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Prospective evaluation of oral mucositis in acute leukemia patients receiving chemotherapy
Abstract
Knowledge of oral mucositis (OM) in patients with acute leukemia (AL) and chemotherapy (CT) has remained limited. Thus, a prospective, longitudinal study was undertaken to characterize clinical features, associated risk factors, and behavior of OM in a cohort of AL patients starting CT.
Prospective and longitudinal study. A cohort of patients, older than 15 years of age with AL, scheduled to receive CT, was followed from March 2006 to October 2007. At baseline and three times per week, for 21 days, patients had an oral examination performed using the Oral Mucositis Assessment Scale (OMAS); also, oral pain and difficulty to swallow were recorded using a visual analog scale. Weekly, salivary flow measurements (Schirmer's test modified version) were done.
A cohort of 29 AL patients was followed for a median time of 21 (range, 14-53) days; 12 (41.4%) developed OM, with a mean OMAS score of 0.181 (SD +/- 0.56) and a mean peak OMAS score of 1.8 (SD +/- 0.56). The OM onset mean time was 9.8 (range, 2-20, SD +/- 6.09) days, with a mean duration of 7 (range, 3-14, SD +/- 4.15) days. OM was significantly correlated with salivary flow [rs = 0.420 (P = 0.0051)], oral pain [rs = 0.47 (P < 0.0001)], ability to swallow [rs = 0.36 (P = 0.0001)], and type of food intake [rs = 0.38 (P < 0.0001)].
OM is a frequent and early side effect of CT closely correlated with oral pain, difficulty to swallow, and impairment in food intake.
... The symptoms associated with OM can profoundly impact the well-being of individuals undergoing cancer treatment, affecting both their physical and psychological dimensions. OM not only diminishes the quality of life for patients but also elevates the risk of infections, disrupts treatment schedules, jeopardizes the success of cancer therapy, and necessitates hospitalization, thereby increasing overall treatment costs [3,4]. ...
... To address these challenges, effective management strategies are imperative, aiming to alleviate symptoms and expedite the healing process from tissue damage [3,4]. An intriguing avenue in this regard is the role of glutamine, an amino acid with physiological significance in cell proliferation and wound healing. ...
... This condition involves atrophy of the epithelium, vascular damage, inflammatory cell infiltration, and ulceration [1]. Approximately 20-80% of patients undergoing chemotherapy will experience OM, and nearly all patients receiving head and neck radiotherapy will develop it [2,3]. OM is a highly painful condition that hampers activities related to the stomatognathic system, including speaking, processing food, eating, and maintaining oral hygiene, thereby negatively impacting the quality of life [4,5]. ...
Introduction: Chemotherapy and head-and-neck radiotherapy administered to cancer patients can lead to the development of oral mucositis (OM), a condition characterized by extensive and excruciating damage to the oral mucosal tissues. Glutamine, an essential amino acid, plays a crucial role in various facets of cellular metabolism, particularly in cell proliferation, wound healing, and leukocyte function, and has been reported to have preventive and therapeutic benefits in oral mucositis. Objective: This study aims to comprehensively review current findings on the potential clinical applications and mechanisms of glutamine in the management of oral mucositis. Review: Several studies have demonstrated the efficacy of glutamine supplementation in diminishing the severity of OM and expediting the healing process. This positive effect is attributed to the modulation of inflammation and the stimulation of pro-regenerative activity in keratinocytes and fibroblasts. Furthermore, glutamine intervention enhances the overall nutritional status of patients, reducing the risk of complications commonly observed in cancer patients. Additionally, it plays a pivotal role in preventing or ameliorating the conditions of sarcopenia and lymphopenia. Conclusion: Glutamine supplementation emerges as a promising intervention for the management of oral mucositis in patients undergoing chemotherapy or head-and-neck radiotherapy. Its multifaceted impact, including inflammation modulation, pro-regenerative activity, and improvement in nutritional status, positions glutamine as a valuable component in the comprehensive care of cancer patients experiencing oral mucositis
... Another study showed that the risk of oral mucositis increases with age (22). However, few studies did not show any relationship between age and oral mucositis (11,16,24,25). Similarly, there was no significant correlation between age and oral mucositis in this study. ...
... This study showed gender was not a risk factor for oral mucositis development. Similarly, other studies did not show any correlation between gender and oral mucositis (11,16,24,26,27). However, according to the studies the incidence of oral mucositis developed by women is higher (10,19,28,29). ...
... The risk of mucositis is triggered by factors such as poor oral hygiene, dental problems, high levels of microorganisms in the mouth flora, and a decrease in salivary secretion (15,32). Ramirez-Amador et al., (2010) found no significant relationship between oral hygiene and mucositis (24). As for this study, dental caries, oral care, and tooth brushing were not found to be risk factors for oral mucositis. ...
Purpose: Oral mucositis is a common complication of cancer treatment that may negatively impact the patient’s cancer treatment outcome. This study was done to determine the incidence of oral mucositis development and risk factors in patients receiving chemotherapy. Material and Methods: This prospective cohort study included 150 participants undergoing outpatient cancer chemotherapy. To determine the development of oral mucositis, the participants were evaluated for the first course of chemotherapy (day 0) and the next course of chemotherapy treatment (day 14). ‘Patient Information Form’ and the World Health Organization’ Mucositis Grading Scale’ were used to collect data for the study. Descriptive statistics, chi-squared test, and logistic regression were used to analyze the results. Results: According to oral mucosal assessment, incidence of oral mucositis was 27.3%. The mean onset and the mean recovery of oral mucositis were 4.16 ± 2.13 days and 8.72 ± 2.32 days. The most common oral problems were mouth dryness (53.3%), dental caries (44%), and decreased sense of taste (32%). In the oral mucosal assessment performed on the 14th day, 9 patients were found to be grade 1. Patients with a history of mucositis (OR = 5.76, Cl = 2.33–14.24, p = 0.00) showed a significantly higher incidence of oral mucositis. Conclusion: In this study, the incidence of oral mucositis and risk factors that may affect the development of oral mucositis in patients receiving chemotherapy were investigated. Mucositis history was found as a risk factor in oral mucositis development. Early recovery of oral mucositis after chemotherapy was observed. Therefore, patients should be followed up in the early period after chemotherapy.
... OM is a frequent condition in individuals submitted to HSCT, which affects their quality of life (Silva et al., 2015;Vera-Llonch et al., 2007). In the present sample there were a great number of participants with leukemia, consequently, the conditioning regimens were mostly MA, which could explain the high incidence of OM (Eslami et al., 2016;Ramírez-amador et al., 2010;Small et al., 2007;Wojciechowicz et al., 2014). ...
... The use of MTX as immunoprophylaxis may also have been a contributing factor to OM high incidence due to its high cytotoxic potential in cells with rapid multiplication. In addition, MTX is responsible for the delay of repair of the tissue damaged by chemotherapeutic conditioning (Ahmed et al., 2017;Cutler et al., 2005;Knoll et al., 2016;Matsukawa et al., 2016;Ramírez-amador et al., 2010;Small et al., 2007). ...
Objetivo: describir la incidencia y el puntaje de la mucositis oral (MO) y las morbilidades relacionadas en individuos sometidos a trasplante de células madre hematopoyéticas (TCMH) a lo largo del período de inmunosupresión. Métodos: Los sujetos con enfermedades onco / hematológicas, mayores de 14 años, sometidos a TCMH alogénico fueron evaluados diariamente por la presencia y clasificación de OM, nivel de dolor, disfagia, disgeusia y xerostomía. El examen comenzó dos días antes de la infusión de células madre hematopoyéticas y finalizó veinte días después. La OM se clasificó de acuerdo con la escala de la OMS y se utilizó la escala analógica visual (EVA) para medir el nivel de dolor. Resultados: se reclutaron 23 individuos, el 83% con enfermedades malignas y el 91% con OM. La mediana del grado máximo de OM fue 3 y el nivel máximo de dolor fue 9. Hubo una mediana de 11 días de uso de medicación opioide. Los sujetos que tuvieron el mayor número de días con dolor en la boca alcanzaron el grado máximo de OM y el mayor número de días y el uso de opioides. Conclusión: Hubo una alta incidencia y puntuaciones más altas de OM, pérdida de masa corporal y dolor en esta muestra.
... In the study carried out by Rodrigues et al. [6], 93.6% of the patients with multiple myeloma, who underwent chemotherapy with melphalan, showed some degree of oral mucositis. The results of Ramírez-Amador et al. [7] found 41.37% of oral mucositis in patients with leukemia. ...
... The oral mucositis is the major cause of painful symptomatology during the chemotherapy, which may lead to oral feeding difficulties, requiring the use of parenteral nutrition or even the interruption of the antineoplastic treatment [7]. Therefore, preventing oral mucositis diminishes suffering and improves better quality of life for these patients. ...
The aim of this study was to evaluate the frequency of oral mucositis in patients with hematologic malignancies and relating to the cancer treatment and chemotherapy regimen. This was a cross-sectional study with 112 patients with hematologic malignancies treated by chemotherapy. The association between oral mucositis and the variables was performed by Pearson’s chi-square test, considering a 5% error probability. The frequency of oral mucositis was low (25%). Its occurrence was associated with hematopoietic stem cell transplantation (PR = 3.33, 95% CI = 1.60–6.91) and the use of melphalan or methotrexate (PR = 5.26, 95% CI = 2.31–11.95). Some chemotherapy drugs, such as melphalan and methotrexate, are more toxic to the oral mucosa, as well as the chemotherapy regimen prior to hematopoietic stem cell transplantation. Furthermore, the low frequency of oral mucositis may be related to preventive non-pharmacological protocols, like cryotherapy during drug infusion and laser therapy. This result suggests the importance of the oral care to patients with hematologic malignancies undergoing chemotherapy.
... OM is a frequent condition in individuals submitted to HSCT, which affects their quality of life (Silva et al., 2015;Vera-Llonch et al., 2007). In the present sample there were a great number of participants with leukemia, consequently, the conditioning regimens were mostly MA, which could explain the high incidence of OM (Eslami et al., 2016;Ramírez-amador et al., 2010;Small et al., 2007;Wojciechowicz et al., 2014). ...
... The use of MTX as immunoprophylaxis may also have been a contributing factor to OM high incidence due to its high cytotoxic potential in cells with rapid multiplication. In addition, MTX is responsible for the delay of repair of the tissue damaged by chemotherapeutic conditioning (Ahmed et al., 2017;Cutler et al., 2005;Knoll et al., 2016;Matsukawa et al., 2016;Ramírez-amador et al., 2010;Small et al., 2007). ...
Objetivo:
Describir la incidencia y el puntaje de la mucositis oral (MO) y las morbilidades relacionadas en individuos sometidos a trasplante de células madre hematopoyéticas (TCMH) a lo largo del período de inmunosupresión.
Métodos:
Los sujetos con enfermedades onco / hematológicas, mayores de 14 años, sometidos a TCMH alogénico fueron evaluados diariamente por la presencia y clasificación de OM, nivel de dolor, disfagia, disgeusia y xerostomía. El examen comenzó dos días antes de la infusión de células madre hematopoyéticas y finalizó veinte días después. La OM se clasificó de acuerdo con la escala de la OMS y se utilizó la escala analógica visual (EVA) para medir el nivel de dolor.
Resultados:
Se reclutaron 23 individuos, el 83% con enfermedades malignas y el 91% con OM. La mediana del grado máximo de OM fue 3 y el nivel máximo de dolor fue 9. Hubo una mediana de 11 días de uso de medicación opioide. Los sujetos que tuvieron el mayor número de días con dolor en la boca alcanzaron el grado máximo de OM y el mayor número de días y el uso de opioides.
Conclusión:
Hubo una alta incidencia y puntuaciones más altas de OM, pérdida de masa corporal y dolor en esta muestra.
... Mucosal injuries affect the entire gastrointestinal tract, from oral cavity to anus [6]. Resulting lesions occurring in epithelium and tunica submucosa are characterised in five clinical phases: (a) initiation, (b) primary damage response, (c) signal amplification, (d) ulceration, and (e) healing [7][8][9][10] (Tab. III). ...
... Primary mucosal cell injuries resulting from oxidative stress lead to the expression of early response genes and activation of DNA transcription factor. The pathophysiology of mucositis involves various factors, such as nuclear factor kappa B (NF-kappa B) protein complex playing an essential role in the immune response to an infectious agent, cyclooxygenase-2 (COX-2) activated by agents related to the inflammation, pro-inflammatory cytokinesin particular interleukin (IL)-1b (IL)-6, and tumour necrosis factor (TNF) [7,8]. Clinically, it begins with non-specific oral discomfort preceded by redness, burning sensation, increased sensitivity to sour and hot foods, then erosion and ulcers occur that make it difficult to take and swallow foods, accompanied by a series of other symptoms that make patient's functioning difficult, of which the following should be listed: pain, swelling, fever, mycosis, bacteraemia and sepsis [4,6,11,12]. ...
Historically, oral mucositis (OM) has been identified as a symptom developing in patients undergoing irradiation due to head and neck cancers, those undergoing therapy in preparation for a stem cell transplant, or receiving special therapeutic protocols due to acute myeloid leukaemia. It results from direct toxic injury to the mucosal epithelial cells by the immunosuppressive regimen. In this article we want to describe pathogenesis, diagnostic and actual possibility of treatment of OM. The literature reports several rating scale for OM that have been used for patients undergoing cancer therapy. The most useful of them are Oral Toxicity Scale and Oral Mucositis Assessment Scale. In the prevention and treatment of OM associated with standard chemotherapy various drugs and agents acting locally and systemically are used. Many of them are still remaining in the course of research.
... Despite considerable improvement in the medical management of cancer patients in recent years, significant complication often accompanies the potential benefits of the treatment. Chemotherapy induced oral mucositis is a frequent oral complications achieved in patients which receives highly mucotoxic drugs (Arora et al., 2008;Sonis, 2009;Ramírez-Amador et al., 2010;Freitas et al., 2014 ) Oral mucositis is associated with intense pain which limits patient's ability to eat and drink normal foods (Silverman, 2007). Severe and wide spread ulcerated mucositis in these group of medically compromised patients both physiologically (by the tumour) and literally (by cancer therapy) will place them at an increased risk of systemic infection and bleeding (Bensadoun, 2012;Sonis, 2009). ...
Backgrounds: Oral mucositis is a frequent adverse side effect of cancer chemotherapy which is associated with intense oral pain. However, it impairs the quality of life of these patients. Low Level Laser Therapy (LLLT) has been increasingly used in recent years, mostly to accelerate wound healing and to reduce pain. In cancer patients, LLLT has been shown to reduce the incidence and severity of oral mucositis. Objectives: The aim of this study is to evaluate the effect of low level laser therapy in the management of chemotherapy induced oral mucositis. Patients and Methods: The study design used was a randomized clinical trial. A total of 67 cancer patients were eligible to participate in the study. Thus, they were divided randomly into two groups: group 1 irradiated with prophylactic or active laser therapy (AlGalnAs laser diode device with a wave length of 940±15nm, 0.3mW, and a probe emitting dose of 4.2 J/cm²) and group 2 received inactive or sham laser therapy (power output equal to zero). However, for the ethical purpose, once the patients developed ulcerative mucositis, they are irradiated with active laser therapy. The oral assessment was performed daily starting from the first day of the chemotherapy by
... Moreover, chemotherapy activated the proinflammatory cytokines. These cytokines enhance damage and apoptosis of particularly basal epithelial cells and submucosal ones [32] . As well as the strong cytotoxic impact of anti-tumor drugs on the basal epithelial cells, connective tissue, and the oral microflora [33] . ...
Background: 5-Fluorouracil (5-FU) is a common anti-tumor drug that is used in the management of different forms of
malignancies. Mucosal inflammation of the oral cavity is the most common adverse effect of its administration. Melatonin has
valuable activities like antioxidant and anti-inflammatory effects. Melatonin has protective effects on different organs against
various side effects caused by anti-cancer treatments.
Aim of the work: To evaluate the protective effect of melatonin against 5-fluorouracil –induced changes in the tongue mucosa
of rats using different histological techniques.
Materials and Methods: Forty adult male rats were randomly divided into four main groups: group I acted as control, group
II was given melatonin at a dose 10 mg/kg/day, group III was given 5-FU at a dose 60 mg/kg on day 0 and 40 mg/kg on day
2, and group IV was given melatonin one hour before 5-FU administration. The specimens of the tongue were processed for
light and scanning electron microscopic study. Immunohistochemical study was done by employing the nuclear marker for
proliferation of the cells (Ki67) antibody.
Results: 5-FU induced structural changes in the tongue mucosa in the form of focal loss of lingual papillae, marked thinning
and shortening of the filiform papillae, separation of the keratin layer from the underlying epithelium, vacuolated cytoplasm
of the basal and suprabasal epithelial cells, and congestion of blood vessels with cellular infilteration in the lamina propria. A
significant decrease in the papillae height, papillae width, ventral epithelial thickness, and percentage of Ki67 immunopositive
cells were also detected. Scanning electron microscopy exhibited atrophy of the filiform papillae with desquamation of their
epithelial covering. Deformed fungiform papillae with ill-defined taste pores were also revealed. On the other hand, these
changes were less pronounced in rats received melatonin before 5-FU administration.
Conclusion: 5-FU induced significant structural changes in the tongue mucosa of albino rats. Melatonin attenuated these
mucosal changes.
... The NFκB increases the levels of proinflammatory cytokines as TNF-α and IL-1β, cyclooxygenase-2 (COX-2), matrix metalloproteinase-9 (MMP-9), inducible nitric oxide synthase (iNOS), and the transforming growth factor β (TGF-β)/SMAD 2/3 pathway (Sonis, 2004(Sonis, , 2009Ribeiro et al., 2017). Proinflammatory cytokines amplify the tissue damage and the apoptosis of specially submucosal and basal epithelial cells (Ramirez-Amador et al., 2010). Macrophages are activated, which promote tissue damage by expressing metalloproteinases and producing additional TNF-α. ...
Oral mucositis (OM) is a common adverse effect resulting from cancer therapy. The OM it has implications that may compromise oncologic treatment and decrease the patient’s quality of life. The therapeutic options to prevent or treat the symptoms of OM are scarce; there is no effective therapy that improves the symptoms. Based on the need for further research for the treatment of OM, the present study objective was to evaluate the effect of telmisartan (TELM) on the OM induced by 5-fluorouracil (5-FU), using as animal model Golden Syrian hamsters. 5-FU followed by mechanical trauma on day 4 was used to induce OM in hamsters. Euthanasia occurred on the day 10. The experiments were constituted by the groups saline, mechanical trauma, 5-FU, and TELM in three doses (1, 5, or 10 mg/kg). Macroscopic, histopathological, and immunohistochemical analyses as well as immunofluorescence experiments were performed on the oral mucosa of the animals. The samples also were used for analysis enzyme-linked immunosorbent assays and quantitative real-time polymerase chain reactions (qPCR). TELM (5 or 10 mg/kg) was able to reduce the inflammatory ulceration and infiltration in the oral mucosa of the animals, decreasing the levels of the cytokines TNF-α and IL-1β. These treatments was minimize the immunostaining for cyclooxygenase-2, matrix metalloproteinase-9, transforming growth factor-β, and smad 2/3. The nuclear transcription factor kappa B (NFκB) p65 and inducible nitric oxide synthase were reduced in the oral mucosa. Finally, TELM (10 mg/kg) increased the PPARγ gene expression and reduced STAT1 and NFκB p65 gene expression relative to the 5-FU group. Therefore, TELM prevents the OM produced by 5-FU on animal model.
... Despite considerable improvement in the medical management of cancer patients in recent years, significant complication often accompanies the potential benefits of the treatment. Chemotherapy induced oral mucositis is a frequent oral complications achieved in patients which receives highly mucotoxic drugs (Arora et al., 2008;Sonis, 2009;Ramírez-Amador et al., 2010;Freitas et al., 2014 ) Oral mucositis is associated with intense pain which limits patient's ability to eat and drink normal foods (Silverman, 2007). Severe and wide spread ulcerated mucositis in these group of medically compromised patients both physiologically (by the tumour) and literally (by cancer therapy) will place them at an increased risk of systemic infection and bleeding (Bensadoun, 2012;Sonis, 2009). ...
Backgrounds: Oral mucositis is a frequent adverse side effect of cancer chemotherapy which is associated with intense oral pain. However, it impairs the quality of life of these patients. Low Level Laser Therapy (LLLT) has been increasingly used in recent years, mostly to accelerate wound healing and to reduce pain. In cancer patients, LLLT has been shown to reduce the incidence and severity of oral mucositis.
Objectives: The aim of this study is to evaluate the effect of low level laser therapy in the management of chemotherapy induced oral mucositis.
Patients and Methods: The study design used was a randomized clinical trial. A total of 67 cancer patients were eligible to participate in the study. Thus, they were divided randomly into two groups: group 1 irradiated with prophylactic or active laser therapy (AlGalnAs laser diode device with a wave length of 940±15nm, 0.3mW, and a probe emitting dose of 4.2 J/cm²) and group 2 received inactive or sham laser therapy (power output equal to zero). However, for the ethical purpose, once the patients developed ulcerative mucositis, they are irradiated with active laser therapy. The oral assessment was performed daily starting from the first day of the chemotherapy by applying WHO grading system. After 24 hours, the assessment of associated oral pain was carried out every two days with visual analog scale before laser application. Consequently, the associations between variables were analyzed statistically using SPSS version 20.
Results: All the patients were presented with some grade of oral mucositis. In the active or prophylactic laser group, the severity of oral mucositis was lower than the inactive or therapeutic laser group. Moreover, the incidence of grade 3 and grade 4 were less observed in the active or prophylactic laser groups than the sham or therapeutic laser groups. In addition, the mean time of healing was significantly lower in the prophylactic laser group than in the therapeutic laser groups (2.05 + 1.89 versus 4.5 + 2.4 days, p> 0,004). Prophylactic laser application was associated with significant reduction of oral pain in comparison with inactive or therapeutic laser therapy (1.18 + 1.09 versus 2.12 + 1.60, p> 0.01).
Conclusions: Prophylactic laser therapy is effective in reducing the incidence of sever oral mucositis and in alleviating associated oral pain.
... Factores tales como, los niveles de neutropenia, el espectro del antibiótico, el uso de esteroides o los niveles de xerostomía, si predisponen a la colonización de la candidiasis 229 . Respecto a la mucositis en estos pacientes la desarrollan en un 75% debido a la toxicidad del tratamiento 230,231 . Las localizaciones más afectadas por la mucositis en los pacientes trasplantados de médula ósea son: el suelo de la boca, la zona ventral de la lengua, la mucosa labial, mucosa yugal. ...
... Among patients with mucositis, self-reported QoL is an important tool that can be used alongside clinical measures to evaluate the effectiveness of medical treatments (Kushner et al. 2008;L opez-Jornet et al. 2009). Indeed, some papers in the literature have analysed the impact of oral mucositis on daily life among patients undergoing transplant (McQuellon et al. 1997;Elting et al. 2008;Guimarães et al. 2008;Kushner et al. 2008;L opez-Jornet et al. 2009;Ozturk et al. 2009;Cheng et al. 2010;Ram ırez-Amador et al. 2010;Manji et al. 2012), and only one was performed in our country, but it used a generic instrument to perform this measurement (Guimarães et al. 2008). There is also very little information on the oral health protocols performed by Brazilian hospitals accredited for organ transplantation. ...
Oral mucositis is a painful condition that occurs in 80% of patients who undergo haematopoietic stem cell transplantation (HSCT). Our objective was to determine the impact of mucositis on quality of life (QoL) of patients subjected to HSCT treated with low-level laser therapy (LLLT). Patients were evaluated: (1) on the first day of treatment; (2) 5 days after autologous or 8 days after allogeneic transplantation; (3) once bone marrow had integrated; and (4) 30 days after discharge. Clinical evaluation was performed using the World Health Organization criteria; oral health QoL was measured using the Oral Health Impact Profile (OHIP-14); and mucositis symptoms with the Patient-Reported Oral Mucositis Symptom (PROMS) scale. The higher the score, the lower the patient's QoL. The OHIP-14 responses showed that at D + 5/D + 8, all domains had the highest scores, while at times 1 and 4, the scores were lower. In the PROMS scale, all domains scored worst at time 2, and the differences between the scores at the four times were statistically significant. The study has shown that QoL improves over time in patients undergoing LLLT therapy for mucositis prevention.
© 2015 John Wiley & Sons Ltd.
New insights into the molecular biology of childhood leukemias have stimulated numerous advances in diagnostic methods, strategies for risk assessment and the development of novel therapy for genetic subtypes of the diseases. Fully revised and updated, this new edition of Childhood Leukemias provides the most comprehensive, clinically-oriented and authoritative reference dedicated to these diseases. Beginning with an overview of history, cell biology, and pathology, subsequent chapters review approaches in the evaluation and management of specific leukemias, new therapeutic development and the unique pharmacodynamics and pharmacogenetics of individual patients. New chapters include epigenetics of leukemias, leukemias in patients with Down syndrome and leukemia in adolescents and young adults. The final section covers the complications associated with the disease or its treatment and supportive care during and after treatment. Authored by leading experts, this is a 'must-have' for any physician or investigator who deals with leukemias in childhood.
Orofacial pain is an important aspect of cancer, antineoplastic treatment, and oral mucosal diseases. It often serves as the key for diagnosis and the initiation of treatment. Pain management is an essential component of successful treatment of oral manifestations of the underlying disease, and it often serves as the desired primary outcome. Treatment of pain associated with oral mucosal diseases is first and foremost directed at the source of the symptoms rather than pain itself. The clinician should be aware of the importance of pain assessment and consider pain palliation as part of the overall management of the patient’s well-being. This chapter reviews aspects of pain experienced by cancer patients and pain associated with oral cancer and oral mucosal diseases. Also reviewed are the clinical aspects of orofacial pain assessment, monitoring, and management. Finally, this chapter highlights the role of the healthcare provider in early detection of pain syndromes associated with malignancies.
What is known and objective:
Chemotherapy (CT)-associated oral mucositis (OM) is one of the most debilitating and painful side effects in oncology patients, with limited effective management options. During CT, matrix metalloproteinases (MMPs) are upregulated, causing damage in mucosal and submucosal tissues, and playing a key role in OM; therefore, the use of subantimicrobial doxycycline as a MMP inhibitor may represent a potential approach for OM management. The aim of this clinical trial was to evaluate the efficacy and safety of low doses of doxycycline in OM development in individuals with acute leukaemia (AL) during CT.
Methods:
Randomized controlled clinical trial (Registration No. NCT01087476) performed in adult AL patients scheduled to receive CT (September 2010-October 2014). Individuals were stratified by leukaemia type and assigned randomly to receive doxycycline hyclate (50 mg/d) (doxycycline group: DG) or placebo (placebo group: PG) before and during CT. Included subjects had a baseline oral examination and thereafter 3 times a week during 21 days. The primary outcome was OM development.
Results and discussion:
One hundred and forty-seven AL subjects were enrolled: 74 in DG and 73 in PG; baseline characteristics between groups were comparable. During follow-up, 15 (10.2%) individuals developed OM; no differences between treatment groups were found (DG:8.1%, PG:12.3%; P = .59). The mean OM Assessment Scale score was 2.51, without differences between groups (DG:2.7, PG:2.4; P = .65). Low baseline blood albumin levels in the OM-affected individuals were identified, revealing the effect of systemic deterioration as a predisposing factor for OM development. No adverse effects were observed.
What is new and conclusion:
Subantimicrobial doses of doxycycline did not reduce the incidence, onset, duration or severity of OM.
Objective:
To assess changes in the salivary expression of IL-1α,-1β,-2,-6,-10,-17 and TNF in acute leukemia (AL) patients before and during chemotherapy, and its association with HSV infection, oral candidiasis (OC) and oral mucositis (OM) onset.
Methods:
Cohort study in AL patients >15 years starting induction chemotherapy at a Mexican oncological center (2013-2014). Oral lesions (OLs) onset was assessed during follow-up, and saliva was obtained at baseline, at visit 2 (days 4-12) and at visit 3 (days 13-21) after chemotherapy; treated with a protease inhibitor and stored at -70°C. An Enzyme-Linked Immunosorbent Assay (ELISA) was performed. Cox proportional hazards regression models were constructed to estimate hazard ratios and its 95% CI (HR, 95% CI) for OLs development.
Results:
Forty-one patients were followed-up, 17 (41.5%) developed OL. OL-patients had higher baseline salivary IL-1α than those without lesions (p=0.040). During visit 2, OL-patients had higher levels of IL-1α (p=0.033), IL-1β (p=0.016), IL-6 (p=0.035) and TNF (p=0.019) than those who did not develop OLs. Patients with HSV infection, OC and OM showed higher salivary TNF levels during follow-up (HR: 3.52, 95% CI: 1.35-9.14, p=0.010).
Conclusion:
AL patients undergoing chemotherapy with high salivary TNF levels were more likely to develop HSV infection, OC and OM. This article is protected by copyright. All rights reserved.
Background:
There are numerous pharmacological and non-pharmacological treatment options available in the treatment of oral mucositis. However, in spite of so many methods and products, medical professionals have not come to a consensus as to which of these offer the best results.
Objectives:
This study was conducted to assess the effect of oral care with honey on children undergoing chemotherapy for the prevention and healing of oral mucositis.
Methods:
This quasi-experimental study was conducted on children undergoing chemotherapy. The study group consisted of 83 children who attended clinics and polyclinics for chemotherapy. All the children were included in the study period. The study was completed with a total of 76 children except for seven patients who were excluded from the study. The data were collected using a form and the World Health Organization Mucositis Assessment Index. The data were analyzed using percentage distributions, means, a chi-square test, a t-test, a variance analysis, and a Friedman test. Ethics approval of the study was obtained from the Institution Ethics Committee.
Results:
It was found that the severity of oral mucositis in the children in the experimental group was significantly less than the control group. The mucositis recovery period in the experimental group was significantly shorter than the control group.
Conclusion:
Regular oral care with honey for children undergoing chemotherapy for hematological cancers prevents mucositis and also accelerates recovery of it when started after mucositis onset.
This study compared the effect of two oral care agents on preventing stomatitis and discomfort for acute leukemic patients.
The aim of this investigation is to appraise labial oral microcirculation in chemotherapy patients to clarify the effects of cytotoxic agents on oral microvessels. Twenty-five patients with diagnosis of head and neck tumors were recruited in the study. All the patients were submitted to chemotherapy. Labial oral microcirculation was evaluated on labial mucosa using oral videocapillaroscopy. The statistical significance was checked with the Mann-Whitney U-test (P < 0.05). The analysis of videocapillaroscopic patterns showed statistically significant variations relative to the diameter of the incoming loop; the diameter of the outgoing loop; and loop tortuosity. This study shows that capillary alterations to patients who receive chemotherapy occur in labial oral microcirculation. Clin. Anat., 2013. © 2013 Wiley Periodicals, Inc.
Mucositis is the result of the cytotoxic effects of many treatments given for hematological malignancies (HMs); it represents a major source of potentially devastating clinical complications and portrays negative consequences on the patient's management, such as a longer hospitalization, the need of analgesic and total parenteral nutrition use, and increased costs. The available measures for the prevention and treatment of mucositis have been substantially palliative, being limited to the control of pain, infection, bleeding and nutrition. However, in the last decade, a better insight into the complex pathogenesis of MBI has led to the development of novel therapeutic options, such as palifermin, which can provide tools potentially allowing a targeted approach to mucositis.
There is a dearth of studies with respect to oral mucositis (OM) in the paediatric and adolescent populations. The purpose of this prospective cohort study was to examine the incidence and risk factors associated with OM in paediatric and adolescent patients receiving chemotherapy. OM assessments were made daily until 14days after chemotherapy using the self-report Mouth and Throat Soreness-Related Questions of the Oral Mucositis Daily Questionnaire (OMDQ MTS). Potential risk factors included age, gender, prior OM, anxiety level, cancer diagnosis, nausea/vomiting, use of growth factor, neutrophil count, liver enzymes, and creatinine value. Multiple logistic, Cox proportional hazards, and ordinal regression analyses were used to determine risk factors for the incidence and time to onset of MTS scores of ⩾2, and MTS scores across 14days by AUC categories, respectively, after adjusting for chemotherapy. A total of 140 patients who were 6-18years of age were evaluated. Forty-one percent (95% CI, 32.6-48.8%) developed OM; of these, 23% and 18% reported a maximum MTS score of 2 and 3-4 as the worst OM, respectively. The mean time to onset of OM was 4.7±2.7days with a mean duration of 6.3±4days. Prior OM (RR 1.90-3.94), a higher level of anxiety (RR 1.27-1.46), WHO grade 1-2 (RR 1.86-4.59) and 3-4 (RR 3.08-9.19) neutropenia were significantly associated with a higher probability of the incidence, earlier onset, and greater severity of OM, after controlling for chemotherapy (p<0.01). OM was associated with indirect cytotoxicity, prior OM, and anxiety level after controlling for chemotherapy where neutropenia was found to be the most important factor.
Mucosal barrier injury (MBI), also known as mucositis, is the result of the cytotoxic effects of many treatments given for hematological malignancies (HMs) and represents a major source of potentially devastating clinical complications and negative consequences afflicting the patient's management, such as a longer hospitalization, the need of analgesic and total parenteral nutrition use, and increased costs. The available measures for the prevention and treatment of MBI have been substantially limited to the control of pain, infection, bleeding and nutrition. However, in the last decade, a better insight into the complex pathogenesis of MBI has led to the development of novel therapeutic options, such as palifermin, which has been one of the major breakthroughs in the management of this condition, potentially allowing a targeted approach to MBI. Nevertheless, and despite these significant advances, MBI still remains a significant clinical problem in the management of HM and an important burden of sufferance for afflicted patients.
Despite therapeutic advances, acute lymphoblastic leukemia (ALL) in adults remains a disease with poor long term outcome and survival rates. Developing countries lack of information about this disease. On the other hand, infections are frequent complications related to mortality and some research studies do not show accurate rates of septic shock or other related factors.
To describe characteristics of adults with acute lymphoblastic leukemia, response to treatment, complications and to evaluate further survival related factors and to compare our experience with other reports of literature.
Between September 2003 to November 2007, the entire cohort of patients with diagnosis of ALL was included. The treatment regimens used were MDACC HyperCVAD (HCVAD) and 0195 (institutional regimen).
Of 40 patients included with the diagnosis of ALL, 92% was B phenotype and 8%, T phenotype, with a median age of 27 years. The median follow up was 28.5 months. Initially, 14% showed central nervous system infiltration; of 51% with available cytogenetics, 16.7% was Philadelphia chromosome positive. There were 36 patients who received treatment: 13 received HCVAD and 23 the 0195 protocol; 78% achieved global complete remission, 85% for the patients with HCVAD and 74% with 0195. The induction death rate was 2.8%. The median disease-free survival was 11.6 months (IC 95%, 2.5-20.8 months) and overall survival was 15 months (IC 95%, 10.6-19.4 months). In 95% of patients, no prophylactic antibiotic therapy was used and treatment related death was 8.4% (2.8% during induction and 5.6% during the rest of treatment). Factors associated with worse survival rate were hyperleukocytosis, T phenotype and lack of early complete remission. During induction, grade 3 to 4 non hematopoietic toxicity was 17%. Incidence of neutropenic febrile episodes was 61% and septic shock was 11%.
With HCVAD, we observed worse complete remission, disease-free survival and overall survival rates compared with the original MDACC reports. Chemotherapy related death rates are similar to other early reports, despite prophylactic antibiotic was not used during myelosuppression.
We evaluated the efficacy of benzydamine oral rinse for prevention of radiation-induced mucositis. Patients with head and neck cancers, who were referred in 2004-2005, received an oral rinse of either benzydamine or placebo. One hundred patients were randomized in this trial. At the end of the study, 19 patients were excluded from the analysis because they did not use the medication for the assigned period. In the benzydamine group, the frequency of mucositis grade > or =3 was 43.6% in contrast to 78.6% in other group (P = 0.001). Grade > or =3 mucositis was 2.6 times more frequent in the placebo group. Intensity of mucositis increased up to fourth week of treatment in both groups to grade 2. In the treated group the grade of mucositis was approximately constant to the end of therapy; but in the control group it raised to grade 3 (P < 0.001). The highest grade of mucositis during the treatment time was significantly different between two groups (P = 0.049). The median interval to observation of grade > or =2 mucositis was 24 days in the placebo group and 28 days in the benzydamine group (P = 0.12). Benzydamine oral rinse seems to be effective, safe, and well tolerated for prophylactic treatment of radiation-induced oral mucositis in head and neck tumours.
In medical research data are often collected serially on subjects. The statistical analysis of such data is often inadequate in two ways: it may fail to settle clinically relevant questions and it may be statistically invalid. A commonly used method which compares groups at a series of time points, possibly with t tests, is flawed on both counts. There may, however, be a remedy, which takes the form of a two stage method that uses summary measures. In the first stage a suitable summary of the response in an individual, such as a rate of change or an area under a curve, is identified and calculated for each subject. In the second stage these summary measures are analysed by simple statistical techniques as though they were raw data. The method is statistically valid and likely to be more relevant to the study questions. If this method is borne in mind when the experiment is being planned it should promote studies with enough subjects and sufficient observations at critical times to enable useful conclusions to be drawn. Use of summary measures to analyse serial measurements, though not new, is potentially a useful and simple tool in medical research.
Four hundred and twenty-nine patients received myeloablative chemotherapy for solid and haematological malignancies in a bone marrow transplantation unit. Regimens appropriate to the tumour type were administered and haemopoietic reconstitution was achieved with peripheral blood progenitor cells (PBPC; n = 275), autologous bone marrow (auto-BMT; n = 69) or allogeneic bone marrow (allo-BMT; n = 85). World Health Organization (WHO) oral mucositis scores were collected prospectively from the start of chemotherapy (d 1) until d 28 or discharge. Oral mucositis (OM) was experienced by 425 (99%) patients and in 289 (67.4%) this was grade III or IV. Strong opiate analgesia was prescribed for a median of 6 d to 47% of patients. Univariate analysis suggested that the area under the OM curve (AUC; sum of daily mucositis grades, d 1-28) was associated with the myeloablative regimen, haemopoietic progenitor source (PBPC > allo-BMT > auto-BMT), use of myeloid growth factors and age. Multivariate analysis showed that the only independent risk factor for mucositis was the conditioning regimen (P < 0.00005). The mean OM AUC for high-dose melphalan (HDM) regimens (52 grade-days) exceeded busulphan (41), busulphan-cyclophosphamide (35), cyclophosphamide-total body irradiation (TBI) (34), cyclophosphamide-carmustine (BCNU) (20) and cyclophosphamide-etoposide-carmustine (CVB) (19). HDM regimens resulted in the highest mean peak OM (3.6), followed by busulphan regimens (2.6), cyclophosphamide/TBI (2.3) and cyclophosphamide-carmustine and CVB (1.4). Busulphan produced significantly delayed OM (median 3 d; P < 0.00005). There was a linear association between the area under the OM curve for each treatment group and the time to reach grade 3 OM (P < 0.00005), but no association with the time to reach grade 4 neutropenia (P = 0.24) or thrombocytopenia (P = 0.73), implying that haematological and mucosal toxicity are not associated. The cytotoxic regimen is the most significant determinant of OM. Studies investigating agents to ameliorate mucosal toxicity should be stratified according to cytotoxic regimen.
Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU), and it is suggested that patients with a partial deficiency of this enzyme are at risk for developing a severe 5FU-associated toxicity. To evaluate the importance of this specific type of inborn error of pyrimidine metabolism in the etiology of 5FU toxicity, an analysis of the DPD activity, the DPD gene, and the clinical presentation of patients suffering from severe toxicity after the administration of 5FU was performed. Our study demonstrated that in 59% of the cases, a decreased DPD activity could be detected in peripheral blood mononuclear cells. It was observed that 55% of patients with a decreased DPD activity suffered from grade IV neutropenia compared with 13% of patients with a normal DPD activity (P = 0.01). Furthermore, the onset of toxicity occurred, on average, twice as fast in patients with low DPD activity as compared with patients with a normal DPD activity (10.0 +/- 7.6 versus 19.1 +/- 15.3 days; P < 0.05). Analysis of the DPD gene of 14 patients with a reduced DPD activity revealed the presence of mutations in 11 of 14 patients, with the splice site mutation IVS14+1G-->A being the most abundant one (6 of 14 patients; 43%). Two novel missense mutations 496A-->G (M166V) and 2846A-->T (D949V) were detected in exon 6 and exon 22, respectively. Our results demonstrated that at least 57% (8 of 14) of the patients with a reduced DPD activity have a molecular basis for their deficient phenotype.
Oral mucositis is a nearly universal and often severe complication following hematopoietic cell transplantation (HCT). The objective of this study was to evaluate factors predicting oral mucositis severity among 133 patients undergoing allogeneic HCT for chronic myelogenous leukemia.
All patients were transplanted between 1992 and 1999, were >or= 18 years of age, received either cyclophosphamide/total-body irradiation (TBI) or busulfan/cyclophosphamide conditioning regimens, and received four doses of methotrexate for graft-versus-host disease prophylaxis post-transplant. Oral mucositis was measured by a trained examiner every 2 to 3 days using the Oral Mucositis Index (OMI). Multiple linear regression analysis was used to identify predictors of mean OMI during days 6 to 12, 1 to 18, and the maximum OMI score between days 1 to 18.
TBI containing conditioning regimens, body mass index >or= 25, and methylenetetrahydrofolate reductase 677 TT genotype were found to be predictive of higher mean OMI scores (P <.05). Pretransplant multivitamin supplement use was associated with lower mean OMI scores compared to those who did not use supplements. Smoking status, race, pretransplant treatment with interferon-alfa or hydroxyurea, and patient/donor ABO compatibility were not associated with mean OMI scores.
Patients who are scheduled to receive conditioning regimens containing TBI, have a pretransplant body mass index >or= 25, or carry the methylenetetrahydrofolate reductase 677 TT genotype should be considered at greater risk of developing oral mucositis following HCT. Future studies should investigate whether multivitamin supplementation before HCT could reduce mucositis severity.
Study on the normal saline vs povidone-iodine mouthwashes for oral mucositis (OM) prophylaxis in patients after high-dose chemotherapy comprising bischloroethyl nitrosourea etoposide ara-C melphalan (BEAM) or high-dose melphalan (HD-L-PAM) followed by autologous peripheral stem cell transplantation indicated that females have higher a incidence of OM compared to men, as reported by [Vokurka et al. 13:554-558, (2005)]. The multivariable analysis of larger cohort of 148 patients compliant with the original study protocol confirmed female gender to be an independent risk factor and predictor for OM. The HD-L-PAM (200 mg/m2) conditioning regimen revealed to be more toxic compared to BEAM as for incidence of OM grades 3-4 World Health Organization score. Body mass index, age, mouthwash solution used, and CD34+ cell number in the autologous graft were verified not to have an impact on OM incidence in this group of patients.
The aim of this study was to evaluate the safety, tolerability and efficacy of a topical gel containing histamine dihydrochloride (HDC) versus a placebo gel in preventing oral mucositis in hematopoietic stem cell transplantation (HSCT) patients. A total of 45 patients post-HSCT were enrolled in a prospective longitudinal, placebo-controlled, double-blind study. Patients were evaluated twice weekly for oral mucositis (OMAS, NCI score), oral pain (VAS), oral function and salivary flow rate. Compliance was assessed using a patient diary. Oral mucositis developed in 85% of the HDC group and 63% of the placebo group. The mean maximal intensity for NCI score was 1.45+/-1 in the HDC group and 1.21+/-1.27 in the placebo group (P=0.37). The mean duration of oral mucositis was 4.7+/-3.6 and 2.33+/-2.23 days in the HDC and placebo groups, respectively (P=0.06). The same trends were measured with OMAS. Visual analogue scale for oral pain and oral function was not significantly different between the two groups. Histamine dihydrochloride was found to be safe. In the search for topical agents for the prevention of mucositis, we found that HDC neither improves nor worsens oral mucositis in HSCT patients. The balance between the pro- and anti-inflammatory effects of HDC should be investigated further in order to acquire a clinically effective topical medication based on its anti-inflammatory properties.
The effect of a synchronizing-recruiting drug schedule vs. myelotoxic therapy on remission rate and of Bacillus Calmette-Guerin on remission duration and survival of adults with acute myelogenous leukemia were studied in a prospective cooperative trial. After randomized remission induction with Arabinosyl Cytosine + vincristine + methotrexate + leucovorin (AVML), thioguanine + Ara-C + Daunorubin (TAD), or Daunorubicin + Ara-C (DA), complete remissions (CR) were consolidated with TAD or AVML, CRs were maintained with BCG vaccination (Tice strain) by the tine technique, or BCNU plus Ara-C (B/A), or no further therapy (NFT). Of 209 evaluable TAD patients, 105 (50%) achieved CR; of 187 DA, 97 (52%) achieved CR. AVML yielded only 15 CR among 59 patients (25%). The time to remission was significantly shorter with DA compared with TAD. Ninety-seven patients were randomized to maintenance therapy (35 B/A, 30 BCG, 32 NFT). There were no differences in remission duration (7, 8, 6 months) or survival (16, 22, 16 months, respectively). Manipulation of the cell cycle, as employed in this study, was not helpful. There may be a marginal effect of BCG, but our data fail to show a statistically significant benefit.
BACKGROUND
An impediment to mucositis research has been the lack of an accepted, validated scoring system. The objective of this study was to design, test, and validate a new scoring system for mucositis that can be used easily, is reproducible, and provides an accurate system for research applications.METHODSA panel of experts, convened to design an objective, simple, and reproducible assessment tool to evaluate mucositis with specific application to multicenter clinical trials, developed a scale that measured objective and subjective indicators of mucositis. Nine centers participated in the study's validation. Paired investigators at each center evaluated patients receiving chemotherapy or head and neck radiation. Objective measures of mucositis evaluated ulceration/pseudomembrane formation and erythema. Subjective outcomes of mouth pain, ability to swallow, and function were measured. Analgesia use for mouth sensitivity was recorded.RESULTSOne hundred eight chemotherapy and 56 radiation therapy patients were evaluated. Seventy-eight percent of chemotherapy patients and 64% of radiation therapy patients had clinically significant mucositis. Cumulative daily mucositis scores demonstrated a high correlation among observers. Using area under the curve analysis, it was found that for chemotherapy patients, the highest correlations (correlation coefficient > 0.92) occurred for the scores that selected the three highest daily values over the course of mucositis assessment. High interobserver correlations were noted for patients receiving radiation therapy. Objective mucositis scores demonstrated strong correlation with symptoms.CONCLUSIONS
The scoring system evaluated was easily used, showed high interobserver reproducibility, was responsive over time, and measured those elements deemed to be associated with mucositis. The use of concomitant symptomatic measurements appeared to be unnecessary. Cancer 1999;85:2103–13. © 1999 American Cancer Society.
BACKGROUND
Benzydamine was evaluated in patients with head and neck carcinoma for treatment of radiation-induced oral mucositis, a frequent complication of radiation therapy (RT) for which there is no predictable therapy or preventive treatment currently available.METHODS
The safety and efficacy of 0.15% benzydamine oral rinse in preventing or decreasing erythema, ulceration, and pain associated with oral mucositis during RT were evaluated in a randomized, placebo-controlled trial conducted in patients with head and neck carcinoma. Subjects were to rinse with 15 mL for 2 minutes, 4–8 times daily before and during RT, and for 2 weeks after completion of RT; study evaluations were conducted before RT and routinely thereafter up to 3 weeks after RT.RESULTSDuring conventional RT, regimens up to cumulative doses of 5000 centigrays (cGy) benzydamine (n = 69) significantly (P = 0.006) reduced erythema and ulceration by approximately 30% compared with the placebo (n = 76); greater than 33% of benzydamine subjects remained ulcer free compared with 18% of placebo subjects (P = 0.037), and benzydamine significantly delayed the use of systemic analgesics compared with placebo (P < 0.05). Benzydamine was not effective in subjects (n = 20) receiving accelerated RT doses (≥ 220 cGy/day). The incidence of adverse events between treatment groups was comparable without significant differences. Early discontinuation because of adverse events occurred in 6% of benzydamine subjects and 5% of placebo subjects, and there was 1 death (related to the primary diagnosis) in a placebo subject.CONCLUSIONS
Benzydamine oral rinse was effective, safe, and well tolerated for prophylactic treatment of radiation-induced oral mucositis. Cancer 2001;92:875–85. © 2001 American Cancer Society.
Background:
Few longitudinal studies have investigated the onset, duration, and resolution of ulcerative mucositis in bone marrow transplant recipients. This study prospectively followed a group of such patients on a daily basis to obtain data on the incidence of ulcerative mucositis, location and duration of lesions, severity with different conditioning regimens, and the relationship of such mucositis to the absolute neutrophil count.
Methods:
Fifty-nine bone marrow transplant recipients on prophylactic acyclovir were examined daily for 26 days after marrow infusion, and all oral ulcerative lesions were recorded.
Results:
Oral ulcers occurred in 76.3% of patients, began at a mean of 5 days after marrow infusion (day + 5), and lasted for a median of 6 days. More than 90% of patients showed complete resolution of ulcers on or before day + 15, and all showed resolution when the absolute neutrophil count was > 500 cells/ml. Persistence of ulcers was noticed in patients who had oral graft-versus-host disease and in some patients who initially developed more severe ulcerations. Ninety-six percent of ulcers were located on nonkeratinized mucosa.
Conclusions:
Ulcerative mucositis occurs in about 75% of bone marrow transplant recipients in the absence of herpes simplex virus infection. Most lesions occur on nonkeratinized mucosae which are vulnerable to trauma, especially if such mucosae are rendered atrophic by conditioning regimens. Oral ulcers may persist beyond day + 15 and after recovery of the neutrophil count in patients who initially develop more severe ulcerations or in patients who develop graft-versus-host disease.
Considerable progress in research and clinical application has been made since the original guidelines for managing mucositis in cancer patients were published in 2004, and the first active drug for the prevention and treatment of this condition has been approved by the United States Food and Drug Administration and other regulatory agencies in Europe and Australia. These changes necessitate an updated review of the literature and guidelines. Panel members reviewed the biomedical literature on mucositis published in English between January 2002 and May 2005 and reached a consensus based on the criteria of the American Society of Clinical Oncology. Changes in the guidelines included recommendations for the use of palifermin for oral mucositis associated with stem cell transplantation, amifostine for radiation proctitis, and cryotherapy for mucositis associated with high-dose melphalan. Recommendations against specific practices were introduced: Systemic glutamine was not recommended for the prevention of gastrointestinal mucositis, and sucralfate and antimicrobial lozenges were not recommended for radiation-induced oral mucositis. Furthermore, new guidelines suggested that granulocyte–macrophage-colony stimulating factor mouthwashes not be used for oral mucositis prevention in the transplantation population. Advances in mucositis treatment and research have been complemented by an increased rate of publication on mucosal injury in cancer. However, additional and sustained efforts will be required to gain a fuller understanding of the pathobiology, impact on overall patient status, optimal therapeutic strategies, and improved educational programs for health professionals, patients, and caregivers. These efforts are likely to have significant clinical and economic impact on the treatment of cancer patients. Cancer 2007;109:820–31. © 2007 American Cancer Society.
Radiation therapy and chemotherapy for malignant tumors in the head and neck region are inevitably associated with injury to oral tissues, including the salivary glands. This often results in salivary gland hypofunction. Until now there has been no effective method of preventing damage caused by cancer therapies. Although not yet supported by sufficient evidence, there are some clinical trials indicating a potential benefit from radical scavengers and saliva stimulants. Other developments are in gene transfer to regain salivary gland function and stem cell transplantation to regenerate a diseased salivary gland. While irradiation on salivary gland tissue is irreversible to a large extent, hyposalivation associated with chemotherapy is usually less severe and reversible. In case of significant residual secretory capacity, supportive care is indicated. These patients are advised to stimulate their salivary glands by mechanical or gustatory stimuli. Alternatively, salivary flow can be stimulated by cholinergic stimulation (eg, pilocarpine or cevimeline). In the case of little or no residual capacity, palliative treatment is the only option. In such patients, nocturnal oral dryness can be alleviated by spraying oral surfaces with water or by applying a saliva substitute, particularly a substitute with gellike properties. During the day, the application of mouthwashes and saliva substitutes is indicated if moistening of oral surfaces with water is not sufficient. Recent developments are focusing on bioactive saliva substitutes and mouthwashes containing antimicrobial peptides to protect oral tissues against microbial colonization and to suppress or cure mucosal and gingival inflammation.
Neural tube defects (NTD) are highly prevalent in the Mexican population. According to data from the Registry and Epidemiological Surveillance of External Congenital Malformations (RYVEMCE), at least 1 in 250 conceptions that reach 20 weeks of pregnancy or more has a NTD. This number is three to four times higher than that observed in other related ethnic groups. A common novel mutation (C677T) in the methylenetetrahydrofolate reductase (MTHFR) gene is considered an associated risk factor for NTD and other malformations. Studies in different populations agree that the prevalence of the homozygote for the mutated allele is higher in cases of NTD than in controls. In a meta-analysis recently published, the mean prevalence of the homozygote for the mutation was 9.2% for different groups of European controls and 16.4% in NTD cases from the same populations. This prompted us to investigate the frequency of the normal (C) and the mutant (T) alleles and the prevalence of the expected (CC, CT and TT) genotypes in 250 healthy Mexican women from different parts of the country. The proportion of CC (17.6%), CT (47.6%), and TT (34. 8%) genotypes found, and the gene frequencies of 0.414 and 0.586% for the C and T alleles, respectively, confirmed the very high prevalence of the mutant allele and the TT genotype in the sample studied. Comparisons with studies done in Holland, Ireland, the United States, Japan, and other ethnic groups showed highly significant differences, with an average OR of 5.8 (95% Cl 3.4-10.3) for a Mexican being homozygous for the mutation. These findings may explain an important part of the high prevalence of NTD observed in our population.
Almost half of 1500 patients (46.9%) treated for acute leukemia developed chemotherapy-related oral infections, oral mucositis, and/or oral hemorrhages at some time during their hospitalization. The frequencies of 34.2% for infections, 16.3% for mucositis, and 13.6% for hemorrhages were each within 1.3% to 3.1% of those previously reported from this institution for smaller groups of patients. The stomatologic disruptions reflected the cytotoxic, myelosuppressive, and immunosuppressive properties of the antileukemia drugs. Because there are as yet no alternatives to the use of potent stomatotoxic drugs for the treatment of acute leukemia, it is essential that their side effects be kept to a minimum by early recognition and appropriate treatment.
Oral mucositis is a major toxicity in the high-dose methotrexate (HD-MTX) treatment for children with acute lymphoblastic leukemia (ALL). The first aim of this study was to evaluate the relationship between the MTX serum concentration and occurrence of oral mucositis in pediatric ALL patients. The second aim was to clarify the relationship between MTX exposure and epidermal keratinocyte cell injury using an in vitro study.
49 patients were treated according to the Japan Association of Childhood Leukemia Study (JACLS) ALL-HR02 protocol. This protocol involves HD-MTX treatment (3 g/m2 for 24-h i.v. infusion). The MTX serum concentrations were measured by a fluorescence polarization immunoassay. The relationship between oral mucositis and MTX serum concentrations 48 and 72 h after administration was determined. The cell toxicity of MTX for human epidermal keratinocytes was analyzed by using a cell viability assay (WST-1 assay). In addition, pharmacokinetic evaluation for clearance, AUC extrapolated from 48 h to infinity (AUC48h-inf) and elimination half-life (t1/2b) were done using the 1-compartmental models.
Oral mucositis occurred in 24 patients (49.0%), in whom 20 patients (83.3% in oral mucositis group) showed WHO severity Grade 1 or 2. Only 4 patients (16.7% in oral mucositis group) showed Grade 3 severity. 22 patients (44.9%) had oral mucositis in the group with a concentration under 10-6 M 48 h after MTX administration. There was no significant deference among the cell viabilities in the concentrations of 10-6 M, 10-5 M and 10-4 M 48 h after the MTX exposure. However, the cell viability obtained 24 h after the MTX exposure was significantly different from the respective cell viability 48, 72 and 96 h after the MTX exposure. In the group with oral mucositis, the clearance decreased significantly (p = 0.042), and the t1/2b (p = 0.025) and AUC48h- yen (p = 0.025) increased significantly compared with the non-symptom group.
It seems that there is no significant relationship between the serum MTX concentration and oral mucositis. This in vitro study has demonstrated that the cell injury was related to the duration of MTX exposure rather than a high MTX concentration.
Chemotherapy-induced oral mucositis is a frequent therapeutic challenge in cancer patients. The purpose of this retrospective study was to estimate the prevalence and risk factors of oral mucositis in 169 acute lymphoblastic leukaemia (ALL) patients treated according to different chemotherapeutic trials at the Darcy Vargas Children's Hospital from 1994 to 2005. Demographic data, clinical history, chemotherapeutic treatment and patients' follow-up were recorded. The association of oral mucositis with age, gender, leucocyte counts at diagnosis and treatment was assessed by the chi-squared test and multivariate regression analysis. Seventy-seven ALL patients (46%) developed oral mucositis during the treatment. Patient age (P = 0.33), gender (P = 0.08) and leucocyte counts at diagnosis (P = 0.34) showed no correlation with the occurrence of oral mucositis. Multivariate regression analysis showed a significant risk for oral mucositis (P = 0.009) for ALL patients treated according to the ALL-BFM-95 protocol. These results strongly suggest the greater stomatotoxic effect of the ALL-BFM-95 trial when compared with Brazilian trials. We concluded that chemotherapy-induced oral mucositis should be systematically analysed prospectively in specialized centres for ALL treatment to establish the degree of toxicity of chemotherapeutic drugs and to improve the quality of life of patients based on more effective therapeutic and prophylactic approaches for prevention of its occurrence.
This study reports the presence of oral mucosal lesions in 26 patients with acute leukemia during the initial weeks of treatment (induction period). For comparison, three groups of patients without malignant disorders (acute disorders, long-term hospitalization, antibiotic treatment) were included. All patients were treated at the University Hospital of Umeå, Sweden. During the period of hospitalization hemorrhages were seen in 14 of the 26 patients with leukemia. No specific location was found. A correlation between presence of hemorrhages and low platelet counts was noted. Eighteen of the patients revealed ulcerations during the period. Ulcerations were predominantly found on the buccal mucosa, the lips, and the tongue. A tendency to an increase in the number and severity of ulcers was noted during the period of induction therapy. A correlation between presence of ulcers and low granulocyte counts was found. Candidiasis-like changes were seen in eight of the patients with leukemia. Compared with the patients with leukemia the patients in the reference groups showed a low prevalence of oral mucosal lesions.
The clinical characteristics of chemotherapy-induced oral mucosal ulceration in a group of patients with acute leukemia were examined in detail in a long-term prospective clinical study. Differences in regional susceptibility within the mouth to the effects of chemotherapy were apparent. A reconstruction of the probable mechanisms involved is presented.
The effect of a synchronizing-recruiting drug schedule vs. myelotoxic therapy on remission rate and of Bacillus Calmette-Guerin on remission duration and survival of adults with acute myelogenous leukemia were studied in a prospective cooperative trial. After randomized remission induction with Arabinosyl Cytosine + vincristine + methotrexate + leucovorin (AVML), thioguanine + Ara-C + Daunorubin (TAD), or Daunorubicin + Ara-C (DA), complete remissions (CR) were consolidated with TAD or AVML. CRs were maintained with BCG vaccination (Tice strain) by the tine technique, or BCNU plus Ara-C (B/A), or no further therapy (NFT). Of 209 evaluable TAD patients, 105 (50%) achieved CR; of 187 DA, 97 (52%) achieved CR. AVML yielded only 15 CR among 59 patients (25%). The time to remission was significantly shorter with DA compared with TAD. Ninety-seven patients were randomized to maintenance therapy (35 B/A, 30 BCG, 32 NFT). There were no differences in remission duration (7, 8, 6 months) or survival (16, 22, 16 months, respectively). Manipulation of the cell cycle, as employed in this study, was not helpful. There may be a marginal effect of BCG, but our data fail to show a statistically significant benefit.
Oral mucositis is a dose-limiting toxicity of 5-fluorouracil (5-FU). This prospective cohort study investigated factors associated with mucositis in patients receiving 5-FU for cancer of the digestive tract. Sixty-three patients (mean age 65 years) completed self-administered questionnaires and had interviews, oral examinations and unstimulated whole salivary flow measurements at baseline and follow-up appointments. The duration of follow-up was 2 months. Predictor variables included sociodemographic data, body surface area, diabetes, smoking, alcohol consumption, salivary flow, oral hygiene, presence of prostheses, performance status, regimen of cytotoxic drugs, hematological data, and herpes simplex virus antibody titer. Forty-six per cent of patients developed at least one episode of oral mucositis during cytotoxic treatment. Pearson's chi-square analysis showed that mucositis was significantly associated with xerostomia at baseline, xerostomia during chemotherapy, and lower baseline neutrophil counts (P < or = 0.05). Multiple logistic regression analysis indicated that xerostomia at baseline (odds ratio, OR = 10.0), or baseline neutrophil level under 4000 cells/mm3 (OR = 3.9) were significant predictors of mucositis. Taking into account the effect of neutrophil level at baseline, xerostomia during chemotherapy (OR = 4.5) was also a significant predictor of mucositis. The results showed that xerostomia and lower baseline neutrophil levels are significantly associated with oral mucositis. These variables should be taken into consideration in the design of intervention studies to reduce the frequency and severity of mucositis. More research is required to investigate the role of saliva and neutrophils in the pathogenesis of chemotherapy-induced mucositis.
An impediment to mucositis research has been the lack of an accepted, validated scoring system. The objective of this study was to design, test, and validate a new scoring system for mucositis that can be used easily, is reproducible, and provides an accurate system for research applications.
A panel of experts, convened to design an objective, simple, and reproducible assessment tool to evaluate mucositis with specific application to multicenter clinical trials, developed a scale that measured objective and subjective indicators of mucositis. Nine centers participated in the study's validation. Paired investigators at each center evaluated patients receiving chemotherapy or head and neck radiation. Objective measures of mucositis evaluated ulceration/pseudomembrane formation and erythema. Subjective outcomes of mouth pain, ability to swallow, and function were measured. Analgesia use for mouth sensitivity was recorded.
One hundred eight chemotherapy and 56 radiation therapy patients were evaluated. Seventy-eight percent of chemotherapy patients and 64% of radiation therapy patients had clinically significant mucositis. Cumulative daily mucositis scores demonstrated a high correlation among observers. Using area under the curve analysis, it was found that for chemotherapy patients, the highest correlations (correlation coefficient > 0.92) occurred for the scores that selected the three highest daily values over the course of mucositis assessment. High interobserver correlations were noted for patients receiving radiation therapy. Objective mucositis scores demonstrated strong correlation with symptoms.
The scoring system evaluated was easily used, showed high interobserver reproducibility, was responsive over time, and measured those elements deemed to be associated with mucositis. The use of concomitant symptomatic measurements appeared to be unnecessary.
Because the etiology of mucositis is multifactorial , approaches to prevention and management have also been multifactorial. Effective prevention and management of mucositis will reduce the pain and suffering experienced during cancer treatment. Oropharyngeal pain in cancer patients frequently requires systemic analgesics, adjunctive medications, physical therapy, and psychologic therapy in addition to oral care and topical treatments. Good oral hygiene reduces the severity of oral mucositis and does not increase the risk of bacteremia. Current approaches to management include frequent oral rinsing with saline or bicarbonate rinses, maintaining excellent oral hygiene, and using topical anesthetics and analgesics. Cryotherapy is a potential adjunctive approach in some cases. There are a number of approaches that appear to represent viable candidates for further study. Biologic response modifiers offer the potential for prevention and for acceleration of healing. Various cytokines will enter clinical trials in the near future; these offer the potential for reduction of epithelial cell sensitivity to the toxic effects of cancer therapy or for stimulation of repair of the damaged tissue. Other approaches include the use of medications to reduce exposure of the oral mucosa to chemotherapeutic drugs that are secreted in saliva. Antimicrobial approaches have met with conflicting results, little effect being seen with chlorhexidine and systemic antimicrobials in the prevention of mucositis in radiation patients. In patients with BMT and patients with leukemia, chlorhexidine may not be effective in preventing mucositis, although there may be reduction in oral colonization by Candida. Initial studies of topical antimicrobials that affect the gram-negative oral flora have shown reductions in ulcerative mucositis during radiation therapy but have not been assessed in leukemia/BMT. Among other approaches that require further study are low-energy lasers and anti-inflammatory medications. These approaches to management have undergone initial study, but additional investigation is needed to determine their effectiveness with respect to the prevention of mucositis and symptom management and to determine appropriate doses and frequencies of intervention. Current studies and our increasing understanding of the pathogenesis of oral mucositis will lead to new approaches to management and improved quality of life for these patients.
The incidence and the severity of chemotherapy-associated oral mucositis were determined in a retrospective analysis of 150 patients with various solid tumors. In addition, possible risk factors for the development of mucositis were identified. Patients were treated with chemotherapeutic regimens appropriate to tumor type and disease stage on an in- or outpatient basis. Mucositis was scored using the World Health Organization (WHO) criteria. Eighty-seven episodes of mucositis occurred in 47 (31%) patients. Twenty-six patients each experienced only one episode, whereas 21 patients had up to eight episodes of mucositis. The 1,281 chemotherapy cycles that have been analyzed included 87 cycles in which mucositis was observed. In 16 patients (11%) only slight oral mucosal changes were recorded (maximum WHO score 1), while 25 patients (17%) experienced mild to moderate mucositis (maximum WHO score 2), and in 6 patients (4%) mucositis was moderate to severe (maximum WHO score 3). No grade 4 mucositis developed. In 24 of the 47 patients with mucositis (51%) clinical features of acute pseudomembranous candidiasis were present. Leukopenia, leukopenic fever, and use of corticosteroids and central venous catheters were associated with the chemotherapy cycles with mucositis. Multivariate analysis identified the administration of paclitaxel, doxorubicin, or etoposide as independent risk factor (adjusted rate ratios 8.06, 7.35, and 6.70, respectively), whereas low body mass was associated with a slightly increased risk (adjusted rate ratio 0.92) for the development of mucositis. In conclusion, almost one-third of patients receiving chemotherapy for solid tumors experienced one or more episodes of mild to more severe oral mucositis, indicating that this is a frequent complication in such patients.
To explore the relationship between oral mucositis and selected clinical and economic outcomes in blood and marrow transplant patients.
Subjects consisted of 92 transplant patients from eight centers who participated in a multinational pilot study of a new oral mucositis scoring system (Oral Mucositis Assessment Scale [OMAS]). In the pilot study, patients were evaluated for erythema and ulceration/pseudomembrane formation beginning on the first day of conditioning and continuing for 28 days. We examined the relationship between patients' peak OMAS scores and days with fever (body temperature > 38.0 degrees C), the occurrence of significant infection, days of total parenteral nutrition (TPN), and days of injectable narcotic therapy (all over 28 days), days in hospital (over 60 days), total hospital charges for the index admission, and vital status at 100 days.
Patients' peak OMAS scores spanned the full range of possible values (0 to 5) and were significantly (P <.05) correlated with all of the outcomes of interest except days with fever (P =.21). In analyses controlling for type of graft (autologous v allogeneic) and study center, a 1-point increase in peak OMAS score was associated with (1) 1.0 additional day with fever (P <.01), (2) a 2.1-fold increase in risk of significant infection (P <.01), (3) 2.7 additional days of TPN (P <.0001), (4) 2.6 additional days of injectable narcotic therapy (P <.0001), (5) 2.6 additional days in hospital (P <.01), (6) 42,749 higher among patients with evidence of ulceration compared with those without (P =.06).
Oral mucositis is associated with significantly worse clinical and economic outcomes in blood and marrow transplantation.
The aim of the present study was to describe patients' experiences of their oral status and their relation to oral complications during radiotherapy and chemotherapy. The sample consisted of 41 consecutive patients admitted for radiotherapy with >40 Gy including the oral cavity for tumours within the head and neck area, or for chemotherapy of haematological malignancies. At the start of radiotherapy or the second/third cycle of chemotherapy, patients rated their experiences of oral symptoms on a 100-mm visual analogue scale with endpoints "no oral discomfort" and "worst imaginable oral discomfort". Mucositis was assessed and unstimulated whole saliva was collected. Patients were examined regularly at every 10 Gy increase of radiotherapy or once a week during chemotherapy, and after completion of the radiotherapy or the chemotherapy cycle. In addition, patients given radiotherapy rated their experiences of oral symptoms 1 month after treatment. Patients receiving radiotherapy experienced a significant increase in oral symptoms over time. One month after treatment several oral symptoms were still present. The severity of mucositis increased over time. The unstimulated salivary secretion rate showed a rapid decrease after the start of radiotherapy, followed by a slow recovery. Patients who received chemotherapy reported fewer oral symptoms, with a peak 1-2 weeks after the start of treatment, and their mucositis score showed a parallel pattern of development. Their unstimulated salivary secretion rate did not change over time. There was good agreement between patient experiences and observations recorded by dental staff.
Benzydamine was evaluated in patients with head and neck carcinoma for treatment of radiation-induced oral mucositis, a frequent complication of radiation therapy (RT) for which there is no predictable therapy or preventive treatment currently available.
The safety and efficacy of 0.15% benzydamine oral rinse in preventing or decreasing erythema, ulceration, and pain associated with oral mucositis during RT were evaluated in a randomized, placebo-controlled trial conducted in patients with head and neck carcinoma. Subjects were to rinse with 15 mL for 2 minutes, 4-8 times daily before and during RT, and for 2 weeks after completion of RT; study evaluations were conducted before RT and routinely thereafter up to 3 weeks after RT.
During conventional RT, regimens up to cumulative doses of 5000 centigrays (cGy) benzydamine (n = 69) significantly (P = 0.006) reduced erythema and ulceration by approximately 30% compared with the placebo (n = 76); greater than 33% of benzydamine subjects remained ulcer free compared with 18% of placebo subjects (P = 0.037), and benzydamine significantly delayed the use of systemic analgesics compared with placebo (P < 0.05). Benzydamine was not effective in subjects (n = 20) receiving accelerated RT doses (> or = 220 cGy/day). The incidence of adverse events between treatment groups was comparable without significant differences. Early discontinuation because of adverse events occurred in 6% of benzydamine subjects and 5% of placebo subjects, and there was 1 death (related to the primary diagnosis) in a placebo subject.
Benzydamine oral rinse was effective, safe, and well tolerated for prophylactic treatment of radiation-induced oral mucositis.
Chemotherapy- and radiotherapy-induced oral mucositis represents a therapeutic challenge frequently encountered in cancer patients. This side effect causes significant morbidity and may delay the treatment plan, as well as increase therapeutic expenses. The pathogenesis of this debilitating side effect can be attributed to the direct mucosal toxicity of cytotoxic agents and ionizing radiation and to indirect mucosal damage caused by a concomitant inflammatory reaction exacerbated in the presence of neutropenia, and the emergence of bacterial, mycotic, and viral infections. The prophylactic and therapeutic armamentarium for the treatment of oral mucositis consists of locally and systemically applied nonpharmacological measures and pharmacotherapeutics.
Oropharyngeal mucositis is a common and significant complication of cancer chemotherapy and limits the delivery of chemotherapy, affects the quality of life, and increases the cost of care. Oral mucositis caused by cancer chemotherapy is associated with specific agents, but the origin of oral mucositis is poorly understood. These drugs may have direct toxic effects on the rapidly dividing cells of the oral mucosa and on cellular elements of the connective tissue. Microbial flora may play a role in the development of ulcerative mucositis. Chemotherapy may be directly toxic and affect the mucosa by systemic circulation and may be related to secretion of some chemotherapeutic drugs in the saliva, resulting in topical exposure to the oral environment. Other potential mechanisms include reduced saliva volume and change in saliva constituents that may affect epithelial maintenance and repair, the physiology of the oral microflora, and the interaction between the oral flora and the epithelium. Improved understanding of the mechanisms whereby specific chemotherapeutic agents cause mucositis may lead to management approaches that will reduce the incidence and severity of mucositis, improving quality of life and ensuring delivery of the necessary chemotherapy to improve cancer cure rates.
Mucositis is a common and vexing complication of autologous progenitor cell transplantation (ABMT). A modified oral mucositis assessment scale (OMAS) has been found to be a reproducible and effective tool for monitoring mucositis after radiation therapy or chemotherapy. We utilized the modified OMAS scale to study clinical parameters associated with the development of mucositis in 79 patients undergoing ABMT. Median patient age was 52; 61% had non-Hodgkin's lymphoma (NHL), 23% multiple myeloma and 14% Hodgkin's disease. Patients were mobilized with G-CSF alone or the combination of etoposide plus G-CSF. Univariable correlates of worse mucositis were prior radiation therapy (P = 0.004), a diagnosis of NHL (P = 0.014), progenitor cell mobilizing regimen containing etoposide (P = 0.001), and ABMT preparative regimen containing etoposide (P = 0.006). Multivariable regression analysis revealed that NHL diagnosis (P = 0.007), prior radiation therapy (P = 0.001), and etoposide in the mobilizing regimen (P = 0.034) were associated with worse post-transplant mucositis. Worsening mucositis correlated with a longer inpatient length of stay. We conclude that several variables contribute to worsening mucositis during autologous transplantation, including etoposide in the progenitor cell mobilizing regimen.
The aim of this pilot study was to investigate the secretion rate from minor salivary glands in 16 patients (mean age 62 years) with myeloma, lymphoma or other malignant haematological diseases receiving chemotherapy (study group). An age- and sex-matched control group (n = 16) was recruited. The secretion rate from the minor salivary glands on the inside of the lower lip, measured using the Periotron method, was in mean 2.8 microliters/cm2/min in the study group compared with 4.5 microliters/cm2/min in the control group (p < 0.01). No difference was found in the secretion rate of paraffin-stimulated whole saliva. There were more individuals who experienced dry mouth in the study group (n = 7) than in the control group (n = 2). The conclusion from this pilot study is that the secretion rate from the minor salivary glands might be reduced in cancer patients treated with chemotherapy.
A multitude of laboratory and clinical research studies of ulcerative oral mucositis induced by cytotoxic cancer therapies have been reported during the past decade. However, a comprehensive understanding of oral mucositis pathogenesis, together with a clear definition of risk factors for development and severity of the lesion, remain under investigation. The literature presents sometimes divergent data regarding these issues, which in turn restrict efforts to develop a unified approach for management of this morbid condition. The current review summarizes these controversies and highlights the need for strategies for stratification of patients enrolled in clinical trials, in relation to both pathophysiologic and associated risk factors.
No single oral mucositis (OM) assessment scale is universally accepted; the most commonly used scales are deficient because they combine subjective and objective measures and do not capture the patient's perspective. Because pain is the hallmark symptom of OM, the authors sought to determine whether a simple measure of patient-reported pain was correlated with objective, physician-assessed measures of OM. The findings of the current study may provide a clinical context for understanding the relation between objective indicators and patients' perceptions of OM.
Three hundred twenty-three patients receiving stomatotoxic chemotherapy and randomized to receive either iseganan or placebo for treatment of OM underwent periodic objective and subjective evaluations of OM. Objective measures included clinician scoring of stomatitis and dysphagia using the National Cancer Institute Common Toxicity Criteria scales. A subjective measure was obtained by having patients complete a questionnaire (with questions based on an 11-point numeric scale) regarding oral pain.
More than 90% of scheduled oral assessments were obtained. Mouth pain scores were closely related to stomatitis and dysphagia; peak mouth pain coincided with peak stomatitis and dysphagia. Analgesic use increased by 0.7 days for each unit rise on the pain scale. Patients receiving iseganan had a significantly lower level of peak mouth pain than did patients receiving placebo (P=0.041).
A separate measurement of patient-reported pain was useful for capturing the patient's perspective on OM and was correlated with the physician's objective assessment. These findings support the use of a simple, patient-reported rating of mouth pain as a clinically relevant and responsive endpoint in clinical trials. This rating system also may provide a straightforward method of following OM in clinical practice.
Mucositis is a common but poorly studied problem among patients with solid tumors. The authors examined the clinical and economic outcomes of oral and gastrointestinal (GI) mucositis among patients receiving myelosuppressive chemotherapy.
A retrospective, random sample of 599 patients who developed chemotherapy-induced myelosuppression was followed for development of oral or GI mucositis and for development of subsequent episodes of bleeding or infection. Multilevel regression models of the risk of bleeding and infection were fit with chemotherapy cycles nested within patients.
Mucositis developed during 37% of 1236 cycles of chemotherapy. Episodes of bleeding were significantly more common during cycles with GI mucositis than during cycles without GI mucositis (13% vs. 8%; P = 0.04). Episodes of infection were significantly more common during cycles with mucositis (especially GI mucositis) than during cycles without mucositis (73% vs. 36%; P < 0.0001). The mean durations of hospitalization were 4 days, 6 days, and 12 days during cycles with no mucositis, oral mucositis, and GI mucositis, respectively. After accounting for the depth and duration of myelosuppression and for other predictive factors, GI mucositis was associated with both bleeding (odds ratio [OR], 2.0; P = 0.01) and infection (OR, 2.24; P < 0.0001), whereas oral mucositis was associated with infection only (OR, 2.4; P < 0.0001).
Mucositis was clinically and economically significant among patients with solid tumors who were receiving myelosuppressive chemotherapy. New preventive and therapeutic agents are needed.
An interest in measuring subjective phenomena such as pain, nausea, anxiety, etc. has led clinicians to develop three types of ratings: the visual analog scale (VAS); the verbal rating scale (VRS), and the numeric rating score (NRS). These ratings are regarded as global scales because they lack criteria to demarcate diverse dimensions or categories that comprise each scale. The purpose of this study was to evaluate validity and consistency of usage for these scales. Criterion for validity consisted of an experimentally controlled intensity for auditory stimuli.
We conducted a prospective, experimentally controlled, clinimetric study at the Audiology Department at the Hospital of Puebla Autonomous University (in Puebla State, Mexico). Participants included 25 medical students, two psychology students, and three practicing physicians. Interventions consisted of pure 1,000 Hz tones in five different intensities applied for 3 sec with a 1-min interval between stimuli at three sessions for each observer. Main outcome measure was validity and consistency of usage for VAS, VRS, and NRS scales.
Correlation coefficients between scale results and standard stimuli were 0.818 for VAS, 0.735 for NRS, and 0.796 for VRS. Mean weighted kappa indices for intraobserver agreement were 0.70, 0.59, and 0.65, respectively, for scales with five categories each. Mean weighted kappa indices for inter-observer variability were 0.61, 0.48, and 0.54 for VAS, NRS, and VRS again with five categories each.
The three instruments appeared reasonably accurate, with VAS having highest scores. VRS appeared sufficiently consistent to be regarded as providing reliable scientific information.
Objective:
To discuss the scope and epidemiology of cancer therapy-induced mucositis.
Data source:
Peer-reviewed articles and book chapters.
Conclusion:
Mucositis is a frequent and costly complication of cancer treatment. The risk of cancer therapy-induced mucositis varies depending on a number of patient- and treatment-related factors.
Implications for nursing practice:
An awareness of the risk factors associated with mucositis will allow nurses to identify cancer patients at greatest risk and incorporate supportive care measures into their management plans.
Complications of cytotoxic chemotherapy are more common in older patients (65 years of age and older) with cancer than in younger patients, and the occurrence of myelosuppression, mucositis, cardiodepression, peripheral neuropathy, and central neurotoxicity can complicate treatment. Age-related physiologic changes that can increase the toxicity of chemotherapy are decreased stem-cell reserves, decreased ability to repair cell damage, progressive loss of body protein, and accumulation of body fat. A decline in organ function can alter the pharmacokinetics of many of the commonly used chemotherapeutic agents in some elderly patients, making toxicity less predictable. Comorbidities increase the risk of toxicity through their effects on the body. Furthermore, the drugs used to treat comorbidities may interact with chemotherapeutic drugs, potentially increasing toxicity in elderly patients. Prospective trials in older patients with lymphoma or solid tumors have found that age is a risk factor for chemotherapy-induced neutropenia and its complications. Anemia may be present because of the disease or its treatment, and, if left uncorrected, it can alter drug activity and increase toxicity. Being able to predict which elderly patients are at greater risk of toxicity on the basis of pretreatment factors would be valuable, and there is a need for prospective trials to determine regimen- and patient-specific prognostic factors. Effective management of the toxicity associated with chemotherapy with appropriate supportive care is crucial, especially in the elderly population, to give them the best chance of cure and survival, or to provide palliation. For example, management of neutropenic complications with colony-stimulating factors makes treatment with standard-dose chemotherapy possible, which can lead to better outcomes. A better understanding of drug activity and toxicity in older patients is necessary for developing guidelines for safe and effective treatment. Few randomized controlled trials of antitumor drugs in older patients with cancer have been conducted, but a number of agents with favorable efficacy and toxicity profiles in elderly patients have been identified.
Our aim was to examine the relationship between mouthrinse matrix metalloproteinases (MMPs) and whole albumin levels (AL) relative to oral mucositis (OM) in allogeneic stem cell transplant (alloSCT) patients. Mouthrinse vertebrate collagenase levels are positively correlated with connective tissue destruction (CTD) in periodontitis and may also be involved in CTD associated with OM. Increases in salivary AL have been noted prior to OM onset and may serve as a predictive tool for OM and as a positive control in this study. A total of 23 alloSCT patients were visited eight times over 4 weeks following the transplant. OM was scored via a previously validated examiner-based ordinal system. Mouthrinse samples were collected and analyzed for MMP-1, 8, 13 (members of the vertebrate collagenase group) and AL. No significant correlation was found for MMP levels relative to OM scores. AL were positively and significantly associated with OM scores (P<0.001). MMP levels may not be an important factor in OM development and severity; however, mouthrinse AL may serve as a more objective measure of OM development and severity.
The objective of this study was to develop a test for detecting salivary gland hypofunction.
Oral Schirmer's test was performed by placing a strip of filter paper on the floor of the mouth and measuring the wetted length after 5 min. The control group consisted of 70 healthy patients, while another group consisted of 61 patients with Sjögren's Syndrome (SS) and a third group of 31 patients who suffered from xerostomia caused by other pathologies.
The mean saliva flow was 40.92 +/- 22.28 mm/5 min in the control group, 27.25 +/- 24.11 mm/5 min in patients with SS and 36.847 +/- 23.4 mm/5 min in the third group. The differences between the control group and the other two groups were statistically different (P > 0.001).
The whole saliva test was used to distinguish between healthy adults and subjects with hyposalivation.
Our objective was to examine the construct validity of the Oral Mucositis Assessment Scale (OMAS) in children receiving doxorubicin chemotherapy.
Children between 6 and 18 years of age with cancer receiving doxorubicin-containing chemotherapy were included. OMAS was measured on days 7, 10, 14, and 17 after chemotherapy. Other measures of mucositis obtained concurrent with OMAS were the World Health Organization (WHO) mucositis scale and pain visual analogue scale (VAS). We also recorded analgesia administration.
Sixteen children were studied for 45 post-chemotherapy cycles and 156 OMAS assessments were performed. OMAS was moderately correlated with WHO scores (r = 0.56; P = 0.0006) whereas correlation with the pain VAS was fair (r = 0.37; P = 0.002). OMAS also had fair correlation with the number of doses of topical analgesia (r = 0.43; P = 0.001) and with the cumulative dose of opioid analgesia (r = 0.38; P = 0.003).
The OMAS is valid for use in mucositis clinical trials for children at least 6 years of age.
Mucositis and xerostomia are the most common oral complications of the non-surgical therapy of cancer. Mucositis, a common sequel of radio- (DXR), chemo-(CXR) and radiochemo-therapy in patients with cancer, or patients requiring haemopoietic stem cell transplants (HSCT), has a direct and significant impact on the quality of life and cost of care, and also affects survival--because of the risk of infection. Apart from dose reduction, preventive and treatment options for mucositis are scarce, although multiple agents have been tested. Evidence suggests that cryotherapy, topical benzydamine and amifostine might provide some benefit in specific situations. The recombinant human keratinocyte growth factor Palifermin (Kepivance) was recently approved as a mucositis intervention in patients receiving conditioning regimens before HSCT for the treatment of haematological malignancies. A number of mechanistically based interventions are in various stages of development. Unfortunately, many other approaches have not been rigorously tested. This paper reviews the clinical features, prevalence, diagnosis, complications, pathogenesis, prophylaxis and management of mucositis.
Oral mucositis is a serious and debilitating side effect of cancer treatment. Greater understanding of the pathobiology of mucositis has recently led to the advent of targeted treatments for specific patient populations; however the treatment for mucositis remains palliative for most patients. Nuclear factor-kappaB (NF-kappaB) and cyclooxygenase 2 (COX-2) are thought to play important roles in the development of mucositis. In this study, 20 patients undergoing cytotoxic chemotherapy had oral mucosal biopsies taken prior to and following administration of cytotoxic chemotherapy. The samples were stained for NF-kappaB and COX-2 using routine immunohistochemistry. The results from this preliminary study demonstrated statistically significant increased oral mucosal staining for NF-kappaB and COX-2 following cytotoxic chemotherapy and provide further support for the role of NF-kappaB and COX-2 in the pathogenesis of mucositis.
The purpose of this study was to assess the relationship between oral mucositis (OM) and adverse clinical and economic outcomes of autologous hematopoietic stem-cell transplantation (HSCT) following high-dose melphalan (Alkeran) conditioning in patients with multiple myeloma. A retrospective study of 115 consecutive autologous HSCT recipients with multiple myeloma who received high-dose melphalan conditioning before transplantation was undertaken at a single academic center. OM severity was assessed twice weekly using a validated scale beginning 3-4 days following conditioning and continuing until hospital discharge or day 28, whichever occurred first. OM was graded, based on presence/extent of erythema/ulceration across eight oropharyngeal sites, as follows: 0 = no erythema or ulceration; I = erythema but no ulceration; II = ulceration, 1 site; III = ulceration, 2 sites; IV = ulceration, 3 sites; and V = ulceration, > or = 4 sites. Analyses examined the relationship between worst OM grade and selected clinical and economic outcomes, including days with fever, days of total parenteral nutrition (TPN),days of parenteral narcotic therapy, incidence of significant infection, and inpatient days and charges. The mean age of study subjects was 54 years; 19 patients (17%) received total-body irradiation, and 55 patients (48%) experienced OM grade > or = II (ie, ulceration). The worst OM grade was significantly (P < 0.05) associated with numbers of days of TPN and parenteral narcotic therapy, length of hospitalization, and total inpatient charges. Worst OM grade was not associated with the number of febrile days or the risk of significant infection. OM is associated with worse clinical and economic outcomes in multiple myeloma patients undergoing autologous HSCT following high-dose melphalan conditioning.
Oral mucositis is a common and debilitatingly painful side effect of many forms of chemotherapy and radiation therapy. The erythematous, atrophic, and ulcerative lesions that develop are a consequence of epithelial damage and death mediated through a complex series of molecular and cellular events. The consequences of mucositis are far-reaching and include chemotherapy dose reductions, breaks in radiation treatment, cessation of cancer therapy, reliance on parenteral nutrition, administration of narcotics, hospitalization, and morbidity. In this review, the underlying molecular and cellular pathobiology of oral mucositis is characterized in five phases: initiation, the primary damage response, signaling and amplification, ulceration, and healing. The roles of reactive oxygen species, transduction and transcription pathways, signaling and functional mediators, and bacteria on the development and resolution of mucositis are described as a dynamic process in which epithelial stem cells are the targets. Insights into the mechanisms of oral mucositis are generating new approaches for effective, targeted treatment.
Oral mucositis is the most common sequela of conditioning chemotherapy (CT) for hematopoietic stem cell transplantation (HSCT) and is the principal cause of most of the associated pain. Tumor necrosis factor-alpha (TNF-alpha) is a key pathogenic component of oral mucositis.
The primary purpose of this study was to describe oral mucositis-related oropharyngeal pain in the setting of HSCT. A secondary purpose was to assess the effectiveness of molecular biology methods for measuring TNF-alpha concentrations in plasma, saliva, and buccal epithelial cells in patients with oral mucositis undergoing HSCT. Methods: This descriptive, correlative study recruited subjects aged >or= 18 years who were scheduled to receive HSCT with CT. Subjects assessed their pain at baseline and 9 days (+/-24 hours) after CT using a pain visual analog scale (VAS) from 0=no pain to 10=worst possible pain, as well as word descriptors of sensory and affective pain. The extent and severity of oral mucositis were evaluated using the Oral Mucositis Assessment Scale. Saliva and blood samples and buccal brush biopsies were obtained at the same time points. Salivary and plasma TNF-alpha concentrations were measured using an enzyme-linked immunosorbent assay. Quantitative real-time polymerase chain reaction testing was used to measure buccal TNF-alpha gene expression. To determine the optimal method of RNA isolation, samples were extracted using 3 different methods: TRIzol, RNeasy, and RLT/TRIzol.
Twenty-five adult men and women (mean age, 46 years; age range, 32-68 years; 64% white) underwent HSCT with CT. Significant differences from baseline to day 9 were observed in the severity of oral mucositis (P<0.001), the overall intensity of oral pain (P<0.05), the overall intensity of oral pain with swallowing (P<0.01), the sensory dimension of oral pain with swallowing (P<0.05), and the sensory and affective dimension of oral pain with swallowing (P<0.05). The severity of oral mucositis was significantly associated with the overall intensity of oral pain (P<0.05). Although mean scores for oral pain were low, 8 subjects had clinically unacceptable pain VAS scores (>3) while receiving opioids. Fourteen subjects had measurable increases in buccal TNF-alpha RNA expression at day 9 (P=0.027 vs baseline), as measured using the TRIzol method, which was found to be the best method for measuring this variable. TNF-alpha RNA content in buccal samples was significantly associated with the worst intensity of oral pain with swallowing (partial R(2)=0.19; P<0.05).
Despite the use of opioids, oropharyngeal pain remained a treatment challenge in approximately one third of these subjects after CT with HSCT. The sensitive assay used to measure TNF-alpha gene expression in buccal cells may be useful in investigating molecular events in oral mucositis-related pain, as well as in evaluating the therapeutic response to investigational agents.
The Prospective Oral Mucositis Audit assessed the incidence, duration, and determinants of severe oral mucositis (OM; WHO oral toxicity scale grades 3 to 4) in patients with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL) receiving high-dose conditioning chemotherapy before autologous stem-cell transplantation.
Patients with MM (n = 109; mean age, 57 +/- 8 years) or NHL (n = 88; mean age, 50 +/- 13 years) were treated with high-dose melphalan (200 mg/m(2)) or carmustine 300 mg/m(2), etoposide 800 mg/m(2), cytarabine 800 to 1,600 mg/m(2), and melphalan 140 mg/m(2) chemotherapy, respectively, in 25 European centers. OM assessments were made daily until 30 days after transplantation or hospital discharge. High quality of OM assessment was ensured by an intensive training program.
Severe OM occurred in 46% (95% CI, 36% to 56%) of patients with MM and 42% (95% CI, 32% to 53%) of patients with NHL, with a mean duration of 5.3 days (95% CI, 4.4 to 6.1 days) and 5.5 days (95% CI, 4.5 to 6.7 days), respectively. Time from start of conditioning to peak OM score was 12.1 +/- 2.6 and 14.6 +/- 2.4 days. Severe OM risk and/or duration was significantly associated with higher chemotherapy dose per kilogram of body weight and poor performance status, but in contrast with some previous reports, this was not related to age.
Severe OM is more common in the transplantation setting than previously reported, justifying effective preventative and therapeutic measures.