
• Symptom interference subscale of the MD Anderson Symptom Inventory (MDASI)

• Comparison of pre- and postintervention symptom severity scores showed a significant reduction in the severity of pain, fatigue, and sleep disturbance and symptom interference (p = 0.000).
• Symptom cluster scores and individual symptom scores declined in both the intervention and control groups.
• The reductions in symptom cluster severity (p < 0.05), pain (p < 0.01), and fatigue (p < 0.05) were significantly greater in the intervention group than in the control group; however, the effect sizes (calculated as partial eta) were extremely small (range 0.041–0.093).

The intervention demonstrated a small statistically significant effect on the symptoms of pain and fatigue and the overall symptom cluster of pain, fatigue, and sleep disturbance.

• The study had a small sample size, with less than 100 patients.   
• The study had risks of bias due to no blinding and no appropriate attentional control condition.
• The sample included baseline and group differences of import.
  • The control group had higher depression scores at baseline than did the intervention group.
  • A greater number of those in the intervention group dropped out of the study, suggesting that the intervention was not well accepted. Intention-to-treat analysis used the last value carried forward. If symptoms worsened, this would produce biased results.
• Although the intervention was called a CBT intervention, whether cognitive reframing or problem solving was a part of the intervention was unclear. The intervention appeared to have been a relaxation or imagery therapy.
• Measurement validity and reliability were questionable.
  • Authors used Z-scores to compare sleep disturbance severity, rather than actual scores; the reason for this was unclear. The actual change in Z-scores for this symptom was larger than the score changes associated with other symptoms, but the Z-score change was not statistically significant.
  • Whether average individual symptom scores were more meaningful than the total score for the cluster was unclear.  
• The intervention may be too expensive or impractical, in terms of training needs, to be feasible.

The intervention was a relaxation or imagery therapy rather than a true CBT. The intervention was associated with short-term statistically significant benefits, but the actual size of the effect was small. Findings suggested that approaches using relaxation and imagery may result in some small benefit for patients, but the effect was weak.