Hyaluronic Acid/Sodium Hyaluronate

Hyaluronic Acid/Sodium Hyaluronate

PEP Topic 
Radiodermatitis
Description 

Hyaluronic acid, also known as hyaluronate, is a carbohydrate substance that is present in connective, epithelial, and nuerve tissues and is a major component of the intracellular matrix. Sodium hyaluronate is the sodium salt of the same substance. Hyaluronic acid or sodium hyaluronate has been used in patients with cancer as an oral spray for treatment of mucositis and as a topical treatment for radiodermatitis.

Effectiveness Not Established

Research Evidence Summaries

Kirova, Y. M., Fromantin, I., De Rycke, Y., Fourquet, A., Morvan, E., Padiglione, S., . . . Bollet, M. A. (2011). Can we decrease the skin reaction in breast cancer patients using hyaluronic acid during radiation therapy? Results of phase III randomised trial. Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology, 100(2), 205–209.

doi:10.1016/j.radonc.2011.05.014
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Study Purpose:

To evaluate the benefit of hyaluronic acid in management of radiodermatitis

Intervention Characteristics/Basic Study Process:

Women who developed a grade 1 dermatitis with radiotherapy were randomized to use either hyaluronic acid cream or a simple urea-based emollient once daily. Patients were advised to shower one-to-two times daily. Clinical evaluation of the skin was done weekly by the radiation oncologist. Pain and quality of life were assessed at the end of treatment on day 30. The study endpoint was a success as defined by disappearance of erythema 30 days after its occurrence.

Sample Characteristics:

  • The study sample (N = 200) was comprised of female patients with breast cancer.
  • Median age was 53 years, with a range of 27–83 years.
  • Median Gy was 28, with a range of 10–52 Gy.

Study Design:

The study used a randomised open-label phase III design.

Measurement Instruments/Methods:

  • The Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer radiation toxicity scale was used.
  • Erythema was measured using calorimetry.

Results:

Overall, 36.5% of participants withdrew prematurely because of worsening of eipthelitis, patient refusal, change in treatment, or use of another product. In the intent to treat population (all registered), there was a 27.3% treatment failure with hyaluronate and a 38.8% treatment failure with emollient. Power analysis showed that 100 per study group were needed. With drop outs, this study was underpowered.

Conclusions:

 The study did not demonstrate any significant differences in epithelitis between those using hyaluronic acid or emollient topically. The study was insufficiently powered to provide any firm conclusions.

Limitations:

  • The baseline sample differences were of import.
  • The study had a risk of bias due to no blinding and sample characteristics.
  • The hyaluronic acid group had a higher skin temperature at erythema area baseline. 
  • Patient compliance with protocol use is not discussed, so it is not clear if use was consistent. 
  • No subgroup analysis was done based on radiation therapy dosage or combined chemotherapy and radiation therapy.

Nursing Implications:

Study findings are inconclusive because of the study limitations. Findings suggest that hyaluronic acid and urea-based emollients topically may provide similar results for prevention of low-grade radiodermatitis.  These findings should be viewed with caution because of the study design limitations and lack of sufficient sample size to meet power requirements.

Liguori, V., Guillemin, C., Pesce, G.F., Mirimanoff, R.O., & Bernier, J. (1997). Double-blind, randomized clinical study comparing hyaluronic acid cream to placebo in patients treated with radiotherapy. Radiotherapy and Oncology, 42, 155–161.

doi: 10.1016/S0167-8140(96)01882-8
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Study Purpose:

To determine if prophylactic use of hyaluronic acid cream postpones acute radiodermatitis or reduces its severity and to evaluate the efficacy of hyaluronic acid to delay the onset of necrosis or to accelerate recovery in case of ulceration

Intervention Characteristics/Basic Study Process:

Hyaluronic or placebo cream was applied to irradiated skin area twice daily. The first application was one-to-two hours after the radiation therapy session and the second was in the evening. The topic treatment was continued over a six-week period.

Sample Characteristics:

  • The study sample (N = 134) was comprised of male (n = 74) and female (n = 60) patients with head and neck (n = 90), breast (n = 30), or pelvic cancer (n = 14).
  • Mean age was 59.9 years in the treatment group and 55.7 years in the placebo group.

Setting:

The study took place at Ospedale San Giovanni and Centre Hospitlier Universitaire, both in Switzerland.

Study Design:

The study used a randomized placebo-controlled double-blind trial design.

Measurement Instruments/Methods:

  • Skin was evaluated using a scale of 0–5 (0 = normal skin, 1 = light epidermal irritation, 2 = erythema with dry desquamation, 3 = exudate less than 50%, 4 = exudate more than 50%, 5 = ulcer).
  • Healing was reported using a 1–4 scale (1 = minimum and maximum lesion diameters, 2 = lesion cleaning, 3 = beginning of proliferation process and proliferation of tissue granulation, 4 = re-epithelialization).
  • Physician global judgment on therapeutic efficacy was evaluated using a 0–3 verbal scale (0 = poor, 1 = fair, 2 = good, 3 = excellent).

Results:

  • Acute radiodermatitis scores were significantly higher in the placebo group (p < 0.01 at 3–7 weeks and p < 0.05 at 8–10 weeks).
  • Global efficacy judgment by both physician and patient showed a significant difference in favor of the intervention (p < 0.01 to p < 0.05).
  • A statistically significant difference in skin reactions was reported in favor of the intervention group based on global efficacy (p < 0.01).
  • A significant difference was reported for the head and neck group in favor of the intervention following observation at week 3 (p = 0.0003), week 4 (p = 0.0001), and week 5 (p = 0.0035).

Conclusions:

The prophylactic use of hyaluronic acid cream is shown to reduce the incidence of high-grade radiodermatitis.

Limitations:

  • Very small numbers for evaluation of healing.
  • Did not allow statistical evaluation to be carried out for this aspect of the study.
  • No discussion of evaluation tools or the reliability or validity of tool.

Pinnix, C., Perkins, G.H., Strom, E.A., Tereffe, W., Woodward, W., Oh, J. L., . . . Yu, T.K. (2011). Topical hyaluronic acid vs. standard of care for the prevention of radiation dermatitis after adjuvant radiotherapy for breast cancer: Single-blind randomized phase III clinical trial. International Journal of Radiation Oncology, Biology, Physics, 83(4), 1089–1094.

doi: 10.1016/j.ijrobp.2011.09.021
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Study Purpose:

To determine effectiveness of an hyaluronic acid-based emulsion to reduce development of greater than or equal to grade 2 radiodermatitis in women receiving adjuvant breast radiation

Intervention Characteristics/Basic Study Process:

Women were randomly assigned to use topical hyaluronic acid on the medical or lateral half of the irradiated breast, and a control, petrolatum-based substance to the other half of the breast. Agents were to be applied three times daily beginning one day before the start of radiation therapy and continuing throughout the treatment period. Agents were not applied within four hours prior to radiation treatment. Patients were not to apply other topical products unless otherwise instructed by the physician. All other agents used were to be documented.

Sample Characteristics:

  • The study sample (N = 65) was comprised of female patients with breast cancer.
  • Mean age of the sample was 55.4 years.
  • Of patients in the sample, 93% had medium or large breast size.
  • Patients were treated with intensity-modulated radiation therapy (IMRT), receiving 50 Gy in 25 daily fractions with or without a boost of 10–16 Gy. 
  • Fifteen percent of the study sample were African American and 15% were Hispanic.

 

Setting:

The study took place at MD Anderson Cancer Center in Houston, TX.

Phase of Care and Clinical Applications:

Patients were undergoing active anti-tumor treatment.

Study Design:

The study used a single-blind controlled trial design.

Measurement Instruments/Methods:

The National Cancer Institute Common Toxicity Criteria (version 3) for skin toxicity grading was used.

Results:

Twelve percent dropped out of the study for a variety of reasons. In weeks 1–5 there were no differences between groups in severity of dermatitis in intent to treat and evaluable patient groups. In week 6 the side of the breast treated with hyaluronic acid was scored worse (p = 0.009). No associations were found between severity of dermatitis and body mass index, breast size, smoking history, diabetes or radiation dose. Forty-nine percent of control areas developed greater than grade 2 dermatitis compared to 61% of evaluable areas using hyaluronic acid emulsion. Overall, 1.4% developed grade 3 radiodermatitis.

Conclusions:

Prophylactic application of a hyaluronic acid-based emulsion did not reduce the incidence of greather than or equal to grade 2 radiodermatitis in this group of women receiving adjuvant radiation therapy for breast cancer.

Limitations:

  • The sample size was small, with less than 100 participants.
  • Findings are not generalizable to other patient groups based on radiation therapy dosage and site.
  • No information regarding patient adherence to the protocol is provided. 
  • Procedures state that the attending physician had discretion to order additional treatments; however, no information is provided as to whether this occurred or not. 
  • The study was ended early.

Nursing Implications:

In the study, hyaluronic acid gel was not as effective as a petrolatum based gel for reducing the severity of radiodermatitis. Authors noted that the radiation therapy approach was forward-planned IMRT, which may also have led to significant reduction in severe dermatitis, since the percent of patients with grade 3 dermatitis in the study was lower than reported elsewhere. Other studies that showed hyaluronic acid to be effective were in patients who had higher doses of radiation. It is also not clear if there is a difference in effect of hyaluronic acid for prevention or treatment of radiodermatitis.

Ravo, V., Calvanese, M.G., Di Franco, R., Crisci, V., Murino, P., Manzo, R., . . . Muto, P. (2011). Prevention of cutaneous damages induced by radiotherapy in breast cancer: an institutional experience. Tumori, 97(6), 732–736.

doi: 10.1700/1018.11089
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Study Purpose:

To evaluate the most efficient topical hydrating treatment in the prevention of cutaneous radio-induced effects in breast cancer

Intervention Characteristics/Basic Study Process:

Topical treatments used in comparison were Pure Vitamin E; Omega 3, 6, and 9; Betaglucan; sodium hyaluronate; Ixoderm; and Xderit. Patients started using the skin emollients at the start of therapy until three months after completion of therapy. They were not allowed to use any other ointments during the course of therapy.  Any patient who developed a grade 2 or higher skin toxicity stopped the topical treatment and were treated with cortisone creams.

Sample Characteristics:

  • The study sample (N = 100) was comprised of feamle patients with breast cancer.
  • In the study sample, 53% had prior chemotherapy and 75% were receiving hormonal agents during and after radiation therapy.

 

Setting:

The study took place in across multiple outpatient sites in Italy.

Phase of Care and Clinical Applications:

Patients were undergoing active antitumor treatment.

 

Study Design:

The study used an observational design.

Measurement Instruments/Methods:

The Radiation Therapy Oncology Group and European Organisation for the Research and Treatment of Cancer skin toxicity grading scale was used.

Results:

There were no grade 2 or 3 toxicities. No differences in toxicities associated with individual agents used could be determined because of the number of different agents used and the small number of patients observed.

Conclusions:

 No conclusions can be drawn from this report regarding any comparisons of topical agents used.

Limitations:

  • The sample size was small, with less than 100 patients.
  • The groups had important differences.
  • The study had a risk of bias due to no control group, no blinding, and no random assignment.
  • Measurement methods were not described.
  • Variation in patients regarding the combination of chemotherapy and radiation therapy could influence results.
  • No description of total radiation therapy dosages. 
  • No patient demographics provided.

Nursing Implications:

 The study does not add much to evidence regarding prevention or management of radiodermatitis.

Systematic Review/Meta-Analysis

Koukourakis, G.V., Kelekis, N., Kouvaris, J., Beli, I.K., & Kouloulias, V.E. (2010). Therapeutics interventions with anti-inflammatory creams in post radiation acute skin reactions: A systematic review of most important clinical trials. Recent Patents on Inflammation & Allergy Drug Discovery, 4(2), 149–158.

doi: 10.2174/187221310791163099
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Purpose:

To investigate through a systematic review what topical treatments are currently advocated to manage acute skin reactions, including creams, ointments, and dressings, and what evidence there is to support the use of these treatments

Search Strategy:

Databases used were  MEDLINE and Cochrane Central Register of Controlled Trials. Keywords searched radiation therapy, epidermis, acute skin reactions, and therapy. Studies were included if they

  • Were written in the English language
  • Were controlled trials
  • Provided information about the post-radiation acute skin reactions
  • Had patients who were eligible for treatment.

No exclusion criteria were identified in the article.

Literature Evaluated:

Total references retrieved, evaluation method, and comments on the literature used were not reported.
 

Sample Characteristics:

  • The final number of studies included in the review was 17, 15 studies in which an agent was used and 2 studies with washing only.
  • The total sample size across studies was 1,968 participants, with a range of 10–194 participants in one arm and 39–366 participants in an entire study.
  • Radiation sites included breast, head and neck, pelvic, chest, and abdomen.

Phase of Care and Clinical Applications:

Patients were undergoing active treatment.

Results:

  • Washing: Significant decrease in itching, erythema, and desquamation was found in the group that washed with soap and water. A higher incidence of moist desquamation was found in the no washing group (33%) as compared to the washing with soap and water group (14%). 
  • Aloe vera: One study showed a benefit at higher cumulative doses. Another showed no difference in maximum severity or time to onset of grade 2 radiodermatitis. Still another showed a detriment in that dry desquamation was higher in the aloe vera arm (70%) as compared to topical aqueous cream (41%). 
  • Biafine (trolamine): Two studies showed no significant decrease in skin reaction when comparing no treatment, Aquaphor, Lipiderm, and Biafine. A third study showed a decrease in less than grade 2 skin reaction, pain, and treatment interruptions. 
  • Hyaluronic acid: Two studies showed a significant benefit (i.e., decreased severity and delayed onset of radiodermatitis) among patients receiving hyaluronic acid as compared to a placebo or unidentified control. 
  • Corticosteroids: Of two randomized, double-blinded studies using corticosteroid cream as a prophylaxis, the study by Bostrom et al. found a 25% compared to 60% incidence of grade IV radiation dermatitis (corticosteroid vs. emollient). The second study did not find significant results in favor of corticosteroid. Another study showed no significant difference between a corticosteroid cream and a placebo. Still another study showed a significant difference between a corticosteroid cream and clobetasone, but most of the patients in both arms experienced moderate-to-maximum skin reactions. 
  • Sulcrafate: A randomized study in head and neck cancer found no difference in erythema, but found a higher incidence of moist desquamation in the topical sulcrafate prophylaxis group. A large (N = 357) randomized study in head and neck (n = 107), breast (n = 229), and anorectal (n = 30) cancer by found no significant difference among the topical sulcrafate, topical aqueous cream, and no cream groups. Another study (N = 44) found a significant reduction in grade 2 radiodermatitis and more rapid healing in the topical sulcrafate group among patients with breast cancer. A different study (N = 39) compared topical sorbolene and sorbolene plus sulcrafate to manage higher than grade 3 skin toxicity and found no differences between the two groups. Another study showed no benefit of using oral sulcrafate as a prophylactic agent for late reaction in prostate cancer. A final study showed no benefit of using oral sulcrafate as a prophylactic agent in preventing skin reactions in head and neck cancer. 
  • Barrier film: A study compared No-Sting barrier film to topical sorbolene as prophylaxis for moist desquamation among patients with breast cancer, showed a significant benefit. Another study  (N = 50 ) examined the use of Dermofilm in reducing pain and irritation. “Favorable” results were reported, but a larger study was recommended.
  • Anti-microbials: No study results were found. The authors cautioned against using antimicrobials as a prophylactic agent related to our knowledge of drug resistance. 
  • Dressings: One study examined healing after radiation treatment among 18 patients and found the mean healing time was 13 days. There was no comparison arm. Another study compared the use of sliver leaf nylon dressings applied to the perineum of 15 patients with anal or gynecologic cancers to historic controls. Patients who received the silver leaf nylon dressings had significantly reduced incidence of grade 3 and 4 reactions. A different study (N = 60) showed a higher incidence of radiodermatitis in the sulcrafate arm among patients with head and neck cancer.  Another study (N = 44) showed a significant benefit to breast cancer patients. One very small study (N = 15) showed a benefit of using sliver leaf nylon dressings to reduce grade 3 and 4 radiodermatitis of the perineum among anal and gynecologic cancers.

Conclusions:

Washing with soap and water consistently demonstrated a benefit. The evidence for the use of aloe vera is mixed with one study showing harm. Biafine did not demonstrate a benefit nor a harm. Hyaluronic acid showed a benefit. Corticosteroid showed mixed results, with one study showing favorable results, two showing no increased benefit, and one study showing mixed results. Most of the evidence on topical sulcrafate shows no increased benefit in preventing and managing radiodermatitis. Dermofilm, a barrier film, showed a significant benefit in reducing moist desquamation among patients with breast cancer in one small study.

Nursing Implications:

Additional studies with a larger sample and a blinded randomized controlled design are needed.

Kumar, S., Juresic, E., Barton, M., & Shafiq, J. (2010). Management of skin toxicity during radiation therapy: a review of the evidence. Journal of Medical Imaging and Radiation Oncology, 54, 264–279.

doi: 10.1111/j.1754-9485.2010.02170.x
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Purpose:

To review the evidence for skin care management and conduct a survey to assess current practices in Australia and New Zealand.

Search Strategy:

Databases searched were MEDLINE, PubMed, CINAHL, Google Scholar, and Google search. Searches were also completed by hand for the time period of 1980 to 2008.

Search keywords were radiation dermatitis, skin reaction, management, skin care, skin toxicity, moist desquamation, dry desquamation, erythema, sorbolene aqueous cream, and aloe vera.

Inclusion and exclusion criteria were not specified.

Literature Evaluated:

Thirty-one references were retrieved. Literature was evaluated on the basis of sample size. Meta-analysis was performed on studies reporting at least grade II skin toxicity.

Sample Characteristics:

  • The final number of studies included was 31.
  • The sample size across studies was 3,174 participants (range 413–506).
  • Participants had various tumor types.
  • All participants received radiation therapy (RT).

Phase of Care and Clinical Applications:

Patients were undergoing the active antitumor treatment phase of care.

Results:

Findings were reviewed for washing, topical aloe vera, topical sucralfate, Biafine cream, corticosteroids, hyaluronic acid, barrier film, dressings, and wheatgrass extract for prophylaxis. For management, interventions included were topical steroid cream, sucralfate, and dressings. Meta-analysis across studies using any topical prophylaxis showed that any intervention was associated with lower odds of development of skin toxicity (p = 0.02). There were no significant results for management interventions. There was consistent evidence in favor of gentle washing with mild soap during RT. There was some evidence in support of corticosteroids, bepanthan, topical hyaluronic acid, calendula, and barrier films. Aloe vera was associated with higher toxicity.

Conclusions:

Evidence did not support the use of sucralfate, Biafine, or dressing for prevention. Evidence regarding interventions for management of skin toxicity was conflicted, and none produced significant effects. Findings support the use of washing. There was some evidence in support of using corticosteroids, bepanthan, barrier films, calendula, and topical hyaluronic acid. Findings suggest that use of any topical therapy for prophylaxis may be more effective than no intervention.

Limitations:

  • Analysis was limited by combining all types of interventions together, which did not allow for differentiation between those agents individually shown to be effective and not effective.
  • Methods for evaluation of the quality of the research were not well described or incorporated into the analysis. 
  • Findings regarding management were questionable because of high heterogeneity among studies included in the meta-analysis. 
  • Actual odds ratios or effect sizes from the meta-analysis were not reported. 
  • Final recommendations stated by the authors were not consistent with the rest of the conclusions stated elsewhere in the article. 
  • The basis for recommendations, concerning evaluation of the quality of the evidence, was not clear. 
  • The authors stated that they weighted studies by sample size, but this method was not described.

Nursing Implications:

Washing during RT should not be restricted. There is some evidence in support of using calendula, hyaluronic acid, no-sting barrier film, bepanthan, and topical steroids. Evidence does not support the use of aloe vera.


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