Brief Article Open Access
Copyright ©2013 Baishideng. All rights reserved.
World J Transl Med. Aug 12, 2013; 2(2): 13-21
Published online Aug 12, 2013. doi: 10.5528/wjtm.v2.i2.13
High-potency sucralfate prevents and rapidly reverses chemo-radiation mucositis in a patient with stage 4b head and neck cancer
Ricky W McCullough, Center for Translational Medicine Research, Mueller Medical International LLC, Foster, RI 02825, United States
Ricky W McCullough, Department of Emergency Medicine, Roger Williams Medical Center, Boston University School of Medicine Teaching Hospital, Boston, MA 02118, United States
Ricky W McCullough, Department of Medicine, Veterans Administration Medical Center, Warren P Alpert Brown University School of Medicine Teaching Hospital, Providence, RI 02904, United States
Author contributions: McCullough RW is the sole contributor to this paper.
Supported by Translation Medicine Research Compassionate Use Program of MMI, No. 2006-001; Data collection was funded as part of Mueller Medical International LLC research on polyanionic saccharides as in-vivo surface active immuno-modulating agents for epithelial mediated processes at its Center for Translational Medicine Research in Foster Rhode Island
Correspondence to: Ricky W McCullough, MD, MSc, Center for Translational Medicine Research, Mueller Medical International LLC, 830 Chaulkstone Avenue, Box 169, Foster, RI 02825, United States. glencopelph@aol.com
Telephone: +1-401-3976203 Fax: +1-401-3978559
Received: August 27, 2012
Revised: March 24, 2013
Accepted: April 27, 2013
Published online: August 12, 2013

Abstract

AIM: To study usefulness of high-potency sucralfate (HPS) in a patient with chemoradiation mucositis and discuss its mechanism of action.

METHODS: HPS, a non-covalently cross-link of sucralfate, cations and bidentate anionic chelators, has a maintains a surface concentration of sucralfate 3 h following administration that is 7-23 fold that possible with standard-potency sucralfate. The accelerated mucosal healing and pain alleviation of HPS in patients with erosive esophageal reflux, prompted its use in this patient with chemoradiation mucositis of the oropharynx and alimentary tract. A literature-based review of the immuno-modulatory effects of sucralfate is discussed.

RESULTS: Within 48 h of intervention: (1) there was complete disappearance of oral mucositis lesions; tenderness with (2) patient-reported disappearance of pain, nausea and diarrhea; patient required (3) no opiate analgesia and (4) no tube-feeding supplements to regular diet. Dysgeusia and xerostomia persisted. A modified Naranjo Questionnaire score of 10 supported the likelihood that HPS intervention caused the observed clinical effects. No adverse reactions noted.

CONCLUSION: In this patient HPS was useful to treat chemo-radiation mucositis of the oropharynx and alimentary tract. HPS may directly or indirectly facilitate an immunomodulatory mechanism involving accelerated growth factor activation, which may be a new target for therapeutic intervention in such patients.

Key Words: Sucralfate, Mucositis, Chemoradiation, Immuno-modulation, Cytokines, Intra-epithelial lymphocytes, Growth factors

Core tip: Mucositis is a debilitating and costly consequence of chemo-radiation. Most mucositis treatments are palliative. Conversely, high-potency sucralfate (HPS) may be definitive. Patients with stage 4b head neck cancer, at high risk for developing mucositis, require gastrostomy tubes as an alternative to oral feeding. The use of HPS in this cancer patient prevented mucositis, allowing continuance of standard oral diet. Midway through chemo-radiation, though noncompliant discontinuation of HPS, by patient led to the emergence oral and alimentary mucositis, 2 d following resumption of HPS, mucositis disappeared, a normal oral diet was maintained and no analgesia was required.



INTRODUCTION

Healing of mucositis erosions induced by chemo-radiation in cancer patients involves a balanced interplay between cytokines (pro- and anti-inflammatory), chemokines and growth factors[1]. Transforming growth factor β (TGFβ), which is upregulated by epithelial growth factor (EGF), TGFα, pro-inflammatory interleukin-1β and interferon γ[2] appears to be key in the pathobiology of oral mucositis, and likely in alimentary mucositis as well. Standard potency sucralfate avidly aid in growth factors[3] activation but has no significant clinical affect on chemo-radiation induced mucositis.

Signs and symptoms of oral mucositis (its associated symptoms and physical findings) have been standardized with most clinicians using the World Health Organization (WHO) grade classification system in Table 1[4]. The severity of mucositis-related alimentary toxicity, have two main grading scales one shown in Table 2, by the European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group[5] and the other by the WHO[4]. In patients with advanced grades of mucositis (Grade 2 and 3), dose reduction is required in 60% of them, and 30% require discontinuation of chemotherapy regimens[6,7].

Table 1 Grade scales for the assessment of oral mucositis.
World Health Organization GradeGrade 1Grade 2Grade 3Grade 4Grade 5
FunctionPainless ulcers, erythema or mild sorenessPainful erythema, edema, or ulcers but can eat solidsPainful erythema, edema, or ulcers and cannot eat solidsAlimentation is not possible; dependence on IV and feeding-tube
Clinical ExamErythema of the mucosaPatchy ulcerations or pseudomembranesConfluent ulcerations or pseudomembranes; bleeding with minor traumaTissue necrosis; significant spontaneous bleeding; life-threatening consequencesDeath
SymptomsMinimal symptoms, normal diet; minimal respiratory symptoms but not interfering with functionSymptomatic but able to eat and swallow modified diet; respiratory symptoms interfering with function but not with activities of daily livingSymptomatic and unable to adequately aliment or hydrate orally; respiratory symptoms interfering with activities of daily livingSymptoms associated with life-threatening consequencesDeath
Table 2 European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group and the World Health Organization toxicity criteria acute chemoradiation morbidity.
Scale for gastrointestinal toxicity
Grade 0Grade 1Grade 2Grade 3Grade 4
Esophagus toxicity gradeNoneMild fibrosis; Slight difficulty in swallowing solids; No pain on swallowingUnable to take solid food normally; Swallowing semi-solid food; Dilation may be indicatedSevere fibrosis; Able to swallow only liquids; May have pain on swallowing; Dilation requiredNecrosis/Perforation Fistula
Small bowel toxicity gradeNoneMild diarrhea; Mild cramping; Bowel movement 5 times dailyModerate diarrhea and colic; Bowel movement > 5 times dailyObstruction or bleeding, requiring surgeryNecrosis/Perforation Fistula
Colorectal toxicity gradeNoneIncreased frequency or change in quality of bowel habits not requiring medication, rectal discomfort not requiring analgesics; Slight rectal discharge or bleedingDiarrhea requiring parasympatholytic drugs, mucous discharge not necessitating sanitary pads, rectal or abdominal pain requiring analgesics; Excessive rectal mucus or intermittent bleedingDiarrhea requiring parenteral support, severe mucous or bloody discharge necessitating sanitary pads/abdominal distension (flat plate radiograph demonstrates distended bowel loops)Acute or subacute obstruction, fistula or perforation; gastrointestinal bleeding requiring transfusion; abdominal pain or tenesmus requiring tube decompression or bowel diversion
World Health Organization colorectalNoneIncrease of 2-3 stools per day over pretreatmentIncrease of 4-6 stools per day, or nocturnal stools, or moderate crampingIncrease of 7-9 stools per day, or incontinence, or severe crampingIncrease of > 10 stools per day or grossly bloody diarrhea, or need for parenteral support
Toxicity grade

Adequate nutritional support is also a major problem. Regardless of cancer type or dose of treatment, 70% of patients with Grade 3 or 4 mucositis, require tube-feeding to supplement caloric and hydration needs. In patients undergoing hematopoietic stem cell transplant (HSCT), nearly 87% require tube-feeding with 80% requiring narcotic analgesics. There are economic issues related to mucositis as it increases the cost of care. Patients with solid tumors receiving chemotherapy who develop oral mucositis are hospitalized 4.3 d longer at a cost increase of 6277 per cycle[8]. Bone marrow transplant patients with oral mucositis require additional days of hospitalization resulting on average in increased hospital charges of 42749 per patient[9].

Episodes of mucositis are predictable. It is the most significant side effect of patients with head and neck cancer[10,11] receiving high-dose chemotherapy or radiation therapy. Incidence of severe oral mucositis approaches 100% in patients with stage 3 or 4b head and neck cancer receiving high dose radiation. Nearly 75% of patients undergoing HSCT experience advanced grades of both oral and gastrointestinal (GI) mucositis, particularly if methotrexate is used to prevent graft-vs-host disease[6]. High rates of alimentary mucositis, upwards of 20%-50%, occur with the use of 5-fluorouracil, capecitabine or tegafur to treat tumor and metastatic sites[6,12,13]. Similarly, 20%-60% of patients receiving chemotherapeutic antimetabolites such as methotrexate develop dose-dependent alimentary mucositis per cycle[6,12].

Clearly effective management of oral and alimentary mucositis would address patients’ pain, rate of infection, nutritional states as well as recurrent hospitalizations, costs of care and optimization of treatment dose. Most FDA cleared interventions garner only a “standard of clinical practice” justification for their use and await expanded evidence-based examination[14]. Few cancer support therapies qualify for advanced guideline status, as the level of clinical efficacy fall short of that established by the Multinational Association of Supportive Care in Cancer (MASCC)[15,16].

The most recent guidelines on the treatment of oral mucositis include use of antimicrobial lozenges, benzydamine, oral cryotherapy, keratinocyte growth factor-1, and low-level laser therapy. To treat alimentary mucositis, MASCC panel recommends amifostine, ranitidine or omeprazole for upper GI mucositis and sulfasalazine 500 mg twice daily, sucralfate enemas, loperamide or octreotide 100 mg subcutaneously twice daily for lower GI mucositis[14].

No single agent satisfactorily addresses the occurrence of mucositis throughout the length of GI tract. Specifically, the 2005 MASCC guidelines recommended against the use of sucralfate for the prevention or treatment of radiation induced oral mucositis.

However, the patient in this report with oral and alimentary mucositis responded to high-potency sucralfate (HPS). HPS is original potency sucralfate with enhanced muco-adherence achieving high mucosal surface concentration.

Its presumed mechanism of action to be discussed later may involve engagement of nascent growth factors and neutralizing the polarity of ion-gated mucosal nociceptors.

MATERIALS AND METHODS

This was an interventional study in a patient with advanced stage 4 head and neck cancer undergoing concurrent chemoradiation and thus prone to develop severe oral and alimentary mucositis. The setting of the study was an outpatient department of medical oncology, radiation medicine and internal medicine. The patient provided informed consent and was enrolled in a compassionate use program sponsored by Mueller Medical International who provided ProThelial™ a proprietary formulation of HPS.

HPS

HPS has been shown to mitigate nausea, vomiting and diarrhea as well as accelerates healing of GI erosions in man and animals. It is prepared by suspending regular-potency sucralfate in a select solution of cations and bidentate anionic chelators[17]. In this patient, doses of HPS suspension containing 1.5 g of sucralfate were self-administered three times daily for 2 d at the onset of mucositis symptoms and signs. Then twice daily dosing was continued throughout treatment course up to 2 wk following cancer therapy.

Outcome measures

There were two primary outcome measures and two secondary outcome measures. Primary measures consisted of the limitation or disappearance of visible oropharyngeal lesions and patient reported alimentary symptoms of pain, nausea, vomiting and diarrhea. Secondary outcome measures comprised of any need for opiate analgesia and tube-feeding supplementation of oral diet, and the score on a modified Naranjo Questionnaire[18]. The latter was employed to assess the probability of the intervention causing the observed clinical effects.

Case presentation

The patient was a 43-year-old male home health aide, divorced, with four children, who seldom drank alcohol and had stopped smoking 2 years prior to presentation to otolaryngologist but had a 17 pack year history of smoking. His mother died of metastatic breast cancer at age 52 years and his father died of unknown cause.

He presented with a 1 year history of swelling in his right neck for which he had received multiple courses of antibiotics with no appreciable change. With progressive swelling he had developed a 6-mo history of fullness in the back of his throat, a sensation occasionally associated with gagging during meals. He was referred to an otolaryngologist for evaluation of neck swelling and worsening gag.

On physical exam he was 73 inches tall, weighed 235 lbs and had an 8 cm × 6 cm neck mass below the right mandible extending to the angle of the jaw. Direct fiberoptic examination of the throat revealed a large mass at the base of the tongue. The biopsy of the right neck mass revealed a poorly differentiated squamous cell carcinoma. A computed tomography (CT) scan of the neck revealed massive right internal jugular lymphadenopathy from the angle of the jaw to the level of the thyroid measuring 6 cm × 4 cm in cross section. There was a 2-cm mass in the right tonsillar area at the base of the tongue which represented the primary tumor. A CT of the brain and chest was negative for metastatic disease.

Formal cancer diagnosis for this patient was squamous cell carcinoma of the base of the tongue classified as a T3N3M0 stage 4b. His case was presented to the hospital tumor board and it was recommended that he undergo a concurrent course of chemoradiation with a modified radical neck dissection.

Clinical course

Per institution protocol for all stage 4b head and neck cancer expected to develop oral and alimentary mucositis, the patient underwent placement of percutaneous G-tube and given a home supply of tube feeding solution. His concurrent chemoradiation consisted of weekly transfusion of Paclitaxel and Carboplatin with radiation totaling 71 Gy for base of the tongue, 71 Gy to the tumor mass itself and an additional radiation dose of 59 Gy to right sided regional nodes.

By week 2 patient develop WHO Grade 2 oral mucositis, and WHO Grade 1-2 esophageal and small bowel mucositis with painful swallowing, nausea, occasional vomiting and frequent loose stools. Patient was prescribed Prothelial™, a potency-enhanced sucralfate suspension 1.5 g, 3 times daily for 2 d, and then a maintenance dose of 1.5 g twice daily.

RESULTS
Primary outcome measures for HPS

All primary outcome measures were met. There was visible resolution of mucosal erosions and patient reported absence of nausea and diarrhea within 48 h. In week 4 feeling well and assuming that he no longer needed it, the patient stopped HPS for 10 d against protocol while under chemoradiation. He suffered a recurrence of oral lesions, nausea, and diarrhea. Two days following resumption of HPS suspension patient’s recurrent symptoms and ulcers had cleared.

Secondary outcome measures for HPS

All secondary outcome measures were met. Patient required no opiate or non-opiate analgesia while on HPS suspension. Additionally while on HPS, the patient did not require use of the feeding tube nor of caloric supplementation as he was able to continue pre-treatment diet, tolerating both solid food and liquids. At the start of chemo-radiation, the patient was 35 lbs overweight for his height of 73 inches, weighing 235 lbs. While on HPS, he maintained his ideal body weight of 198 lbs.

Naranjo Algorithm for HPS

The Naranjo Algorithm is a validated questionnaire designed to determine the likelihood that an observed clinical effect in a patient exposed to a drug can be attributed to the drug or other factors[18]. Though generally used to investigate adverse drug reactions, the Naranjo Questionnaire, in its most basic sense, is a validated method to assess whether a drug or intervention can be linked to a subsequent clinical reaction (or response). Thus it was reasonable to use the algorithm to assess the likelihood that the observed but unexpected clinical response in this patient was due to HPS.

Most patients with stage 4b head and neck cancer treated with radiation, Paclitaxel and Carboplatin concurrently develop oral and alimentary mucositis due to required concurrent chemo-radiation[10,11,19] and indeed by week 2 this patient developed symptomatic oral and alimentary mucositis of the GI tract. Relevant to Naranjo Algorithm is that patient symptoms and signs disappear within 2 d of introduction of HPS, recurred when the patient stopped the sucralfate intervention for 10 d, but then disappeared 2 d following the resumption of HPS.

Table 3 shows the Naranjo score of 10 in this patient treated with HPS. Ordinarily, a score > 9 implies a definite drug-effect association, a score between 5-8 implies probable association, a score between 1-4 implies a possible association while a score of “0” implies doubtful association. The Naranjo score of 10 for HPS implies that there was likely a “definite” probability that the intervention was associated with the observed clinical improvement in this patient.

Table 3 Modified naranjo probability of intervention-caused response.
QuestionsYesNoDon’t knowCase report
1Are there previous conclusive reports on this response?1000 don’t know
2Did the response appear after the intervention was administered?2-10+2 Yes
3Did the response disappear when the intervention was discontinued?+100+1 Yes
4Did the response reappear when the intervention was re-administered?+2-10+2 Yes
5Are there alternative causes that could on their own have caused the reaction?-1+20+2 No
6Did the reaction reappear when a placebo was given?-1+10+1 No
7Was the intervention detected in the blood in concentrations known to be toxic?+1000 No
8Was the response more apparent when the dose was increased, or less apparent when the dose was decreased?+1000 No
9Did the patient have a similar response to the same or similar intervention in any previous exposure?+100+1 Yes
10Was the response confirmed by any objective evidence?+100+1 Yes
Patients total score10
DISCUSSION

Rubenstein et al[15] reviewed 38 agents and modalities prescribed by physicians from 1985 through 2004 for the management of both oral and alimentary mucositis. By mechanism of action these agents are grouped as anti-inflammatories, anti-infectives, anti-oxidants, immuno-modulators, muco-adhesives, cytoprotectants, anti-ulcerants and biophysical interventions. HPS is a muco-adhesive cytoprotectant that appears to facilitates immuno-modulatory prevention and reversal of mucositis through out the GI tract.

MASCC guidelines[15] do not recommend the use of standard potency sucralfate to treat or prevent mucositis. However, in the patient of this report, HPS prevented oral and alimentary mucositis. When HPS was inadvertently discontinued, when both oral and alimentary mucositis recurred, due to patient’s inadvertent non-compliance, HPS treated it fairly rapidly within 48 h.

For this patient the use of HPS obviated the need to reduce or in any way alter an aggressive treatment regimen for the cancer. There was no use of opiate analgesia. Tube-feed supplementation was unnecessary as well. Obviously, an expanded evaluation of HPS is required as these responses were observed in a single patient.

Translational medicine view

Mucositis is a long-standing unmet medical need in supportive care of cancer treatment. A positive clinical effect of HPS on oral and alimentary mucositis stands in stark contrast to the exclusion of sucralfate from MASCC guidelines - guidelines that greatly impacts medical practice and research. Indeed, expanded clinical trials are necessary to ascertain the permanence (if any) of this HPS observation. Nevertheless the question remains as to mechanism whereby HPS could possibly ameliorate signs and symptoms of mucositis. The following mechanism proposed in this report utilized methods of translational medicine to integrate basic science input from multi-disciplines of study. This mechanism of action for HPS centers on the efficient activation of mucosal growth factors near the site of mucosal injury or assault. From the viewpoint of translational medicine, efficient activation of nascent mucosal growth factors is a therapeutic target for others in the field, focusing efforts on the discovery of other, potentially better, agents to treat and prevent mucositis. The remainder of this report is devoted to a fundamental standard of translational medicine - understand the actions of an intervention so as to use its principle to unearth additional potentially better interventions.

Understanding sucralfate: Its potency and multi-modal mechanism of action

Sucralfate is a polyanionic disaccharide that exerts the totality of its clinical effects through physical contact with the mucosa. It is non-systemic. The classic understanding of sucralfate’s mode of action is that it acts as a “bandage”, as a physical barrier covering the mucosal, supplemented by chemo-adsorption actions of sucralfate against pepsin and bile salts[20].

However, Hollander et al[21] reported other near-immediate mucosal effects following administration of sucralfate. Within 10 min of contact on the mucosa and at appropriate doses, sucralfate initiates epithelial regeneration and stimulates (1) secretion of a mucus gel; (2) the release of bicarbonate beneath this gel; and (3) the secretion of somastatin and prostaglandin E. Unknown at the time of their report, these effects were mediated by direct engagement of focal growth factors by sucralfate. “In appropriate doses” is the operative phrase. The effects of sucralfate reported by Hollander et al[21] occurred at doses five to twenty times the allowable human dose of 14 mg/kg. Rats received single doses of 70-280 mg/kg. In man, the latter high oral doses can result in bezoar formation in man.

Potency enhancement of sucralfate

Potency of sucralfate is defined as the extent of clinical effect associated with surface concentration of sucralfate achieved following administration. Standard potency sucralfate cannot treat or prevent oral or alimentary mucositis. However, the potency of sucralfate can be greatly enhanced by suspending standard potency sucralfate in a solution of multivalent cations buffered by multi-dentate anionic chelators. The resultant “cross-linked” sucralfate is believed to facilitate orderly layering of sucralfate on the mucosa and upon itself. Orderly layering on the mucosa and upon itself could account for the multifold elevation of surface concentration of sucralfate in HPS per dose without a commensurate increase in its formulary strength in grams per milliliter. Three hours following administration, HPS maintains mucosal concentrations of sucralfate at least 7 fold that expected for standard potency sucralfate of equal formulary strength[17]. On ulcerated or irritated enteric lining the mucosal concentrations of sucralfate from HPS is 23 fold above that expected for standard potency sucralfate of equal formulary strength.

These multiples of surface concentration achieved by HPS are equivalent to the augmented doses of sucralfate used unsuspectingly by Hollander et al[21]. This potency enhancement effect is retained when HPS suspension is dehydrated and administered as a powder in a capsule.

Immuno-modulatory and depolorization mechanism of action

The exact mechanism of action of HPS is unknown. However, relying on the literature across several disciplines of biomedical sciences, a case can be made that HPS (as well as other polyanionic compounds) provides two significant effects on contact: firstly an immuno-modulatory effect through non-specific but high-affinity interactions with growth factors and secondly, an ionic depolarization of activated (“firing”) ion-gated nociceptors embedded in the mucosa. Ion-gated nociceptors embedded within the mucosa give rise to pain, nausea and vomiting. Polyanionic stabilization of ion-fluxes in activated nociceptors reduce their firing, and thereby the sensation of pain, nausea and vomiting on contact. Activated growth factors of the GI tract maintain normal mucosal function and epithelial integrity. The following outlines salient features of GI function that are most likely influenced by the topical application of HPS.

Mucosal physiology of GI tract

The mucosal lining of the GI tract is tasked with both digestive and defensive functions[22,23]. For the purposes of defense, the GI lining has an embedded array of specialized mucosal receptors (nociceptors)[23,24], intra-mucosal (epithelial) lymphocytes[25-34] sub-mucosal immune cells[35-42] and sub-mucosal sensory and effector neurons[23,24]. Mucosal nociceptors are gated-ion type receptors that register acidity, pressure, stretch and pain and are innervated by A-fiber and C-fiber neurons[23-25].

Specialized mucosal lymphocytes known as intra-epithelial lymphocytes (IELs) are responsible for surveillance and detection of unwanted agents, toxins and substances[23-25]. There are three major subpopulations of such cells[26,31,32]. Two major subpopulations of α-β IEL’s (αβ-IELs) that filter luminal contents for foreign antigens or toxins and are generally responsible for signaling the presence of unwanted agents by active expression of pro-inflammatory cytokines[31,32]. The third subpopulation of surveillance lymphocytes known as γ-δ IEL’s (γδ-IELs) are tasked with (1) controlling and temporizing the signaling functions of the first two subpopulations of αβ-IELs; (2) defend against microbial invasions; (3) support epithelial cells; and (4) focal elaboration and feedback secretion of transforming TGFβ[26-30]. γδ-IELs are subject to direct modulation by neighboring epithelial cells. The communications between IEL’s and epithelial cells are conducted via cytokines[28,29,33,43-45].

Submucosal immune cells, namely mast cells, are stimulated (up-regulated) by pro-inflammatory cytokines released from upregulated IELs. Up-regulated mast cells release pro-inflammatory cytokines that in turn affect (or up-regulate) sub-mucosal neurons[35-42]. Submucosal neurons up-regulate by pro-inflammatory cytokines from IEL-stimulated mast cells then elaborate and release neuron-derived cytokines and effector substances like substance-P, vasoactive intestinal protein and neurokinins[23,31,32,34].

In turn, neuro-cytokines and effector substances released by up-regulated neurons can (1) stimulate epithelial cells to secrete fluids[23,24,46]; (2) stimulate sub-mucosal muscularis and the circular muscles of the gut to contract while simultaneously causing the longitudinal muscles to relax[23-25,47,48], (actions that result in intestinal cramping and bloating); and (3) stimulate capillary vessels to expand and increase their flow[23,24]. Additionally, stimulated sub-mucosal sensory neurons release pain substances within the sub-mucosa and into the bloodstream; they also transmit up-regulating neuronal signals outside the GI tract into dorsal root ganglia of the spine[23,24,49,50] to affect segments of the GI that are proximal and distal to the area of IEL activation.

These mucosal-mediated actions are defensive and lead to a “functional mucosal syndrome”, a syndrome wherein the clinical symptoms of nausea, vomiting, pain[24,49], colic, ileus[47,48], even diarrhea[50-52] arises from mucosal mediated defensive actions provoked by antigen stimulated firing of αβ-IELs. These actions structure substantially the mucosal immuno-neuronal physiology that is indirectly affected by HPS on the instance of its contact with the mucosa.

These defensive functions of the epithelium are led by an exaggerated presence of pro-inflammatory cytokines that are secreted out of balance relative to the presence of anti-inflammatory cytokines. Activated growth factors similar to fibroblast growth factor, EGF, and TGF[53-57] are tasked with restoring cytokine balance. The consequence of disproportionate concentration of pro-inflammatory cytokines is a feedback secretion of growth factors, and more importantly, a feedback increased expression of growth factor receptor sites on nascent enteric epithelial cells[58]. Activated growth factors, once inserted into their tyrosine kinase membrane receptors, spawn the release of anti-inflammatory cytokines, with a feedback reversal of expressed pro-inflammatory cytokines[58] as well as re-epithelialization of the mucosa[55].

HPS facilitate local engagement of mucosal growth factors

HPS engagement of the mucosal surface may lead to focal movement growth factors, which facilitate conformational changes to enable their insertion into tyrosine membrane receptors[53]. In this way HPS supports the “immuno-balancing” efforts of growth factors by direct physical engagement of growth factors[53,54]. Thusly, HPS accelerates a growth factor-dependent correction of “cytokine imbalance”, reversing “functional mucosal syndrome”, with the reversal of nausea, vomiting, diarrhea, ileus, cramping, and bloating[47,48,50,52]. Active engagement of growth factors by HPS accelerates healing of erosions and ulcerations[53,54,56].

Potency-enhanced sucralfate or HPS appears useful for treatment and prevention of chemo-radiation induced mucositis in both the upper and lower GI tract. Given that severe cases of mucositis lead to dehydration, systemic infections and unwanted reduction or postponement of optimal cancer treatment this observation in reported here could be significant. Disciplined investigations on the use of HPS in patients with mucositis are necessary to assess reproducibility of this observation and to establish efficacy and safety. The suggested mechanism of action is testable by multi-array cytokine analysis of mucosal biopsies prior to, during and following treatment with HPS. Obviously, like HPS, any other non-systemic polysaccharides suitable for potency-enhancement could be investigated for efficacy in the treatment of oral and alimentary mucositis.

COMMENTS
Background

An imbalance favoring pro-inflammatory cytokines over anti-inflammatory cytokines is likely involved in the disease process of chemo-radiation induced oral and alimentary mucositis. Cancer patients suffering from mucositis have limited therapeutic support options. As a result poorly treated mucositis can lead to suboptimal cancer treatment, dehydration, costly re-hospitalizations and untimely deaths.

Research frontiers

In 2012 the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology reviewed 64 clinical studies involving 11 interventions for mucositis. They found only one intervention adequate for guideline recommendation. Evidence supported limited use of recombinant human KGGF-1 (palifermin) for prevention (but not treatment) of oral mucositis if given three d prior to conditioning and three d following autologous stem cell transplantation in hematological malignancies. Inconclusive evidence prohibited guideline recommendations for any other intervention. Standard potency sucralfate was not recommended.

Innovations and breakthroughs

High potency sucralfate (HPS) is new. It is a suspension of standard potency sucralfate in a cationic solution of multi-dentate chelators. HPS hyper-concentrates sucralfate on the mucosal lining such that 3 h following its administration, the surface concentration of sucralfate remains 7-23 fold greater than otherwise expected - 7 fold greater on normal mucosal and 23 fold greater on ulcerated lining. Sucralfate of standard potency binds mucosal growth factors, yet fails to demonstrate substantial clinical effects. However the use of HPS in this patient resulted in simultaneous prevention and treatment of oral and intestinal mucositis. It is assumed therefore that there is an augmented interaction between HPS and mucosal growth factors.

Applications

The use of HPS infers that there are additional mechanisms of action for sucralfate than previously thought. These would include immuno-modulation centered on engagement and activation of mucosal growth factors as well the depolarization of ion-gated nociceptors resulting in rapid relief of mucosal pain. There may be other applications of HPS particularly in clinical scenarios dependent on epithelial healing and repair.

Peer review

This paper explores HPS may directly or indirectly facilitate an immunomodulatory mechanism involving accelerated growth factor activation, which may be a new target for therapeutic intervention in such patients. It is an interesting and very well written article.

Footnotes

P- Reviewers Gokhan K, Mario K S- Editor Zhai HH L- Editor A E- Editor Zheng XM

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