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Prospective Oral Mucositis Audit: Oral Mucositis in Patients Receiving High-Dose Melphalan or BEAM Conditioning Chemotherapy—European Blood and Marrow Transplantation Mucositis Advisory Group
Abstract
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.
... Cancer is the second most frequent cause of death, causing millions of deaths each year [1]. Chemotherapy has an important role in its treatment, in spite of being associated with substantially distressing side effects, such as oral mucositis (OM) [2][3][4][5][6][7][8][9][10][11][12][13]. Severe OM interferes with oral intake, sometimes leading to parenteral nutrition and an increased need for systemic analgesics. ...
... OM is a common adverse reaction associated with chemotherapy, with variable incidence and degree of severity, correlated with the classes of medication and protocols used. While the complication occurs in approximately 40% of the patients receiving standard dosing regimens, it was reported to reach percentages of 100% in patients receiving high-dose chemotherapy or in those who have undergone stem cell or bone marrow transplantation [2,12,[47][48][49][50]. The VIF values ranged from 1 to 2.286, meaning there was no collinearity of the independent variables in the regression model. ...
... OM is a common adverse reaction associated with chemotherapy, with variable incidence and degree of severity, correlated with the classes of medication and protocols used. While the complication occurs in approximately 40% of the patients receiving standard dosing regimens, it was reported to reach percentages of 100% in patients receiving high-dose chemotherapy or in those who have undergone stem cell or bone marrow transplantation [2,12,[47][48][49][50]. ...
Objectives. Oral mucositis (OM) is a common adverse reaction associated with chemotherapy. We conducted a six-month longitudinal study to estimate the cumulative incidence of OM during the first six months of chemotherapy in adult patients with cancer other than head and neck cancer. Secondary objectives were as follows: (a) to scrutinize the oral health status of these patients and its evolution during chemotherapy, as assessed by oral health indices; (b) to estimate adherence to prescribed oral hygiene protocol during chemotherapy; and (c) to analyze ulceration-free survival in these patients. Methods. Sixty-four patients participated. Dental health and oral hygiene were assessed at baseline and at the end. Every month, blood tests were performed and oral lesions were recorded. This study was observational, with the only intervention being instruction in the hygiene protocol. The cumulative incidence of OM was estimated with the patient as the unit of analysis. A repeated measures ANOVA was applied to analyze the monthly blood test results. Ulceration-free survival analysis was conducted with adherence to the oral hygiene protocol as a grouping factor, followed by Cox proportional-hazards regression. Results. The six-month cumulative incidence rate was 43.75%, 95%CI (31.58–56.67%) for OM grade 2 or higher. The hazard ratio of ulceration associated with adherence to the hygiene protocol was 0.154, 95%CI (0.049–0.483), adjusted for age, sex, baseline hygiene index, and class of treatment. Conclusions. Compliance with hygiene recommendations would decrease the OM risk by more than six times, compared to non-compliance.
... Since there are no standardized scoring systems, there are no sufficient data about prevalence and incidence of oral mucositis based on chemotherapy and/or radiotherapy [9,10]. In patients undergoing hematopoietic system transplantation, this rate is about 65-85%, in conventional chemotherapy patients 20-40%, and in head and neck radiotherapy patients it is about 100% [11,12]. Severity and duration of mucositis varies depending on the received chemotherapy and concomitant radiotherapy. ...
... Eur Res J 2017;3(1):[11][12][13][14][15] Preventive effect of selenium in cisplatin-induced oral mucositis ...
... Eur Res J 2017;3(1):[11][12][13][14][15] Dogan et al ...
... 24 However, this may be driven by dosimetric parameters (ie, calculating the risk per kilogram of body weight or per square meters of body surface area). 24,25 An individual's low baseline performance status may be related to increased mucositis risk. 25 There is inconsistent evidence regarding the influence of age, smoking, oral hygiene, and body mass index on mucositis risk. ...
... 24,25 An individual's low baseline performance status may be related to increased mucositis risk. 25 There is inconsistent evidence regarding the influence of age, smoking, oral hygiene, and body mass index on mucositis risk. 24,26 The risk of mucositis may be influenced by genetic variants in drug-metabolizing pathways, immune signaling, and Table 1). ...
... An increased risk of mucositis has been reported with increasing doses of radiation, 27 myeloablative conditioning before HCT, 28 and chemotherapy, such as methotrexate and melphalan. 25 Altered, fractionated RT (eg, accelerated fractionation of 6 fractions per week or 2 daily fractions of 2 Gy each) may be associated with increases in mucositis frequency and duration. 29,30 Conversely, intensitymodulated radiation therapy, which enables the design of radiation scattering, can allow a reduction in toxicity, for example, by planning a cumulative exposure <30 Gy, when possible. ...
Oral mucositis (OM) is a common, highly symptomatic complication of cancer therapy that affects patients' function, quality of life, and ability to tolerate treatment. In certain patients with cancer, OM is associated with increased mortality. Research on the management of OM is ongoing. Oral mucosal toxicities are also reported in targeted and immune checkpoint inhibitor therapies. The objective of this article is to present current knowledge about the epidemiology, pathogenesis, assessment, risk prediction, and current and developing intervention strategies for OM and other ulcerative mucosal toxicities caused by both conventional and evolving forms of cancer therapy.
... In all cases, "risk" is defined as an increased risk of mucositis unless specified. Clear doseresponse relationships were identified for both OM and GI-M, with increasing doses of melphalan [23,24], methotrexate (MTX) [25], and radiation [26][27][28][29][30] predictive of OM, GI-M, and late rectal morbidity (radiation only). Unsurprisingly, the volume of bowel exposed to radiation was a strong predictor of acute and late GI toxicity reported across several studies [21,[31][32][33][34][35][36][37][38][39][40][41]. ...
... Similarly, the evidence was unclear regarding the impact of BMI on mucositis risk, with evidence indicating that low BMI [23,88] and a BMI > 25 [51] were predictive of OM risk. In contrast, while the evidence may be limited, there are consistent reports detailing baseline performance status, with low KPS [34] and ECOG performance status [24] predictive of OM and GI-M risk. Smoking was also identified as a predictor of OM in HNC patients and transplant recipients [69,88,89]. ...
... Similarly, Lunberg et al. [98] and Goutham et al. [99] reported no significant effect of TGFB on OM despite a positive association identified for GI-M. Several studies, including a large prospective trial in 381 participants [100], also failed to identify any demographic influence on mucositis risk, including age, sex, BMI, and race [24,48,[101][102][103]. ...
PurposeDespite advances in personalizing the efficacy of cancer therapy, our ability to identify patients at risk of severe treatment side effects and provide individualized supportive care is limited. This is particularly the case for mucositis (oral and gastrointestinal), with no comprehensive risk evaluation strategies to identify high-risk patients. We, the Multinational Association for Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO) Mucositis Study Group, therefore aimed to systematically review current evidence on that factors that influence mucositis risk to provide a foundation upon which future risk prediction studies can be based.Methods
We identified 11,018 papers from PubMed and Web of Science, with 197 records extracted for full review and 113 meeting final eligibility criteria. Data were then synthesized into tables to highlight the level of evidence for each risk predictor.ResultsThe strongest level of evidence supported dosimetric parameters as key predictors of mucositis risk. Genetic variants in drug-metabolizing pathways, immune signaling, and cell injury/repair mechanisms were also identified to impact mucositis risk. Factors relating to the individual were variably linked to mucositis outcomes, although female sex and smoking status showed some association with mucositis risk.Conclusion
Mucositis risk reflects the complex interplay between the host, tumor microenvironment, and treatment specifications, yet the large majority of studies rely on hypothesis-driven, single-candidate approaches. For significant advances in the provision of personalized supportive care, coordinated research efforts with robust multiplexed approaches are strongly advised.
... Five patients were in complete morphologic remission (CMR), one in very good partial remission (VGPR) and 2 in partial remission (PR) prior to transplantation. Serum and saliva samplings were performed at the same time on specific days of the peritransplantation period as follows: day of hospital admission (day −3/−7), day of transplantation (day 0) and day +7 and day +14 post-transplantation. OM grade was established according to WHO criteria [9]. As a control group, 10 age-and sex-matched patients were selected (average age: 41.9 ± 18.35 years, 9 females and 1 male). ...
... For more details of patients' demographics see Table S1. The conditioning regimen was BEAM (BCNU, etoposide, cytosine arabinoside, melphalan) protocol in Hodgkin and non-Hodgkin lymphoma prior to the transplantation [9], while in MM it was high-dose melphalan (≥200 mg/m 2 ) [9]. Patients with severe chronic disease (diabetes, autoimmune diseases, acute or chronic inflammatory diseases, etc.) and previous malignancy were excluded from the study. ...
... For more details of patients' demographics see Table S1. The conditioning regimen was BEAM (BCNU, etoposide, cytosine arabinoside, melphalan) protocol in Hodgkin and non-Hodgkin lymphoma prior to the transplantation [9], while in MM it was high-dose melphalan (≥200 mg/m 2 ) [9]. Patients with severe chronic disease (diabetes, autoimmune diseases, acute or chronic inflammatory diseases, etc.) and previous malignancy were excluded from the study. ...
Background:
Oral and enteral mucositis due to high-dose cytostatic treatment administered during autologous and allogeneic stem-cell transplantation increases mortality. Salivary secretory immunoglobulin A (sIgA) is a basic pillar of local immunity in the first line of defense. Altered salivary sialoglycoprotein carbohydrates are important in the pathologies in the oral cavity including inflammation, infection and neoplasia. Therefore, we assessed whether changes in the salivary and serum IgA glycosylation correlated with development and severity of oral mucositis.
Methods:
Using capillary electrophoresis, comparative analysis of serum and salivary IgA total N-glycans was conducted in 8 patients with autologous peripheral stem-cell transplantation (APSCT) at four different stages of transplantation (day -3/-7, 0, +7, +14) and in 10 healthy controls.
Results:
Fourteen out of the 31 structures identified in serum and 6 out of 38 in saliva showed significant changes upon transplantation compared with the control group. Only serum core fucosylated, sialylated bisecting biantennary glycan (FA2BG2S2) showed significant differences between any two stages of transplantation (day -3/-7 and day +14; p = 0.0279).
Conclusion:
Our results suggest that changes in the serum IgA total N-glycan profile could serve as a disease-specific biomarker in patients undergoing APSCT, while analysis of salivary IgA N-glycan reflects the effect of APSCT on local immunity.
... The incidence of oral mucositis (OM) is underreported by clinicians and ranges from about 15% in chemotherapy-treated cancer patients to more than 90% in total body irradiation (TBI) included myeloablative-conditioned hematopoietic cell transplant (HCT) recipients [7]. Severe OM (WHO grade [3][4] was reported in 44% after high-dose melphalan or BEAM-conditioned autologous HCT in one of the few multicenter prospective studies with special attention on well-trained examinations of OM [8]. Incidence rates of gastrointestinal mucositis are even more difficult to establish because proper scoring tools are lacking and related symptoms such as nausea or diarrhea are multifactorial and influenced by treating agents and administrated supportive care drugs. ...
... The duration and incidence of fever, antibiotic therapy, parenteral narcotic use, total parenteral nutrition, and the length of stay in a hospital are all correlated with the severity of oral mucositis graded by WHO scale, as is the risk for significant infections and mortality [8]. Spielberger et al. showed that the recombinant human keratinocyte growth factor Palifermin significantly reduced both the incidence of oral mucositis and febrile neutropenia in patients receiving a AHCT after conditioning therapy containing total body irradiation, although Palifermin had no effect on the duration of neutropenia [103]. ...
Survival in patients with hematological malignancies has improved over the years, both due to major developments in anticancer treatment, as well as in supportive care. Nevertheless, important and debilitating complications of intensive treatment regimens still frequently occur, including mucositis, fever and bloodstream infections. Exploring potential interacting mechanisms and directed therapies to counteract mucosal barrier injury is of the utmost importance if we are to continue to improve care for this increasingly growing patient population. In this perspective, I highlight recent advances in our understanding of the relation of mucositis and infection.
... Engraftment. The median times taken for neutrophil and platelet engraftment were 12 (IQR, [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] days and 16 (IQR, 10-37) days, respectively, for the overall cohort. All patients who underwent ASCT were analyzed, including those who did not undergo engraftment (n = 10). ...
... The overall incidence of severe oral mucositis (grade 3 or 4) was 61.5%; improved supportive care, even without the use of palifermin, led to a significant reduction in its incidence in patients who received transplants after 2012 (46.5%), which matches international data. 23,24 Similarly, the incidence of other major organ toxicities was not in excess of what was previously reported in patients with NHL using mainly BEAM conditioning and did not differ between the two study groups. 7,25,26 All patients developed febrile neutropenia, and bacteremia was detected in nearly one third (30%) of patients with at least one febrile episode. ...
PURPOSE
Published experience with autologous stem-cell transplantation (ASCT) in non-Hodgkin lymphoma (NHL) from the Indian subcontinent is extremely limited. Here, we describe the activity and outcomes of this treatment modality at a large tertiary care center in India.
PATIENTS AND METHODS
We retrospectively analyzed adult patients with NHL who were eligible for ASCT and autografted between January 1, 2002, and December 15, 2020, at our transplant unit. Toxicities, complications, and long-term outcomes were compared between patients who underwent transplant during 2002-2012 (group A) and 2013-2020 (group B).
RESULTS
Overall, 80 patients (group A, n = 37; group B, n = 43) underwent ASCT using peripheral blood stem cells. At a median follow-up of 57.6 months, the 5-year event-free survival (EFS) and overall survival (OS) were 43.5% and 47.6%, respectively, for all patients. More recently (group B), patients had reduced 100-day transplant-related mortality (2.3% v 21.6%, P < .01), improved 3-year EFS (52.9% v 37.3%, P = .04), and superior OS (at 3-year; 63.4% v 43.2%, P = .02). Patients in group B also tolerated the procedure better, with improved resource utilization. In multivariate analysis, an International Prognostic Index (IPI) ≥ 3 at diagnosis adversely affected EFS (hazard ratio [HR] = 2.82, P = .009) and OS (HR = 2.84, P = .01) after ASCT. Low pretransplant serum albumin levels were associated with inferior EFS (HR = 2.68, P = .02) and transplant-related mortality (odds ratio = 10.80, P = .02) after ASCT.
CONCLUSION
It is feasible to achieve comparable short- and long-term outcomes in patients with NHL undergoing ASCT in a resource-poor country with improved supportive care and expertise of the transplant team and center.
... Almost in all patients, a severe mucositis of III/IV° is observed after myeloablative conditioning [8]. The most toxic conditioning leading to OM are total body irradiation (TBI)-based, busulfan-based, and carmustine, etoposide, cytarabine, and melphalan (BEAM) conditioning [6,9,10]. ...
... During conventional chemotherapy, patients with acute lymphoblastic leukemia, acute myeloblastic leukemia, and non-Hodgkin's lymphoma are at the highest risk of developing OM [9]. ...
Introduction
Oral mucositis is regarded by patients as one of the worst and debilitating complications of conditioning and hematopoietic cell transplantation (HCT). Prevention of mucositis is one of the priorities of supportive therapy during and after conditioning.
Objectives
The primary objective of the study was the analysis of efficacy of keratinocyte growth factor (KGF, palifermin) used in prophylaxis of oral mucositis in patients undergoing allo-HCT. The secondary objectives of the study included the analysis of the influence of palifermin on clinical course of oral mucositis and early transplant outcomes, as well as analysis of the contraindications of palifermin in patients undergoing allo-HCT.
Patients and methods
A total number of 253 allo-HCT performed between 2003 and 2018 in patients aged 0–19 years in a single center were analyzed. Overall, in 161 HCTs, palifermin was administered.
Results
Patients receiving KGF were transplanted earlier in the context of calendar year, and more often received ATG, mainly due to the higher rate of unrelated donor transplants. Allo-HCT patients who were administered palifermin had shorter time of mucositis (median: 9 vs. 13 days, p < 0.001), lower mucositis grade (median: 2° vs. 3°; p < 0.001), shorter period of total parenteral nutrition (median: 19 vs. 22 days; p = 0.018), and lower incidence of episodes of febrile neutropenia (median: 39.1% vs. 83.1%; p < 0.001).
Conclusions
The use of palifermin has decreased duration and severity of oral mucositis in children after allo-HCT. Palifermin is a safe and well-tolerated compound in children undergoing allo-HCT.
... Sample collection was based on the protocols described previously 14,15 . In brief, following oral cavity rinse with 25 Statistical analysis. Statistical analysis was performed using IBM SPSS22 software (IBM, Armonk, NY, USA). ...
... The predictive role of the female sex regarding OM in APSCT has been confirmed by earlier studies 23,24 , however, no in-depth analysis like our study has been reported. The dose of chemotherapy applied over a larger body surface area (BSA) per body mass in women may explain the sex difference 25 . Furthermore, women have increased risk of cytotoxicity and oral mucositis possibly partially due to hormone-related posttranslational modifications 26 . ...
Oral mucositis (OM) is a frequent complication of stem cell transplantation-associated toxicity in haematological malignancies, contributing to mortality. Therapy still remains mainly supportive. We assessed risk factors in retrospective analysis of 192 autologous peripheral stem cell transplantation patients with lymphoma and multiple myeloma (MM), respectively. Futhermore, we examined the hormone levels both in serum and saliva during transplantation in 7 postmenopausal female patients with lymphoma compared to healthy controls using electrochemiluminescence immunoassay (ECLIA). Multivariable analysis revealed neutrophil engraftment (p < 0.001; p = 0.021) and female sex (p = 0.023; p = 0.038) as independent predictive factors in the combined patient group and in the lymphoma group, and neutrophil engraftment (p = 0.008) in the MM group. Of the 85 female participants 19 were pre-and 66 postmenopausal. Fifteen of the pre-, and 49 of the postmenopausal women developed ulcerative mucositis (p = 0.769), more often with lymphoma than MM (p = 0.009). Serum estrogen decreased significantly both in postmenopausal controls and transplantated patients compared to premenopausals, with no difference in saliva. Serum progesterone level was significantly (p = 0.026) elevated at day + 7 of transplantation, while salivary progesterone increased at day + 7 and + 14. Our results indicate a predominantly negative effect of female sex hormones on oral immunity with role in the aetiopathogenesis of OM.
... In terms of toxicity, OM remains an important comorbidity in ASCT and can lead to dehydration, malnutrition, fever, bacteremia and lower overall survival [26,27]. The frequency of BEAM-induced OM is 40-60% [27]. ...
... In terms of toxicity, OM remains an important comorbidity in ASCT and can lead to dehydration, malnutrition, fever, bacteremia and lower overall survival [26,27]. The frequency of BEAM-induced OM is 40-60% [27]. In our series, there were less OM ! 2 in PT group compared with Ct group. ...
Despite the use of fluoroquinolone (FQ) prophylaxis, neutropenic fever (NF) is the most frequent cause of hospital readmission in ambulatory care programs for patients treated with autologous stem cell transplantation (ASCT). We analyzed the impact of intensifying primary prophylaxis with the addition of piperacillin/tazobactam (PT) to FQ. Between January 2002 and August 2018, 154 lymphoma patients conditioned with BEAM were included (40% received ceftriaxone (Ct) plus FQ and 60% PT plus FQ). NF and hospital readmission were required in 84 vs. 41% (p < .0001) and 12 vs. 1% (p = .007) of patients within the Ct and PT groups, respectively. The multivariate analysis showed that PT plus FQ retained its independent protective factor for NF (odds ratio (OR): 0.13; p < .001) and for hospital readmission (OR: 0.07; p = .01). The use of PT and FQ prophylaxis may effectively prevent episodes of NF and hospitalizations in lymphoma patients managed in our at-home ASCT care model.
... [1] The chemotherapy regimen and dosages are the main factors that determine the occurrence and severity of oral mucositis. The incidence can be, for instance, 90% in patients treated with 5-uorouracil, [2] 75% when treating with docetaxel and capecitabine, 70% in patients treated with pralatrexate, 98% (grade 3 and 4) with cyclophosphamide and etoposide, [3] 86% when treating with melphalan, [4] and 50% in patients receiving high doses of methotrexate. [5] Chemotherapy is also associated with salivary gland dysfunction. ...
Background
Given the suffering experienced by cancer patients, effective solutions must be found to prevent painful and debilitating side effects of anticancer treatment. This trial aims to study the effect of preconditioning with photobiomodulation in preventing oral mucositis and xerostomia in cancer patients undergoing chemotherapy alone for the first time, and to examine its role in affecting patients' quality of life.
Materials and Methods
This is a prospective, randomized, double-blind clinical trial including 45 patients divided into three age- and sex-matched groups. Group 1: received basic oral care instructions before undergoing chemotherapy. Group 2: received basic oral care instructions plus photobiomodulation using an intraoral 650 nm diode laser. Group 3: received basic oral care instructions plus photobiomodulation using 650 nm diode laser intraorally and 980 nm extraoral.
Results
In Group 2 and Group 3, 73.3% and 80% of patients did not develop mucositis, respectively, while the remaining patients in both groups had only mild erythema. In contrast, all patients in Group 1 had oral mucositis that ranged from mild erythema to ulceration > 3 cm2. There were statistically significant differences between the three groups in oral mucositis assessment scale after a week and after 2 weeks (p = .000). Regarding LENT SOMA scale, there was a statistically significant difference between the three groups studied (P = .037). There was also a statistically significant difference in the Oral Health Impact Profile (OHIP-14) between the three groups studied (P = .003 after a week, P = .023 after 2 weeks).
Conclusions
Preconditioning before starting chemotherapy, whether with the intraoral red laser alone or in combination with the extraoral infrared laser, has shown significant results in preventing oral mucositis and dry mouth, and it has also played a major role in improving the quality of life of patients.
Trial registration
This trial was registered in ISRCTN registry under no ISRCTN70634383 (https://doi.org/10.1186/ISRCTN70634383) on 24/07/2023.
... For example, the incidence of oral mucositis is 90% in patients treated with 5-fluorouracil, 4 75% in patients treated with docetaxel and capecitabine, 70% in patients treated with pralatrexate, 98% (Grade 3 and 4) when cyclophosphamide and etoposide are combined, 2 86% when treating with melphalan, 5 and it can reach 50% in patients receiving high doses of methotrexate. 6 The progression and severity of mucositis also depend on the patient characteristics. ...
Background: Given the suffering experienced by cancer patients, effective solutions must be found to prevent the most painful and debilitating side effects of anticancer treatment. The use of photobiomodulation (PBM) with specific parameters has been proposed to prevent oral mucositis in adults undergoing hematopoietic stem cell transplantation as well as in head and neck cancer patients receiving radiotherapy alone without chemotherapy. No recommendations were possible for patients undergoing chemotherapy alone. This systematic review aims to analyze the effectiveness of preconditioning by PBM in preventing chemotherapy-induced oral mucositis.
Methods: This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, PRISMA, Checklist and registered at the International Prospective Register of Systematic Reviews (PROSPERO). We searched and identified articles of the subsequent bibliographic databases: PubMed and Cochrane. Revised Cochrane risk-of-bias tool for randomized trials (RoB 2.0) was used to assess the risk of bias of studies included in this review.
Results: There were only six clinical trials examining the efficacy of PBM therapy in the primary prevention of chemotherapy-induced oral mucositis. All of the studies used lasers, except for one study that compared lasers with light-emitting diodes. The wavelength ranges from 630 to 830 nm. Irradiation parameters varied among the included studies. All studies showed good results for the use of PBM in the prevention of oral mucositis except for one study that found no benefit for the laser application.
Conclusions: PBM has been shown to be effective in preventing oral mucositis when applied to healthy tissues. Finding the optimal protocol has been difficult due to the variability between studies, and therefore, further well-designed, controlled, blinded studies are recommended to precisely determine irradiation parameters and the number of sessions. This review has been registered at the International Prospective Register of Systematic Reviews (PROSPERO) under number CRD42023397771
... A baseline visit was performed for all participants at the initiation day followed by further assessment at the beginning of each cycle. Assessment of OM was done by a self-assessment daily questionnaire which was based on the Patients Reported Oral Mucositis Questionnaire Scale (PROMS) and Oral Mucositis Daily Questionnaire (OMDQ) and also by WHO oral mucositis grading scales depending on the subjective expression of patients [19][20][21][22][23][24]. Patients were asked to complete the questionnaire from day 1 of the first course of chemotherapy to the last day (14 to 21) of the fourth cycle and reminded of the continuous implementation of the instructions. ...
Purpose
Oral mucositis (OM) is a common complication of cancer treatment that has an impact on a patient’s quality of life and the outcome of cancer therapy. This trial evaluated the effect of thyme honey oral gel for the prevention of chemotherapy-induced OM.
Methods
One hundred ten breast cancer patients who received their first cycle of chemotherapy with adriamycin (60 mg/m²) and cyclophosphamide (600 mg/m²) were randomly recruited into two groups: group A were patients who followed general oral hygiene recommendations and rinsing saline 3 times a day, and group B were patients with similar protocol but supplied with our formulated oral gel to be applied 2 to 4 times a day. Patients were assessed by the World Health Organization (WHO) oral mucositis grading scales and self-assessment daily questionnaire.
Results
The use of thyme honey was associated with diminishing incidence of OM grade ≥ 2 (95% CI, 0.12 to 0.90; P = 0.030), duration of OM (− 3.36 days; 95% CI, − 5.50 to − 1.22; P = 0.037) and delayed occurrence of OM grade ≥ 2 (95% CI, 0.10 to 0.80; P = 0.017).
Conclusion
Thyme honey can be considered as a prophylactic agent for OM and decrease the severity of its symptoms.
Trial registrations
This protocol was registered at the Iranian Registry of Clinical Trials: registration number IRCT201506063106N25, on June 12, 2015; approved by the institutional review board at the Deputy of Research, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran; and approved by the Ethics Committee of Medical Researches of Pharmaceutical Sciences Branch of Islamic Azad University, Tehran, Iran—reference number 5936, on August 17, 2014.
... Our findings indicate that the release of TNF-α and IL-6 both locally and systemically are intricately linked to the development and severity of mucositis following conditioning therapy in HSCT, and interventions aimed to alter their production may help improve the management of mucositis. The incidence of both oral and GI mucositis, and their clinical tempo were comparable to that described in the literature, and in line with the postulated pathophysiology of chemotherapy-induced mucositis, which is a complex sequence of interdependent phases of progression and healing [6,9,11,27]. However, the proportion of patients experiencing moderate-severe GI mucositis were higher in our study (26.8% vs 10-15% reported in literature) [3]. ...
Purpose
The study aimed to characterize the incidence of both oral and gastrointestinal (GI) mucositis, its’ associated temporal changes in local and systemic pro-inflammatory cytokines, and to explore predictive clinical and immunological factors associated with their occurrences in hematopoietic stem cell transplant (HSCT).
Methods
Autologous HSCT patients aged 18 years old and above were recruited from Hospital Ampang, Malaysia, between April 2019 to December 2020. Mucositis assessments were conducted daily, whilst blood and saliva were collected prior to conditioning regimen, on Day 0, Day+7 and 6-month. Baseline and inflammatory predictors in a repeated time measurement of moderate-severe mucositis were assessed by multiple logistic regression and generalized estimating equations, respectively.
Results
Of the 142 patients analyzed, oral mucositis and diarrhea (representing GI mucositis) were reported as 68.3% and 95.8%, respectively. Predictive factors for moderate-severe oral mucositis were BEAM or busulphan-based regimens (odds ratio (OR)=9.2, 95% confidence interval (CI)=1.16–72.9, p-value (p) = 0.005) and vomiting (OR=4.6, 95% CI 1.68–12.3, p = 0.004). Predictive factors for moderate-severe GI mucositis were BEAM or busulphan-based regimens (OR=3.9, 95% CI 1.05–14.5, p = 0.023), female sex (OR = 3.3, 95% CI 1.43–7.44, p = 0.004) and body mass index (OR=1.08, 95% CI 1.02–1.15, p = 0.010). Cytokines analyses were performed in 96 patients. Saliva and plasma interleukin-6 (OR=1.003, 95% CI 1.001–1.004, p < 0.001 and OR=1.01, 95% CI 1.001–1.015, p = 0.029), and plasma tumor necrosis factor-alpha (OR=0.91, 95% CI 0.85–0.99, p = 0.019) were predictive of moderate-severe oral mucositis in a time-dependent model.
Conclusion
This study provides real-world evidence and insights into patient- and treatment-related factors affecting oral and GI mucositis in HSCT.
... OM is a frequent and painful side effect of the oncological treatment [1]. Often related to head and neck radiotherapy and some chemotherapies protocols, this condition consists in an inflammation of the oral mucosa, which due to the reduction of the basal epithelium renewal rate, can cause atrophic changes and, consequently, ulceration. ...
The association of more than one wavelength for photobiomodulation therapy (PBMT) to treat oral mucositis (OM) is unusual in the literature. Thus, this study aims to compare the simultaneous irradiation effects with their isolated application to treat OM. In order of that, 48 male Syrian hamsters were divided into 4 groups: Chemotherapy (Ch), which received only a OM induction protocol (5-Fluorouracil chemotherapy and superficial oral mucosa scratches); Red laser (RL), which received the OM induction and a PBMT protocol at 660 nm; Infrared laser (IRL), which received the OM induction, and a PBMT protocol at 808 nm; and the RL+IRL group, which received the simultaneous application, of 660 nm and 808 nm wavelengths. Clinical (OM grade classification), histological (light microscopy analysis with H&E and collagen staining), immunohistochemical (TNF-α expression), and biochemical (TNF-α and hydroxyproline concentration) analyzes were performed after 7 and 10 days. Mainly on the 10th day, the RL and IRL groups showed lower OM grades and faster microscopic repair process, with greater expression of collagen fibers and lower TNF-α levels, besides the higher hydroxyproline concentrations, mainly in comparison with the Ch group. In conclusion, in this study, the simultaneous protocol did not present superior results than the isolated irradiations. This article is protected by copyright. All rights reserved.
... Oral mucositis (OM) is an inflammatory condition of the oral mucosa caused by chemotherapy and/or radiotherapy. After high dose melphalan and autologous hematopoietic stem cell transplantation (ASCT), OM is seen in 90% of the patients, with severe forms in 46% of the patients [1]. It is clinically characterized by erythema, edema, and ulcerations and negatively affects patients' quality of life. ...
Background
Oral mucositis is a frequently seen complication in the first weeks after hematopoietic stem cell transplantation recipients which can severely affects patients quality of life. In this study, a labelled and label-free proteomics approach were used to identify differences between the salivary proteomes of autologous hematopoietic stem cell transplantation (ASCT) recipients developing ulcerative oral mucositis (ULC-OM; WHO score ≥ 2) or not (NON-OM).
Methods
In the TMT-labelled analysis we pooled saliva samples from 5 ULC-OM patients at each of 5 timepoints: baseline, 1, 2, 3 weeks and 3 months after ASCT and compared these with pooled samples from 5 NON-OM patients. For the label-free analysis we analyzed saliva samples from 9 ULC-OM and 10 NON-OM patients at 6 different timepoints (including 12 months after ASCT) with Data-Independent Acquisition (DIA). As spectral library, all samples were grouped (ULC-OM vs NON-OM) and analyzed with Data Dependent Analysis (DDA). PCA plots and a volcano plot were generated in RStudio and differently regulated proteins were analyzed using GO analysis with g:Profiler.
Results
A different clustering of ULC-OM pools was found at baseline, weeks 2 and 3 after ASCT with TMT-labelled analysis. Using label-free analysis, week 1–3 samples clustered distinctly from the other timepoints. Unique and up-regulated proteins in the NON-OM group (DDA analysis) were involved in immune system-related processes, while those proteins in the ULC-OM group were intracellular proteins indicating cell lysis.
Conclusions
The salivary proteome in ASCT recipients has a tissue protective or tissue-damage signature, that corresponded with the absence or presence of ulcerative oral mucositis, respectively.
Trial registration
The study is registered in the national trial register (NTR5760; automatically added to the International Clinical Trial Registry Platform).
... OM is a frequent and painful side effect of the oncological treatment [1]. Often related to head and neck radiotherapy and some chemotherapies protocols, this condition consists in an inflammation of the oral mucosa, which due to the reduction of the basal epithelium renewal rate, can cause atrophic changes and, consequently, ulceration. ...
The association of more than one wavelength for photobiomodulation therapy (PBMT) to treat oral mucositis (OM) is unusual in the literature. Thus, this study aims to compare the simultaneous irradiation effects with their isolated application to treat OM. In order of that, 48 male Syrian hamsters were divided into 4 groups: Chemotherapy (Ch), which received only a OM induction protocol (5-fluorouracil chemotherapy and superficial oral mucosa scratches); Red laser (RL), which received the OM induction and a PBMT protocol at 660 nm; Infrared laser (IRL), which received the OM induction, and a PBMT protocol at 808 nm; and the RL+IRL group, which received the simultaneous application, of 660 nm and 808 nm wavelengths. Clinical, histological, immunohistochemical and biochemical analyses were performed. The RL and IRL showed the best results overall. In conclusion, in this study, the simultaneous protocol did not present superior results than the isolated irradiations.
... Almost 100% of patients undergoing radiotherapy for head and neck cancer develop mucositis while the severity and incidence of mucositis in the head and neck cancer patients who receive induction chemotherapy is 20-50% [11,12]. Of note, adding chemotherapy to radiation (the current standard of care) increases OM risk. ...
Introduction:
Oral mucositis (OM) is among the most common, damaging, and intolerable side effects of radiation therapy to the head and neck. The ulcerative lesions associated with the condition are of such intensity as to interfere with patients' ability to comply with optimal treatment.
Areas covered:
The increasing unmet clinical need, recent clinical trial successes and the commercial potential have catalyzed interest in the development of effective intervention for OM associated with radiation therapy for cancers of the head and neck. A range of small molecules are under development - some still in the pre-clinical stage, but others close to NDA submission. This review will focus on those drugs which have recently been assessed in a clinical trial and those which are still under clinical study as a prevention or treatment for radiation-associated OM.
Expert opinion:
In response to the unmet clinical need, the commercial potential, and the breadth and value of halo indications of a successful OM product, both the biotechnology and pharmacological industries have been actively pursuing an agent to prevent/treat radiation-associated OM. This effort has been catalyzed by the identification of multiple drug targets which contribute to OM's pathogenesis. The lessons learned from the many trials which have previously stumbled, has led to standardization of clinical trial design, endpoint efficacy definitions, rater assessment and data interpretation over the past decade. Consequently, results of recently completed clinical trials provide optimism that effective treatment options should be available in the not-too-distant future.
... When receiving conditioning treatment before a bone marrow transplant, the UM incidence is abnormally high (70-80%). While concurrent chemotherapy and radiation to improve distant metastasis and central tumor control for head and neck malignancies, as well as continuous chemotherapy infusions for various cancers, result in severe UM in around 60-70% of patients [6,7]. ...
The survival prediction of children undergoing hematopoietic stem-cell transplantation is essential for successful transplantation. However, the performance of current algorithms for predicting mortality in this patient group has not improved over recent decades. This paper proposes a new feature selection technique for survival prediction problems using the Mud Ring Algorithm (MRA). Experiments and tests were initially performed on 13 real datasets with varying occurrences to compare the suggested algorithm with other algorithms. After that, the constructed model classification performance was compared to other techniques using the bone marrow transplant children’s dataset. Modern techniques were used to acquire their classification results, which were then compared to the suggested outcomes using a variety of well-known metrics, graphical tools, and diagnostic analysis. This investigation has demonstrated that our suggested approach is comparable and outperformed other methods in terms of results. In addition, the results showed that the constructed model enhanced prediction accuracy by up to 82.6% for test cases.
... • Oral mucositis (OM) common side effect of high-dose (HD) melphalan (MEL) [1]. • OM does not only result in severe pain, discomfort, and difficulties in eating and drinking, but also in prolonged hospitalization, increased costs, substantial risk for systemic infections and higher mortality [2]. ...
Progression free survival and overall survival five years after oral cryotherapy implemented in high-dosed melphalan conditioning for the prevention of oral mucositis
... Our study corroborates this, and suggested superiority of PTCy in terms of OM prevention. Our results are different from earlier research by Wardley et al. [18] and Blijlevens et al. [21]. Their research identified high-dose melphalan as a major regimen-related risk factor. ...
Purpose
Oral mucositis is a common complication during haematopoietic stem cell transplantation (HSCT). This study aimed to assess the incidence of severe mucositis in patients undergoing different HSCT regimens.
Methods
This single-centre retrospective study reviewed daily oral assessment for 467 consecutive patients who underwent different transplant regimens for matched unrelated or related allogeneic HSCT with post-transplant methotrexate, haploidentical or mismatched HSCT with post-transplant cyclophosphamide (PTCy), or autologous HSCT. Oral care and cryotherapy with melphalan were used. Patient demographic data, oral mucositis WHO grade, use of total parenteral nutrition (TPN) and patient-controlled analgesia (PCA) were collected.
Results
Grade 3–4 oral mucositis was common in myeloablative total body irradiation (TBI)-based regimens cyclophosphamide/ TBI (CyTBI) (71%) and fludarabine/ TBI (FluTBI) with PTCy (46%), as well as reduced-intensity fludarabine/melphalan (FluMel) (43%) and carmustine/etoposide/cytarabine/melphalan (BEAM) autologous HSCT (41%). In contrast, grade 3–4 oral mucositis was less common in reduced-intensity haploidentical regimen melphalan/fludarabine/TBI with PTCy (19%), all non-myeloablative regimens (0–9%) and high-dose melphalan autologous HSCT (26%). TPN and PCA use were correlated to oral mucositis severity.
Conclusions
Severe oral mucositis was associated with myeloablative TBI, methotrexate and melphalan in combination with methotrexate and in BEAM. Use of PTCy was preferable over methotrexate to prevent oral mucositis.
... Indeed, previous studies suggested that oral mucositis and enterocolitis in neutropenic patients may contribute to an increased intestinal permeability, precipitating intestinal barrier failure and bacterial translocation. 32,33 Blijlevens et al. 34 reported in a multicentre study a higher incidence of fever and MDI in patients with severe mucositis after auto-HSCT. Oral mucositis has been associated with an excess risk of α-haemolytic streptococcal 35 and anaerobic bacteraemia. ...
Background
Early antibiotic discontinuation according to the Fourth European Conference on Infections in Leukaemia (ECIL-4) recommendations is not systematically applied in high-risk neutropenic patients with haematological malignancies.
Methods
A retrospective multicentre observational study was conducted over 2 years to evaluate the safety of early antibiotic discontinuation for fever of unknown origin (FUO) during neutropenia after induction chemotherapy or HSCT, in comparison with a historical cohort. We used Cox proportional hazards models, censored on neutropenia resolution, to analyse factors associated with febrile recurrence.
Results
Among 147 included patients in the ECIL-4 cohort, mainly diagnosed with acute leukaemia (n = 104, 71%), antibiotics were discontinued during 170 post-chemotherapy neutropenic episodes. In comparison with the historical cohort of 178 episodes of neutropenia without antibiotic discontinuation, no significant differences were observed regarding febrile recurrences [71.2% (121/170) versus 71.3% (127/178), P = 0.97], admission in ICUs [6.5% (11/170) versus 11.2% (20/178), P = 0.17], septic shock [0.6% (1/170) versus 3.9% (7/178), P = 0.07] and 30 day mortality [1.4% (2/147) versus 2.7% (4/150), P = 0.084]. In the ECIL-4 cohort, the rate of bacteraemia in case of febrile recurrence was higher [27.1% (46/170) versus 11.8% (21/178), P < 0.01] and antibiotic consumption was significantly lower (15.5 versus 19.9 days, P < 0.001). After early antibiotic discontinuation according to ECIL-4 recommendations, enterocolitis was associated with febrile recurrence [HR = 2.31 (95% CI = 1.4–3.8), P < 0.001] and stage III–IV oral mucositis with bacteraemia [HR = 2.26 (95% CI = 1.22–4.2), P = 0.01].
Conclusions
After an FUO episode in high-risk neutropenia, compliance with ECIL-4 recommendations for early antibiotic discontinuation appears to be safe and mucosal damage was associated with febrile recurrence and bacteraemia. Prospective interventional studies are warranted to assess this strategy in high-risk neutropenic patients.
... Oral mucositis is one of the most common side effects of anti-cancer treatments such as radiation therapy, chemotherapy, and immunotherapy 40,41 . It occurs in almost all patients receiving radiation therapy for head and neck cancers [42][43][44] . Clinically, its symptoms include anorexia, malnutrition (significant weight loss), and systemic infections. ...
Objective:
Several studies have reported that the controlling nutritional status (CONUT) score is a prognostic predictor for survival among patients with different types of cancer. We assessed the prognostic value of changes in the CONUT score during treatment and the ΔCONUT-EBV DNA score in patients with advanced nasopharyngeal carcinoma (NPC).
Methods:
We retrospectively analyzed 433 patients with advanced NPC having no evidence of metastasis from January 2007 to June 2011; the patients underwent radical concurrent chemoradiotherapy (CCRT) at Sun Yat-sen University Cancer Center and were grouped based on their ΔCONUT and ΔCONUT-EBV DNA scores. Kaplan-Meier curves were used to compare the patient outcomes according to the cut-off ΔCONUT score and the ΔCONUT-EBV DNA scoring system.
Results:
Among all patients, overall survival (OS) was independently predicted by a high ΔCONUT score (P = 0.031) and high EBV DNA (P < 0.001). The ΔCONUT-EBV DNA score [OS area under the curve (AUC) = 0.621; progression free survival (PFS)-AUC = 0.612; distant metastasis-free survival (DMFS)-AUC = 0.622] was more predictive of OS, PFS, and DMFS in patients with advanced NPC than the ΔCONUT score (OS-AUC = 0.547; PFS-AUC = 0.533; DMFS-AUC = 0.522) and pretreatment plasma EBV DNA levels alone (OS-AUC = 0.600; PFS-AUC = 0.591, DMFS-AUC = 0.610). The ΔCONUT-EBV DNA score was significantly correlated with OS, PFS, and DMFS in patients with advanced NPC treated with CCRT.
Conclusions:
The ΔCONUT-EBV DNA score may be useful in clinical practice as a convenient biomarker for predicting the outcomes in patients with advanced NPC treated with CCRT.
... The use of myeloablative conditioning therapy using total body irradiation (TBI), methotrexate for graft-versus-host disease prophylaxis, and poor performance status are associated with increased risk for oral mucositis. In one study, BMI ≥ 25 and presence of (Wardley et al. 2000;Robien et al. 2004;Fanning et al. 2006;Blijlevens et al. 2008). Mucositis can cause pain, discomfort with swallowing and speech, localized bleeding, impaired nutrition, and increased infection risk. ...
Hematopoietic stem cell transplant results in a variety of treatment-related side effects other than pain. The side effects encountered may include prolonged, late, or permanent side effects of prior cancer therapy in addition to treatment-related effects from transplant chemotherapy, prolonged cytopenias, and therapy used for supportive care during transplant. Systemic side effects to address during and after transplant may include fatigue, delirium, and malnutrition. Gastrointestinal side effects may include mucositis, nausea, vomiting, diarrhea, and constipation. In this chapter we discuss the recognition, approach, and therapeutic interventions for the management of these non-pain-related side effects of Hematopoietic stem cell transplant.
... Both inflammation and oxidative stress are also linked as side effects at the gastrointestinal level (mucositis) of chemotherapy (CT) and radiotherapy (RT). This side effect occurs in 20-40% of patients receiving CT for solid tumors, 60-80% of those undergoing hematopoietic stem cell transplantation and in almost all patients receiving RT for head and neck cancers [5][6][7]. Mucositis is a very complex process that leads to inflammatory and/or ulcerative lesions, which can affect any part of the gastrointestinal tract, damaging the mucosa. The specific mechanism of mucositis, along with its clinical presentation, depends on the anatomical site involved (oral or gastrointestinal) and on the type of CT and RT [8,9]. ...
Intestinal epithelial cells (IECs) play a pivotal role in maintaining intestinal homeostasis. Different noxious agents, among them also anticancer therapies, can impair intestinal epithelial integrity triggering inflammation and oxidative stress. A frequent complication of chemotherapy is gastrointestinal mucositis, strongly influencing the effectiveness of therapy, increasing healthcare costs, and impairing patients’ quality of life. Different strategies are used to treat gastrointestinal mucositis, including products from natural sources. Our study focused on the effect of pomegranate (Punica granatum L.) juice extract on IEC-6 cells, both during inflammatory conditions and following treatment with 5-fluorouracil (5-FU). The polyphenolic profile of pomegranate juice was characterized in detail by Online Comprehensive two dimensional Liquid Chromatography-Mass Spectrometry. The evaluation of pomegranate juice extract in IEC-6 indicates a significant inhibition in proinflammatory factors, such as cytokines release, cyclooxygenase-2 and inducible nitric oxide synthase expression, and nitrotyrosine formation. Pomegranate also inhibited oxidative stress and adhesion protein expression. In 5-FU-treated IEC-6, pomegranate also inhibited both inflammatory and oxidative stress parameters and apoptosis. It promoted wound repair and tight junction expression. These results suggest a potential use of pomegranate as an adjuvant in the treatment of intestinal inflammatory and oxidative stress states, which also occur during chemotherapy-induced mucositis.
... The maximum BSA used for dosage calculation was 2 m 2 to prevent obese patients from increased therapy-related toxicity. In this regard, it has been reported that severe oral mucositis-one major clinical toxicity of HDT and known risk factor for infections-was increased with higher dose/weight ratio in NHL patients receiving carmustine [40]. Other toxicities that are exemplarily known to increase with dose are etoposide induced mucositis or carmustine associated pulmonary toxicity [41]. ...
Autologous hematopoietic stem cell transplantation (auto-HSCT) provides a potentially curative treatment option for relapsed and refractory lymphomas. Obesity displays an emerging epidemic risk factor for global mortality and is associated with an increased mortality in cancer patients. To date, the impact of obesity on the outcome of lymphoma patients undergoing auto-HSCT is understudied. We conducted a retrospective single-center study assessing 119 lymphoma patients who underwent auto-HSCT. Overall survival (OS) served as the primary endpoint whereas progression free survival (PFS), cumulative incidence of non-relapse related mortality (NRM) and cumulative incidence of relapse were analyzed as secondary endpoints. Obese patients (Body mass index, BMI≥30) had significantly lower OS (45.3% vs. 77.9%; p = 0.005) and PFS (29.8% vs. 67.2%; p<0.001) compared to non-obese patients at 48 months post-transplantation. The cumulative incidence of NRM displayed no significant differences while the cumulative incidence of relapse was significantly increased in patients with BMI≥30 (66.2% vs. 21.5%; p<0.001). Patients with a BMI<25 and overweight patients (BMI 25–30; 76.1% vs. 80.9%; p = 0.585), showed no significant difference in OS, whereas patients with BMI≥30 exhibited significant lower OS when compared to either of both groups (76.1% vs. 45.3%; p = .0.021 and 80.9% vs. 45.3%; p = 0.010). Furthermore, in a multivariate analysis, obesity was identified as an independent risk factor for death (Hazard ratio 2.231; 95% CI 1.024 to 4.860; p = 0.043). Further studies are needed to evaluate the reasons for the higher relapse rate causing higher mortality in obese patients.
In recent era, cancer is a major global health hazard and is mostly treated with either radio or chemotherapy. The above treatment procedure induces a secondary concern named as oral mucositis (OM). The disorder OM is specifically associated with oral mucosa and leads to bleeding, pain, difficulty in swallowing of solids, as well as fluids and speech difficulty. Curcumin is explored for prevention as well as treatment of OM. The article was organized via collection of enormous literatures by using the keywords like oral mucositis, chemotherapy, anti-inflammatory, curcumin, and clinical trials from search engines of different domains like Scopus, PubMed/MEDLINE, Science Direct, and Google Scholar with an increasing order of their year of publications. A numerous antineoplastic therapies resulted OM, as a devastating side effect. Moreover, the expanded pathogenesis of the disease permits a sound predictability over the patient’s risk, thereby directing its adaptability and management protocols towards the achievement of novel therapeutics. An augmented interest towards curcumin as a potential therapeutic emerged because of its easy accessibility, antioxidant, anti-inflammatory, antiulcer, antimicrobial, and wound-healing abilities along with reduced side effects. Curcumin can potentially alter OM and OM-induced weight loss but showed a great heterogeneity.
Introduction
Carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) are a widely used high-dose chemotherapy regimen for autologous stem cell transplantation transplant (ASCT) in lymphoid malignancies. During BCNU shortages, some centers switched to fotemustine-substituted BEAM (FEAM). Neutropenic enterocolitis (NEC) is a life-threatening complication occurring after intestinal mucosa damage related to intensive chemotherapy. NEC mortality may be up to 30%–50%. In our study, we compared NEC incidence, symptoms, mortality, and transplant outcome in terms of overall survival (OS) and progression-free survival (PFS) in the BEAM vs. FEAM groups. Furthermore, we compared the cost of hospitalization of patients who did vs. patients who did not experience a NEC episode (NECe).
Methods
A total of 191 patients were enrolled in this study (N = 129 and N = 62 were conditioned with BEAM and FEAM, respectively). All patients received bed-side high-resolution ultrasound (US) for NEC diagnosis.
Results and discussion
NEC incidence and NEC-related mortality were similar in the BEAM and FEAM groups (31% and 40.3%, p = 0.653, and 5% and 8%, p = 0.627, respectively). At a median follow-up of 116 months, no difference was noted between BEAM vs. FEAM groups in terms of OS and PFS (p = 0.181 and p = 0.978, respectively). BEAM appeared equivalent to FEAM in terms of NEC incidence and efficacy. The high incidence of NEC and the low mortality is related to a timely US diagnosis and prompt treatment. US knowledge in NEC diagnosis allows to have comparable days of hospitalization of patients NECpos vs. patients NECneg. The cost analysis of NECpos vs. NECneg has been also performed.
Infectious complications of autologous hematopoietic stem cell transplantation (AHSCT) are the most common adverse effects of the therapy, resulting in prolonged hospitalization and deterioration of patient well‐being. Identifying predictors of these complications is essential for improving patient outcomes and guiding clinical management. This study aimed to examine thrombospondin‐1 (THBS‐1) serum levels as a potential biomarker for predicting bacteremia in AHSCT recipients. Blood samples were collected from 30 patients undergoing BeEAM/BEAM (bendamustine/carmustine, etoposide, cytarabine, melphalan) conditioning regimen at subsequent time points during AHSCT. THBS‐1 levels were quantified using ELISA kits. Patients who developed bacteremia ( n = 11) during the AHSCT course had lower THBS‐1 concentration compared with those without ( n = 19) (22.88 ± 11.53 µg/mL vs. 15.24 ± 5.62 µg/mL, p = .0325). The ROC curve analysis revealed that THBS‐1 serum concentration at the first day of BeEAM/BEAM regimen had an area under the curve of 0.732 (95%CI: 0.5390.925, p = .0186) with an optimal cut‐off value of 16.5 µg/ml resulting in 82% Sensitivity and 53% Specificity for predicting bacteremia with a median of 11 days before its occurrence. Patients with lower THBS‐1 concentrations experienced febrile neutropenia significantly earlier, with a median difference of 5 days ( p = .0037). Patients with a low concentration of THBS‐1 had a higher risk of bacteremia and a shorter time to febrile neutropenia, indicating its potential value as a complications biomarker. Patients with lower serum THBS‐1 concentrations, indicating an increased risk, may be more suitable for an inpatient AHSCT procedure, where close monitoring and immediate intervention are accessible. image
Malignant tumor diseases constitute the 2nd most common cause of death and due to our extended life expectancy cancer per se has substantially increased, being highly prevalent after cardiovascular diseases. Evidence also generated from the COVID-19 pandemic, that defined gender differences exist in symptom and disease courses, and have advocated the need to assess gender, ethnic/racial and minority differences in cancer care and treatment more meticulously. It is becoming increasingly evident that in novel cancer care/precision oncology, representation of minorities, elderly and frail patients in clinical trials remains largely unbalanced, thus distribution of cancer success is iniquitous. This article focusses on these aspects and suggests solutions, how this can be improved.
Radiation therapy is a vital integrated part of modern comprehensive cancer management. Aside from the typical use of radiotherapy in treatment of cancer, low-dose radiation (LDR), typically <100 mGy, shows the capacity to improve wound healing by promoting fibroblast-to-myofibroblast differentiation, matrix deposition, keratinocyte proliferation and angiogenesis. Moreover, animal studies have shown LDR attenuates systemic acute inflammatory response by regulating inflammatory cytokines, thus alleviating damage associating with chronic diabetic and burn wounds. Wounds can be classified as open or closed. Open wounds, such as cuts, burns or ulcers, can arise from external factors such as accidents, surgery and trauma or internal factors, such as diabetes mellitus, whereas closed wounds may occur due to blunt force trauma. Additionally, wounds can be either acute or chronic, depending on their healing capacity. These disruptions of the skin’s structural and functional integrity go through four distinct phases to achieve complete wound healing, namely, haemostasis, inflammation, cellular migration and proliferation and remodelling. Photobiomodulation and low-dose ionizing radiation have been studied for their effects on the cellular and molecular processes involved in wound healing. Similarly, both methods of low-dose radiation treatment have also been examined for their cancer therapy-associated adverse effects. In this paper, the molecular and cellular effects of low-dose radiation on wound healing and cancer cells are discussed. Additionally, the protective effects of low-dose radiation against conventional cancer treatments such as high-dose radiation and chemotherapy are also discussed.
Objective:
This study aimed to compare the historical incidence rate of severe oral mucositis (OM) in head and neck cancer patients undergoing definitive concurrent chemoradiation therapy (CRT) versus a prospective cohort of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with prophylactic photobiomodulation therapy (PBMT).
Methods:
This US-based, institutional, single-arm, phase Ⅱ prospective clinical trial was initiated in 50 patients (age ≥ 18 years, Karnofsky Performance Scale Index > 60, with locally advanced HNSCC (excluding oral cavity) receiving definitive or adjuvant radiation therapy (RT) with concurrent platinum-based chemotherapy (CT). PBMT was delivered three times per week throughout RT utilizing both an intraoral as well extraoral delivery system. Primary outcome measure was incidence of severe OM utilizing both the National Cancer Institute Common Toxicity Criteria, version 4.0 (NCI-CTCAE) Grade ≥3 and the World Health Organization Mucositis Grading Scale (WHO) Grade ≥3 versus historical controls; secondary outcome measures included time to onset of severe OM following therapy initiation.
Results:
At baseline, all patients included in final analysis (N = 47) had OM Grade 0. Average RT and CT dose was (66.3 ± 5.1) Gy and (486.1 ± 106.8) mg/m2, respectively. Severe OM was observed in 11 of 47 patients (23%, confidence interval: 12, 38). OM toxicity grade trended upward during treatment, reaching a maximum at 7 weeks (WHO: 1.8 vs. NCI-CTCAE: 1.7). Subsequently, OM grade returned to baseline 3 months following completion of RT. The mean time to onset of severe OM was (35 ± 12) days. The mean time to resolution of severe OM was (37 ± 37) days.
Conclusions:
Compared to historical outcomes, PBMT aides in decreasing severe OM in patients with locally advanced HNSCC. PBMT represents a minimally invasive, prophylactic intervention to decrease OM as a major treatment-related side effect.
In 2018, 17 million new cases of cancer were diagnosed worldwide and it is estimated that cancer incidence rates will increase by 62% by 2040. The most common cancers diagnosed worldwide are lung, breast, bowel or prostate cancers and these make up to 40% of new diagnoses yearly.
Stem cell transplantation (SCT) has expressed its increase since the first transplant in 1957 to more than one million in 2014 (Gratwohl et al. Lancet Hematol 2(3):91–100, 2015). During many years, SCT has been limited tomatchdonors related. With the discovery of the major histocompatibility complex identification, human leukocyte antigen (HLA) and graft-versus-host disease (GvHD) recognition, the possibility of allogeneic transplantations, and, more recently, haploidentical transplantations have significantly increased. With the advances of the different types of SCT, the management of these patients has become increasingly complex. SCT process begins when there is a patient, with diseases diagnosis, who after his treatment has the recommendation to be consolidated with SCT. Since the transplant indication, pre-transplant evaluation, transplantation itself, and even post-transplant follow-up, a specific care is required for each phase of SCT and for a long period, even after the procedure success. In addition to the transplant doctor, the multidisciplinary team has a fundamental and primary role to make all phases of SCT occur more safely and effectively for the patient. There are numerous studies that clearly show the relationship between pharmaceutical activities in SCT and improvements in various quality metric, clinical, humanistic, and financial outcomes in the United States and Europe SCT services. The pharmacist role must be related to medicine management, patient care, care transitions, and education and is also extended to the scope of research. American and European SCT societies have endorsed these roles of pharmacists as factors that add value to the SCT process (Clemmons A. Pharmacy (Basel) 8(1):3, 2020).
Abstract Background Oral mucositis (OM) is known to be the most common and challenging side effect of conditioning chemotherapy in haematopoietic cell transplant (HCT). This side effect causes significant morbidity and may delay the treatment plan, as well as increase therapeutic expenses. There are few clinical trials in the literature that indicate any kind of treatment or prevention methods are effective. Therefore, the aim of this study is to perform a systematic review of literature and examine the effectiveness of oral cryotherapy (OC) in management of chemotherapy-induced OM in patients with haematological malignancies undergoing a HCT. Methods A systematic literature search was conducted, using the electronic databases PubMed, Embase, MEDLINE and Scopus. A total of 322 papers were identified and 9 papers were analysed based on defined inclusion and exclusion criteria. The quality of the chosen primary studies was appraised using the COCHRANE risk of bias assessment tool. Results Nine randomized controlled trials, analysing 658 participants; control group (n = 289, age mean ± SD; 41.15 ± 21) and treatment group (n = 369, age mean ± SD; 39.15 ± 20), were included in this systematic review. Seven studies had significantly addressed the effectiveness of OC (p value
The aim of the present study was to analyze the relationship of OM with possible risk factors such as oral health condition, immunological status and IL-1β profile in patients submitted to hematopoietic stem cell transplantation (HSCT). Fifty-four individuals submitted to HSCT were included. All patients received previous dental treatment and photobiomodulation (PBM) as the institutional OM preventive protocol. OM scores, immune status, and IL-1β levels were determined during the conditioning period and at D+3 and D+8 after HSC infusion. IL-1β gene polymorphism was also analyzed during conditioning. Possible associations of OM with risk factors were analyzed using conditional Fisher's exact test. OM was observed in 34 patients (62.9%) classified as Grade 1 (13 patients/24.1%), Grade 2 (14 patients/25.9%), Grade 3 (3 patients/5.5%), and Grade 4 (4 patients/7.4%). Allogeneic HSCT individuals exhibited a higher OM grade than autologous subjects. Moreover, an association was observed between severe OM and severe gingivitis (p = 0.01), neutropenia (p = 0.03), and leukopenia (p = 0.04). A significant association between OM and lower IL-1β levels was detected at three time points, i.e., conditioning (p = 0.048), D+3 (p = 0.01), and D+8 (p = 0.005). The results showed that IL-1β gene polymorphism was not associated with OM. Our study provided important insights into the scope of OM risk factors in the setting of HSCT. Patients submitted to HSCT with severe gingivitis prior to chemotherapy and with severe neutropenia and leukopenia exhibited a higher OM grade. Further investigation will be necessary to better understand the exact role of IL-1β in the context of OM pathobiology and to validate cytokine analysis in larger cohorts.
Mucositis is a generalized term used to denote either oral or gastrointestinal mucositis as a consequence of cancer therapy. This chapter will describe the epidemiology of mucositis in relation to radiation therapy for head and neck cancers, chemotherapy, and hematopoietic stem cell transplantation. Clinical features, risk factors and pathogenesis of mucositis are covered in depth. In addition, the current consensus on mucositis management and economic consequences are reviewed in this chapter. Although considered to have a different pathogenesis, targeted therapy related oral mucosal adverse effects are often referred in the literature as mucositis or stomatitis. This entity is described in this chapter, too.
Oral mucositis (OM) is a common complication of cancer therapy. The clinical presentation varies in severity and dynamics over time based on the cancer therapy modality (radiotherapy to the head and neck, chemotherapy, hematopoietic stem cell transplantation). OM poses a risk for spread of infection locally and systemically, as well as associated with increased consumption of opioids, need for total parenteral nutrition, and increased stay at the hospital.
Objective
Ulcerative mucositis (UM) is a devastating complication of most cancer therapies with less recognized risk factors. Whilst risk predictions are most vital in adverse events, we utilized Machine learning (ML) approaches for predicting chemotherapy-induced UM.
Methods
We utilized 2017 National Inpatient Sample database to identify discharges with antineoplastic chemotherapy-induced UM among those received chemotherapy as part of their cancer treatment. We used forward selection and backward elimination for feature selection; lasso and Gradient Boosting Method were used for building our linear and non-linear models.
Results
In 2017, there were 253 (unweighted numbers) chemotherapy-induced UM patient discharges from 21,626 (unweighted numbers) adult patients who received antineoplastic chemotherapy as part of their cancer treatment. Our linear model, lasso showed performance (C-statistics) AUC: 0.75 (test dataset), 0.75 (training dataset); the Gradient Boosting Method (GBM) model showed AUC: 0.76 in the training and 0.79 in the test datasets. The feature selection derived from stepwise forward selection and backward elimination methods showed variables of importance––antineoplastic chemotherapy-induced pancytopenia, agranulocytosis due to cancer chemotherapy, fluid and electrolyte imbalance, age, anemia due to chemotherapy, median household income, and depression. Higher importance variable derived from GBM in the order of importance were antineoplastic chemotherapy-induced pancytopenia>co-morbidity score>agranulocytosis due to cancer chemotherapy>age>and fluid and electrolyte imbalance. Further, when the analysis was stratified to females only, the ML models performed better than the unstratified model.
Conclusion
Our study showed ML methods performed well in predicting the chemotherapy-induced UM. Predictors identified through ML approach matched to the clinically meaningful and previously discussed predictors of the chemotherapy-induced UM.
Candidemia is a major complication in hematopoietic cell transplantation (HCT), and antifungal prophylaxis with fluconazole decreases the incidence of this complication. We compared two strategies of fluconazole prophylaxis in hematologic patients receiving autologous HCT between 1997 and 2017. From 1997 to 2003, fluconazole prophylaxis (400 mg/d) was given to all HCTs, started with the conditioning regimen (early prophylaxis), and given until neutrophil engraftment or the need of non-prophylactic antifungal therapy. From 2004 on, fluconazole (400mg daily) was started only if (and when) the patient developed oral mucositis (late prophylaxis). Among 571 HCT, 270 received early prophylaxis, 112 received late prophylaxis, and 189 did not receive fluconazole because they did not develop oral mucositis. The incidence of candidemia was 1.8%, zero, and 1.1% in the early, late and no prophylaxis, respectively (p=0.31). Among patients receiving fluconazole, the median duration of prophylaxis was 17 days (range 6-36) and 6 days (range 2-16) in the early and late prophylaxis respectively (p<0.001). The initiation of fluconazole prophylaxis guided by the occurrence of oral mucositis (late prophylaxis) was as good as early fluconazole prophylaxis.
The aim of this multicentre, longitudinal study was to determine salivary changes in relation to oral mucositis (OM) in multiple myeloma patients following high-dose melphalan and autologous hematopoietic stem cell transplantation (ASCT). Unstimulated and stimulated whole-mouth saliva samples (UWS and SWS) were collected before ASCT, 1×/wk during the hospitalisation phase, and 3 and 12 months post-ASCT. During the hospitalisation period OM was scored 3×/wk (WHO system). Flow rate, pH, total protein concentration (Nanodrop), albumin, lactoferrin, neutrophil defensin-1 (HNP1), total IgA and S100A8/A9 (ELISA) were determined. Mixed models were used to evaluate differences between ulcerative (u)OM (≥2 WHO, n = 20) and non-uOM (n = 31) groups. Until 18 days after ASCT, flow rate, pH, total IgA and HNP1 levels decreased in UWS and/or SWS, while log lactoferrin levels were significantly increased (UWS: p = 0.016 95% CI [0.36, 3.58], SWS: p < 0.001 95% CI [1.14, 3.29]). Twelve months post-ASCT, salivary protein levels were similar to baseline except for log total IgA, which was higher (UWS: p < 0.001 95% CI [0.49, 1.29], SWS: p < 0.001 95% CI [0.72, 1.45]). No differences between uOM and non-uOM groups were observed. Changes in salivary proteins indicated an inflammatory reaction in salivary glands coinciding with mucosal and systemic reactions in response to high-dose melphalan.
Gastrointestinal side effects are the dose-limiting toxicity of high-dose melphalan (HDM) in autologous hematopoietic stem-cell transplantation, but there are limited contemporary data on the incidence and severity of gastrointestinal toxicity associated with this regimen. We retrospectively studied 100 consecutive patients who received HDM alone or in combination with other conditioning agents. Patients had a median age of 56 (range 20–73); underlying diseases were myeloma (42%), lymphoma (42%), or amyloidosis (16%) and melphalan dosages were 200 (40%), 140 (59%), or 100 mg/m² (1%). Ninety-seven percent of patients experienced diarrhea with a range of 1–18 bowel movements per day, 88% developed nausea, and 60% experienced vomiting. Abdominal CT scans rarely altered patient management, but stool studies were useful in identifying a treatable infectious source. Grade ≥ 2 diarrhea was associated with longer duration of diarrhea, longer length of stay, worse hypoalbuminemia, higher use of antibiotics, abdominal imaging, electrolyte repletions, and anti-diarrheal agents. Risk factors for severe diarrhea were female sex, melphalan dose, age > 50, creatinine clearance < 60 ml/min, and having a plasma cell neoplasm as opposed to lymphoma. Female sex was also associated with more severe nausea and vomiting. In summary, diarrhea remains an important toxicity of HDM and novel therapies for chemotherapy-induced diarrhea for patients undergoing stem-cell transplantation are needed. Grade 2 or higher diarrhea is associated with significant clinical consequences and should be used as the primary endpoint in prospective clinical trials.
Objective:
To clinically assess the effectiveness of topical chamomile oral gel in the prevention of chemotherapy-induced oral mucositis.
Material and methods A parallel single-blind randomized clinical trial conducted on forty-five patients who were undergoing chemotherapy. Patients were assigned to three equal groups. Group I received conventional symptomatic treatment that included anti-fungal agents (Miconaz oral gel) 1 , topical anesthetics and anti-inflammatory agent (BBC oral spray) 2 three times per day for three weeks, group II received 3% chamomile topical oral gel, whereas group III patients were given both conventional symptomatic treatment and chamomile topical oral gel. All patients were clinically assessed for pain and oral mucositis severity at three separate time intervals: one week, two weeks and three weeks. Results
Most patients experienced oral mucositis with more severity reported in the conventional group (grade III= 6.7%) compared to the other two groups, neither of which developed more than grade II. Mean pain scores showed no significant difference between the groups, but intragroup analysis showed that pain score increased in the conventional treatment group more than the other two groups.
Conclusion
Topical chamomile 3% gel has demonstrated in this study to lower the severity of the mucositis with lower pain scores compared to the other two groups.
Oral mucositis is a common and distressing complication in patients receiving high‐dose chemotherapy followed by hematopoietic stem cell transplantation (HSCT). We reported previously in a single‐center retrospective analysis that zinc‐L‐carnosine (polaprezinc [PZ]) reduced the incidence of oral mucositis associated with HSCT. To verify the accuracy of the prophylactic effect of PZ against oral mucositis, we carried out a multi‐institutional prospective randomized controlled study. Patients were randomly allocated to either the prevention group, in which PZ lozenge treatment was started before chemotherapy, or the control group, in which administration of PZ lozenges was initiated immediately after the onset of Grade 2 oral mucositis. Oral mucositis was evaluated daily from the start of chemotherapy to 35 days after transplantation. A total of 91 patients were enrolled, and 88 patients (47 in the control group and 41 in the prevention group) were eligible for data analysis. The incidence of Grade ≥2 but not Grade ≥3 oral mucositis was significantly reduced in the prevention group compared to the control group (44.7% in control group vs 22.0% in the prevention group, P = .025). There were no significant differences in the incidence rates of other adverse events or the rate of engraftment (95.6% vs 97.2%, P = .693) between the two groups. These findings suggest that PZ lozenge is effective for prophylaxis against Grade ≥2 oral mucositis associated with chemotherapy in patients undergoing HSCT without any influence on the HSCT outcome.
Goal: The aim of this study was to describe the incidence of oral mucositis (OM) in patients undergoing autologous hematopoietic stem cell transplantation (auto-HSCT), relating it to the main clinical factors. Methodology: Descriptive analysis based on a randomized clinical study was conducted with patients undergoing HSCT at the University Hospital of Federal University of Juiz de Fora between January 2018 and June 2019. The World Health Organization oral toxicity scale was used to assess the degree of oral mucositis and adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) 4.0 version. Results: Thirty-eight patients were evaluated. The incidence of OM and severe oral mucositis (SOM) was 57.9% and 21.0%, respectively. The mean duration of OM was 7.2 ± 2.6 days and the lomustine, etoposide, cytarabine and cyclophosphamide protocol (LEAC) presented the longest mean time 8.1 ± 3.1 days (p-value 0.02). The number of viable CD34+ cells and the onset day of neutropenia were predictors of SOM. Conclusion: The incidence of OM in patients undergoing HSCT was lower than reported in the literature, being more severe in patients who received less CD34+ cells and in patients with early onset of neutropenia.
Introduction: Oral mucositis (OM) is a common toxicity of cytotoxic cancer regimens and remains one of the most painful, injurious, and treatment-disrupting side effects of radiation and ablative therapy. Despite its frequency and impact, approved definitive preventive or therapeutic options remain limited.
Areas covered: This review focuses on mechanistically active small molecules and biologicals that are under clinical development for the prevention of oral mucositis. The authors have excluded those compounds and devices for which their indication is limited to symptoms management.
Expert opinion: OM remains a significant unmet clinical need. The commercial opportunities for an effective treatment have been characterized as a global market of $1 billion (US). The formulations of drugs under development vary considerably but share some several commonalities in their development scheme. All new agents are given prophylactically and are being evaluated in patients treated with concomitant chemoradiation therapy for head and neck cancer. The primary efficacy outcome for most trials is dependent on the assessment of mucositis using the scoring scale established years ago by the World Health Organization. The development activity for OM is robust with a diverse range of agents. New drug applications for effective therapeutic options for OM should be ready for review within the next few years.
The aim of this prospective, two center study was to investigate the dynamics of the microbial changes in relation to the development of ulcerative oral mucositis in autologous SCT (autoSCT) recipients. Fifty-one patients were diagnosed with multiple myeloma and treated with high-dose melphalan followed by autoSCT. They were evaluated before, three times weekly during hospitalization, and three months after autoSCT. At each time point an oral rinse was collected and the presence or absence of ulcerative oral mucositis (UOM) was scored (WHO scale). Oral microbiome was determined by using 16S rRNA amplicon sequencing and fungal load by qPCR. Twenty patients (39%) developed UOM. The oral microbiome changed significantly after autoSCT and returned to pre-autoSCT composition after three months. However, changes in microbial diversity and similarity were more pronounced and rapid in patients who developed UOM compared to patients who did not. Already before autoSCT, different taxa discriminated between the 2 groups, suggesting microbially-driven risk factors. Samples with high fungal load (>0.1%) had a significantly different microbial profile from samples without fungi. In conclusion, autoSCT induced significant and reversible changes in the oral microbiome, while patients who did not develop ulcerative oral mucositis had a more resilient microbial ecosystem.
Purpose
Limited data about oral mucositis (OM) in stem cell transplant patients with underlying hematological disease is available in Germany. The purpose of this feasibility study was to determine the incidence, treatment patterns, patients’ adherence, and costs of OM.
Methods
Prospective, noninterventional single-center observational study. Inclusion criteria: allogenic/autologous stem cell transplant patients ≥ 18 years, high-dose chemotherapy. OM assessment: WHO Oral Toxicity Scale. Adherence was measured in patient interviews. Preventive and therapeutic measures were extracted from patients’ charts.
Results
Forty-five patients (25 allogenic, 20 autologous) were enrolled. Twenty-six (58%) patients developed OM (54% grade I/II, 46% grade III/IV). Age ≥ 65 (31% vs 69%, p = 0.021) was associated with a lower OM incidence. A positive history of smoking (1.77 vs 2.69, p = 0.036) was associated with a lower OM grade, patients with unrelated donors (2.63 vs 1.29, p = 0.014) were associated with higher OM grades and females (80% vs 47%, RR = 1.71, p = 0.035) with a higher incidence. OM patients were less adherent to recommended daily mouth rinses (35% vs 68%, p = 0.027). More analgesic treatment (80% vs 32%, p = 0.001) and intravenous opioids (24% vs 0%, p = 0.023) were prescribed in OM patients. Total drug treatment and nutrition costs were 824€ (p = 0.037) higher in autologous transplanted patients.
Conclusion
Initial risk and consecutive OM assessment, determination of patients’ adherence, resource consumption, and costs are prerequisites to evaluate OM care. In the best case, several centers will follow the same methodological approach and the collected data will serve as a basis for benchmarking analyses to optimize OM care where required.
In recent years, significant improvements have been made in the management of neutropenia and thrombocytopenia and other potentially life-threatening complications of ablative chemotherapy. While these complications are of particular concern to physicians, patients receiving ablative therapy for bone marrow or blood stem cell transplants are often troubled by other side effects such as nausea, vomiting, diarrhea and mouth sores. The purpose of the study was to gain a better understanding of patients' experiences while undergoing a transplant. The same professional medical interviewer conducted in-depth interviews with 38 subjects (10 men, 28 women; mean age 46.9 years) who had received ablative therapy for bone marrow and/or peripheral blood stem cell transplants. Participants were consecutively identified through physician and patient referrals, cancer and BMT patient support groups, and newspaper advertisements. Twenty-eight patients (74%) received autologous stem cell transplants and 10 patients (26%) received allogeneic transplants. Participants reported mouth sores, nausea and vomiting, diarrhea, and fatigue as the most troubling side effects of their transplants. Mouth sores were selected as the single most debilitating side effect (42%), followed by nausea and vomiting (13%). Many patients mentioned that mouth sores made it difficult or impossible to eat (n = 23), swallow (n = 21), drink (n = 17), and/or talk (n = 8). Twenty patients reported pain in the mouth, throat, and/or esophagus. Two-thirds (66%) of patients reported receiving opioid analgesics, most frequently morphine, to relieve oral pain. For many, opioids caused incapacitating side effects, including hallucinations, a feeling of loss of control and a decrease in mental acuity. Patients receiving ablative chemotherapy identify oral mucositis as a significant cause of suffering and morbidity. Effective interventions to alleviate this complication are urgently needed.
The use of autologous peripheral blood progenitor cells (PBPC) expedites hematologic recovery and reduces the costs of transplantation in comparison with autologous bone marrow; however, its efficacy in patients with Hodgkin's disease has been questioned. We evaluated the results of autologous PBPC transplantation in a population of unselected and uniformly treated patients with primary refractory or relapsed Hodgkin's disease.
Forty consecutive adult patients with primary refractory (n = 7) or relapsed (n = 33) Hodgkin's disease received high-dose BEAM (BCNU, etoposide, ara-C, and melphalan) followed by autologous PBPC infusion. Twenty-four patients (60%) received high-dose BEAM as outpatients. Consolidative radiation therapy was administered to 14 patients (35%).
Thirty-seven patients (92%) achieved a post transplant complete response. The 3-year progression-free survival (PFS) was 69%, and the 3-year overall survival (OS) was 77%, with a median follow-up of surviving patients of 28 months. Severe non-hematologic toxicities included gastrointestinal side effects (diarrhea 17%, mucositis 25%), and interstitial pneumonitis (15%). One patient died of acute transplant-related complications (mortality rate 2.5%). Strong predictors of poor PFS were chemoresistant versus chemosensitive/untested disease (actuarial PFS 89% versus 22%, P = 0.0000) and stage IIB-IV versus I-IIA at relapse/progression (86%, versus 46%, P = 0.005). All five patients with elevated lactate dehydrogenase at the time of transplantation died of their disease. There was a trend toward worse PFS for patients receiving a higher number of CD34+ cells (> or = 11 x 10(6) per kg).
High-dose BEAM chemotherapy with autologous PBPC transplantation is associated with low mortality and results in satisfactory PFS for patients with primary refractory or relapsed Hodgkin's disease. The subset of patients with progressive disease at the time of transplantation performs poorly and may benefit from alternative strategies.
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.
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) $25,405 in additional hospital charges (P <.0001), and (7) a 3.9-fold increase in 100-day mortality risk (P <.01). Mean hospital charges were $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 incidence of anaerobic bloodstream infections (BSI) in patients who underwent bone marrow transplantation (BMT) recently
increased at our institution. A retrospective case-control study of patients undergoing BMT from January 1995 through December
1998 was performed to determine the microbiological characteristics, epidemiology, and outcome of anaerobic BSI and to identify
independent risk factors for infection. Anaerobic BSI occurred in 23 patients, for a rate of 4 BSIs per 100 BMT procedures,
and it accounted for 17% of all BSIs that occurred during the study period. Infection occurred at a mean (± standard deviation)
of 7 ± 4 days after BMT and 7 ± 5 days after the onset of neutropenia. Fusobacterium nucleatum was the most frequently isolated pathogen (in 17 patients), followed by Leptotrichia buccalis (in 4), Clostridium septicum (in 1), and Clostridium tertium (in 1). Two case patients (9%) died. Severity of mucositis was an independent predictor of anaerobic BSI (odds ratio, 4.4;
P = .01). Controlling mucositis is critical for the prevention of anaerobic BSI in this patient population.
High-dose therapy has become a common treatment for myeloma. The objective of this study (Intergroupe Francophone du Myélome [IFM] 9502 trial) was to compare in a prospective and randomized trial the 2 most widely used conditioning regimens before autologous stem cell transplantation in newly diagnosed symptomatic patients younger than 65 years old: 8 Gy total body irradiation plus 140 mg/m(2) melphalan (arm A) versus 200 mg/m(2) melphalan (arm B). A total of 282 evaluable patients were compared--140 in arm A and 142 in arm B. Baseline characteristics and disease response to 4 cycles of the VAD regimen performed before randomization and autologous stem cell transplantation were identical in the 2 treatment arms. In arm B, hematologic recovery was significantly faster for both the duration of neutropenia and thrombocytopenia, transfusion requirements were also significantly lower, and the median duration of hospitalization was significantly shorter. In arm A, the incidence of severe mucositis was significantly increased. The median duration of event-free survival was similar in both arms (21 vs 20.5 months, P =.6), but the 45-month survival was 65.8% in arm B versus 45.5% in arm A (P =.05). This difference might be attributed in part to better salvage regimens after relapse in arm B compared with arm A. We conclude that 200 mg/m(2) melphalan is a less toxic and at least as effective conditioning regimen when compared with 8 Gy total body irradiation with 140 mg/m(2) melphalan. This regimen should be considered as the standard of care before autologous stem cell transplantation in multiple myeloma.
We have undertaken a retrospective sequential-cohort analysis of 131 lymphoma patients treated with the BEAM regimen and autologous stem cell transplantation, to compare BEAM at standard doses (sBEAM; n = 67 from May 1990 to April 1995) and BEAM with escalated etoposide dose from 800 to 1600 mg/m(2) (eBEAM; n = 64 from May 1995 to June 1999). Transplant-related mortality and incidence of secondary malignancies were similar in both groups. Disease progression was significantly lower in indolent lymphoma (IL) patients receiving eBEAM (7 vs 43%), although survival was comparable due to a higher toxic mortality in the eBEAM group. The 5-year event-free survival and overall survival were better in Hodgkin's disease (HD) patients treated with eBEAM (70 and 77%, respectively) compared to sBEAM (58 and 69%, respectively), but the difference was not statistically significant. In aggressive lymphomas, no difference was detected between groups. Our results indicate that while escalation of the etoposide doses in the BEAM conditioning regimen does not appear to improve outcome, encouraging results in IL and HD may warrant further studies.
Combination chemotherapy can cure patients with non-Hodgkin's lymphoma (NHL), but those who suffer treatment failure or relapse still have a poor prognosis. High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) can improve the outcome of these patients. We evaluated an intensified high-dose sequential chemotherapy program with a final myeloablative course.
Inclusion criteria were age 18-65 years, histologically proven primary progressive or relapsed aggressive NHL and eligibility for HDCT. The therapy consists of two cycles DHAP: dexamethasone 40 mg (day 1-4), high-dose cytarabine 2 g/m2 12q (day 2), cisplatin 100 mg/m2 (day 51); patients with partial (PR) or complete remission (CR) received cyclophosphamide 4 g/m2 (day 37), followed by peripheral blood stem cell (PBSC) harvest; methotrexate 8 g/m2 (day 1) plus vincristine 1.4 mg/m2 (day 51); and etoposide 500 mg/m2 (day 58-62). The final myeloblative course was BEAM: cytarabine 200 mg/m2 12q (day 81-84), etoposide 150 mg/m2 12q (day 81-84), melphalan 140 mg/m2 (day 80), carmustin 300 mg/m2 (day 80) followed by PBSCT.
Fifty-seven patients (median age 43 years, range 24-65) were enrolled: 23 (40%) patients were refractory to primary therapy and 34 (60%) patients had relapsed NHL. The response rate (RR) after 2 cycles of DHAP was 72% (9% CR, 63% PR) and at the final evaluation (100 days post transplantation) 43% (32% CR, 11% PR). Toxicity was tolerable. Median follow-up was 25 months (range 1-76 months). Freedom from second failure (FF2F) and overall survival (OS) at 2 years were 25% and 47% for all patients, respectively. FF2F at 2 years for patients with relapse and for patients refractory to primary therapy were 35% and 9% (P=0.0006), respectively. OS at 2 years for patients with relapse and for patients refractory to primary therapy were 58% and 24% (P=0.0044), respectively.
We conclude that this regimen is feasible, tolerable and effective in patients with relapsed NHL. In contrast, the results in patients with progressive disease are unsatisfactory. This program is currently being modified by addition of rituximab for patients with relapsed aggressive NHL.
To describe patient-reported outcomes of mouth and throat soreness (MTS) and related sequelae on daily activities from a phase III study of palifermin in the autologous hematopoietic stem-cell transplantation (HSCT) setting and to compare patient self-evaluations with clinicians' assessments of oral mucositis using objective scales.
Patients (n = 212) received palifermin (60 microg/kg/d) or placebo for 3 days before total-body irradiation (12 Gy), etoposide 60 mg/kg, and cyclophosphamide 100 mg/kg, and 3 days after HSCT. Patients completed a daily questionnaire (Oral Mucositis Daily Questionnaire [OMDQ]) evaluating MTS severity and its effects on daily functional activities. Patients' self-assessment data were compared with clinicians' assessments of oral mucositis using the objective scales.
Palifermin reduced the incidence and duration of severe oral mucositis, as assessed by both clinicians and patients. Comparisons between patient and clinician assessments demonstrated that the average daily scores between mucositis grade and subjective (MTS) instruments were similar, although patients reported MTS onset, peak, and resolution earlier (1 to 3 days) than clinicians' assessments. Patients receiving palifermin reported statistically significant improvements (P < .001) in daily functioning activities (swallowing, drinking, eating, talking, sleeping) and required significantly less narcotic opioids (P < .001); improvement in the patient's overall physical and functional well-being was also reported. This was confirmed by the results of the Functional Assessment of Cancer Treatment questionnaire.
These results support the clinical benefit of palifermin in the HSCT setting, providing evidence that a patient's self-assessment instrument (OMDQ) may serve as an alternative tool to assess oral mucositis severity in clinical trials.
Oral mucositis (OM) is a frequent complication of myeloablative therapy and HSCT. We evaluated the feasibility, reliability, and validity of a new patient self-reported daily questionnaire on OM and its impact on daily functions. This OM Daily Questionnaire (OMDQ), containing 10 items, was developed for use in palifermin clinical trials. In a phase 3 study, 212 patients received palifermin or placebo for three consecutive days before conditioning and three consecutive days after HSCT. Compliance rates were consistently >80% for most patients. Mouth and throat soreness (MTS) and MTS-Activity Limitations (MTS-AL) (swallowing, drinking, eating, talking, and sleeping) scores on consecutive days were highly correlated (days 7,8 = 0.70-0.86; test-retest reliability). Correlations among items measuring the same construct ranged between 0.5 and 0.8 (internal consistency reliability). The WHO Oral Toxicity scale was the clinical comparator to assess the criterion, discriminative, and evaluative validities of MTS-related questions. Most correlation coefficients between the WHO and MTS ranged between 0.45 and 0.55. Patients with more severe WHO OM grades had higher MTS mean scores. Changes in MTS scores were similar, but patients detected changes 1-3 days earlier than clinicians. In conclusion, the OMDQ is a feasible, reliable, valid, and responsive patient-reported measure of OM 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.
Melphalan-based autologous stem cell transplant (Mel-ASCT) is a standard therapy for multiple myeloma, but is associated with severe oral mucositis (OM). To identify predictors for severe OM, we studied 381 consecutive newly diagnosed myeloma patients who received Mel-ASCT. Melphalan was given at 200 mg/m2 body surface area (BSA), reduced to 140 mg/m2 for serum creatinine >3 mg/dl. Potential covariates included demographics, pre-transplant serum albumin and renal and liver function tests, and mg/kg melphalan dose received. The BSA dosing resulted in a wide range of melphalan doses given (2.4-6.2 mg/kg). OM developed in 75% of patients and was severe in 21%. Predictors of severe OM in multiple logistic regression analyses were high serum creatinine (odds ratio (OR)=1.581; 95% confidence interval (CI): 1.080-2.313; P=0.018) and high mg/kg melphalan (OR=1.595; 95% CI: 1.065-2.389; P=0.023). An OM prediction model was developed based on these variables. We concluded that BSA dosing of melphalan results in wide variations in the mg/kg dose, and that patients with renal dysfunction who are scheduled to receive a high mg/kg melphalan dose have the greatest risk for severe OM following Mel-ASCT. Pharmacogenomic and pharmacokinetic studies are needed to better understand interpatient variability of melphalan exposure and toxicity.
Mucositis is an inevitable side-effect of the conditioning regimens used for haematopoietic stem cell transplantation. The condition is better referred to as mucosal barrier injury (MBI) since it is primarily the result of toxicity and is a complex and dynamic pathobiological process manifested not only in the mouth but also throughout the entire digestive tract. A model has been proposed for oral MBI and consists of four phases, namely inflammatory, epithelial, ulcerative and healing phases. A variety of factors are involved in causing and modulating MBI including the nature of the conditioning regimen, the elaboration of pro-inflammatory and other cytokines, translocation of the resident microflora and their products, for example, endotoxins across the mucosal barrier, exposure to antimicrobial agents and whether or not the haematopoietic stem cell graft is from a donor. Neutropenic typhlitis is the most severe gastrointestinal manifestation of MBI, but it also influences the occurrence of other major transplant-related complications including acute GVHD, veno-occlusive disease and systemic infections. The pathobiology, clinical counterparts and the means of measuring MBI are discussed together with potential approaches for prevention, amelioration and, perhaps, even cure. Bone Marrow Transplantation (2000) 25, 1269-1278.
Background. Cancer is most common in older age groups, but little information is available with regard to the impact of age on chemotherapy toxicity. This study was undertaken to determine if age is an independent risk factor for 5-fluorouracil (5-FU) toxicity.Methods. Toxicity data from a prospective, randomized, multiinstitution trial of 5-FU-based treatment for advanced colorectal cancer were analyzed. Toxicity for each organ system was graded. Individual organ toxicity proportions were compared using chi-square analysis. A logistic regression was performed using age (younger than 70 years vs. 70 years or older), sex, treatment arm, performance status, and length of therapy as model parameters to predict severe toxicity. Toxicity in 331 patients was analyzed.Results. Advanced age was significantly associated with the occurrence of any severe toxicity (58 vs. 36%, P < 0.001), leukopenia (24 vs. 10%, P < 0.005), diarrhea (24 vs. 14%, P = 0.01), vomiting (15 vs. 5%, P = 0.01), severe toxicity in more than 2 organ systems (10 vs. 3%, P = 0.02), and treatment mortality (9 vs. 2%, P = 0.01). By univariate analysis, age (P < 0.001) and sex (P < 0.0001) were independent predictors of severe toxicity. Twenty-two of 27 women age 70 years or older had severe toxicity.Conclusions. Age 70 years or older and sex are risk factors for severe toxicity from 5-FU-based chemotherapy. Advanced age does not contraindicate the use of this type of chemotherapy, but close monitoring for multiple organ toxicities and vigorous supportive care of those with toxicity are required. Dosing decisions in older patients are difficult and must integrate assessments of organ function, comorbidities, overall physical status, and goals of treatment, in an effort to ensure the best possible outcome for these patients.
BACKGROUNDA frequent complication of anticancer treatment, oral and gastrointestinal (GI) mucositis, threatens the effectiveness of therapy because it leads to dose reductions, increases healthcare costs, and impairs patients' quality of life. The Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology assembled an international multidisciplinary panel of experts to create clinical practice guidelines for the prevention, evaluation, and treatment of mucositis.METHODS
The panelists examined medical literature published from January 1966 through May 2002, presented their findings at two separate conferences, and then created a writing committee that produced two articles: the current study and another that codifies the clinical implications of the panel's findings in practice guidelines.RESULTSNew evidence supports the view that oral mucositis is a complex process involving all the tissues and cellular elements of the mucosa. Other findings suggest that some aspects of mucositis risk may be determined genetically. GI proapoptotic and antiapoptotic gene levels change along the GI tract, perhaps explaining differences in the frequency with which mucositis occurs at different sites. Studies of mucositis incidence in clinical trials by quality and using meta-analysis techniques produced estimates of incidence that are presented herein for what to our knowledge may be a broader range of cancers than ever presented before.CONCLUSIONS
Understanding the pathobiology of mucositis, its incidence, and scoring are essential for progress in research and care directed at this common side-effect of anticancer therapies. Cancer 2004;100(9 Suppl):1995–2025. © 2004 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.
BACKGROUND
Oral and gastrointestinal (GI) mucositis can affect up to 100% of patients undergoing high-dose chemotherapy and hematopoietic stem cell transplantation, 80% of patients with malignancies of the head and neck receiving radiotherapy, and a wide range of patients receiving chemotherapy. Alimentary track mucositis increases mortality and morbidity and contributes to rising health care costs. Consequently, the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology assembled an expert panel to evaluate the literature and to create evidence-based guidelines for preventing, evaluating, and treating mucositis.METHODS
Thirty-six panelists reviewed literature published between January 1966 and May 2002. An initial meeting in January 2002 produced a preliminary draft of guidelines that was reviewed at a second meeting the same year. Thereafter, a writing committee produced a report on mucositis pathogenesis, epidemiology, and scoring (also included in this issue), as well as clinical practice guidelines.RESULTSPanelists created recommendations from higher levels of evidence and suggestions when evidence was of a lower level and there was a consensus regarding the interpretation of the evidence by the panel. Panelists identified gaps in evidence that made it impossible to recommend or not recommend use of specific agents.CONCLUSIONS
Oral/GI mucositis is a common side effect of many anticancer therapies. Evidence-based clinical practice guidelines are presented as a benchmark for clinicians to use for routine care of appropriate patients and as a springboard to challenge clinical investigators to conduct high-quality trials geared toward areas in which data are either lacking or conflicting. Cancer 2004;100(9 Suppl):2026–2046. © 2004 American Cancer Society.
The purpose of this study was to describe the incidence, onset, duration, severity, and other relevant characteristics of mucositis and pain in patients undergoing bone marrow transplant (BMT) who were receiving high-dose chemotherapy (cytoxan, busulfan, and etoposide) without total body irradiation. A descriptive, longitudinal design was used to study a sequential sample of 47 patients undergoing allogeneic and autologous BMT. Each day, from 9 days prior to BMT through 21 days after BMT, nine anatomic regions of patients' mouths were assessed for extent and severity of mucositis. Oral pain was measured using the Short-Form McGill Pain Questionnaire. Forty-two patients (89%) developed mucositis, which, on average, began 3 days after transplant, lasted 9.5 days, and resolved by 12.6 days post-transplant. Thirty-six patients (86%) reported pain that began, on average, 4.5 days after transplant, lasted 6.5 days, and resolved by 11 days post-transplant. During the initial weeks following BMT, systematic assessment of the oral cavity areas that are at high risk for mucositis should assist nurses in detecting early oral complications and in initiating specific interventions. Additionally, attention needs to be given to the assessment and management of mucositis-related oral pain. Future nursing research should be conducted to examine efficient clinical methods of assessing mucositis and oral pain and to test prophylactic and therapeutic interventions.
5-Fluorouracil (5-FU) has been widely used for over 30 years. Recently, investigators have described interactions between toxicity with 5-FU and age and gender. Pharmacokinetics of infusional 5-FU are known to be gender dependent, with drug clearance being lower in females. The full impact of age and gender on both toxicity and response has not been fully explored and is worthy of further investigation. 439 patients were entered into a phase III trial comparing a novel thymidylate synthase (TS) inhibitor Tomudex (raltitrexed, formerly ZD1694) with 5-FU and leucovorin (LV) for the treatment of advanced colorectal cancer. Approximately 20-24% of patients in each treatment group were aged 70 years or older and 41% of the patients were female. In a multiple regression analysis, female patients receiving 5-FU + LV experienced significantly more grade 3/4 leucopenia, whilst those receiving raltitrexed had more rises in transaminase levels. Grade 3/4 leucopenia and mucositis were significantly correlated with age (especially > 70 years) only in patients receiving 5-FU + LV. Patients receiving 5-FU + LV were significantly more at risk of experiencing grade 3/4 haematological and non-haematological toxicity in the first three cycles than patients receiving raltitrexed. Female gender and increased age predict for increased grade 3/4 toxicity in patients receiving modulated 5-FU. Further studies with modulated 5-FU which utilise a modified dose reduction schema for female patients, or patients aged 70 years or over, may be appropriate.
A meta-analysis of six North Central Cancer Treatment Group (NCCTG) trials involving patients receiving their first ever fluorouracil (5-FU)-based chemotherapy was undertaken to explore the association of sex with reports of the incidence and severity of stomatitis.
Data were obtained on a total of 731 patients (402 men and 329 women). Comparisons of incidence and severity rates and average stomatitis across sex were performed using standard binomial testing and t tests, respectively. Logistic regression analysis and a weighted analysis using data summarized to study level served as evidence of cross-validation.
Women reported stomatitis both more often and with greater severity than did men. The incidence of any stomatitis for women was 63% versus 52% for men (P =.002). The incidence of severe or very severe stomatitis for men and women was 22% and 12%, respectively (P =. 0006). On average, women reported stomatitis of roughly 0.4 points higher than men on a 0 to 4 ordinal scale (P <.00001). Comparison of results across treatment and placebo arms was carried out to validate the initial findings. Logistic regression modelling further confirmed the results conditional on the presence of a number of potentially confounding covariates. Women were also 11% more likely than men to experience leukopenia of common toxicity criteria grade >/= 1, (70% v 59%, respectively; P <.00001) and grade 3+ (18% v 11%, respectively; P =.004).
More women than men reported 5-FU-induced stomatitis. The precise mechanism resulting in different degrees of stomatitis across sex is not evident.
The management of cancer in the older aged person is an increasingly common problem. The questions arising from this problem are: Is the patient going to die with cancer or of cancer? Is the patient able to tolerate the stress of antineoplastic therapy? Is the treatment producing more benefits than harm?
This article explores a practical, albeit evolving, approach to these questions including a multidimensional assessment of the older person and simple pharmacologic interventions that may ameliorate the toxicity of antineoplastic agents. Age may be construed as a progressive loss of stress tolerance, due to decline in functional reserve of multiple organ systems, high prevalence of comorbid conditions, limited socioeconomic support, reduced cognition, and higher prevalence of depression. Aging is highly individualized: chronologic age may not reflect the functional reserve and life expectancy of an individual. A comprehensive geriatric assessment (CGA) best accounts for the diversities in the geriatric population. The advantages of the CGA include: Recognition of potentially treatable conditions such as depression or malnutrition, that may lessen the tolerance of cancer treatment and be reversed with proper intervention;Assessment of individual functional reserve;Gross estimate of individual life expectancy; andAdoption of a common language to classify older cancer patients.
The CGA allows the practitioner to recognize at least three stages of aging: People who are functionally independent and without comorbidity, who are candidates for any form of standard cancer treatment, with the possible exception of bone marrow transplant.People who are frail (dependence in one or more activities of daily living, three or more comorbid conditions, one or more geriatric syndromes), who are a candidate only for palliative treatment; andPeople in between, who may benefit from some special pharmacological approach, such as reduction in the initial dose of chemotherapy with subsequent does escalations.
The pharmacological changes of age include decreased renal excretion of drugs and increased susceptibility to myelosuppression, mucositis, cardiotoxicity and neurotoxicity. Based on these findings, the proposal was made that all persons aged 70 and older, treated with cytotoxic chemotherapy of dose intensity comparable to CHOP, receive prophylactic growth factor treatment, and that the hemoglobin of these patients be maintained ≥12 gm/dl.
Outcomes research typically assesses three major health care outcomes, including quantity of life, quality of life (QOL), and health care cost. This article highlights the impact of treatment-associated mucositis on health care costs and QOL. After a background description of the economic analyses of overall cancer treatment costs and of the incremental costs associated with other treatment side effects, data from a retrospective study of mucositis-specific costs are presented. The second half of this article reviews current knowledge about the effect that mucositis has on QOL. Because the empirical work that specifically evaluates mucositis and QOL is quite limited, studies examining proxies for mucositis grading are described. These include studies comparing the QOL of patients currently undergoing treatment, in which symptoms likely to be associated with mucositis are worse, with that of patients who have completed treatment. Also discussed are investigations examining both the relationship between specific mucositis-associated symptoms, such as pain and difficulty swallowing, and QOL and the weighting of different domains of mucositis-associated problems. Finally, several future research directions are suggested, with the intent of expanding knowledge about the economic and QOL impact of mucositis in patients treated for head and neck cancer.
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.
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.
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.
Oral and gastrointestinal mucositis is a toxicity of many forms of radiotherapy and chemotherapy. It has a significant impact on health, quality of life and economic outcomes that are associated with treatment. It also indirectly affects the success of antineoplastic therapy by limiting the ability of patients to tolerate optimal tumoricidal treatment. The complex pathogenesis of mucositis has only recently been appreciated and reflects the dynamic interactions of all of the cell and tissue types that comprise the epithelium and submucosa. The identification of the molecular events that lead to treatment-induced mucosal injury has provided targets for mechanistically based interventions to prevent and treat mucositis.
A frequent complication of anticancer treatment, oral and gastrointestinal (GI) mucositis, threatens the effectiveness of therapy because it leads to dose reductions, increases healthcare costs, and impairs patients' quality of life. The Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology assembled an international multidisciplinary panel of experts to create clinical practice guidelines for the prevention, evaluation, and treatment of mucositis.
The panelists examined medical literature published from January 1966 through May 2002, presented their findings at two separate conferences, and then created a writing committee that produced two articles: the current study and another that codifies the clinical implications of the panel's findings in practice guidelines.
New evidence supports the view that oral mucositis is a complex process involving all the tissues and cellular elements of the mucosa. Other findings suggest that some aspects of mucositis risk may be determined genetically. GI proapoptotic and antiapoptotic gene levels change along the GI tract, perhaps explaining differences in the frequency with which mucositis occurs at different sites. Studies of mucositis incidence in clinical trials by quality and using meta-analysis techniques produced estimates of incidence that are presented herein for what to our knowledge may be a broader range of cancers than ever presented before.
Understanding the pathobiology of mucositis, its incidence, and scoring are essential for progress in research and care directed at this common side-effect of anticancer therapies.
The occurrence of toxic complications following hematopoietic stem cell transplantation (HSCT) is highly variable and dependent on a multitude of host, donor, and treatment factors. The increasingly broad indications for HSCT and the need to provide this treatment option to older and/or more debilitated patients emphasizes the importance of refining our methods of predicting and ameliorating these toxicities. Late complications (occurring after day 100) also pose a threat to quality of life after HSCT. Genetic polymorphisms in key molecular pathways in the host are likely to contribute significantly to the observed variability in the development HSCT-associated complications. Hepatic veno-occlusive disease and acute lung injury, two of the most serious organ toxicities that occur, represent useful paradigms for the identification of genetic polymorphisms in enzyme systems that modulate local and systemic responses to oxidant stress during transplant conditioning therapy. Ongoing studies in this area are providing clues to the prevention of adverse clinical outcomes based on the genetic milieu. This review of studies in HSCT that explore genetic risk factors for transplant complications indicates that significant progress is being made in this rapidly evolving area. However, further large-scale clinical and translational studies are needed before genomic screening can be widely used to individualize treatment.
Oral mucositis is a complication of intensive chemotherapy and radiotherapy with no effective treatment. We tested the ability of palifermin (recombinant human keratinocyte growth factor) to decrease oral mucosal injury induced by cytotoxic therapy.
This double-blind study compared the effect of palifermin with that of a placebo on the development of oral mucositis in 212 patients with hematologic cancers; 106 patients received palifermin (60 microg per kilogram of body weight per day) and 106 received a placebo intravenously for three consecutive days immediately before the initiation of conditioning therapy (fractionated total-body irradiation plus high-dose chemotherapy) and after autologous hematopoietic stem-cell transplantation. Oral mucositis was evaluated daily for 28 days after transplantation.
The incidence of oral mucositis of World Health Organization (WHO) grade 3 or 4 was 63 percent in the palifermin group and 98 percent in the placebo group (P<0.001). Among patients with this degree of mucositis, the median duration of mucositis was 6 days (range, 1 to 22) in the palifermin group and 9 days (range, 1 to 27) in the placebo group. Among all patients, regardless of the occurrence of mucositis, the median duration of oral mucositis of WHO grade 3 or 4 was 3 days (range, 0 to 22) in the palifermin group and 9 days (range, 0 to 27) in the placebo group (P<0.001). As compared with placebo, palifermin was associated with significant reductions in the incidence of grade 4 oral mucositis (20 percent vs. 62 percent, P<0.001), patient-reported soreness of the mouth and throat (area-under-the-curve score, 29.0 [range, 0 to 98] vs. 46.8 [range, 0 to 110]; P<0.001), the use of opioid analgesics (median, 212 mg of morphine equivalents [range, 0 to 9418] vs. 535 mg of morphine equivalents [range, 0 to 9418], P<0.001), and the incidence of use of total parenteral nutrition (31 percent vs. 55 percent, P<0.001). Adverse events, mainly rash, pruritus, erythema, mouth and tongue disorders, and taste alteration, were mild to moderate in severity and were transient.
Palifermin reduced the duration and severity of oral mucositis after intensive chemotherapy and radiotherapy for hematologic cancers.