RESOURCE TYPE: Expert opinion  

PROCESS OF DEVELOPMENT: Clinical review

This article provides an overview of the mechanisms of action of immune checkpoint blockade and clinical effects in metastatic melanoma. The focus is the adverse effect profile and therapeutic management. The side effect profile includes a review of a meta-analysis of 1,265 patients from 22 clinical trials who received ipilimumab. Eighty-two to ninety-five percent of patients experienced treatment-related side effects. Incidence tables are provided as well as a checklist for important questions during patient visits, blood test recommendations, and organ-specific side effects. Diarrhea and colitis are described with a table of trade, treatment, and follow-up. Other organ-specific side effects are also reviewed. Recommendations for management algorithms are discussed.

Comprehensive clinical studies have shown a major benefit of anti-CTLA-4 antibody ipilimumab and two anti-PD-1 antibodies nivolumab and pembrolizumab in various tumors, including melanoma. These agents enhance an autoimmune phenomenon that affects various organs. Persistent diarrhea and colitis are evidenced early in treatment and can be serious adverse effects. The clinical significance is the debilitating effect they have on patients, with electrolyte disturbances and protracted weight loss. Intestinal perforation is a serious risk. Grade 1–2 diarrhea is treated with loperamide and electrolyte replacement. An endoscopy should be considered with persistent low-grade diarrhea because it diagnoses the true extent of the colitis. For grade 3–4 diarrhea/colitis, immunotherapy should be discontinued and high-dose corticosteroids initiated. Symptoms improve markedly with this regimen. Treatment with infliximab (5 mg/kg) is used in rare cases in which steroids do not induce a response. Colitis is associated with ocular inflammation, and observing for this side effect is imperative. Comprehensive study data identify that the timely and consistent use of corticosteroids allows for control and regression of symptoms in the majority of cases.

This is an overview of a complex multidisciplinary side-effect management concern with new checkpoint inhibitors. Further study would be necessary for a nurse to acquire in-depth knowledge for patient care.

Immuno-oncology is becoming a mainstay of pharmacological cancer treatment. Knowledge of side effects of these checkpoint inhibitors, especially diarrhea and colitis, is essential to their prevention, treatment, and management. Early recognition and intervention can reduce sequelae for patients.

RESOURCE TYPE: Expert opinion

PHASE OF CARE: Active antitumor treatment

N/A

Expert opinion level information

Currently, limited research evidence regarding interventions for the prevention and management of various side effects associated with immunotherapies exists. Corticosteroids are suggested to treat most side effects.

To determine if implementing two interventions would cause a reduction in catheter-associated urinary tract infections (CAUTIs) in an inpatient surgical oncology unit (The first intervention was designed to decrease the use of Foley catheters, and the second intervention was designed to initiate early removal while preventing reinsertion of the Foley catheter.)

The first intervention was the development of a hospital-wide guideline outlining the indications for Foley catheter use. There were six defined reasons for the use of a Foley catheter in a patient. If the patient did not meet one of these criteria, then Foley catheter use was not recommended. The second intervention included two measures. The first was aimed at the early removal of the catheter by designing a daily electronic query sent to the attending physician regarding continuing use of the Foley catheter, and the second was direct personal contact with the primary medical team to determine the medical necessity of continued Foley catheter use. They also focused on the prevention of catheter reinsertion by following a developed algorithm for the healthcare team.

• N = 2,843
• KEY DISEASE CHARACTERISTICS: Cancer of the liver, pancreas, colon, head and neck, urologic, or gynecologic organs requiring inpatient surgery
• OTHER KEY SAMPLE CHARACTERISTICS: CAUTIs were defined as the presence of symptomatic urinary tract infection (UTI) or asymptomatic bacteremic UTI in patients with an indwelling catheter in place for greater than 48 hours.

• SITE: Single site    
• SETTING TYPE: Inpatient    
• LOCATION: Vidant Medical Center, Greenville, NC

• PHASE OF CARE: Active antitumor treatment

This study design was a pre/post design with preintervention data obtained in a retrospective manner followed by the authors obtaining postintervention data.

• The authors used total device days for Foley catheters, utilization rate, total number of CAUTI’s, and hand hygiene compliance pre- and postintervention as measurement instruments to determine the effectiveness of their interventions.

There was a significant reduction in the use of Foley catheters after the interventions were put in place (P < 0.0001). There also was a significant reduction in CAUTI rates for patients who did require a Foley catheter after interventions were put into place, from 4.6 to 0 (P = 0.03). For patients who required a Foley catheter and had a diagnosed CAUTI during the postintervention time period, none of the Foley catheters were reinserted. The preintervention group had four patients with positive CAUTIs who had a Foley reinserted.

Even though the study was limited to one inpatient surgical oncology unit, the findings support other similar studies of best practice indicating use of Foley catheter insertion criteria as well as algorithm guidelines for care after catheter removal. Because infections can be detrimental in the oncology population, healthcare teams working with these patients should explore the literature surrounding the prevention of CAUTIs and ways of implementing best practices.

• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Other limitations/explanation: Retrospective study; self-reporting of hand hygiene compliance; single-unit study

Oncology nurses need to be diligent with hand hygiene, not only among themselves but with other members of the healthcare team. They also need to adhere to Foley catheter bundles, including the daily verification of continuing need for the catheter, the use of catheter securement devices, keeping tubing below the level of the bladder, keeping the bag off of the floor, and providing perineal care at least twice per day. If the institution does not have a catheter bundle, nurses need to lead the initiative to implement one. This study demonstrated successful institutional approaches for protocol implementation and ongoing auditing and interventions with care providers.

To determine the influence of dignity therapy on depression and anxiety in palliative care unit inpatients diagnosed with a terminal illness and experiencing high levels of distress

Dignity therapy (DT) is brief psychotherapy aimed at decreasing the loss of dignity for patients with a life-limiting illness. This nonblinded, phase II, randomized, controlled trial involved a control group receiving standard palliative care (SPC) and an intervention group receiving SPC plus DT. Participants received a baseline assessment of anxiety and depression, an explanation of DT, and a copy of the DT questions at T1 of the study. They were then randomized into two groups. Within two to three days, the intervention group received audio recorded 30–60-minute DT sessions that were transcribed verbatim within the next two to three days and transformed into a written narrative. The DT therapist read the narrative to the patient and received corrections, returning the final narrative to the patient. Follow-up measurements of depression and anxiety in both groups were conducted on days 4 (T2), 15 (T3), and 30 (T4). 

• N = 80  
• AGE RANGE = 28–90 years
• MALES: 46.25%, FEMALES: 53.75%
• KEY DISEASE CHARACTERISTICS: Life-threatening terminal illness (cancer = 92.55%; noncancer = 7.5%) with a prognosis of six months or fewer
• OTHER KEY SAMPLE CHARACTERISTICS: 95% Caucasian; 5% African American; two patients had Lou Gehrig disease; one patient had trigeminal neuralgia; inclusion criteria were no evidence of dementia or delirium and a Mini Mental State score of 20 or more; read and spoke Portuguese; written informed consent; available for four to five research encounters

• SITE: Single site    
• SETTING TYPE: Inpatient  
• LOCATION: S. Bento Menni’s 10-bed tertiary inpatient palliative medicine unit in Lisbon; recruitment took place over 36 months (May 2010 through May 2013)

• PHASE OF CARE: End-of-life care
• APPLICATIONS: Palliative care 

This nonblinded, phase II, randomized, controlled trial involved a control group receiving SPC and an intervention group receiving SPC plus DT.

• Hospital Anxiety and Depression Scale (HADS): Symptoms of depression and anxiety were measured with HADS at T1, T2, T3, and T4 of follow-up. Scores for anxiety and depression subscales also were reported separately.

Terminally ill patients experience high levels of depression and anxiety. DT was suggested as a feasible offering to people with increased or severe psychological distress. Participants who received DT experienced depression and anxiety score reductions, suggesting psychological benefits at least to the 30-day measurement period.

• Small sample (< 100)
• Risk of bias (no blinding)
• Findings not generalizable
• Intervention expensive, impractical, or training needs
• Other limitations/explanation: Relatively small sample size (N < 100) leaves findings nongeneralizable; specific training in the delivery of DT required

DT can be offered to patients with terminal conditions near the end of life (six-month prognosis). DT implementation requires careful training in the practice. Additional randomized, controlled trials testing DT against other psychological interventions in other populations of severely ill or terminally ill patients are needed.

• FINAL NUMBER STUDIES INCLUDED = 9 
• TOTAL PATIENTS INCLUDED IN REVIEW = 890 patients, 441 assigned to intervention groups and 449 assigned to control groups
• KEY SAMPLE CHARACTERISTICS: The mean age was 59 years (20–91), and 65.6% of patients were women. Cancer diagnoses included multiple myeloma, breast, metastatic breast, colorectal, ovarian, endometrial, and gastrointestinal tract cancers. Chemotherapy included (a) PLD/vincristine/capecitabine; (b) PLD/paclitaxel; (c) PLD 4; (d) capecitabine alone or in combination with cyclophosphamide; (e) capecitabine alone or in combination with cisplatin, or cisplatin with docetaxel; (f) capecitabine; (g) 5-fluorouracil; or (h) capecitabine alone or in combination with cisplatin, or cisplatin and docetaxel.

PHASE OF CARE: Active treatment

Eight studies (two retrospective, two prospective comparative trials, four RCTs) for preventive efficacy and three studies (one RCT and two non-RCTs) for treatment efficacy. Random-effects meta-analysis did not reveal any significant associations between ppx pyridoxine supplementation and HFS development (RR = 0.95%, 95% CI [0.87, 1.05]) or any significant preventive efficacy against HFS in subgroup meta-analyses of study design, chemotherapeutic agents, pyridoxine dose, HFS severity, publication year, or observation period. However, pyridoxine did show significant efficacy in treating HFS (RR = 1.75, 95% CI [1.09, 2.8]) but did not show efficacy in the only RCT (RR = 1.12, 95% CI [0.58, 2.14]).

No evidence to support the use of pyridoxine supplements to prevent HFS during chemotherapy exists.

• Only four RCTs
• Chemotherapeutic agents included PLD or capecitabine

Further nursing research on the alternative uses of topical and oral therapies for HFS is warranted given that no evidence of clinical benefit was revealed.

The objective of this systematic review was to review published data on the efficacy and safety of tunneled indwelling pleural catheters (TIPCs).

Databases searched were MEDLINE, EMBASE, and ISI Web of Science through 2009. A manual search was conducted of reference lists for relevant additional studies.

Search keywords were malignant pleural effusion (MPE), tunneled indwelling pleural catheter (TIPC), and palliative care.

Studies were included if they reported on

• Adult patients
• Patients with MPE
• Patients treated with TIPCs.

Studies with and without control were included.

Studies were excluded if they reported on non-malignant effusions, empyema, chylothoras, long-bore chest tubes, or non-tunneled catheters. Studies in which all patients underwent thorascopy, video-assisted thorascopic surgery (VATS), or pleurodesis were excluded. Studies were excluded if they weren't published in English. Studies without primary data also were excluded.

• A total of 1,011 references were retrieved, which generated 25 eligible reports.
• Data were abstracted independently by two authors, and discrepancies were resolved by discussion and consultation with a third author.
• Abstractors were not blinded to any study details.
• The GRADES system was used for evaluation of quality.
• Case studies and one randomized controlled trial had low-level evidence.

This systematic review pertains to the dyspnea Putting Evidence Into Practice topic in that one outcome of the review evaluated “symptomatic improvement” with emphasis, although not exclusive focus, on dyspnea.
 

• The final number of studies included was 19.
• The total sample size was 1,370 patients.
• The sample range across studies was 8–263.
• The average age was 63 years.
• Of the sample, 50.5% were women.
• Most patients had recurrent MPE with failed thoracentesis or other treatment.
• The majority of the patients had a lung cancer diagnosis, but some also had breast cancer, mesothelioma, and a few other cancers.

• Patients were undergoing end-of-life care.
• The study has clinical applicability for palliative care.

Symptom relief was variably defined in the studies. Three studies reported symptom improvement without further delineation. One study rated dyspnea improvement on a three-point scale. The remaining studies reported symptomatic relief as “relief of dyspnea” or “improvement in respiratory performance,” “increased exercise tolerance,” “ improvement of pain,” and “catheter was useful.” When combined, 628 of the 657 patients (95.6%) experienced some degree of improvement in their symptoms, although the magnitude of improvement cannot be determined. Serious complications were rare. The most common complications were cellulitis (32 of 935, 3.4%) and obstruction or clogging (33 of 895, 3.7%) or unspecified malfunction of the catheter (11 of 121, 9.1%). The quality of the studies was low, as evaluated by the GRADES system.

Authors suggest that TIPC may improve symptoms for patients with MPE.

Based on the low-quality evidence in the form of the case studies, evidence is insufficient to demonstrate the effectiveness of TIPCs. 

More rigorous studies need to be conducted to establish evidence with respect to dyspnea.

Studies reviewed did not ensure that patients studied had depression or anxiety, so validity of examining impact of Reiki intervention on these problems is questionable. Two of the three studies had high risk of bias. No studies showed a statistically significant benefit.

There is insufficient evidence to evaluate efficacy of Reiki for anxiety and depression.

• Very few studies
• Poor quality studies

The evidence regarding effects of Reiki for anxiety or depression is insufficient to draw any conclusions. If Reiki is to be seen as a serious option for treatment, well-designed research to investigate effects is needed.

• FINAL NUMBER STUDIES INCLUDED = 3
• TOTAL PATIENTS INCLUDED IN REVIEW = 391
• SAMPLE RANGE ACROSS STUDIES: 849–1,840 patients
• KEY SAMPLE CHARACTERISTICS: Two studies included immunosuppressed men and women with cancer and the third investigated immunosuppressed men and women with cancer who had undergone allogeneic hematopoietic cell transplantations (HCTs).

PHASE OF CARE: Active antitumor treatment

A trial comparing voriconazole to liposomal amphotericin B as an empirical treatment for suspected fungal infection in neutropenic patients with cancer in which 6.8% of the patients died showed a significant benefit of using liposomal amphotericin B over voriconazole. No benefits were found between antifungal agents in the other two trials evaluated.

For the empirical treatment of patients with cancer who are immunosuppressed, liposomal amphotericin B is significantly more effective than voriconazole. Voriconazole and fluconazole did not have different outcomes in patients undergoing allogeneic HCT who were given either of these antifungal agents prophylactically. Treatment of aspergillosis comparing voriconazole with amphotericin B was not investigated.

Overall, there were so few trials comparing these antifungal agents (though large sample sizes) that except for one finding, results were inconclusive. These trials also could not be pooled for analysis due to their heterogeneity in study design.

For treatment of suspected fungal infections (neutropenic fever without overt fungal infection), liposomal amphotericin B is recommended. Careful evaluation for side effects of visual disturbances, dyspnea, and hypokalemia is critical.

To provide a consensus statement derived from published articles as well as expert opinion about antiemetic therapy in children younger than 18 years

This resource is a guideline, developed by the Multinational Association of Supportive Care in Cancer (MASCC) and European Society of Medical Oncology (ESMO).

A panel of 23 oncology professionals determined the level of evidence and confidence according to EMSO and MASCC criteria. Between 2004 and June 2009, eight articles were published regarding 5-HT₃ receptor antagonists (RAs) in pediatric populations (two regarding safety issues, four dose-finding or -optimizing studies, and two comparative studies), four articles reported on the NK1 RA aprepitant (one randomized study, two case reports, and one study on the liquid formulation of aprepitant), and two miscellaneous studies looked at the impact of an antiemetic pump and the value of metopimazine when added to ondansetron. Recommendations were classified using the MASCC level of scientific confidence and consensus.

Pertinent information from the published literature from 2004 to June 2009 was retrieved and reviewed for the creation of this guideline.  

Database searched was Medline.

Search keywords were antiemetics, chemotherapy-induced emesis, children, neoplasms, nausea, vomiting, serotonin antagonists, neurokinin 1 receptor antagonists, phenothiazines, butyrophenones, cannabinoids, corticosteroids, and metoclopramide.

No inclusion criteria were identified.

Articles were excluded if they were review articles or addressed emesis not caused by chemotherapy.

• All patients were in active treatment.
• This guideline has application for pediatrics.

• No designated 5-HT₃ RA was recommended. (The MASCC level of confidence was moderate and level of consensus was high. The ESMO level of evidence was II and grade of recommendation was B.)
• No verifiable, high-level evidence-based consensus was possible on the dose of the individual 5-HT₃ RAs.
• Corticosteroids were found to be effective antiemetics for CINV, especially when combined with a 5-HT₃ RA. (The MASCC level of confidence was moderate and level of consensus was high. The ESMO level of evidence was II and grade of recommendation was B.) Safety issues when administering corticosteroids in children must strongly be considered.                                                                                                       
• No recommendations was made regarding ​neurokinin 1 (NK1) RAs, but they showed promising activity. The guideline panel recommended development of more well-designed, three-agent trials testing the addition of a NK1 RA to draw firm conclusions for a recommendation.                                                                       
• The guideline recommended that all pediatric patients receive antiemetic prophylaxis with a combination of a 5-HT₃ RA and dexamethasone for the acute phase of highly emetogenic chemotherapy. (The MASCC level of confidence was moderate and level of consensus was high. The ESMO level of evidence was III and grade of recommendation was B.)                                                                                                          
• For the acute phase of moderately emetogenic chemotherapy, all pediatric patients are recommended to receive antiemetic prophylaxis with a combination of a 5-HT₃ RA and dexamethasone. (The MASCC level of confidence was moderate and level of consensus was high. The ESMO level of evidence was II and grade of recommendation was B.)                                                                                                          
• For the acute phase of low and minimal emetogenic chemotherapy, not enough studies in children have been produced to make a recommendation.

Children receiving chemotherapy should receive a 5-HT₃ RA and dexamethasone for antiemetic prophylaxis both in highly emetogenic and moderately emetogenic chemotherapy. A significant lack of well-designed randomized studies exist to evaluate the problem of chemotherapy-induced emesis in children. Optimal dosing in children and management of delayed and anticipatory CINV in children is not yet clear. Investigation is needed regarding the potential role of NK1 RAs and the 5-HT₃ RAs palonosetron and transdermal granisetron for future consideration in pediatrics.

To determine the role of an neurokinin 1 (NK1) antagonist in multiple-day chemotherapy, in addition to standard of a 5-HT₃ receptor antagonists and dexamethasone

Oral aprepitant 125 mg was given 1 hour before chemotherapy on day 1 and 80 mg oral aprepitant was given daily during chemotherapy and for 2 days after completion of the treatment course. Patients also received 1 mg IV granisetron and 8 mg IV dexamethasone daily prior to chemotherapy. Use and choice of rescue medication was at the discretion of the physician.

• The study reported on 78 participants.
• Mean age was 40, with a range of 18–71 years.
• The sample was 18% female and 82% male.
• The most frequent diagnoses were germ cell cancer and sarcoma. Other diagnoses were myeloma, lymphoma, and thymus cancer.

The setting was a single site in Germany.

Patients were in active treatment.

The study design was a prospective trial.

• The National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 3.0 for toxicity assessment was used with nausea rated as yes or no.
• Complete response (CR) was defined as no nausea or vomiting and no use of rescue medication.

• 65.8% had CR in the acute phase.
• 68.4% had CR in the delayed phase.
• 57.9% had CR in the overall phase.
• Preexisting nausea (p < 0.05), pretreatment anxiety (p = 0.0001), and patients with brain metastases (p = 0.04) were associated with lower CR rates.
• No patients discontinued because of adverse events.
• Most common events were hiccups (7.7%), diarrhea, and constipation.

Aprepitant appears to be well-tolerated. CR rates were only slightly above those commonly seen with 5-HT₃ receptor antagonists and dexamethasone.

• No control comparison or blinding with associated risk of bias was used.
• Methods of nausea and vomiting measurement were not clearly stated.
• Use of rescue medications was not stated.
• Definition of nausea as a single yes or no measure is questionable.
• Timing of measures was not stated.

Further well-defined research to fully evaluate multiple drug chemotherapy-induced nausea and vomiting regimens is warranted.