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Hatakeyama, H., Takahashi, H., Oridate, N., Kuramoto, R., Fujiwara, K., Homma, A., . . . Fukuda, S. (2015). Hangeshashinto improves the completion rate of chemoradiotherapy and the nutritional status in patients with head and neck cancer. ORL: Journal for Oto-Rhino-Laryngology and Its Related Specialties, 77, 100–108. 

Study Purpose

To investigate the effect of hangeshashinto to relieve chemotherapy-induced oral mucositis

Intervention Characteristics/Basic Study Process

Patients were to gargle three times daily with 2.5 g hangeshashinto (TJ-14) in 50 ml of water and rinse the oral cavity for about five seconds. Patients were instructed not to swallow it and not eat or drink anything for 30 minutes. Patients who received the intervention were compared to patients who did not. Measurements were done at baseline and at eight weeks.

Sample Characteristics

  • N = 57, only 12 received the intervention  
  • MEAN AGE = 59.5 years
  • AGE RANGE = 40–75 years
  • MALES: 93%, FEMALES: 7%
  • CURRENT TREATMENT: Combination radiation and chemotherapy
  • KEY DISEASE CHARACTERISTICS: Oropharyngeal and hypopharyngeal cancers; total radiation dose of 70 Gy and cisplatin
  • OTHER KEY SAMPLE CHARACTERISTICS: The majority of patients had stage IV disease.

Setting

  • SITE: Single site   
  • SETTING TYPE: Inpatient    
  • LOCATION: Japan

Phase of Care and Clinical Applications

  • PHASE OF CARE: Active antitumor treatment

Study Design

  • Nonrandomized two-group prospective study

Measurement Instruments/Methods

  • Common Terminology Criteria for Adverse Events (CTCAE)
  • Bioimpedance for body composition
  • Measurement of food intake

Results

No significant differences in maximum grade of mucositis or daily morphine dose existed. Oral intake and body weight were improved in those who took the hangeshashinto, but no comparative information on this measure from the control group was provided. The radiation completion rate was higher in the treated group (p = 0.045). Twenty-five percent of patients would not continue to use the gargle because of the bitter taste, nausea, vomiting, and refusal to wait 30 minutes before eating.

Conclusions

The findings do not show a benefit of hangeshashinto gargle on mucositis severity or associated pain.

Limitations

  • Small sample (< 100)
  • Risk of bias (no blinding)
  • Risk of bias (no random assignment)
  • Measurement/methods not well described
  • Measurement validity/reliability questionable
  • Subject withdrawals ≥ 10%  
  • Very few patients actually received the intervention. Little comparative information is provided. The timing of measurement was not clearly reported.

Nursing Implications

This study did not show the effectiveness of hangeshashinto to prevent or reduce the severity of oral mucositis in patients with head and neck cancer receiving combined radiation and chemotherapy. Multiple report limitations are noted.

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Hata, T., Honda, M., Kobayashi, M., Toyokawa, A., Tsuda, M., Tokunaga, Y., . . . Mishima, H. (2015). Effect of pH adjustment by mixing steroid for venous pain in colorectal cancer patients receiving oxaliplatin through peripheral vein: A multicenter randomized phase II study (APOLLO). Cancer Chemotherapy and Pharmacology, 76, 1209–1215. 

Study Purpose

To evaluate whether mixing dexamethasone with an oxaliplatin intravenous infusion can reduce venous pain associated with the infusion

Intervention Characteristics/Basic Study Process

Patients receiving either ​capecitabine and oxaliplatin (CapeOX) or S-1 plus oxaliplatin (SOX) chemotherapy were randomly assigned to the experimental or control groups. In the experimental group, 1.65 mg of dexamethasone was mixed with a 5% glucose solution in which 130 mg/m2 was dissolved. The resulting mixture was infused over two hours. Those in the control group received the same infusion without the addition of dexamethasone. Patients were evaluated over four treatment cycles.

Sample Characteristics

  • N = 48
  • MEAN AGE = 66 years (range = 46–81 years)
  • MALES: 79%, FEMALES: 21%
  • KEY DISEASE CHARACTERISTICS: All patients had colorectal cancers and were receiving regimens containing oxaliplatin.

Setting

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

Phase of Care and Clinical Applications

  • PHASE OF CARE: Active antitumor treatment

Study Design

Randomized, controlled trial

Measurement Instruments/Methods

  • Verbal Rating Scale (VRS) for pain
  • National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0

Results

The incidence of grade 2 or greater venous pain based on the CTCAE was 33.3% in patients receiving steroids and 56% in those who did not (based on only 22 patients). The relative risk of venous pain was 0.60 (95% CI, 0.31–1.16).

Conclusions

Patients who received dexamethasone with oxaliplatin tended to experience less venous pain.

Limitations

  • Small sample (< 100)
  • Risk of bias (no blinding)
  • Measurement validity/reliability questionable
  • Other limitations/explanation: The study was slightly underpowered.

Nursing Implications

In this study, the incidence of severe venous pain during oxaliplatin infusion was lower with the addition of dexamethasone to the infusion. It has been suggested that mixing dexamethasone may be an option for patients with venous pain or phlebitis caused by chemotherapy. Additional research confirming the efficacy of this approach is needed.

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Hassler, M.R., Elandt, K., Preusser, M., Lehrner, J., Binder, P., Dieckmann, K., . . . Marosi, C. (2010). Neurocognitive training in patients with high-grade glioma: A pilot study. Journal of Neuro-Oncology, 97, 109–115.

Study Purpose

To evaluate the effectiveness of small group neurocognitive training to improve cognitive impairment in patients with brain tumors

Intervention Characteristics/Basic Study Process

Pre- and post-intervention cognitive testing was performed. The 10-week-long intervention consisted of 90-minute weekly group sessions of holistic mnemonic training, which included exercises to train perception, concentration, attention, memory, retentiveness, verbal memory, and creativity.

Sample Characteristics

  • A total of 11 patients were enrolled in the study.
  • Participants' ages ranged from 23–73 years (median = 50 years).
  • The sample was 64% male and 36% female.
  • Patients had been diagnosed with glioblastoma multiforme (n = 6) or anaplastic gliomas (n = 5).
  • Time since initial diagnosis ranged from 10–42 months (median = 15 months).
  • Every participant had received treatment that included surgery, radiation therapy, and adjuvant chemotherapy with temozolomide. One subject also received hydroxyurea and imatinib in addition to temozolomide.
  • Three subjects had tumor recurrence 3–28 months prior to study participation; none underwent additional surgery, and further treatment with radiation or chemotherapy was not provided. 
  • All subjects were taking antiepileptic medications; however a variety of drugs were used. 
  • Subjects varied in professional and educational background, but actual information was not provided.

Setting

  • Single site
  • Outpatient setting
  • Vienna, Austria

Phase of Care and Clinical Applications

  • Patients were undergoing long-term follow-up.
  • The study has applicability for late effects and survivorship.

Study Design

Pilot study with pre-/post-test design

Measurement Instruments/Methods

  • Trail Making Test–A (TMT-A)    
  • Trail Making Test–B (TMT-B)
  • Hopkins Verbal Learning Test (HVLT)
  • Controlled Oral Word Association Test (COWAT)

Results

Although comparison of mean group differences found improvement in all neuropsychological tests, separate dependent t-tests revealed statistically significant improvement only in verbal memory total learning (p < 0.05) as measured by the HVLT. Significant improvement was not seen in verbal memory delayed recall (p = 0.11) as measured by the HVLT, psychomotor speed (p = 0.22) as measured by the TMT-A, sustained attention (p = 0.17) as measured by the TMT-B, or verbal fluency (p = 0.29) as measured by the COWAT.

Conclusions

Significant improvement was found in verbal memory (total learning). However, it is not possible to distinguish whether the improvement was a benefit of the intervention or resulted from practice effects associated with the repeated measures occurring 12 weeks from baseline. Additionally, any assumptions regarding effectiveness of the intervention would need to be supported by a larger sample with an appropriate comparison control group.

Limitations

  • The sample was small, with less than 30 participants.
  • The lack of a comparison control group or randomization limited the generalizability of results and the feasibility of the intervention.

Nursing Implications

Although neurocognitive training has been suggested as a potential intervention for cognitive impairment, further studies are needed (including feasibility). Effectiveness of this intervention cannot be established based on this pilot study.

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Hashemi, A., Bahrololoumi, Z., Khaksar, Y., Saffarzadeh, N., Neamatzade, H., & Foroughi, E. (2015). Mouth-rinses for the prevention of chemotherapy induced oral mucositis in children: A systematic review. Iranian Journal of Pediatric Hematology and Oncology, 5, 106–112.

Purpose

STUDY PURPOSE: To evaluate studies on basic oral care interventions to update evidence-based practice guidelines for preventing oral mucositis in patients with cancer receiving chemotherapy
 
TYPE OF STUDY: Systematic review

Search Strategy

DATABASES USED: PubMed and Google Scholar
 
KEYWORDS: Cancer, chemotherapy, children, mouthwash, and mucositis
 
INCLUSION CRITERIA: All papers were published between 2000 and December 2014 and used the terms mucositis, chemotherapy, mouth rinses, oral care, oral care protocol, dental care, dental cleaning, oral decontamination, and oral hygiene. Both research and clinical work were included.
 
EXCLUSION CRITERIA: Review articles, clinical case reports, literature reviews, and other nonresearch articles were excluded. Articles not written in English also were excluded. 

Literature Evaluated

TOTAL REFERENCES RETRIEVED: 151
 
EVALUATION METHOD AND COMMENTS ON LITERATURE USED: No evaluation method was identified.

Sample Characteristics

  • FINAL NUMBER STUDIES INCLUDED = 30
  • TOTAL PATIENTS INCLUDED IN REVIEW = Not reported
  • KEY SAMPLE CHARACTERISTICS: Chlorhexidine, benzydamine, sodium bicarbonate, granulocyte macrophage colony-stimulating factor, iseganan, sucralfate, and normal saline were reviewed. No sample characteristics were reported.

Phase of Care and Clinical Applications

PHASE OF CARE: Active antitumor treatment
 
APPLICATIONS: Pediatrics and palliative care

Results

None of the mouth rinses were definitely effective in preventing chemotherapy-induced oral mucositis in children. Normal saline had a preventive effect in patients receiving chemotherapy, radiotherapy, and hematopoietic stem cell transplantation, but other studies have shown less efficacy than chlorhexidine or honey with saline. Benzydamine was less effective than chlorhexidine.

Conclusions

There was limited evidence for agents to prevent or manage oral mucositis in children.

Limitations

  • Few studies for any single agent used
  • Few data bases used  
  • Limited sample information provided  
  • No quality of research evaluation

Nursing Implications

Mouth rinses are an important component to oral care in the prevention of mucositis in pediatric patients receiving chemotherapy. Nurses need to continue research to develop evidence-based practice guidelines for this debilitating side effect of chemotherapy.

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Hart, S.L., Hoyt, M.A., Diefenbach, M., Anderson, D.R., Kilbourn, K.M., Craft, L.L., . . . Stanton, A.L. (2012). Meta-analysis of efficacy of interventions for elevated depressive symptoms in adults diagnosed with cancer. Journal of the National Cancer Institute, 104, 990–1004.

Purpose

To evaluate the effectiveness of psychotherapeutic and pharmacologic therapy, in depressed patients with cancer, by means of a meta-analysis and systematic review

Search Strategy

  • Researchers consulted the MEDLINE,® CINAHL®, EMBASE, PsycInfo, and Cochrane Collaboration databases. 7,700 references were retrieved.
  • Vocabulary terms appropriate to each database were used and are available as a separate file online.
  • Inclusion criteria consisted of the following characteristics: Patients were older than 17 years; had a cancer diagnosis at the time of the study; had symptoms of depression that had been measured; were randomized to study groups, to compare the intervention to any control condition; and had elevated symptoms of depression as defined by the authors.
  • The study was excluded if eligibility did not include elevated symptoms of depression.

Literature Evaluated

Researchers used the PEDro scale to evaluate study quality.

Sample Characteristics

  • 10 studies were included. One was eliminated from the meta-analysis because it was an outlier in the calculated effect size.
  • 6 psychotherapy trials involved a total of 1,273 patients. 4 pharmacologic trials included 362 patients.
  • Most participants were women, and their mean age was 51.

Phase of Care and Clinical Applications

Multiple phases of care

Results

Across all included trials, Hedges's g = 0.43 (95% CI, 0.48–1.54, p < 0.001) in favor of the intervention. Analysis of effect size at various follow-up periods showed that effect declined over time. Hedges's g effect size at 24 months poststudy entry was 0.19 and was not statistically significant. Follow-up at 18 months still showed a significant effect (g = 0.37, p < 0.001). Overall effect of pharmacologic interventions was g = 0.44 (p < 0.001); of cognitive behavioral therapy, g = 0.83 (p < 0.001); and of problem-solving therapy, g = 0.33 (p < 0.001).

Conclusions

For patients with cancer who had elevated symptoms of depression, psychotherapeutic and pharmacologic interventions were at least moderately effective in reducing symptoms of depression; however, efficacy may decline over time. Comparison of approaches showed that cognitive behavioral therapy had a substantially larger effect than did problem-solving therapy or medications.

Limitations

Although the heterogeneity in analysis was not high, samples did vary substantially in terms of cancer stage, time elapsed since diagnosis, ethnicity, gender, and sample size.

Nursing Implications

Antidepressants, problem-solving therapy, and cognitive behavioral therapy were effective in reducing symptoms of depression in patients with cancer who had elevated symptoms of depression. Assessment of the symptoms of depression can identify patients who can benefit from these treatments. Since medication, problem-solving therapy, and cognitive behavioral therapy were efficacious, treatment selection should be based on each patient's characteristics and preferences. It appears that efficacy may diminish over time, pointing to the need for long-term follow-up and management of depression in patients such as those who met the research criteria.

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Harris, S.R., Schmitz, K.H., Campbell, K.L., & McNeely, M.L. (2012). Clinical practice guidelines for breast cancer rehabilitation: Syntheses of guideline recommendations and qualitative appraisals. Cancer, 118(8 Suppl.), 2312–2324.

Purpose & Patient Population

To identify and review clinical practice guidelines (CPGs) related to the assessment and management of physical impairment outcomes of breast cancer and the interventions used to treat the disease. The patient population was patients with breast cancer. 

Type of Resource/Evidence-Based Process

Relevant health science databases were searched to identify evidence-based CPGs. The CPGs were evaluated using the AGREE II Instrument. The recommendations for updating current guidelines and for future guidelines were developed. Nineteen guidelines were included. Databases used were MEDLINE®, Google, Google Scholar, Physiotherapy Evidence Database (PEDro), Grey Matters and Intuit, CINAHL®, and Embase (OvidSP). Keywords were breast cancer, rehabilitation, and guidelines. CPGs were included if they focused on breast cancer-related upper-extremity physical impairments, upper-extremity or breast lymphedema, pain, fatigue, chemotherapy-induced peripheral neuropathy (CIPN), cardiotoxicity, or bone health. CPGs also had to be evidence-based recommendations related to weight management in breast cancer, published between 2001–2011 in a peer-reviewed journals or endorsed by a national or multinational government agency or health professional provider group, and available in English. CDPs were excluded if they pertained specifically to metastatic breast cancer. 

 

Phase of Care and Clinical Applications

  • Late effects
  • Survivorship

Results Provided in the Reference

Volume measurements using an opto-electric volumeter (perometer) and bioimpedance spectroscopy are recommended to be used in place of arm circumference measures. The use of compression garments is recommended in the management of lymphedema, but only limited evidence support compression bandaging with manual lymph drainage based on the reviewed guidelines.

Guidelines & Recommendations

High-quality evidence is insufficient to make clinical recommendations in the form of guidelines. There is an urgent need for updating the guidelines on lymphedema. Recommendations include physical therapy beginning the first day after surgery and active stretching exercises after removal of drains. Progressive resistive exercises with light weights within four to six weeks after surgery is also recommended. There is insufficient evidence regarding use of laser treatment and electrical stimulation, and there are published precautions for their use in people with neoplasms. Compression garments and bandaging and complete decongestive therapy are currently recommended.

Limitations

The AGREE II Instrument fails to assess the quality of evidence supporting the guideline’s recommendations.

Nursing Implications

The findings from this review have highlighted the importance of conducting more rigorously designed studies related to lymphedema assessment ,measurement, and management. Nurse scientists can play a key role in this needed area.

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Harris, A.C., & Jackson, J.M. (1977). Lactulose in vincristine-induced constipation. Medical Journal of Australia, 2, 573–574.

Study Purpose

To measure the efficacy of lactulose as a treatment for vincristine-induced intractable constipation or for the prevention of vincristine-associated constipation in patients with cancer.

Intervention Characteristics/Basic Study Process

Patients received lactulose 20 ml BID to 25 ml TID.

Sample Characteristics

  • The study reported on a sample of eight patients with lymphoma or leukemia.
  • Patients were aged 22 to 67 years.
  • Six patients (five women and one man) had protracted problems with constipation.
  • Two men received prophylactic treatment with lactulose immediately after vincristine therapy was initiated.

Setting

  • Inpatient
  • Royal Perth Hospital in Western Australia

Study Design

This was a descriptive study.

Measurement Instruments/Methods

Time-to-first bowel movement after vincristine treatment and initiation of lactulose therapy.

Results

All patients obtained relief of constipation within two days of initiating lactulose.

Limitations

  • The sample size was small.
  • Patients were not randomized.
  • Side effects and duration of use were not reported.
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Hardy, J., Randall, C., Pinkerton, E., Flatley, C., Gibbons, K., & Allan, S. (2016). A randomised, double-blind controlled trial of intranasal midazolam for the palliation of dyspnoea in patients with life-limiting disease. Supportive Care in Cancer, 24, 3069–3076. 

Study Purpose

To investigate the effect of a short-acting intranasal benzodiazepine on dyspnea, which is extremely common in those with life-limiting disease and negatively impacts quality of life (QOL)

Intervention Characteristics/Basic Study Process

Participants were given six identical bottles of nasal spray, three of which contained a placebo and three of which contained midazolam (benzodiazepine being studied) with the concentration of 0.5 mg per spray. The bottles were numbered one through six  in random sequence. Patients were instructed to inhale a total of three times on each occasion of use with the total dose of active drug delivered being 1.5 mg. The participants were asked to use bottle number 1 on the first day, number 2 on the second day, and so on, using no single nasal spray for more than 24 hours. The dosages were not to be delivered more frequently than every four hours, and if participants did not experience dyspnea on a certain day, they were not required to use a nasal spray that day. The participants were formally assessed by investigators at baseline, day 7, and day 14. The participants were also contacted by phone throughout the study on specific days to ensure compliance. The participants formally scored the first dose administered each day, and at the end of each study day, participants documented how many times they used the nasal spray and if there was any benefit using a variety of tools and surveys.

Sample Characteristics

  • N = 62
  • MEDIAN AGE = 70 years
  • AGE RANGE = 62–78 years
  • MALES: 48%, FEMALES: 52%
  • CURRENT TREATMENT: Not applicable. Patients were instructed to continue baseline medications and treatment of underlying condition, and no further information on this matter was collected.
  • KEY DISEASE CHARACTERISTICS: Participants were from two different countries—participants in New Zealand had a greater proportion of participants with cancer, and participants in Austrailia had a larger proportion of participants with respiratory diseases. 
  • OTHER KEY CHARACTERISTICS: All participants had dyspnea related to either a life-limiting disease or the treatment of the disease with the average score being > 3/10 on a scale of 1–10 with 10 being the worst breathlessness. All participants had an adequate performance status and were able to operate the nasal spray independently. Study participants were in or outpatients recruited across four sites in Australia and New Zealand. Any participants receiving sustained-release opioids were to continue to take these medications throughout the study period and any of those on dependent supplemental oxygen were also instructed to continue at the same flow rate for the duration of the study.

Setting

  • SITE: Multi-site
  • SETTING TYPE: Blend of inpatients and outpatients
  • LOCATION: The participants were recruited from an oncology/palliative care department in a hospital in Australia and from three palliative care services in New Zealand.

Phase of Care and Clinical Applications

  • PHASE OF CARE: Symptom management, palliation, end of life
  • APPLICATIONS: Palliative care

Study Design

  • Randomized, double-blind, placebo-controlled crossover design with participants taking both placebo or the trial medication at various times

Measurement Instruments/Methods

The Covi Anxiety Scale (CAS) and the Cancer Dyspnea Scale (CDS) were completed by clinicians and examined verbal reports, patient behaviors, and somatic symptoms of anxiety. Participants documented how many times they had used the nasal spray in 24 hours and if they found any benefit in a daily log. Participants rated dyspnea, anxiety, and drowsiness on an 11-point numerical rating scale (NRS).

Results

No significant benefit of the intranasal midazolam on anxiety scores was noted. No difference at any time point of investigation existed between the midazolam and the control group, and no difference in the dyspnea scores or positive change in dyspnea existed between the control bottles of nasal spray and the midazolam when looking closer into age, gender, baseline anxiety, depression, and disease. The greatest benefit was seen at 30 minutes after the use of both the control spray and the midazolam, with no difference between the two groups. When questioned about adverse events, participants revealed that side effects worse than they were at baseline were low grade and most likely from the use of the nasal spray, with the most common being nasal cavity irritation and sinus reactions.

Conclusions

The study failed to demonstrate a meaningful benefit of intranasal midazolam on dyspnea or anxiety. Though the nasal cavity is thought to be a good way to deliver the effects of medications quickly, intranasal midazolam did not effectively relieve the participants’ dyspnea.

Limitations

  • Small sample (< 100)
  • Baseline sample/group differences of import: The sample contained patients with a variety of diseases, with the majority having cancer or respiratory diseases. Further studies should target a single disease type because of the differences in characteristics and presentations of dyspnea.
  • The sample size was limited because participants had to be able to operate the nasal spray device and have an adequate performance status; this is unfortunate since many terminally ill patients needed to be excluded from the study. 
  • The study participants had low anxiety scores at baseline, which may have affected the study results of the intervention in question, and measures may have been subject to floor effects.
  • Many of the older adult patients in the study found the nasal sprays difficult to use, and several of the bottles were faulty and did not delivery a reliable spray, which may have resulted in a less-than-planned dose delivered.

Nursing Implications

The study findings demonstrated that intranasal midazolam was not effective in relieving dyspnea. This study magnified the importance of finding ways to better control dyspnea in terminally ill patients and the impact on quality of life if not done. The effectiveness of benzodiazepines on dyspnea needs further investigation, and nurses should continue with the administration of low-dose opioids to treat patient dyspnea, as this remains the evidence-based medication of choice.

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Hardy, J. R., Carmont, S. A., O'Shea, A., Vora, R., Schluter, P., Nikles, C. J., . . . Mitchell, G. K. (2010). Pilot study to determine the optimal dose of methylphenidate for an n-of-1 trial for fatigue in patients with cancer. Journal of Palliative Medicine, 13, 1193–1197.

Study Purpose

To identify a dose of methylphenidate to test formally in a subsequent N-of-one trial of fatigue.

Intervention Characteristics/Basic Study Process

Patients with fatigue 4/10 or more at baseline received titrated doses of methylphenidate beginning at 5 mg/day up to 15 mg twice daily (BID) at three-day intervals.

Sample Characteristics

  • In total, nine patients (20% male, 80% female) were included.   
  • Age ranged from 56 to 86 years.
  • Patients had breast, ovarian, and other cancers.
  • No demographic information was available.

Setting

  • Single site  
  • Outpatient  
  • Queensland, Australia

Phase of Care and Clinical Applications

Patients were undergoing the transition phase on “stable treatment,” not on chemotherapy.

Study Design

The study was a prospective trial.

Measurement Instruments/Methods

  • Wu Cancer Fatigue Scale
  • Functional Assessment of Cancer Treatment–Fatigue (FACT-F)
  • Edinburgh Depression Scale
  • Daily toxicity and symptom diaries
  • Karnofsky Performance Status (KPS)
  • Global Impression of Change
     

Results

  • Nine patients began taking 5 mg of methylphenidate daily; seven patients increased to 5 mg BID; six patients increased to 10 mg BID; five patients received the maximum dose of 15 mg BID, and three patients were unwilling to increase the dose to the maximum because they were satisfied with the response at a lower dose.
  • No statistical information was provided; overall, fatigue and depression improved until day 9 of the study (5 mg BID dose of methylphenidate) after which the rate of improvement was slower.
  • There was little correlation between performance status and maximum tolerated dose.
  • Although toxicity was difficult to measure due to small numbers and side effects at baseline, no patient discontinued due to toxicity.
     

Conclusions

Methylphenidate 5 mg BID was chosen as the ideal dose to test against placebo.

Limitations

  • The study had a small sample size, with less than 100 patients.
  • The study lacked a control group.
  • There was significant attrition.
  • There was one treatment site in one country.
  • The study lacked racial/ethnic diversity.
  • The aim of the study was not to determine if methylphenidate was effective in managing fatigue but rather to find an ideal dose to use for a future randomized, controlled trial.

Nursing Implications

Nurses in research can use a 5-mg BID dose of methylphenidate to test against placebo.

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Hardy, J., Quinn, S., Fazekas, B., Plummer, J., Eckermann, S., Agar, M., … Currow, D.C. (2012). Randomized, double-blind, placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain. Journal of Clinical Oncology, 30, 3611–3617.

Study Purpose

To determine whether ketamine, delivered subcutaneously with dose titration over five days, has greater clinical benefit than placebo when used in conjunction with opioids and standard adjuvant therapy in the management of cancer pain

Intervention Characteristics/Basic Study Process

  • Patients received either a continuous subcutaneous infusion of ketamine on a five-day, escalating-dose schedule (100 mg, 300 mg, and 500 mg over 24 hours) or placebo (normal saline) given over five days. 
  • Patients were assessed every 24 hours for pain (least, average or best)  using the Brief Pain Inventory (BPI). No dose change occurred if 80% of ketamine was delivered, pain improvement was greater than 2, and no more than four breakthrough pain doses were needed.
  • Dose reductions occurred if toxicity was unacceptable. The drug was discontinued at 500 mg if no response to pain occurred or toxicity became intolerable.

Sample Characteristics

  • The study reported on 149 patients with a mean age of 63.
  • The sample was 55% male and 45% female.
  • Patients had refractory pain secondary to cancer or its treatment.
  • For 48 hours prior to beginning the study, participants could have no change in baseline opioid dosing. 
  • Patients were excluded if they had received ketamine within the past six months, had radiotherapy to a site of pain within two weeks, or received any other procedure that may affect pain.

Setting

This was a multisite, inpatient study conducted in Australia.

Phase of Care and Clinical Applications

  • Patients were in the late effects and survivorship phase of care.
  • This study has clinical applicability for palliative care.

Study Design

This was a randomized, double-blinded, placebo-control study.

Measurement Instruments/Methods

  • The Common Terminology Criteria for Adverse Events v 3.0, Clinician-Administered Dissociative States Scale, and BPI were used.
  • A positive response was defined as a clinically relevant improvement in pain.

Results

  • Findings showed no significant differences between study groups. Pain declined somewhat over time in both groups. The decline in worst pain ratings was lower in the ketamine group (p = 0.034). No differences were found between groups in use of rescue medication.
  • More patients withdrew from the ketamine arm. The incidence of adverse events was higher with ketamine.
  • The most common events were light headedness, hypoxia, and somnolence. Psychotoxicity significantly increased each day, and, by day 3, the odds of psychotoxicity development were significantly higher in the ketamine group (OR = 2.53; 95% CI [1.11, 5.78]; p = 0.027).

Conclusions

Ketamine was only associated with improvement in worse pain compared to placebo, and it was associated with more adverse events and psychotoxicity.

Limitations

  • A risk of bias exists because of the sample characteristics.
  • The findings are not generalizable.
  • Entry inclusion criteria included an average pain score of 3 or more on BPI. This may not reflect clinically acceptable pain of 3 or 4. 
  • Concerns exist regarding the aggressive dosing and short duration of the study. The short duration of the study over five days with rapid escalation of ketamine may have been overly aggressive. A question exists around whether more careful titration of ketamine may have altered results.

Nursing Implications

Ketamine as an adjunct to opioids to manage chronic refractory cancer pain only appeared to affect worst pain rating and may cause adverse effects and increase psychotoxicity. Incidence of adverse events with ketamine infusion adjunctively with opioids in the management of refractory pain should be reevaluated when considering the patient population of advanced cancer.

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