STUDY PURPOSE: To assess the benefits and harms of pharmacologic interventions for treating patients with leukemia experiencing disseminated intravascular coagulation (DIC) to update a prior systematic review

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED = 4 studies 
• TOTAL PATIENTS INCLUDED IN REVIEW = 388
• SAMPLE RANGE ACROSS STUDIES: 10–132

PHASE OF CARE: Not specified or not applicable

Interventions included human activated protein C versus heparin, recombinant human soluble thrombomodulin versus heparin, tanexamic acid versus placebo, and dermatan sulfate versus heparin. Only one study was found for each intervention. No significant differences in bleeding with protein C or dermatan sulfate existed. Recombinant human soluble thrombomodulin was associated with improvement in bleeding symptoms compared to heparin, and lower scoring of hemorrhagic problems with tranexamic acid compared to placebo.

Insufficient high quality evidence exists to fully evaluate these interventions.

• Limited number of studies included
• Mostly low quality/high risk of bias studies
• Low sample sizes
• Some studies included patients with DIC from other causes, and the findings were not reported separately for patients with leukemia, further reducing the relevant samples for consideration.

Extremely limited evidence regarding the effects of pharmacologic interventions for the management of DIC and associated bleeding exists compared to usual practice using heparin.

To determine the effectiveness of octreotide in reducing treatment-related diarrhea during radiation therapy to the pelvis

Patients were randomized to receive octreotide acetate or placebo. Patients in the treatment group were given 100 µg subcutaneous octreotide acetate on day 1 followed by 20 mg intramuscular octreotide acetate on days 2 and 29. Patients in the control group received placebo by the same routes on the same days.

• The study reported on 125 patients.
• Patients had histologic proof of cancer in the pelvis without distant metastases and were receiving radiation therapy, either as definitive treatment or adjuvantly.                           

This was a multisite, collaborative trial of North Central Cancer Treatment Group.

Patients were undergoing the active treatment phase of care.

This was a double-blinded, randomized control trial.

A Bowel Function Questionnaire and a Uniscale Quality of Life (QOL) measure were used.

No statistically significant differences were found between groups. Octreotide did not reduce the severity or incidence of diarrhea during pelvic radiation therapy. Abdominal cramps were worse in patients on the octreotide arm, but the difference was not statistically significant (p = 0.053). Patients receiving octreotide experienced significantly more problems with nocturnal bowel movements (70% versus 45%, p = 0.004), clustering (90% versus 69%, p = 0.004), and blood with bowel movements (57% versus 35%, p = 0.01).

Octreotide did not result in improvement in diarrhea in this population and was associated with more problems. Octreotide did not have an effect on the severity or incidence of diarrhea during pelvic radiation therapy. Some gastroinstestinal (GI) symptoms were worse in patients receiving octreotide compared to placebo.

• The subjects in the treatment groups were different. More patients in the control group had histories of rectal surgery or primary rectal cancer.
• Not all patients completed the day 29 dose of study medication. Only 49 (79%) of 62 of patients in the placebo arm and 43 (69%) of 62 of patients in the octreotide arm received a second dose.
• No intention-to-treat analysis was conducted.

More clinical research is needed to evaluate the effective prevention of diarrhea during pelvic radiation therapy. Long-acting octreotide (LAO) should not be used outside of a controlled clinical trial setting.

Patients receiving pelvic external beam radiation therapy were randomly assigned to receive sulcrafate (2 gm four times per day) or placebo.

The study reported on 123 evaluable patients. The treatment group consisted of 62 patients, and the placebo group consisted of 61 patients. The two groups were balanced in terms of factors such as diagnosis, functional status, radiation dosage, and tumor status. 

This was a double-blind, randomized controlled trial.

• Patients reported the number bowel movements, use of protective clothing, and symptoms of cramping, blood, nocturnal bowel movements, and fecal incontinence weekly via a questionnaire.
• Physicians assessed diarrhea, tenesmus, cramping, bleeding, nausea, and constipation using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).

More patients in the treatment group reported fecal incontinence and a need for protective clothing than in the control group (34% versus 16%, p = 0.04). Physician-reported severity of nausea was worse in the treatment group compared to the control group (p = 0.3), although this was not a specific study endpoint.

Sulcrafate did not decrease pelvic radiation therapy-related bowel toxicity by any of the endpoints measured and seems to have aggravated some gastrointestinal symptoms.

Although the patient questionnaire approximated the physician scale, provider assessments of subjective data such as cramping and straining can be unreliable if not obtained directly from the subject.

To identify if the cool pad pillow topper (CPPT) decreases sleep disturbance, minimizing the effects of hot flashes. The CPPT is a commercial product promoted to improve quality of sleep disrupted by hot flashes.

The intervention arm of pre- and postmenopausal women received during four weeks standard care consisting in booklets with advice on exercise, physical activity, diet, and the reduction of caffeine and alcohol plus the CPPT. The CPPT is an approved commercial product that removes heat from the body and can be placed on top, outside, or inside the pillowcase.

• N = 75  
• MEAN AGE: 49.5 years (intervention group mean = 51 years, and control group mean = 51.2 years)
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Breast cancer in endocrine therapy, pre- or postmenopausal, night hot flashes
• OTHER KEY SAMPLE CHARACTERISTICS: Insomnia symptoms, anxiety, depression, exercise, alcohol intake, smoking status

• SITE: Not stated/unknown    
• SETTING TYPE: Outpatient    
• LOCATION: The Beatson West of Scotland Cancer Centre, Glasgow

• PHASE OF CARE: Transition phase after active treatment
• APPLICATIONS: Elder care, palliative care

• Randomized phase II clinical trial, control with routine information and intervention group information plus the CPPT

The instruments for the intervention group were the sleep diaries to evaluate amount of time asleep and changes in sleep disturbance. The number of hot flashes and the severity at night were evaluated with the hot flash score (HFS), both completed daily for four weeks from the point of randomization; they also record number of alcohol units consumed, if any sleeping pills were taken, and the frequency nightwear changed. The Functional Assessment of Cancer Therapy-Breast (FACT-B) and Hospital Anxiety and Depression Scale (HADS) were used at two points—at randomization and at the end of the study.

CPPT is effective as a self-management strategy to reduce sleep disturbance and the severity/frequency of hot flashes. CPPT did not impact quality of life (QOL) or anxiety but reduction in depression was observed. The CPPT appears to be an effective intervention in conjunction with current standard care.

• Small sample (less than 100)
• Risk of bias (no blinding)
• No main limitations are founded in the well-designed study

Nurses could recommend the use of the CPPT as no risk or harm is expected and it helps control hot flashes and sleep disturbances associated with endocrine therapies. This is a pilot only; would recommend additional research to note if results are reproducible.

RESOURCE TYPE: Consensus-based guideline  

PROCESS OF DEVELOPMENT: Review of selected literature and retrospective review of 63 patients hospitalized for CID

PHASE OF CARE: Active antitumor treatment

No specific broad search and literature review were used. A few study findings are cited. No information was provided regarding the strength of evidence cited.

• Recommends CID severity grading using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE)
• Notes the lack of and need for information identifying risk factors and development of a predictive model for CID severity
• Outlines methods for patient evaluation of possible causes of diarrhea and workup to include complete and differential blood count, blood chemistry, and stool analysis
• Recommends dietary management eliminating caffeine, alcohol, lactose, and high-fat foods
• Identifies loperamide or high-dose loperamide as first-line treatment, octreotide for intractable grade 1 or 2 diarrhea, and fluid/electrolyte replacement for grade 3 or 4 diarrhea
• Recommends consideration of long-acting octreotide for patients who had grade 3 or 4 diarrhea in a previous chemotherapy cycle as prophylaxis

• Mainly consensus-based guideline

Algorithm and consensus recommendations are provided for management of CID. Although these guidelines are aimed specifically at colorectal cancer cases, principles are likely to apply to other tumor types. Whether the mechanisms of diarrhea, and, therefore, effective treatments, are the same with various chemotherapy agents is unclear, and research is limited in this area. Prophylactic use of octreotide is suggested for patients who had diarrhea in a previous cycle of treatment in order to attempt to avoid the need for dose reductions or treatment delays.

To evaluate the efficacy of supersaturated calcium phosphate rinse (SCPR) with customary care (topical mouth solutions) on measures of severity and consequent interventions and complications  

In the treatment group, patients rinsed their mouths four times daily with the SCPR. In the control group, patients received customary topical mouth care with the extract of salvia leaves (twice daily), providone-iodine mouth solution (1% water solution of iodide with polyvinylpyrrolidone) once daily, and fluconazole mouth solution (50 mg fluconazole, 50 mg glycerine, 10 g vitamin A, and 10 g vitamin E with or without 2.5 g benzociaine) twice daily.

The SCPR treatment was administered from the first day of conditioning until patients reached the absolute neutrophil count of greater or equal to 0.2 g/l (a value that was considered an indication of the beginning of neutrophil recovery). Patients self-assessed the level of pain in the mouth and pharynx using a 0–10 visual analog scale (VAS) and measured swallowing problems using a 0–5 VAS.

The same experienced hematologist performed a physical examination of the oral cavity each day throughout the study, ranking cases according to the World Health Organization (WHO) scale for grading oral toxic effects of cancer treatment.

• The study reported on a sample of 40 patients. The SCPR group mean age was 38, with a range of 19–57 years. The control group mean age was 26, with a range of 20–57 years.
• The SCPR group had 13 males and 7 females, and the control group had 11 males and 9 females.
• The SCPR group had 8 patients with acute myelogenous leukemia (AML), 5 with acute lymphocytic leukemia (ALL), 2 with chronic myelogenous leukemia (CML), 3 with paroxysmal nocturnal hemoglobinuria (PNH), and 2 with other cancers (osteomyelfibrosis, myelodysplastic syndrome, severe aplastic anemia).
• The control group consisted of 12 patients with AML, 5 patients with ALL, 1 patient with PNH, and 2 patients with other (see above).
• In the SCPR group, 9 patients were receiving busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg), 5 patients were receiving total body irradiation (TBI) of 12 Gy and 120 mg/kg cyclophosphamide, and 6 were receiving treosulfan (42 g/m²) and fludarabine (150 mg/m²).
• In the control group, 9 patients were receiving busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg), 5 were receiving TBI (12 Gy) and 120 mg/kg cyclophosphamide, 4 were receiving treosulfan (42 g/m²) and fludarabine (150 mg/m²), 1 was receiving treosulfan (20 g/m²) and cyclophosphamide (160 mg/kg) and 1 was receiving cyclophosphamide (200 mg/kg). 
• In the SCPR group, 5 patients were receiving transplants from sibling donors and 15 from unrelated donors. In the control group, 4 were receiving transplants from sibling donors and 16 from unrelated donors.

This was a single-site study conducted in an inpatient setting. The study was conducted at the Department of Hematology and Bone Marrow Transplantation at the Medical University of Silesia in Katowice, Poland, in 2009.

• Patients were undergoing the active treatment phase of care.
• This study has clinical applicability for end of life and palliative care.

This was a prospective randomized, non-blinded, controlled trial with 40 consecutive patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). Half of the patients received treatment with the supersaturated rinse, and the remaining half received customary care with topical mouth solutions. Patients enrolled in this study underwent transplantation in the Medical University of Silesia in Katowice, Poland, in 2009.

The World Health Organization scale (WHO) was used to measure severity of mucositis. Duration was recorded in days. Peak mean pain in mouth was recorded using a 0–10 visual analog scale (VAS). Peak mean swallowing problems were recorded using a 0–5 VAS. Days to absolute neutrophil count of more than 0.5 g/L and days to platelets of more than 20 g/L were recorded.  

Interventions and complications were measured in terms of duration of analgesics used (days), duration of total parenteral nutrition (TPN) (days), use of granulocyte colony-stimulating factor (G-CSF), incidence of acute graft-versus-host disease (aGVHD), degree of aGVHD, and incidence of infectious complications.

• Compared with the control group, the SCPR mouth rinse group demonstrated significantly lower means measures of oral toxicity, peak mouth pain, and disease course duration.
• WHO oral toxicity scores were statistically lower in the SCPR group (p = 0.02) compared to the control group.
• Disease course for the SCPR group was statistically shorter (p = 0.02) and peak mouth pain was statistically lower in the SCPR group (p = 0.005).
• Days of analgesic needs were shorter for the SCPR group (p = 0.047).
• The need for patients needing TPN in the SCPR group was lower (p = 0.02), and the mean days of TPN was lower in the SCPR group (p = 0.009).

The findings in this prospective randomized, controlled study confirm findings in a 1992 report of a double-blind, prospective, randomized, controlled trial of 95 patients undergoing HSCT. In that trial, SCPR produced statistically significantly lower measures of pain duration, disease course duration, use of analgesics (morphine), and duration of time to absolute neutrophil recovery than did a fluoride rinse, demonstrating the SCPR regimen has a significant positive effect on oral mucositis associated with chemotherapy and radiotherapy.

• The sample size was small with fewer than 100 patients.
• The iodine solution (red) contrasted dramatically in color with the SCPR solution (colorless), thus making it difficult to disguise the difference and, therefore, making the study unblinded.
• The red color of the iodine solution may have obscured assessment of the oral cavity.
• It may be able to generalize these results to other settings because the control group treatment is not necessarily widely accepted as the standard of care for the prevention and treatment of mucositis. 

These results warrant confirmation in controlled, multicenter, randomized trials. The use of a supersaturated calcium phosphate rinse holds promise for the prevention and early resolution of oral mucositis and appears to have no significant side effects when used four times daily in patients receiving stem cell transplant.

Databases searched were Cochrane Breast Cancer Specialised Register, MEDLINE, EMBASE, CINAHL, SPORTDiscus, PsycINFO, SIGLE, ProQuest Digital Dissertations, and Conference Papers Index through July 2004.

Treatment evaluated aerobic (walking or cycle ergometer interval training) or resistance exercise, or a combination of both. Exercise programs were of moderate or low intensity, and the interventions included a mixture of supervised and self-directed programs, delivered individually, or in groups.

To be included in this meta-analysis, the exercise intervention had to be of at least six weeks' duration and had to coincide with the adjuvant treatment regimen rather than follow it. Trials in which the exercise intervention was part of a complex intervention (e.g., complete decongestive lymphatic therapy) and trials restricted to local muscular endurance (e.g., training of shoulders, back, or legs only) instead of including all major muscle groups or restricted to stretching exercises were also excluded.

Seven randomized trials and two nonrandomized, controlled trials involving 452 participants met the inclusion criteria. Five trials, involving 317 participants, were used in the meta-analysis specifically for the outcome of fatigue.

• Sample size was common among included trials, with only two trials having more than 30 participants.  Median sample size was 42 patients.
• Women were undergoing adjuvant (including neoadjuvant) treatment (including chemotherapy, hormonal therapy, or radiotherapy, sequentially or concurrently) for stage I, II, and III breast cancer.

Outcomes were physical fitness, psychological distress, symptoms (pain and fatigue), quality of life, body weight or lean body mass, and immune function. Fatigue was evaluated predominantly using the Piper Fatigue Scale. Meta-analysis of the trials in which fatigue was included as an outcome did not identify a statistically significant improvement in fatigue for participants in the exercise intervention groups compared to the control (nonexercising) groups. Statistically significant improvements for cardiorespiratory fitness, anxiety, sleep disturbance, and nausea relief were found.

The methodologic quality of the studies was overall moderate.

• The absence of blinding of the outcome assessor was the most prominent methodologic flaw.
• The conclusions that can be drawn from this review are limited based on the inclusion of only a small number of trials, together with a considerable degree of clinical heterogeneity regarding adjuvant cancer treatments and exercise interventions.

To facilitate dose escalation of strong opioids by using an opioid-tramadol combination

Of 70 patients, 35 were treated conventionally, with increasing transdermal fentanyl (group F). The other 35 patients received oral tramadol added to their fentanyl before each increment of their transdermal opioid (group T). Patients started fentanyl therapy by taking 25, 50, 75, or 100 mcg/hour, the amount based on equianalgesic dosing. Maximum tramadol dose was 400 mg/day. Rectal tramadol was not used.

• The sample was composed of 70 patients with intractable cancer pain whose visual analog pain score was greater than 3.
• All patients were receiving palliative care and not in the active treatment phase of disease.

The study was conducted in Italy.

Randomized open-label, prospectively evaluated study

Authors used a visual analog scale (VAS) to measure pain.

• In group F, 33 patients completed the study; in group T, 34 patients completed the study.
• Pain was equal in both groups; VAS scores did not differ. However, pain control in the tramadol group was achieved at slower escalation of fentanyl dose. The combination of a strong opioid with a weak opioid, to treat severe cancer pain, allowed a more gradual increase of analgesic delivery. Therefore, the combination minimized periods of overdosing and underdosing.
• Application time for patches was significantly higher in group T. In group T, no patient's fentanyl patch dose changed before the patient reached the maximum tramadol dose of 400 mg per day.
• Regarding adequacy of treatment, patients’, relatives’, and physicians’ judgments did not differ.

The combination of a strong opioid and a weak opioid, to treat severe cancer pain, allowed a more gradual increase of analgesic delivery. Therefore, the combination treatment minimized periods of overdosing and underdosing. Combination treatment as specified is a useful alternative, especially when disease and pain progress quickly.

Severe nausea and vomiting occurred in six patients in group T and three in group F, possibly due to a synergistic effect between fentanyl and tramadol. This study was insufficiently powered to show statistically significant differences relating to uncommon or serious side effects.

The greater number of fentanyl dose changes associated with higher fentanyl consumption in group F may support the hypothesis that tolerance is a pharmacologic effect, rather than a result of the rapid progression of disease. Additional study of the synergistic effect of tramadol and fentanyl, with respect to severe nausea and vomiting, is needed.

To evaluate the use of hypnosis in the management of anticipatory nausea and vomiting

Patients received two hours of training in progressive relaxation, followed by a one-hour hypnosis program. No drugs were given in association with the hypnotherapy. After the intervention, patients immediately went to their scheduled chemotherapy.

• The study consisted of 16 adults with anticipatory nausea and vomiting from at least four previous courses of chemotherapy.
• The majority of the sample was female (n = 14).
• Median age was 44 years.
• Patients did not have metastatic disease to the brain or gastrointestinal (GI) tract.
• Cancer types included were ovarian, Hodgkin, testicular, lung, and breast.
• Chemotherapy received included cisplatin, carboplatin, cyclophosphamide, dacarbazine, doxorubicin, and epirubicin.
• All patients had to have previously undergone four cycles of 5-HT₃ and developed nausea and vomiting.
• The sample was a convenience sample.

All patients were from an outpatient setting.

A Visual Analog Scale (VAS) was used to measure complete response (CR) (mild nausea with no vomiting), major response (moderate to severe nausea and one vomiting episode), or no response (none of the above).

In all of the 16 patients in the study, anticipatory nausea and vomiting disappeared. Major responses (moderate to severe nausea, with one vomiting episode) to chemotherapy-induced emesis control occurred in 14 of the 16 patients.

• The study included a very small population.
• No interrater reliability was reported.
• No control group was used.
• Patients with brain metastasis or cognitive disabilities were excluded.

Caution should be used regarding patient selection; some patients should not be hypnotized.

To investigate the effects of dexmethylphenidate (d-MPH) on fatigue and cognitive function in women undergoing adjuvant chemotherapy for early breast cancer

Participants were randomized to a placebo group or a treatment group receiving d-MPH. The treatment group was started on 5 mg twice a day of d-MPH. If this was well-tolerated, the dose was increased one week later to 10 mg twice a day. The treatment group then continued taking d-MPH at a maximum of 10 mg twice a day until the end of the final cycle of chemotherapy. If participants did not tolerate 10 mg twice a day, the dose was reduced to 5 mg twice a day for the remainder of their treatment.

• The total number of participants was 57.
• The treatment group had 29 participants, and the placebo group had 28 participants.
• The median age of the treatment group was 50, with a range of 36–72.
• The median age of the placebo group was 51, with a range of 37–74.
• All participants were female.
• All participants had breast cancer.
• All participants were scheduled to receive four or more cycles of adjuvant chemotherapy and were enrolled after at least one cycle of chemotherapy.

Three hospital-based outpatient clinics in Toronto, Canada

Prospective, randomized, double-blind, placebo-controlled trial

• Mini-Mental State Examination ((MMSE) for global cognitive functioning
• High Sensitivity Cognitive Screen (HSCS) for memory, language, attention, concentration, visual-motor, spatial, and self-regulation
• Hopkins Verbal Learning Test-Revised (HVLT-R) for immediate and delayed recall (alternate forms used)
• Functional Assessment of Cancer Therapy-General (FACT-G) for cancer-related quality of life
• Functional Assessment of Cancer Therapy (FACT-F) for cancer-related quality of life pertaining to fatigue symptoms
• Hospital Anxiety and Depression Scale (HADS)

No difference was seen between groups on any of the cognitive assessments completed at baseline, end of chemotherapy, and at six-month follow-up.

The study failed to demonstrate a beneficial effect of d-MPH on either fatigue or cognitive dysfunction during adjuvant chemotherapy for breast cancer.

• No baseline assessment of cognitive function was conducted prior to chemotherapy treatment; the baseline assessment was completed after the participant already had received at least one cycle of chemotherapy. 
• No descriptive information was provided regarding the sample (e.g., educational level, disease stage).
• The study was closed early because of failure to achieve the accrual goal. This primarily was due to patient reluctance to take additional medication in general and d-MPH in particular. 
• HSCS is subject to substantial practice effect and is not recommended for serial measures.
• The sample size was insufficient to achieve the necessary statistical power.