To study the safety and efficacy of TJ-14 in preventing or treating chemotherapy-induced mucositis versus a placebo in patients with gastric cancer

Patients who identified a Common Terminology Criteria for Adverse Events (CTCAE version 4) grade 1 or greater mucositis were randomized on a one-to-one ratio and stratified according to age, chemotherapy regimen, institution, and previous treatment for oral mucositis. Participants received either TJ-14 or a placebo beginning with their next cycle of chemotherapy. The placebo was prepared to mimic the intervention. TJ-14 and the placebo were given three times per day. Patients were instructed to dissolve 2.5 g (total daily dose 7.5 g) of either TJ-14 or the placebo in 50 mL of regular drinking water and to rinse the oral cavity for 10 seconds. Treatment began on the first day of the protocol treatment, continued till the final day, and was administered as much as possible for one course of treatment. No other mouthwash prophylactic interventions for oral mucositis were allowed during the trial period. Assessments took place during the screening cycle from the beginning of the protocol treatment or the appearance of mucositis until all symptoms disappeared.

• N = 91
• AVERAGE AGE = 68 years
• MALES: 62.2% (TJ-14); 60.9% (placebo), FEMALES: 37.8% (TJ-14); 39.1% (placebo)
• KEY DISEASE CHARACTERISTICS: Patients with gastric cancer who developed an oral mucositis score > 1 on the CTCAE scale during the screening cycle of chemotherapy.
• OTHER KEY SAMPLE CHARACTERISTICS: None

• SITE: Multi-institutional facilities           
• SETTING TYPE: Cancer center
• LOCATION: Japan

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

Randomized, double-blinded, controlled, phase II trial

• The National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0
• Time to resolution of mucositis was defined by the authors as the time from the initiation of the protocol treatment or the first day of mucositis to the day when the patient was symptom-free.
• Patients self-reported the ability to eat solid foods.
• Physical examinations, laboratory evaluations, and the reporting of adverse events were used to evaluate safety.

In this study, 40% of patients in the intervention group and 41.3% of patients in the placebo group experienced ≥ grade 2 oral mucositis, and there was no difference between the groups (p = .588). In addition, there was no difference between the two groups concerning the duration of oral mucositis (p = .937).

This study did not demonstrate any beneficial effects of TJ-14 in reducing the incidence of chemotherapy-induced oral mucositis.

• Small sample (< 100)
• Other limitations/explanation: It is possible that dose reductions in chemotherapy affected the duration of the treatment instead of the standard treatment, which postpones chemotherapy because of mucositis.

No prophylactic or treatment-related benefits of TH-14 were evident in this study regardless of the grade of chemotherapy-induced oral mucositis. Nurses should consider other interventions for the prevention and treatment of oral mucositis.

Low-power laser therapy (LPLT) versus placebo

Only dentists knew the randomization.

Low level intensity laser: InGaAIP diode laser—660 nm, 46.7 mW

Predental care

Oral care: Extrasoft toothbrushes; dental paste with a peroxidase system after meals, and alcohol-free chlorhexidine solution until neutrophil recovery TID

Evaluations were performed daily by one dentist (not blinded) and three nurses (blinded).

Crossover allowed for control group patients who developed grade 4 oral mucositis.
 

The sample was comprised of 38 patients with HSCT.

Adults M =36.5/36.8

Women = 7/8
Men = 12/11

Autologous HSCT = 5/5

Allogenic HSCT = 14/14
 

Centro de Transplante de Medula Ossea

January 2004-May 2005

Randomized, placebo-controlled, quantity and prospective clinical trial

WHO scale

OMAS

VAS
 

All patients completed the study; none were lost to follow-up or excluded.

LPLT less intense oral mucositis
Grade 0 = 1, 63.2%, 12 of 19 versus 10.5%, 2 of 19 (p < 0.001)

6 LPLT, 31.5% WHO Grade 2

94.7% WHO 0–2

Control group was the opposite (data not provided) (p < 0.001).

Mucositis-free survival hazard ration grade 2, 3, and 4 was 0.41 (p = 0.002); the hazard ration grade for grade 3 and 4 was 0.07.

OMAS = 84.2% (16) patients receiving laser treatment stayed on a weighted average zone of 0–2.9 versus 26.3% (5) (p = 0.007).

Patients receiving laser treatment presented with small extension of ulcerous area (p = 0.003).

Control group showed mucositis earlier (D + 5) than laser group (D + 6) (p = 0.67, NS).

Longer duration 6 versus 9 (p = 0.13, NS)

Longer to heal (p = 0.15)
 

No differences in presence and intensity of pain

No differences in blood cultures

The level of agreement among evaluators was 81.7%.

Sample size

Implies difference when p value is not significant

Narrative frequently does not match p values.
 

To assess the efficacy of preventive low-laser therapy to reduce grade 3 and 4 oral mucositis (OM) in patients receiving chemoradiation

Both groups received cisplat 100 mg/m² for three cycles every three weeks, radiation 70.2 Gy (1.8 Gy per day five times per week), and the same oral hygiene. The intervention group received low-level laser therapy five times per week before every fraction of radiation. The energy and energy density were the same for each patient. A dentist applied the laser tip to the mucosa of the lips, the right and left buccal mucosa, the left and right lateral tongue border, the buccal floor, and the ventral tongue. The placebo group had the laser tip touched to the same sites, but there was no laser light.

• N = 94   
• AGE: 10–18 years
• MALES: Laser group: 89%, placebo: 85%; FEMALES: Laser group: 11%, placebo: 15%
• KEY DISEASE CHARACTERISTICS: Patients with squamous cell carcinoma of the head and neck
• OTHER KEY SAMPLE CHARACTERISTICS: Had to be ineligible for surgery, be able to tolerate chemo/radiation, have Eastern Cooperative Oncology Group status of 0 or 1, have had an intact oral mucosa at the start of the study

• SITE: Single site  
• SETTING TYPE: Outpatient   
• LOCATION: Brazilian National Cancer Institute in Rio de Janeiro

• PHASE OF CARE: Active antitumor treatment

• Prospective, randomized, double-blind, placebo-controlled, phase III trial

• World Health Organization Oral Mucositis Scale
• Oral Mucositis Assessment Scale
• Visual analog scale for pain
• The European Organization for Research and Treatment of Cancer QLQ-C30

A significant decrease was seen in the rate of grades 3 and 4 OM in the treatment group. Relative risk ratio (6.4% with laser versus 40.5% control) 0.158 (CI 95%). The treatment group reported better physical, emotional, fatigue, and pain scores and had less pain, fewer problems swallowing, and less trouble with social eating.

Low-level laser light therapy is effective in reducing grades 3 and 4 OM in patients with squamous cell carcinoma of the head and neck undergoing concurrent chemotherapy and radiation.

• Small sample (< 100)
• Findings not generalizable
• Intervention expensive, impractical, or training needs

Nurses who work in facilities with access to low-level laser light therapy should advocate for the use of it for their patients with head and neck cancer undergoing radiation and chemotherapy. There may be a role for nurses in learning to administer low-level laser light therapy.

Participants were randomly assigned to the intervention or control group. The intervention one was a closed, structured group that met weekly for 10 two-hour sessions. It included didactic material, experiential exercises, and homework assignments (practicing relaxation exercises) and focused on learning to cope better. The control group participants received a condensed version of the intervention during a five- to six-hour seminar; it provided information but lacked the therapeutic group environment and support. Participants were assessed initially, post-treatment, at three months, and at nine months. The study was advertised by letters and posters, and participants phoned for eligibility screening.

• N = 100
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Stage 0, I, or II breast cancer

• SITE: Multi-site
• LOCATION: Several hospitals and medical practices in Miami, FL

• Outcomes measured: Distress (mood disturbance, depressive symptoms, and thought intrusion and avoidance), perceptions of benefit from having breast cancer, and general optimism regarding the future
• Scales: Profile of Mood States (POMS), Center for Epidemiological Studies-Depression (CES-D), Impact of Events Scale (IES), Life Orientation Test-Revised (LOT-R), and a 17-item measure of perceived benefits

The intervention group showed reduced prevalence of moderate depression per the CES-D. The intervention also influenced two measures of positive well-being—increasing reports of experiencing benefit from having had breast cancer and increasing general optimism about the future.

An implication here is that it is important to collect information on positive experiences as well as negative. Responding to adversity presents an opportunity to experience growth and positive change.

Although this is a well-designed RCT, several flaws exist.

• The sample is made up of volunteers who were relatively educated, affluent, and motivated. Only 26% identified themselves as an ethnic minority.
• The participants had non-metastatic cancers and were free from physical and mental health comorbidities at the time of recruitment, so generalizability is constrained.
• The measure of benefit finding is new; more information is needed regarding its validity.
• Levels of distress reported in this sample were generally low.

• FINAL NUMBER STUDIES INCLUDED = 23
• TOTAL PATIENTS INCLUDED IN REVIEW = Not listed
• KEY SAMPLE CHARACTERISTICS: Pediatric patients receiving antiemetics for CINV

PHASE OF CARE: Active antitumor treatment
 
APPLICATIONS: Pediatrics

Based on published evidence, many pediatric patients may not be receiving appropriate antiemetic therapy. The patients who were most likely to not receive recommended antiemetic therapy were those receiving highly emetogenic chemotherapy, which put those patients at an increased risk for experiencing CINV.

This study took place in the United Kingdom, which may have different medication availability and prescription practices than other locations.

In the pediatric population, antiemetic prescription practices may not be in line with published evidence. Current best-practice sources should be consulted to ensure pediatric patients are adequately medicated to prevent CINV.

Patients in the study group received 300 mg/m² amifostine 15–30 minutes before radiation therapy (RT) on days 1–5 of each week. Patients in both the study group and the control group received 90 mg/m² carboplatin once per week before RT. Treating physicians and patients reported data.

• The study enrolled 50 patients. Of these, 45 were assessable (22 in the study group and 23 in the control group).
• More men than women participated.
• The mean age was 59 years with a  range of 45–74 years.

The study was conducted between January 1997 and January 1998.

The Radiation Therapy Oncology Group/ European Organization for Research and Treatment of Cancer (RTOG/EORTC) 0–4 grading system was used.

• Mucositis increased from baseline to grade 2 more rapidly in the control group by week 3.
• In the control group, 23 patients (100%) experienced grade 2 mucositis versus only two patients (91%) in the study group (p < 0.0001).
• Most patients receiving amifostine (77.2%) experienced mild mucositis (grade 2) versus only 21% in the control group (p = 0.0001).
• During week 5, 52% of patients in the control group had grade 4 mucositis versus 4.5% of patients in the study group (p = 0.0006).
• The majority of patients in the control group (95.7%) experienced moderate to severe mucositis versus 63.6% of patients in the study group (p = 0.0098).
• Incidence of side effects was low with nausea and vomiting (4.5%) and hypotension (13.6%) most common.

• The sample size was small, and the study was not blineded.
• Limited mucositis data were presented.

To evaluate the efficacy of adding powdered ginger to prevent chemotherapy-induced nausea and vomiting (CINV) in women with breast cancer receiving moderately emetogenic chemotherapy

Women with breast cancer were randomized to receive either 500 mg ginger or placebo twice a day for three days, during the course of three cycles of chemotherapy.

• N = 150 patients (450 chemotherapy cycles)  
• MEAN AGE = 48.6 years
• AGE RANGE = 25-79 years
• FEMALES: 100%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Breast cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Chemotherapy-naïve patients receiving at least three cycles of doxorubicin-based chemotherapy

• SITE: Single site   
• SETTING TYPE: Outpatient    
• LOCATION: Namazi Hospital in Iran

PHASE OF CARE: Active antitumor treatment

Double-blind, randomized, longitudinal

Not described; only states that participants were asked to “record the episodes of vomiting and nausea severity”

No significant difference in nausea or vomiting existed when comparing the ginger group to the placebo group.

The results of this study do not indicate that powdered ginger capsules (1 g daily) are effective in reducing CINV in women with breast cancer receiving chemotherapy.

Measurement/methods not well described

Powdered ginger capsules may not offer CINV relief for patients receiving chemotherapy.

To compare the efficacy between topical alpha ointment, which contains natural henna, and topical 1% hydrocortisone cream in the healing of radiation-induced dermatitis in patients with breast cancer

Patients in both arms were instructed to wash the area of the treatment field daily. The intervention included topical alpha ointment, which contains natural henna (i.e., Lawsonia inermis Linn), applied twice a day in a thin layer over the chest wall field commencing the last day of treatment and continuing for three weeks. The active control included topical 1% hydrocortisone cream applied twice a day in a thin layer over the chest wall field commencing the last day of treatment and continuing for three weeks. The patient’s dermatitis area was examined independently by two physician raters each week. The patient’s reported skin burning, pain, pruritus, and amount of discharge were recorded during the weekly physician visit. The primary endpoint of the study was speed measured in cm/week of dermatitis healing (i.e., complete reepithelialization of moist desquamation).

• N  = 60 (30 in each arm)    
• AGE = 28–81 years old in the alpha ointment arm; 25–72 years old in the hydrocortisone cream arm
• MALES: Not described, FEMALES: Not described
• KEY DISEASE CHARACTERISTICS: Newly pathologically proven, locally advanced breast cancer (treated with modified radical mastectomy, followed by sequential adjuvant chemotherapy and chest wall radiotherapy [45–50.4 Gy])
• OTHER KEY SAMPLE CHARACTERISTICS: Grade 2 and/or 3 radiation-induced dermatitis

• SITE: Single site  
• SETTING TYPE: Outpatient  
• LOCATION: Shirez, Iran

• PHASE OF CARE: Transition phase after active treatment

• Open-label, randomly-assigned, actively-controlled phase II clinical trial of alpha ointment in the management of grade 2 or 3 radiodermatitis of the breast

• Skin toxicity: Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
• Cumulative radiation dose (Gy)
• Dermatitis area (cm²)
• Dermatitis healing (complete reepithelialization of moist desquamation)
• Healing rate (cm/week)
• Patient-reported “skin burning” (0 = no complaint, 1 = mild, 2 = moderate, 3 = severe)
• Patient-reported “pain” (0 = no complaint, 1 = mild, 2 = moderate, 3 = severe)
• Patient-reported “pruritus” (0 = no complaint, 1 = mild, 2 = moderate, 3 = severe)
• Patient-reported “amount of discharge” (0 = no complaint, 1 = mild, 2 = moderate, 3 = severe)

Originally, 63 patients were assessed for eligibility, and three were ineligible. Of the remaining 60 patients, with 30 in each arm, none were lost to follow-up. There was no statistically significant difference in mean age, dermatitis area, dermatitis grade, and total radiation dose between members of the two arms. The mean area of grade 2 and 3 radiodermatitis was significantly less in the alpha ointment arm (51.64 ± 59.04 cm²) as compared to the hydrocortisone arm (74.77 ± 71.20 cm², p = 0.007) during the second week but not at baseline, the first week, or the third week. There was no difference in patient-reported burning throughout the study. Alpha ointment significantly decreased patient-reported pain (p < 0.001), pruritus (p = 0.009), and the amount of discharge (p = 0.010) at three weeks as compared to hydrocortisone cream.

Alpha ointment significantly enhanced radiation dermatitis healing as compared to hydrocortisone cream. Alpha ointment also reduced patient-reported pain, pruritus, and the amount of discharge, but not skin burning.

• Small sample (< 100)
• Risk of bias (no blinding)
• Other limitations/explanation: The treatments were not blinded. However, one treatment was an ointment while the other was a cream. Did not control for breast size or smoking. Said that “sex” was a variable collected, but did not mention whether males were included in the study. “Sex” was not reported in any of the published statistical analyses. Two physician raters were used to determine the dermatitis area; however, the authors did not include an assessment of inter-rater reliability or how the “final” dermatitis area was determined.

Alpha ointment with an active ingredient of henna may be an effective treatment to manage grades 2 and 3 radiodermatitis. Additional studies are needed.

To compare the efficacy and safety of (arm 1) combined treatment with L-carnitine (4 g/day) plus celecoxib (300 mg/day) plus antioxidants (lipoic acid 600 mg/day, carbocysteine 2.7 g/day) plus megestrol acetate (MA) 320 mg/day versus (arm 2) MA 320 mg/day alone (considered standard of care) for the treatment of advanced neoplastic disease-associated symptoms in gynecologic patients with progressive or recurrent disease previously treated with one or more lines of chemotherapy

Primary endpoints included increase in lean body mass (LBM), decrease in resting energy expenditure (REE), decrease in fatigue, and an improvement in global quality of life (QOL). Secondary endpoints included appetite, grip strength, Glasgow Prognostic Score (GPS), Eastern Cooperative Oncology Group (ECOG) performance score, and serum markers of inflammation and oxidative stress: C-reactive protein (CRP), interleukin 6 (IL-6), tumor necrosis factor (TNF), leptin, reactive oxygen species (ROS), glutathione peroxidase (GPx), and superoxide dismutase (SOD). 

Baseline anthropometric measures, physical examination, vital signs, tumor site, stage, chemotherapy regimen, weight loss in previous three to six months, performance status, Glasgow Prognostic Score, and QOL were assessed. After baseline assessment, randomization was completed by a biostatistician to arm 1 or arm 2. Treatment duration was planned for four months. All patients received 150 UI/kg of low molecular weight heparin subcutaneously for the treatment duration. Endpoints were assessed at baseline (before treatment) and at 4, 8, and 16 weeks, although all analysis was presented as a comparison between baseline and 16 weeks. Safety was monitored with weekly evaluations of adverse events and toxicity. All patients also received psychosocial counseling.

• The study reported on 124 patients.
• Mean patient age was 60.5 years (SD = 12.74), with a range of 35–76 years.
• The sample was 100% female.
• Patients had histologically confirmed advanced-stage gynecologic tumors with progressive or recurrent disease after one or more lines of chemotherapy, loss of at least 5% of ideal or preillness body weight in the previous three months, and life expectancy of more than six months. Patients could be treated with concomitant antineoplastic chemotherapy with palliative intent (low-dose regimens). All had cancer of the endometrium, cervix, or ovary (mostly stage IV, with five patients having stage IIIC).
• Patients with mechanical obstruction, history of thromboembolism, cardiac disease, cerebrovascular events, inflammatory bowel disease, or gastrointestinal ulcers were excluded.

This multisite study was conducted in an inpatient setting in Italy.

• Patients were undergoing long-term follow-up care.
• The study has clinical applicability for end-of-life and palliative care, and late effects and survivorship.

This was an open-label, randomized, controlled, prospective study.

• LBM: dual-energy x-ray absorptiometry assessment    
• REE: indirect calorimetry  
• Fatigue: Multidimensional Fatigue Symptom Inventory–short form
• QOL: European Organization for Research and Cancer Core Quality of Life questionnaire (EORTC QLQ-C30, Italian version)
• Secondary endpoints: Grip strength: dynamometer; appetite: visual analog scale, performance status (ECOG scale), GPS, and serum markers for inflammation and oxidative stress: IL-6, TNF, CRP, leptin, ROS, GPx, and SOD

Groups were similar in patient characteristics. At 16 weeks, LBM increased significantly (p = 0.032) in arm 1 with a mean difference of +4.65 kg compared to arm 2. REE changes were decreased significantly in arm 1 (p = 0.046) compared to arm 2. Arm 1 had significant decreases in fatigue symptoms (p = 0.049) and a higher mean QOL score (p = 0.042) compared to arm 2. Arm 1 gained a significant amount of weight with a mean increase of 0.5 kg per week over 16 weeks (p = 0.002). REE and fatigue decreased in arm 1 significantly at 16 weeks but not in arm 2. Both arms had significantly increased appetite (p < 0.05) and decreased ECOG scores. There was no difference between groups in appetite. Serum markers for inflammation and oxidative stress decreased significantly in arm 1 at 16 weeks. No significant arm 2 findings resulted. Leptin increased significantly in arm 1 and moderately but nonsignificantly in arm 2. Two patients had grade 3 diarrhea in arm 1.

The multimodal arm (arm 1) had improved physical, inflammatory, oxidative stress markers and QOL compared to MA alone, but did not appear to make a difference in appetite.

• There are challenges to clinical application due to the complexity of symptoms and clinical management; which component of the multimodal arm 1 intervention had the effect is unclear.
• The sample included patients with gynecologic cancers only.
• Safety and toxicity were described and measured minimally. 
• Although the study reports significant improvements in fatigue and anorexia, there is no description of how these were measured.

Study findings support multimodal approaches, including psychosocial support, for symptom management. More work should include patient-reported outcomes, toxicity, and safety of the intervention.