STUDY PURPOSE: To assess the evidence of effectiveness of these agents on bone pain and quality of life (QOL)

TYPE OF STUDY: Systematic review

• FINAL NUMBER STUDIES INCLUDED = 25 
• TOTAL PATIENTS INCLUDED IN REVIEW = 3,044 with bisphosphonates or denosumab, 762 with radioisotopes
• SAMPLE RANGE ACROSS STUDIES: 22–1,597 patients
• KEY SAMPLE CHARACTERISTICS: Multiple tumor types, including lung cancer

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

Thirteen studies examined use of bisphosphonates and/or denosumab. Twelve studies used various radioisotopes. No randomized studies using bone-modifying agents were found. One randomized study compared zoledronic acid versus ibandronate. Most of these studies were examining effects to prevent skeletal events. Overall for those with NSCLC, a mean of 67% of patients had a decrease in pain score (3 studies, 225 patients). Of patients given samarium, 60%-95% experienced a decrease in pain. Overall radioisotopes appeared to reduce pain with rapid onset, lasting one to three months. Data were limited for individuals specifically with NSCLC. Most studies did not include QOL measurement; in the five studies that did, only two showed improvement.

Limited evidence exists that bisphosphonates or denosumab reduce or prevent pain from bone metastases or impact QOL in patients with NSCLC . Radioisotopes appear to have a palliative effect on pain, but no high-level evidence for this was found.

• No quality evaluation

Although some evidence exists that bone-modifying agents prescribed to prevent skeletal events may reduce associated pain, the evidence is limited, particularly for patients with NCSLC. Radioisotopes appear to reduce pain for a limited amount of time, and repeated use can have significant adverse effects on bone marrow. Authors of this report suggest that efficacy for pain relief may be tumor dependent, and that, due to potential bone marrow suppression, radioisotopes should be reserved for patients who are not receiving active anticancer therapy and pain that is not appropriate for palliative radiotherapy.

To evaluate the effectiveness of topical silver sulfadiazine to prevent radiation dermatitis in women receiving radiotherapy for breast cancer

Patients were randomized to intervention and control groups and were matched by the investigator in terms of the flatness of the chest wall. Patients in the intervention group were instructed to apply 1% silver sulfadiazine cream to the irradiated field every eight hours for three consecutive days. No application was done on the days they received radiation therapy. Use of the cream was continued for one week after completion of radiotherapy. Both groups were educated in general skin care. No other creams were to be applied to the radiation field. Skin in the field was examined weekly by a random radiation oncologist who was not informed of patient group assignment.

• The study sample was comprised of 102 female patients with breast cancer.
• Mean age was 48.4 years.
• Chemotherapy had to be completed at least three weeks prior to study entry.  

The study took place in an outpatient setting in Iran.

Patients were undergoing active antitumor treatment.

The study used a single blind randomized controlled trial design.

The Radiation Therapy Oncology Group scoring of skin toxicity was used.

 From the second week onward, patients who received the silver sulfadiazine cream showed lower grades of skin injury (p < 0.002).

Silver sulfadiazine was more effective than no treatment in reducing the severity of radiation-induced dermatitis.

• The study had a risk of bias due to no blinding.
• Measurement validityand reliability are questionable.
• Patient adherence to use was not evaluated. 

Silver sulfadiazine was more effective than no skin treatment to reduce severity of radiation-induced dermatitis. It would be more helpful to determine the difference between this approach and other topical treatments, which have been shown to have some efficacy.

To assess the efficacy of continuous infusion pump delivery of bupivacaine at TRAM flap donor site; to assess the safety of continuous infusion pump delivery of bupivacaine at TRAM flap donor site

Patients received 0.375% bupivacaine or isotonic saline through a continuous infusion pump in the suprapubic area and caudal to the donor site incision. All patients received narcotic via PCA programmed for demand-only mode, with no basal rate. Patients could receive oral narcotics. Pain at rest was evaluated four times per day while patients were awake. Overall satisfaction was assessed every four hours for the first three days.

• The sample was composed of 48 patients, 23 in the intervention group and 25 in the control group.
• In the intervention group, mean patient age was 50.3 years; in the control group, 47.6 years.
• All participants were female.
• All participants were undergoing unilateral mastectomy with TRAM flap reconstruction.

• Single site
• Inpatient
• M.D. Anderson Cancer Center, Houston, Texas

Prospective randomized, double-blinded trial

• Amount of PCA narcotic used
• Type and amount of oral narcotic used
• Pain score, on a 10-point visual analog scale (VAS), measured four times daily when patient was at rest
• Patient satisfaction as measured every four hours for three days

• During the first two postoperative days, total PCA use was lower in the continuous infusion group than in the control group. (In both groups, measures of the intensity of abdominal pain at rest reflected significantly lower pain with each postoperative day. Measures were not significantly different between groups.)
• Patient satisfaction was higher in the continuous infusion versus the control group (P = 0.032).

Continuously infused bupivacaine reduced patients' need for PCA opioids early in the postoperative period.

• Pain from the mastectomy site may have been a confounding factor.
• The study had a small sample size, with fewer than 100 patients.
• Limitations may include individual differences regarding pain perception, pain threshold, and the appropriateness of requests for pain medication.

Postoperative mastectomy-TRAM patients may benefit from continuous infusion of anesthetic to an operative site. Ongoing research to determine the most effective dosage and the most effective anesthetics is warranted.

Patients were randomized to one of two arms.

• Arm A was given topical granulocyte-macrophage colony-stimulating factor (GM-CSF) (Leucomax) mouthwash three times per day. The mouthwash consisted of 400 mcg GM-CSF in 250 mL water. Patients were instructed to rinse with 25 mL for 3 minutes and repeat 10 times within 30 minutes. They were to repeat this process at three identical times each day.
• Arm B was given a solution of 4 mL povidone-iodine in 125 ml water with amphotericin B. They were to rinse with 10 mg four times per day according to the same instructions as Arm A.

Both groups were instructed to continue using the respective mouthwashes until complete response (CR). A third, independent investigator randomized patients without knowing individual mucositis ratings.

• The study reported on 31 patients, with 15 in Arm A and 16 in Arm B.
• Patients' ages ranged from 39–77 years, with a median age of 58 years.
• All patients had solid tumor diagnoses.
• The World Health Organization (WHO) oral mucositis scale was used to grade patients after they had received fluorouracil (5FU)-based chemotherapy. Two investigators independently rated mucositis severity.

The study was conducted between March 1998 and June 1999.

This was a prospective, randomized, controlled study.

Every three days, objective and subjective evaluations were conducted.

• Patients who received the GM-CSF treatment experienced shorter duration (5.3 versus 8.1 [p = 0.0008]) and quicker resolution (2.8 versus 4.1 [p = 0.0011]) of mucositis.
• No side effects were reported, and the treatment was well tolerated.

• The sample size was small.
• Application of mouthwash findings is complicated.
• The treatment has a high cost.

To investigate the short- and long-term effects of a psychosocial side-by-side couple's intervention on disease distress, post-traumatic growth, communication, and dyadic coping among women with breast and gynecologic cancers and their partners

The side-by-side intervention consisted of four meeting sessions between a participating couple and a therapist on a biweekly, face-to-face basis at the couple’s home. Each meeting session lasted two hours. Each of the four sessions focused on a certain theme and had specific objectives.

The Couples Control Program was the control group. Control group couples received only one two-hour session where they were given written educational materials about breast and gynecological cancers. The therapist used a structured protocol when interacting with participants.

• The sample included 72 participants.
• Age range of participants was 25–80 years, with a median age of 52 for the combined sample of women and their partners.
• Males (partners) represented 50% of the sample; mean age of partners (all men) was 52.2 years (SD = 11.3).
• The study involved women with breast or gynecologic cancers and their partners. Patients’ treatments for their disease included surgery (90%), radiation therapy (72%), chemotherapy (69%), and hormone therapy (60%).
• There were significant differences between groups for cancer-specific distress (F (1,71) = 6.2, p = 0.02) and fear of progression (F (1,71) = 8.6, p = 0.005) at pretesting.

• Multisite
• Outpatient setting
• Couples were recruited in three regional hospitals in Germany.

Active antitumor treatment phase

 A two-site, controlled, parallel-group study with random assignment (balanced randomization [1:1]) was used.

Psychosocial distress:

• Questionnaire on Stress in Cancer Patients (QSC-R23) was used to assess cancer-specific distress. This questionnaire was given to the women only (patients). Internal reliability was good (alpha 0.87).
• Fear of Progression Questionnaire (FoP-Q) was used to assess fear of cancer progression in both the women and their partners. Internal reliability was good (alpha 0.87).
• Avoidance-Defense Scale, which is a subscale of the Dealing With Illness Inventory–Revised, assessed how much women and their partners used avoidant behaviors in dealing with the disease. Internal consistency was alpha 0.54 and 0.51 for women and men, respectively.

Benefit finding:

• Post-Traumatic Growth Inventory was used to assess an individual finding meaning and benefit from the experience of severe life events; this inventory was done for women and their partners.  Reliability was good (alpha 0.92 and 0.91 for women and men, respectively).

Relationship satisfaction:

• Quality of Marriage Index (QMI) was used to assess marital satisfaction for women and their partners. Reliability was good (alpha 0.95).

Communication:

• Communication subscale of the Partnership Questionnaire was used to assess communication quality for both women and their partners. Reliability was good (alpha 0.86 and 0.82 for women and men, respectively).

Dyadic coping:

• Dyadic Coping Inventory was used to assess how partners cope with stress in their relationship; they report on their own behavior, their perceived partner’s behaviors, and their perceived behavior on themselves as a couple. This was measured for women and their partners. Reliability was not reported.

Sample description and differences:

• Baseline data showed that women in both groups (intervention and control) were somewhat distressed and that both men and women showed high average dyadic coping at baseline in both groups. Furthermore, participants in the intervention group showed significantly higher levels of fear of disease progression than their control group counterparts (M = 39 [SD = 9.2] versus M = 32.8 [SD = 8.6], F (1, 71) = 8.6, p =0.005).
• The only significant difference between groups was in their continuation with the long-term assessments at 12-month assessment: More couples dropped from the control group (45%) compared with the intervention group (17%) X² (df) = 1) = 6.7, p < 0.001. In addition, women who dropped in the control group after the post-treatment had lower communication quality (M = 16 [SD = 3.6]) at baseline than those who continued in the study (M = 19.9 [SD = 4.9], F (1, 25) = 4.6, p = 0.04.  

The following changes were observed in the outcome variables:

• Women in the intervention group showed less avoidant behavior over time compared to women in the control group who showed an increase in avoidant behavior. The interaction between intervention, time, and gender was a significant predictor t (395) = 2.56, p = 0.011 (β = 0.31 [SD=0.12]). Males in the intervention group had an increase in avoidance from pre to first follow-up (third assessment ), whereas males in the control group maintained a high level of avoidance across time.
• Couples in the intervention group showed a higher level of dyadic coping at all assessments (pre, post, follow-up 1, and follow-up 2), whereas couples in the control group showed decline across post through follow-up 1, with an increase in dyadic coping at follow-up 2.

Side-by-side intervention showed clear benefit compared to the control group in fear of disease progression and avoidant behavior. This benefit was short-term and did not carry through to long-term assessments. There was also clear benefit in dyadic coping and communication, but both were also short-term. 

Side-by-side intervention has shown potential benefit in faster post-traumatic growth compared to control group.

• The sample was small, with less than 100 participants.
• There were baseline sample/group differences of import.
• The study had risk of bias due to no blinding and no random assignment, as well as the sample characteristics.*
• The intervention was expensive, impractical, and/or required training needs.*
• Subject withdrawals were 10% or higher.
• Other limitations/*explanation: The study was too complex to be readily comprehensible. Based on the descriptions in the study, it is not clear when the different sessions of intervention occurred, and the timeline was confusing. The reporting was too detailed and presented in a way that loses the reader in the detail. The study design required assessments over time (about 16 months), which leads to attrition challenges. The attrition affected, and possibly contributed to, some bias in the results. The study was thorough but also a case where too much was done. In short, the study was far from parsimony.

The findings indirectly indicate that the interdisciplinary team caring for women with cancer should involve the services of psychologists, family therapists, or advanced practice nurses with specialized training in mental and relationship wellness for patients and their partners.

Nursing care should include an assessment of a couple's distress level and communication patterns over the trajectory of a breast or gynecologic cancer illness.  

Attrition and recruitment in long-term studies involving caregivers remain serious threats, and future research designs and methodologies should include clear plans to manage these challenging aspects.

To test the hypothesis that depression and fatigue would be decreased more in the Sisters Tell Others and Revive Yourself (STORY) intervention group than in controls

The STORY intervention was a therapeutic activity delivered to a group via teleconference, using information and storytelling to increase social connections among African American women with breast cancer. A series to teleconferences was facilitated by two social workers with groups of 10 patients. The series was done weekly for eight weeks, and every other week for two weeks. Participants received small stipends during the study. Patients were randomly assigned to the STORY intervention or usual care. This particular report used secondary analysis to determine the impact of this intervention on depression and fatigue.

• N = 168
• MEAN AGE: 56.7 years
• RANGE: 32-83 years
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: All had breast cancer.

• SITE: Single site
• SETTING TYPE: Not specified
• LOCATION: Southeastern United States

• Randomized, controlled trial

• Profile of Mood States Short Form (POMS-SF)

There was no significant difference in fatigue or depression between study groups.

The psychoeducational intervention delivered via teleconference as tested here did not demonstrate an effect on fatigue or depression.

• Risk of bias (no blinding)
• Risk of bias (no appropriate attentional control condition)
• Unintended interventions or applicable interventions not described that would influence results
• Measurement validity/reliability questionable
• The single instrument used may not have been the best for measurement of these symptoms.
• The educational content regarding how to manage fatigue and depression are not described, and from the description that is provided, it is not clear that patients were educated about evidence-based approaches to combat fatigue.
• It is unclear whether levels of fatigue and depression were high enough to expect to see a reduction with an intervention.

The psychoeducational and supportive intervention tested did not show an effect on depression or fatigue. This report does provide information regarding using a teleconference approach to provision of a group intervention, which might be applicable in a number of situations to facilitate patient involvement in this type of activity. Further research regarding the most effective methods of delivery of educational and supportive interventions is needed.

Intervention consisted of physiotherapy, group exercises, and psycho-oncologic interventions. Patients received a brochure with instructions for nine muscle strength and nine stretching exercises for large muscle groups. Outcomes were assessed at baseline, start of intervention (T1), end of intervention (T2), and at a three-month follow-up (T3).

• N = 63
• AGE: In the intervention group, 56% were aged 51–70 years
• KEY DISEASE CHARACTERISTICS: Patients with breast cancer with cancer-related chronic fatigue
• OTHER KEY SAMPLE CHARACTERISTICS: Control group patients were slightly younger, but otherwise both groups were well balanced. Intervention group: 56% married, 59% working, most patients had received chemotherapy (66%) and radiation therapy (81%), and 78% received hormonal therapy
• EXCLUSION CRITERIA: Evidence of psychiatric disease or patients who were less than six weeks to preceding surgery or chemotherapy

• PHASE OF CARE: Active treatment, inpatient rehabilitation

• Randomized controlled trial
  • Structured physical training intervention (N = 32)
  • Control (N = 31)

• Linear analogue scale (LASA)
• Multidimensional Fatigue Inventory (MFI)
• Functional Assessment of Cancer Treatment (FACT)

Trial outcome index for fatigue in the FACT-F questionnaire showed improvement in fatigue from T1–T3. The interaction of time and group were statistically significant (p = 0.003). For MFI measures, interaction between group and time effects was significant for physical fatigue between T2–T3 (p = 0.028). The mean MFI total score was higher for both the control and intervention group in comparison to the mean MFI total score for healthy women in the age group of 40–50 years at the three-month follow-up.

• Small sample size

Future research should incorporate better measures for the intensity of the exercise.

To compare the efficacy and safety of two filgrastim formulations for controlling chemotherapy-induced neutropenia and to evaluate the noninferiority of the test drug against the original

Patients with grade 4 neutropenia were randomized 1:1 to Eurofarma filgrastim or Roche filgrastim. Doses were administered subcutaneously daily 5 mg/kg until absolute neutrophil count was 10,000/mm³ or greater or until the 15th day of the chemotherapy cycle (V14). Only a single event of febrile neutropenia was considered during the study period per patient. Neutrophil counts were drawn every two days.

• N = 219   
• AGE = 49–51 years
• MALES: Not specified
• FEMALES: Not specified
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Breast cancer stages II–IV
• OTHER KEY SAMPLE CHARACTERISTICS: Full dose of TAC or AT chemotherapy

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

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

Phase III, open-label, noninferiority, randomized, two-group trial

• Kolmogorov-Smirnov test with Lilliefors correction used to evaluate standard distribution of the outcome variables
• Lillifors correction also used to adjust the estimated population parameters (mean and variance, standard deviation)

To assess the noninferiority of the test drug to the original the 90% confidence interval for the difference in the rates of grade 4 neutropenia between the two groups were initially calculated.

No significant difference (p = 0.9971) in the rate of grade 4 neutropenia existed in the total number of patients in each group during the first chemotherapy cycle.

Risk of bias (no blinding)

The increased surveillance of patients’ neutrophils may have produced better outcomes. The difference between the two drugs was negligible. Strong patient teaching is warranted, regardless of the process of events during the chemotherapy cycle.

To see if topical aloe vera gel would be beneficial in reducing the skin side effects of radiation therapy (RT).

Participants were stratified according to bra cup size, history of lymphocele drainage, and smoking. Participants were randomized to use of aloe vera or an aqueous cream for control.

• The sample was comprised of 208 participants with breast cancer.
• Median age was 57.5 years (range 28–89).
• Patients had undergone lumpectomy or partial mastectomy.
• Median radiation dose was 60.15 Gy.

Mater Centre, Australia, and the Royal Brisbane Hospital Centre, Australia

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

• Weekly assessment form based on Dische’s Morbidity Rating Scale was used to record skin reactions.
• Researchers observed for erythema, itching, pain, and extent of treatment area affected by dry or moist desquamation. The areas affected by moist desquamation were identified according to site.
• Weight, skin type, tumor stage, and previous skin cancer were also recorded.
• Weekly assessments were performed using the Radiation Therapy Oncology Group (RTOG) scale.
• Skin changes recorded were itching, skin texture, tanning, erythema, time to skin change, and dose at first skin change.

Aqueous cream was significantly better than aloe vera gel in reducing the incidence of dry desquamation and moderate or higher pain (p < 0.001). Participants with cup size D or more in either treatment arm experienced a significantly greater incidence of moderate or higher erythema compared with smaller-breasted women (p < 0.02). For non-chemotherapy participants, the aloe vera arm experienced a significantly reduced incidence of moderate or higher erythema (p = 0.02). The control group arm experienced a significantly reduced incidence of moderate or higher pain (p = 0.03). The most important predictors of development of skin reaction were radiation dose, breast size, patient smoking, and damage to the lymphatic system manifested by one or more lymphocele drainage. Cumulative dose was greater than 2,700 cGy, and there was a delay to onset of erythema (p = 0.013).

Aqueous cream is superior to aloe vera in reducing the acute RT skin reactions of dry desquamation and pain.

• The consistency and appearance of the two study preparations were quite dissimilar, so participants may have guessed the identity of their study preparation.
• Ninety percent of the final skin assessments were conducted over the telephone, so the research nurse was not able to view the participant’s skin and had to rely on the subjective assessment.

To clinically evaluate the use of a polymeric membrane for the management of radiodermatitis in terms of skin integrity, management of desquamation, relief of pain and inflammation, and healing time

Patients with Radiation Therapy Oncology Group (RTOG) scores of 1–3 and early signs of skin reactions were followed for four weeks during treatment. Study data and patient assessments were obtained weekly. The polymeric dressing provided a mild cleansing agent activated by exudate that supported natural debridement. The dressing also contained glycerine, which provided moisture, and surfactant, which has been reported to reduce tension between healthy and unhealthy tissue.

• N = 23  
• MEAN AGE = 63.6 years (range = 38–82 years)
• MALES: 32%, FEMALES: 68%
• KEY DISEASE CHARACTERISTICS: Various tumor types including breast, head and neck, and prostate
• OTHER KEY SAMPLE CHARACTERISTICS: Highest radiotherapy dosage was 74 Gy in 37 fractions

• SITE: Single-site  
• SETTING TYPE: Outpatient    
• LOCATION: United Kingdom

• PHASE OF CARE: Active antitumor treatment

Observational

• Numeric pain scale
• Wong and Baker FACES^® scale
• Patient diary
• RTOG skin rating

From baseline to week 3, RTOG scores improved. Diary pain scoring showed an overall reduction in pain from an average of 6.5 to 1.6. Fixation of the dressing was a challenge, particularly among patients with breast and gynecologic cancers. Themes from a qualitative analysis of patient diaries identified skin improvement, a cooling effect of the dressing, and pain reduction.

Polymeric dressing use may be helpful for the prevention and treatment of radiodermatitis.

• Small sample (< 30)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Measurement/methods not well described
• Other limitations/explanation: The frequency and timing of dressing changes was not described. The way in which data were presented did not enable the reader to determine how many patients had a significant improvement or decline in skin condition, though group trends were shown. Who measured skin condition and how it was measured was not clear.

Polymeric dressings may be helpful for the prevention and treatment of radiodermatitis. Additional, well designed, clearly reported studies are warranted. Keeping this specific dressing in place was found to be a challenge for some patients.