Palifermin Prevention and Treatment

PAIN CHILD INTERNATIONAL MUCOSITIS EVALUATION SCALE ChIMES 1. Which of these faces best describes how much pain you feel in your mouth or throat now? Circle one. 2. Which of these faces best shows how hard it is for you to SWALLOW your salivaspit today because of mouth or throat pain? Circle one. 3. Which of these faces shows how hard it is for you to EAT today because of mouth or throat pain? Circle one. Not hard 1 Little bit hard 2 Little more hard 3 Even harder 4 Very hard 5 Can’t swallow No hurt 1 Hurts a little bit 2 Hurts a little more 3 Hurts even more 4 Hurts a whole lot 5 Hurts worst Can’t tell Not hard 1 Little bit hard 2 Little more hard 3 Even harder 4 Very hard 5 Can’t eat Can’t tell Not hard If yes, did you need the medicine because you had a sore mouth or throat? Yes No I can’t tell 5. Have you taken any medicine for any kind of pain today? 6. Please ask an adult to look in your mouth. Can he or she see any mouth sores in your mouth today? 1 Little bit hard 2 Little more hard 3 Even harder 4 Very hard 5 Can’t drink Can’t tell 4. Which of these faces shows how hard it is for you to DRINK today because of mouth or throat pain? Circle one. FUNCTION PAIN MEDICATION You will need some help from your parent or another adult to answer these questions. APPEARANCE The photos shown on the introduction page are examples of what mouth scores may look like. Yes No Yes No Fig. 11.3 ChIMES tool with permission from Tomlinson et al. [ 2010 ] Table 11.2 Prevention and treatment of oral mucositis Intervention Level of support Population studied Grade a Prevention Aloe Vera Weak unreliable evidence the solution was benefi cial for the prevention of moderate to severe mucositis Head and neck cancer receiving radiotherapy 2C Amifostine Weak unreliable evidence from 11 low quality trials that amifostine is benefi cial for the prevention of any mucositis Combinations of head and neck cancer, other solid tumors and hematologic malignancies receiving radiotherapy, stem cell transplant, non- myeloablative chemotherapy or a combination 2C Antibiotic polymyxin tobramycinamphotericin [PTA]—lozengespaste Weak unreliable evidence that PTA lozenges may be benefi cial for the prevention of any mucositis Head and neck cancer receiving radiotherapy 2C Cryotherapy Found to be benefi cial in the prevention of all the outcome categories of mucositis—any, moderate and severe mucositis Hematologic malignancies with chemotherapy or stem cell transplantation 2B Glutamine Weak evidence that glutamine is benefi cial for the prevention of severe mucositis Combinations of head and neck cancer, other solid tumors and hematologic malignancies receiving radiotherapy, stem cell transplant, non- myeloablative chemotherapy or a combination 2B Granulocyte colony-stimulating factor G-CSF Weak unreliable evidence that G-CSF is effective for the prevention of severe mucositis Combinations of head and neck cancer, other solid tumors and hematologic malignancies receiving radiotherapy, stem cell transplant, non- myeloablative chemotherapy or a combination 2C Honey Weak unreliable evidence with substantial heterogeneity that honey may be benefi cial in the prevention of any mucositis Head and neck cancer receiving radiotherapy 2C Palifermin keratinocyte growth factor Found benefi cial for the prevention of all outcome categories of mucositis, moderate mucositis and severe mucositis Combinations of head and neck cancer, other solid tumors and hematologic malignancies receiving radiotherapy, stem cell transplant, non- myeloablative chemotherapy or a combination 2B Low-level laser therapy Weak unreliable evidence that laser is benefi cial for the prevention of severe mucositis Combinations of head and neck cancer, other solid tumors and hematologic malignancies receiving radiotherapy, stem cell transplant, non- myeloablative chemotherapy or a combination 2B Sucralfate Evidence that sucralfate is effective in the prevention of severe mucositis, with a 33 reduction in severe mucositis in treatment group compared to placebo Mostly head and neck cancer receiving radiotherapy, some trials with participants with other cancer types 2B Treatment Low-level laser therapy Limited evidence that low-level laser is benefi cial in reducing the severity of oral mucositis Children with mixed cancers and adults with hematologic malignancies 2B Patient controlled analgesia PCA Unreliable evidence that less opiate is used per hour and duration of the pain is slightly reduced with PCA. No evidence that PCA is better than continuous morphine in controlling pain Adult leukemia or lymphoma undergoing high-dose chemotherapy and total body irradiation prior to stem cell transplant 2B Adapted from Eilers and Million 2011 a Per Guyatt et al. 2006 ; see Preface D. Mills and A.M. Maloney undergoing allogeneic HSCT while Vitale et al. 2014 showed no signifi cant benefi t in children undergoing autologous HSCT although there was a trend toward decreased mucositis severity. Further studies are required to assess whether palifermin will be effective for other chemother- apy modalities and in the pediatric population.

11.4.2 Low-Level Laser Therapy

LLLT is an emerging therapy in the prevention and treatment of OM. LLLT is local application of a monochromatic, narrowband, coherent light source. The action of LLLT is disputed, but a cytoprotective effect before and during oxidative stress has been reported following its use. Red and infrared LLLT is believed to have an anti-infl ammatory effect Bjordal 2012 . The current Multinational Association of Supportive Care in Cancer MASCC and International Society of Oral Oncology ISOO guidelines for adult patients receiving high-dose chemotherapy or chemotherapy and HSCT recom- mend LLLT if the institution is able to support the technology and training in LLLT Keefe and Gibson 2007 . A meta-analysis by Bensadoun and Nair 2012 reported reduced risk of OM as well as reduced duration and severity of OM with both red and infrared LLLT. Pediatric data are limited and confl icting. In a randomized, placebo-controlled trial of 21 pediatric oncology patients with chemotherapy- related OM, Kuhn et al. 2009 showed that LLLT reduced the duration of OM. This result has been supported by Abramoff et al. 2008 who similarly showed a reduction in OM frequency with LLLT as well as decreased pain and OM sever- ity in those presenting with OM. These results con- fl ict with Cruz et al. 2007 who showed no benefi t for prevention in children with cancer in a random- ized trial. As with palifermin, further data are required to support LLLT in the pediatric population given the younger age and therefore likely improved ability to heal compared to an older cohort.

11.4.3 Glutamine

Glutamine is considered a conditionally essential amino acid as stress and catabolic states lead to its depletion Storey 2007 . Theoretically, glutamine repletion may prevent damage to normal tissues such as the oral mucosa during cytotoxic thera- pies Storey 2007 . Adult studies showed benefi t with Saforis AES-14, an oral L-glutamine swish-and-swallow suspension, but after United States Food and Drug Administration FDA approval, the drug was discontinued Posner and Haddad 2007 . Studies in pediatric patients are confl icting; Anderson et al. 1998 and Aquino et al. 2005 showed benefi t in pediatric patients undergoing cytotoxic therapies and HSCT, while Ware et al. 2009 showed no benefi t. In the review by Storey 2007 , it is concluded that stud- ies, though promising, show an inconsistent ben- efi t in pediatric patients and are limited by small patient numbers as well as a variety of glutamine dosages, dose intervals and administration tech- niques which hamper the ability to make fi rm conclusions about glutamine effi cacy.

11.4.4 Cryotherapy

Cryotherapy has not been systematically studied in pediatric oncology patients but has shown ben- efi t in the prevention of OM from short-acting chemotherapeutic agents such as 5-fl uorouracil 5-FU in adult patients Posner and Haddad 2007 . Administration of ice chips simply causes vasoconstriction and therefore decreased blood fl ow to the oral mucosa during bolus infusions of 5-FU. Benefi t of this intervention on longer- acting agents is unclear although the recent Cochrane review did show potential decrement of OM incidence with prophylactic cryotherapy in adult patients Posner and Haddad 2007 ; Eilers and Million 2011 .

11.5 Oral Care

The purpose of basic oral care is to reduce symp- toms of oral pain and bleeding related to cancer therapy and to prevent soft tissue infections that may have systemic sequelae. In addition, mainte- nance of good oral hygiene reduces the risk of future dental complications Rubenstein et al. 2004 . A study by Clarkson and Eden 1998 examining the dental health of children with cancer found that 43 of patients had untreated decay and only 35 had been seen by a dentist since diagnosis. Their study exemplifi ed the lack of dental preventive care for pediatric oncology patients and stressed the need to continue to pro- vide primary oral hygiene during pediatric cancer therapy Clarkson and Eden 1998 . A European multidisciplinary group, in collaboration with the United Kingdom Childhood Cancer Study Group UKCCSG and the Paediatric Oncology Nurses Forum PONF, was established in 2001 princi- pally to produce comprehensive, evidence-based guidelines on mouth care for children and adoles- cents being treated for cancer. The potential ben- efi ts of such guidelines include improved patient care, consistency of care, the promotion of inter- ventions of proven benefi t and a reduction in use of ineffective or potentially harmful practices Glenny et al. 2010 . The UKCCSG-PONF Mouth Care for Children and Young People with Cancer guidelines used the agreed-upon methodology of SIGN Scottish Intercollegiate Guidelines Network to aid them in their development of evidence-based guidelines Glenny et al. 2010 . A consensus approach was utilized to establish the scope and basic structure of the guidelines. Three key areas were identifi ed and covered by the guidelines: 1 dental care and basic oral hygiene, 2 methods of oral assess- ment, and 3 drugs and therapies Glenny et al. 2010 . The group conducted a systematic review of the literature to examine these three key areas and, where no evidence existed, a consensus opin- ion on best practice was determined Glenny et al. 2010 . Additionally, the American Academy of Pediatric Dentistry AAPD has published guide- lines on the dental management of pediatric patients receiving chemotherapy, HSCT or radia- tion AAPD 2013 . The overarching purpose of these guidelines is to recognize that the pediatric dental professional plays an important role in the care of pediatric oncology patients. The AAPD guidelines focus on basic oral hygiene and dental care for pediatric oncology patients before, during and after cancer therapy. The AAPD and UKCCSG-PONF guidelines make recommendations in fi ve areas, as summarized in Table 11.3 : 1 orodental care at the time of can- cer diagnosis, 2 oral hygiene at diagnosis and dur- ing cancer treatment, 3 orodental care during cancer treatment, 4 orodental care after cancer therapy, and 5 prevention and treatment of xero- stomia Glenny et al. 2010 . The UKCCSG-PONF guidelines emphasize the importance of oral assessment throughout cancer treatment utilizing the discussed oral assessment tools. Frequency of oral assessment should be determined on an individual basis and should be increased if oral complications arise Glenny et al. 2010 . The AAPD describes the importance of identifying and stabilizing, or elim- inating, existing and potential sources of infection or local irritants in the oral cavity. Emphasis on the education of patients and parents on the importance of oral care should occur throughout therapy as well as in regard to the potential short- and long-term effects of therapy. The AAPD fur- ther elaborates on care when the use of radiation will affect the orofacial region with the goal of reduction of radiation to healthy oral tissue through consultation with the radiation oncologist and utilization of lead-lined stents, prostheses and shields to spare structures such as the salivary glands. Patients who receive radiation therapy involving the masticatory muscles should be edu- cated on daily oral stretching exercises to decrease the potential of trismus AAPD 2013 . Finally, for patients that experience xerosto- mia, the AAPD recommends fl uoride rinses and gels for the prevention of caries as well as the use of humidifi cation for symptomatic relief.

11.6 Oral Infections

Patients experiencing OM are predisposed to infections of the oral cavity. Viral, fungal and bac- terial infections may arise with incidence depen- dent on the use of prophylactic anti- infective regimens, oral status prior to chemotherapy, and secondary to the duration and severity of neutro- penia. The most frequent documented source of sepsis in the immunocompromised cancer patient is the mouth Allen et al. 2010 . In adults, chemo- therapy and radiotherapy in patients with head