Practice insights on patient care—management overview for chemoradiation toxic mucositis—guidelines,guideline-supported therapies and high potency polymerized cross-linked sucralfate (ProThelial)

Abstract

Aim

To offer a practice insight for the management of chemoradiation toxic mucositis.

Method

Review chemoradiation toxic mucositis, its pathobiology and breadth of symptom presentation. Review mucositis guidelines and guideline-supported anti-mucositis therapies. Offer guidance on guidelines and an abbreviated review of high potency cross-linked sucralfate for management of chemoradiation toxic mucositis.

Result

There are six major mucositis guidelines but only one that is current and regularly updated. Guidelines from the Multinational Association Supportive Cancer Care suggest 14 interventions gleaned from controlled trials, 12 of which are off-label uses of therapies that offer statistically significant but incrementally beneficial outcomes. Several evidence-based limitations of guidelines are discussed. Data on high potency polymerized cross-linked sucralfate confirming complete prevention and rapid (2–3 days) elimination, sustained throughout cancer treatment is verified as high quality evidence in accordance to standards adopted by Agency for Healthcare Research and Quality. A 96–97% reduction in mucositis duration qualifies as a positive Glasziou treatment effect, which is discussed as an additional measure of evidence-based medicine.

Conclusion

Statistically significant but fractional treatment effects of guideline-supported interventions are not likely to substantially alter the course of mucositis when it occurs nor completely prevent its onset. Complete prevention and rapid sustained elimination should be the goal, therefore high potency polymerized cross-linked sucralfate may be useful. Where guidelines fail, institution-based protocols led by oncology pharmacists could succeed. In an effort to eliminate toxic mucositis, enhance compliance to chemoradiation regimens, and improve survival, such protocols for practice may verify pharmacoeconomic benefits, if any, in using high potency polymerized cross-linked sucralfate to manage toxic mucositis.

Keywords

Chemoradiation mucositis polymerized cross-linked sucralfate symptom management cancer supportive care

Get full access to this article

View all access options for this article.

References

Radvnsky

Pasce

Siddiqui

. Prevention and management of radiation-induced dermatitis, mucositis and xerostomia. Am J Health Syst Pharm 2013; 70: 1025–1032. doi: 10.2146/ajhp120467.

Leveque

Delpeuch

Gourieux

. New anticancer agents: role of clinical pharmacy services. Anticancer Res 2014; 34: 1573–1578. PMID 24692684.

Foote

. The importance of planned dose of chemotherapy on time: do we need to change our clinical practice? Oncologist 1998; 3: 3675–3368.

Cairo

. Dose reductions and delays: limitations of myelosuppressive chemotherapy. Oncology (Williston Park) 2000; 14: 21–31. [11033835].

Russo

Haddad

Posner

et al.

Radiation treatment breaks and ulcerative mucositis in head and neck cancer. Oncologist 2008; 13: 886–898. doi: 10.1634/theoncologist.2008–0024.

Herrmann

Jakubek

Trott

. The importance of the timing of a gap in radiotherapy of squamous cell carcinomas of the head and neck. Strahlenther Onkol 1994; 170: 545–549.

Withers

Taylor

Maciejewski

. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 1988; 27: 131–146.

Tarnawski

Fowler

Skadowski

et al.

How fast is repopulation of tumor cells during the treatment gap?

Int J Radiat Oncol Biol Phys 2002; 54: 229–236.

Hebers

AHE

deHaan

AFJ

vander Velden

WJFM

et al.

Mucositis not neutropenia determines bacteremia among hematopoietic stem cell transplant recipients. Transpl Inf Dis 2014; 16: 279–285. doi: 10.1111/tid.12195/.

10.

Gratwohl

Brand

Frassoni

et al.

The acute and chronic leukemia Working Parties and the Infectious diseases Working Partiey of the European Group for Blood and Marrow Transplantation (EBMT). Cause of death after allogeneic haematopoietic stem cell transplantation (HSCT) in early leukemias: an EBMT analysis of lethal infectious complications and changes over calendar time. Bone Marrow Transpl 2005; 36: 757–769.

11.

Deeg

Sandmaier

. Who is fit for allogenic transplantation? Blood 2010; 116: 4762–4770.

12.

Surveillance, Epidemiology, and End Results (SEER) Program. Cancer Facts & Figures, http://cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf (2015, accessed 12 September 2017).

13.

McCullough

. US oncology-wide incidence, duration, costs and deaths from chemoradiation mucositis and anti-mucositis therapy benefits. Future Oncol 2017; 30: 2823–2852.

14.

Cairo

. Dose reductions and delays: limitations of myelosuppressive chemotherapy. Oncology (Williston Park) 2000; 14: 21–31.

15.

Foote

. The importance of planned dose of chemotherapy on time: do we need to change our clinical practice? Oncologist 1998; 3: 365–368.

16.

Medicare-managed care manual. Chapter 4. pp.29–30, https://cms.gov/Regulations-and-Guidance/Guidance/Manuals/downloads/mc86c04.pdf (accessed 12 September 2017).

17.

Samson DJ, Ratko TA, Rothenberg BM, et al. Comparative effectiveness and safety of radiotherapy treatments for head and neck cancer. Comparative effectiveness review No. 20. (Prepared by Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. 290-02-0026.) Rockville, MD: Agency for Healthcare Research and Quality, May 2010, www.effectivehealthcare.ahrq.gov/reports/final.cfm.

18.

Ratko TA, Douglas GW, de Souza JA, et al. Radiotherapy treatments for head and neck cancer update. Comparative effectiveness review No. 144. (Prepared by Blue Cross and Blue Shield Association Evidence-based Practice Center under Contract No. 290-2007-10058.) AHRQ Publication No. 15-EHC001-EF. Rockville, MD: Agency for Healthcare Research and Quality, December 2014, www.effectivehealthcare.ahrq.gov/reports/final.cfm.

19.

Carr D, Goudas L, Lawrence D, et al. Management of cancer symptoms: pain, depression, and fatigue. Evidence report/technology assessment No. 61 (Prepared by the New England Medical Center Evidence-based Practice Center under Contract No 290-97-0019). AHRQ Publication No. 02-E032. Rockville, MD: Agency for Healthcare Research and Quality, July 2002.

20.

Donnelly

Blijlevens

NMA

Verhagen

CAH

. Can anything be done about oral mucositis. Ann Oncol 2003; 14: 505–507. doi:10.1093/annonc/mdg179.

21.

Miyamoto

. Reducing the incidence and severity of oral mucositis – can it be done? US Oncolog Dis 2007; 3: 18–21.

22.

Nooka

Johnson

Kaufman

et al.

Pharmacoeconomic analysis of palifermin to prevent mucositis among patients undergoing autologous hematopoeitic stem cell transplantation. Biol Blood Marrow Transpl 2014; 20: 852–885.

23.

Sonis

. Mucositis as a biological process; a new hypothesis for the development of chemotherapy induced stomatotoxicity. Oral Oncol 1998; 34: 39–43.

24.

Elting

Cooksley

Chambers

et al.

The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis. Cancer 2003; 98: 1531–1539. DOI 10.1002/cncr.11671.

25.

Nguyen

Reyland

Barlow

. Mechanisms of taste bud cell loss after head and neck irradiation. J Neurosci 2012; 32: 3474–3484. PMID: 22399770.

26.

Hesketh

. Chemotherapy-induced nausea and vomiting. N Engl J Med 2008; 358: 2482–2494. DOI: 10.1056/NEJMra0706547.

27.

Stein

Voigt

Jordan

. Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management. Ther Adv Med Oncol 2010; 2: 51–63. DOI: 10.1177/1758834009355164.

28.

Mayer

Travers

Wyss

et al.

Why do patients with cancer visit emergency departments? Results of a 2008 population study in North Carolina. J Clin Oncol 2011; 29: 2683–2688.

29.

Uramoto

Iwashige

Kagami

et al.

Prediction of emergency hospitalization of outpatients receiving cancer chemotherapy. Anticancer Res 2007; 27: 1133–1136.

30.

Barbera

Taylor

Dudgeon

. Why do patients with cancer visit the emergency department near the end of life. Can Med Assoc J 2010; 182: 563–568.

31.

Hensley

Hagerty

Kewalramani

et al.

American society of clinical oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol 2008; 27: 127–145.

32.

Bensinger

Schuber

Ang

et al.

NCCN task force report: prevention and management of mucositis in cancer care. J Natl Compr Can Netw 2008; 6: S1–S21.

33.

Lalla

Bowen

Barasch

et al.

MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer 2014; 120: 1453–1461. DOI: 10.1002/cncr.28592.

34.

Peterson

Boers-Doets

Bensadoun

et al.

Management of oral and gastrointestinal mucositis: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015; 26: v139–v151.

35.

Harris

Eilers

Harriman

et al.

Evidence-based interventions for cancer treatment-related mucositis: putting evidence into practice. Clin J Oncol Nurs 2008; 18: 80–96. doi:10.1188/14.CJON.S3.80-96.

36.

Clarkson JE, Worthington HV, Furness S et al. Interventions for treating oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev 2010. Art No:CD001973. DOI: 10.1002/14651858.CD001973.pub4.

37.

Worthington HV, Clarkson JE, Bryan G et al. Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev 2011. Art No: CD000978. DOI: 10.1002/14651858.CD000978.pub5.

38.

Bowen

Elad

Hutchins

et al.

Methodology for the MASCC/ISOO mucositis clinical practice guidelines update. J Support Cancer Care 2013; 21: 303–308.

39.

Somerfield

Padberg

Pfister

et al.

ASCO clinical practice guidelines: process, progress, pitfalls, and prospects. Classic Pap Curr Comments 2000; 4: 881–886.

40.

Hadorn

Baker

Hodges

et al.

Rating the quality of evidence for clinical practice guidelines. J Clin Epidemiol 1996; 49: 749–754.

41.

McCullough

. Single agent anti-mucositis protocol for oral and gastrointestinal mucositis and other implications on current concepts regarding chemoradiation induced mucositis and its management from a phase IV post-market surveillance of ProThelial-high potency polymerized cross-linked sucralfate (HPPCLS). Eur J Oncol Pharm 2015; 9: 1–11. www.ejop.eu .

42.

Bhatt

Vendrell

Nau

et al.

Implementation of a standardized protocol for the prevention and management of oral mucositis in patients undergoing hematopoietic cell transplantation. J Oncol Pharm Pract 2010; 16: 195–204.

43.

Svanberg

Birgegard

Ohrn

. Oral cryotherapy reduces mucositis and opioid use after myeloablative therapy – a randomized controlled trial. Supp Care Cancer 2007; 15: 1155–1161. doi: 10.1007/s00520-0245-8.

44.

Nolan

Morley

Vanden

HTL

. Therapeutic hypothermia after cardiac arrest. Circulation 2003; 108: 118–121. doi: 10.1161/01.CIR.0000079019.02601.90.

45.

Svanberg

Ohrn

Birgegard

. Five-year follow-up of survival and relapse in patients who received cryotherapy during high-dose chemotherapy for stem cell transplantation shows no safety concerns. Eur J Cancer Care 2012; 21: 822–828. doi: 10.1111/ecc.12009.

46.

Howick

Friedmann

Tsakok

et al.

Are treatments more effective than placebos? A systemic review and meta-analysis. PLOS One 2013; 8: e62599–e62599. [with correction published in 2016 PLoS One 2016; 11: e0147354 (which did not change, but rather strengthened conclusion of earlier publication)].

47.

Atkins

Best

Briss

et al.

Grading quality of evidence and strength of recommendations. Brit Med J 2004; 328: 1–8.

48.

Guyatt

Oxman

Kunz

et al.

Grade: what is “quality of evidence” and why is it important to clinicians?

Brit Med J 2008; 336: 995–998.

49.

Cohen

. Statistical power analysis for the behavioral sciences, 2nd ed. Hillsdale, NJ: Lawrence Earlbaum Associates, 1988.

50.

Coe R. It’s the effect size, stupid. What effect size is and why it is important. In: Paper presented at the annual conference of the British Educational Research Association, University of Exeter, England, 12–14 September 2002, https://leeds.ac.uk/educol/documents/00002182.htm (assessed 15 October 2017).

51.

Glasziou

Chalmers

Rawlins

et al.

When are randomized trials unnecessary? Picking signal from noise. Brit Med J 2017; 334: 349–351.

52.

Higgins

JPT

Green

. Cochrane handbook for systemic reviews of inventerions 4.2.6, The Cochrane Library, Chichester UK: John Wiley & Sons Ltd, 2006.

53.

Kavanagh

. The GRADE system for rating clinical guidelines. PLoS Med 2009; 6: e1000094–e1000094. doi:10.1371/journal.pmed.1000094.

54.

Kashimura K and Ozawa K. Sucralfate preparations. US Patent 5,968,906, 1999.

55.

McCullough

. Single agent anti-mucositis protocol now a possibility. 66 patient multi-institutional phase IV post-market surveillance of prothelial (high potency polymerized cross-linked sucralfate). J Supp Care Cancer 2015; 23: S114–S115. [Abstract].

56.

McCullough

. A 66 patient multi-institution phase IV post-authorization surveillance of ProThelial (high potency polymerized cross-linked sucralfate) – single agent efficacy for the prevention and rapid reversal of chemo-radiation induced oral, esophageal and intestinal mucositis. Brit J Med Med Res 2015; 10: 1–17. DOI:10.9734/BJMMR/2015/19755.pdf.

57.

McCullough

. Elimination of unplanned treatment breaks and dose reductions caused by mucositis: positive implications for survival outcomes and cost reductions using high potency polymerized cross-linked sucralfate in 55 patients undergoing radiation for head and neck cancer with and without chemotherapy. Kor J Clin Oncol 2017; 13: 10–24. https://doi.org/10.14216/kjco.17002 .

58.

McCullough

. Actual duration of patient-reported mucositis: far longer than 2 to 4 weeks and may be avoidable altogether. Kor J Clin Oncol 2016; 12: 1–6. doi: https://doi.org/10.14216/kjco.16001.

59.

Elting

Cooksley

Chambers

et al.

Risk, outcomes and costs of radiation-induced oral mucositis among patients with head-and-neck malignancies. Int J Radiat Oncol Bio Phys 2007; 68: 1110–1120. DOI 10.1016/j-ijrobp.2007.01.053.

60.

Elting

Keefe

Sonis

et al.

Patient reported measurements of oral mucositis in head and neck cancer patients treated with radiotherapy with or without chemotherapy. Cancer 2008; 113: 2704–2713.

61.

Franco

Martini

Di Muzio

et al.

Prospective assessment of oral mucositis and its impact on quality of life and patient-reported outcomes during radiotherapy for head and neck cancer. Med Oncol 2017; 34: 81, 1–8. PMID 28386836.

62.

Thompson DC, Rivara F and Thompson R. Helmets for preventing head and facial injuries in bicyclists. Cochrane Database Syst Rev 2009; Art No: CD001855.

63.

Cannegieter

Rosendaal

Briet

. Thromboembolic and bleeding 10 complications in patients with mechanical heart valve prostheses. Circulation 1994; 89: 635–641.

64.

Bonow

Carabello

Chatterjee

et al.

ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Valvular Heart Disease). J Am Coll Card 2007; 49: e1–e148. American College of Cardiology Web Site, www.acc.org/clinical/guidelines/valvular/index.pdf.

65.

CSJ

. Role of pharmacists in optimizing the use of anticancer drugs in the clinical setting. Inter Pharm Res Pract 2014; 3: 11–24.

66.

Pharmacy Practice Model Summit. Executive summary. Am J Health Syst Pharm 2011; 68: 1079–1085.

67.

American College of Clinical Pharmacy. Standard of practice for pharmacists, http://accp.com/docs/positions/guidelines/standardsofpractice.pdf. (accessed 11 September 2017).

68.

American Society of Health-System Pharmacists. ASHP long range vision for the pharmacy work force in hospitals and health systems. Am J Health Syst Pharm 2007; 64: 1320–1330.