Incidence Of Stomatitis Research Articles

Comparison of 5-FU vs capecitabine in combination with mitomycin or cisplatin in the treatment of anal cancer.

3576 Background: The patterns of capecitabine use as an alternative form of fluoropyrimidine to infusional 5-FU in the non-operative management of anal cancer in the real world are poorly described. Our objectives were to determine the frequency of capecitabine use, compare the observed outcomes between oral and intravenous fluoropyrimidines, and examine for variations in treatment-related adverse events between the two agents. Methods: All anal cancer patients who received either capecitabine or infusional 5-FU as part of their chemoradiation treatment from 2004 to 2013 at any 1 of 6 cancer centers in British Columbia were included. Chi-square and Wilcoxon-Mann tests were used to assess for associations between treatment groups and clinical characteristics and outcomes. Results: A total of 486 patients were identified: median age was 59 (IQR 53-67) years, 175 (36%) were men, 418 (86%) had ECOG 0/1, and 30 (6%) were HIV positive. Median total radiation dose was 54 cGy (IQR 50-54) and 47 (10%) underwent a colostomy prior to chemoradiation. Baseline characteristics were balanced between the two groups with respect to age, gender, ECOG, and HIV status (all p > 0.05). Prior to 2010, only 5-FU was utilized. From 2010 to 2013, 155 and 82 patients (65% vs 35%) received capecitabine vs 5-FU, respectively. Overall (68% vs 67%, p = 0.831) and disease-free survival rates (59% vs 59%, p = 0.926) at 3 years were similar in the capecitabine vs 5-FU groups. Rates of subsequent abdomino-perineal resection were also similar (10% vs 14%, p = 0.164). Patients who received 5-FU were more likely to report adverse effects (76% vs 57%, p < 0.01). The capecitabine group had a lower incidence of stomatitis (7% vs 43%, p < 0.01) whereas the 5-FU cohort reported less frequent hand-foot syndrome (1% vs 7%, p < 0.01). The rates of myelosuppression, nausea/vomiting, diarrhea, and rash were similar between the two groups (all p > 0.05). Conclusions: This represents one of the largest population-based studies to demonstrate a preference for capecitabine in place of 5-FU in the management of anal cancer. Survival outcomes were similar between the two treatment groups, but capecitabine may be better tolerated in the real world.

Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial

Stomatitis is a class effect associated with the inhibition of mTOR and is associated with everolimus therapy for breast cancer. Topical steroids might reduce stomatitis incidence and severity, and the need for dose reductions and interruptions of everolimus. Anecdotal use of topical steroid oral prophylaxis has been reported in patients with breast cancer. We aimed to assess dexamethasone-based mouthwash for prevention of stomatitis in patients with breast cancer. This US-based, multicentre, single-arm, phase 2 prevention study enrolled women aged 18 years and older with postmenopausal status who had histologically or cytologically confirmed metastatic hormone receptor-positive, HER2-negative breast cancer. Beginning on day 1 of cycle 1, patients received everolimus 10 mg plus exemestane 25 mg daily, with 10 mL of alcohol-free dexamethasone 0·5 mg per 5 mL oral solution (swish for 2 min and spit, four times daily for 8 weeks). After 8 weeks, dexamethasone mouthwash could be continued for up to eight additional weeks at the discretion of the clinician and patient. The primary endpoint was incidence of grade 2 or worse stomatitis by 8 weeks assessed in the full analysis set (patients who received at least one dose of everolimus and exemestane and at least one confirmed dose of dexamethasone mouthwash) versus historical controls from the BOLERO-2 trial (everolimus and exemestane treatment in patients with hormone receptor-positive advanced breast cancer who were not given dexamethasone mouthwash for prevention of stomatitis). This trial is registered at ClinicalTrials.gov, number NCT02069093. Between May 28, 2014, and Oct 8, 2015, we enrolled 92 women; 85 were evaluable for efficacy. By 8 weeks, the incidence of grade 2 or worse stomatitis was two (2%) of 85 patients (95% CI 0·29-8·24), versus 159 (33%) of 482 patients (95% CI 28·8-37·4) for the duration of the BOLERO-2 study. Overall, 83 (90%) of 92 patients had at least one adverse event. The most frequently reported grade 3 and 4 adverse events in the safety set were hyperglycaemia (seven [8%] of 92 patients), rash (four [4%]), and dyspnoea (three [3%]). Serious adverse events were reported in 20 (22%) patients; six (7%) were deemed treatment related, with dyspnoea (three [3%]) and pneumonia (two [2%]) reported most frequently. 12 (13%) of 92 patients had adverse events suspected to be related to treatment that led to discontinuation of everolimus and exemestane (the most common were rash, hyperglycaemia, and stomatitis, which each affected two [2%] patients). Prophylactic use of dexamethasone oral solution substantially reduced the incidence and severity of stomatitis in patients receiving everolimus and exemestane and could be a new standard of oral care for patients receiving everolimus and exemestane therapy. Novartis Pharmaceuticals Corporation.

Abstract P4-16-01: Evaluation of miracle mouthwash (MMW) plus hydrocortisone or prednisolone mouth rinses as prophylaxis for everolimus-associated stomatitis: Results of a randomized phase II study

Abstract Background: Oral stomatitis is a frequent adverse event (AE) associated with mTOR-inhibitor therapy, and can impact adherence. In BOLERO-2, patients (pts) with hormone receptor-positive (HR+) metastatic breast cancer (MBC) treated with exemestane plus everolimus (EVE), the incidence of all-grade (G) stomatitis or related AEs was 67%, with 24%/8% of pts developing G2/G3 stomatitis or related AEs, respectively (Perez et al ASCO 2013 Abs 7029). In BOLERO-2, 24% of pts required EVE dose reduction for stomatitis (Rugo et al Ann Oncol 2014;25:808). This study evaluated 2 steroid-based mouth rinses for the prevention or amelioration of oral stomatitis in pts with MBC treated with EVE. Methods: This prospective randomized phase II study enrolled postmenopausal pts (planned accrual=100) with HR+ MBC within the US Oncology Network who were initiating therapy with an aromatase inhibitor plus EVE (10 mg/day)(AIE). Pts were randomized 1:1 to prophylactic therapy with 1 of 2 oral rinses (ARM 1: MMW 480 ml recipe: 320 mL oral Benadryl, 2 g Tetracycline, 80 mg Hydrocortisone, 40 mL Nystatin suspension, water; or ARM 2: Prednisolone (P) 15mg/5mL oral solution, 1.8% alcohol). Pts were instructed to swish/expectorate 10 ml of the assigned rinse 4x daily starting with D1 of EVE treatment, for a total of 12 wks. The primary objective was to determine the incidence of G≥2 stomatitis or related oral AEs during the first 12 wks of treatment. Based on a historical estimate that ≥37% of pts receiving AIE develop G≥2 stomatitis, 50 pts for each arm were required to detect a reduction of the incidence of G≥2 stomatitis from 37% to <20%, with alpha = 0.05, 80% power, and a 1-sided test. Secondary objectives included assessment of AEs (all grades), determination of the percentage of pts requiring dose interruption/reduction of EVE or discontinuation of therapy due to toxicity, and evaluation of the impact of the oral rinses on the duration and severity of stomatitis. Results: As of 5/30/2016, a total of 104 pts have been randomized and 100 pts have received treatment (49 MMW; 51 P). Median age was 61 yrs (range 31-82 yrs). The incidence of stomatitis and related oral AEs (any grade) during the first 12 wks was 29% (n=14/49) and 27.5% (14/51) in the MMW and P arms respectively. The incidence of G2 oral AEs was 12% (6/49) and 8% (4/51) with MMW and P respectively. There was only 1 G3 oral AE (MMW arm), and no G4 events. There was 1 EVE dose reduction (MMW) and 4 EVE dose delays (3 MMW, 1 P) during the first 12 wks of treatment. No pts stopped the steroid mouth rinse therapy due to mouth rinse-related toxicity. Conclusion: These prospective data provide evidence of a reduced incidence of mTOR-associated oral AEs with prophylactic use of a steroid mouth rinse. The 29%/27.5% incidence of all-grade and 12%/8% incidence of G2 oral AEs, with only 1 G3 event, compare favorably with the 67% and 24%/8% incidence of all-grade and G2/3 stomatitis, respectively, in BOLERO-2. These data also show the safety and tolerability of these 2 steroid mouth rinses. Prophylactic use of steroid mouth rinses substantially decreases the incidence of G2/3 stomatitis and the need for EVE dose modifications. Citation Format: Jones VE, McIntyre KJ, Paul D, Wilks ST, Ondreyco SM, Sedlacek SM, Melnyk Jr. AM, Oommen SP, Wang Y, O'Shaughnessy JA. Evaluation of miracle mouthwash (MMW) plus hydrocortisone or prednisolone mouth rinses as prophylaxis for everolimus-associated stomatitis: Results of a randomized phase II study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-16-01.

Abstract P2-11-08: Stomatitis in patients treated with first-line everolimus (EVE) plus letrozole (LET): Results from BOLERO-4 trial

Abstract Background Stomatitis is the most frequent adverse event reported in trials of mTOR-inhibitors, including EVE. In the pivotal phase 3 BOLERO-2 study, stomatitis incidence in the EVE + exemestane (EXE) arm was 59%. The BOLERO-4 study (NCT01698918) evaluated the efficacy and safety of first-line EVE + LET in postmenopausal pts with HR+, HER2− metastatic or locally advanced breast cancer (ABC). BOLERO-4 also assessed the effectiveness of an alcohol-free dexamethasone (0.5 mg/ 5ml; DEX) oral rinse for treating stomatitis in a subset of pts (USA). Methods Postmenopausal pts with HR+, HER2− ABC previously untreated for advanced disease received EVE (10 mg/day) + LET (2.5 mg/day).At disease progression, pts were offered EVE (10 mg/day) + EXE (25 mg/day). Pts who had at least one episode of stomatitis received oral stomatitis daily questionnaire (OSDQ), which is a 6 question pt-reported outcome (PRO) survey (Stiff et al, JCO. 2006). A subset of these pts (USA) was randomized (1:1) to receive DEX or standard of care (SOC). The primary objective of investigator-assessed progression-free survival in the first-line setting for ABC was presented previously. A secondary objective was to evaluate the effectiveness of the DEX oral rinse in reducing the severity and duration of stomatitis, using OSDQ data. Results Of the total 202 pts enrolled in this study, 52 pts were enrolled in USA, of which, 24 (46.2%) were randomized to receive DEX (n=11) or SOC (n=13), upon confirmation of stomatitis. The median duration of first stomatitis episode was longer per OSDQ (DEX, not estimable vs SOC, 13.7 wk) compared with physician-reported duration (DEX, 1.6 wk vs SOC, 1.9 wk). PRO OSDQ results were similar in both arms. Among the 202 pts enrolled, 89 (44.1%) filled the OSDQ at their first stomatitis episode. The median time from treatment initiation to first stomatitis episode was 1.7 wk; median duration of stomatitis was 13.7 wk (OSDQ) vs 2.1 wk (physician reported). The majority of pts experiencing stomatitis had moderate/little/no soreness, moderate/low/no pain, and stomatitis had low/no effect on daily activities (Table 1). Table 1. OSDQ Key Results (N=87)Questions (Score)First Day of Stomatitis Episode, n (%)End of First Stomatitis Episode, n (%)Overall healthPoor (0-4)20 (23.0)23 (26.4)Moderate (5-7)40 (46.0)32 (36.8)Perfect (8-10)27 (31.0)32 (36.8)Mouth and throat sorenessNo/a little/moderate (0-2)64 (73.6)84 (96.6)A lot or extreme (3-4)23 (26.4)3 (3.4)Mouth pain severityNo/low/moderate (0-4)51 (58.6)73 (83.9)Severe (5-7)24 (27.6)10 (11.5)Unbearable (8-10)12 (13.8)4 (4.6)Effect on daily activitiesNo/low (0-4)70 (80.5)78 (89.7)Moderate (5-7)11 (12.6)4 (4.6)High (8-10)6 (6.9)5 (5.7) Conclusions Overall, patient-reported median duration of stomatitis was longer than that reported by physicians, most likely due to differences in perceptions and the challenges in collecting and cleaning PRO data. Overall good health score was maintained in the majority of pts experiencing stomatitis and stomatitis had low/no effect on daily activities. However, these results, especially in the randomized subset need to be interpreted with caution owing to the small sample size, missing data and lack of commercially available DEX in most countries. Citation Format: Villanueva C, Tsugawa K, Toyama T, Noh W, Jeong J, Cardoso F, Sriuranpong V, Srimuninnimit V, Ozguroglu M, Kendall S, Falkson C, Cianfrocca M, Manlius C, Lin JCJ, Ringeisen F, Ridolfi A, Royce M. Stomatitis in patients treated with first-line everolimus (EVE) plus letrozole (LET): Results from BOLERO-4 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-11-08.

Comparison of 5-FU versus capecitabine in combination with mitomycin or cisplatin in the treatment of anal cancer.

680 Background: Capecitabine is used as an alternative fluoropyrimidine to infusional 5-FU in the non-operative management of anal cancer due to its ease of administration. However, its patterns of use and long-term outcomes in the real world are poorly described. Our objectives were to determine the frequency of capecitabine use, compare the difference in outcomes, and examine the difference in treatment-related adverse events between oral and intravenous fluoropyrimidines. Methods: All anal cancer patients who received either capecitabine or infusional 5-FU as part of their curative intent chemoradiotherapy from 2010 to 2013 at any 1 of 6 comprehensive cancer centers in British Columbia were included. Chi-square and Wilcoxon-Mann tests were used to assess for associations between treatment groups and clinical characteristics and outcomes. Results: A total of 237 patients were identified; median age was 59 (IQR 53-67) years, 71 (30%) were men, 202 (85%) had ECOG 0/1, and 12 (5%) were HIV positive. Median total radiation dose was 54 cGy (IQR 50.4-54.0) and 21 (9%) underwent a colostomy prior to chemoradiation. Baseline characteristics were balanced between the two groups with respect to age, gender, ECOG, and HIV status (all p > 0.05). Overall, 155 patients (65%) received capecitabine. Comparing patients who received capecitabine vs 5-FU, overall (69% vs 74%, p = 0.388) and disease-free survival rates (68% vs 71%, p = 0.637) at 5 years from diagnosis were similar between treatment groups. There were no differences with respect to rates of subsequent colostomy (16% vs 23%, p = 0.185) and abdominoperineal resection (11% vs 12%, p = 0.777). However, patients who received capecitabine were less likely to report adverse effects (51% vs 26%, p < 0.001) than those who underwent 5-FU. The capecitabine group had a lower incidence of stomatitis (6% vs 40%, p < 0.001) whereas the 5-FU cohort reported less frequent hand-foot syndrome (1% vs 8%, p = 0.036). Conclusions: This population-based study demonstrates a preference for capecitabine use in place of 5-FU in the curative management of anal cancer. Survival outcomes are similar between the two treatment groups, but capecitabine may be better tolerated.

Association of Single Nucleotide Polymorphisms in STAT3, ABCB1, and ABCG2 with Stomatitis in Patients with Metastatic Renal Cell Carcinoma Treated with Sunitinib: A Retrospective Analysis in Japanese Patients.

Signal transducer and activator of transcription (STAT) 3 is a key factor in homeostasis of the oral mucosa by regulating the production of inflammatory cytokines. Sunitinib is a substrate of P-glycoprotein (multidrug resistance (MDR)-1/ABCB1) and breast-cancer resistance protein (BCRP/ABCG2). In this retrospective study, we evaluated the association between sunitinib-induced stomatitis and STAT3, ABCB1, and ABCG2 polymorphisms in patients with metastatic renal cell carcinoma (mRCC). Fifty-two Japanese patients with RCC treated with sunitinib were retrospectively genotyped to elucidate a potential association between STAT3, ABCB1, and ABCG2 polymorphisms and stomatitis development. Stomatitis occurred in 22 out of 52 patients. The TT+TC genotypes at STAT3 rs744166 had an odds ratio of 5.00 against CC genotype for the stomatitis development (95% confident interval, 0.97-25.8). In the Kaplan-Meier method for the cumulative incidence of stomatitis, a statistically significant difference was observed between the TT+TC and CC genotypes in STAT3 rs744166 (p=0.037). Both multiple logistic regression analysis and Cox proportional-hazards regression analysis show STAT3 rs744166 TT+TC genotypes and serum creatinine in each patient were significant independent factors for stomatitis development. In conclusion, STAT3 polymorphism may be a novel risk factor for sunitinib-induced stomatitis in patients with mRCC.

A network meta-analysis for toxicity of eight chemotherapy regimens in the treatment of metastatic/advanced breast cancer.

ObjectiveTo compare the incidence of toxicity of 8 different chemotherapy regimens, including doxorubicin + paclitaxel, doxorubicin, capecitabine, CMF (cyclophosphamide + methotrexate + 5-fluorouracil), FAC (fluorouracil + doxorubicin + cyclophosphamide), doxorubicin + docetaxel, doxorubicin + cyclophosphamide and paclitaxel in the treatment of metastatic/advanced breast cancer.ResultsThis network meta-analysis included 8 randomized controlled trials (RCTs). The findings revealed that, with regard to capecitabine alone regimen exhibited higher incidence of nausea/vomiting than doxorubicin + paclitaxel regimen, doxorubicin alone regimen and paclitaxel alone regimen in the treatment of patients with metastatic/advanced breast cancer (OR = 32.48, 95% CI = 1.65~2340.57; OR = 22.75, 95% CI = 1.03~1923.52; OR = 59.63, 95% CI = 2.22~5664.88, respectively). Furthermore, doxorubicin + cyclophosphamide regimen had lower incidence of febrile neutropenia than doxorubicin + docetaxel (OR = 0.17, 95% CI = 0.03~0.96). No significant difference in the incidence of stomatitis was observed among eight chemotherapy regimens.Materials and MethodsWe initially searched PubMed, Cochrane Library and Embase databases from the founding of these databases to January 2016. Eligible studies investigating the 8 different chemotherapy regimens for treatment of metastatic/advanced breast cancer were included for direct and indirect comparison. The odds ratio (OR) and surface under the cumulative ranking curves (SUCRA) value of the incidence of toxicity among eight chemotherapy regimens were analyzed.ConclusionsCapecitabine alone regimen and doxorubicin + docetaxel regimen may have a more frequent toxicity in the treatment of metastatic/advanced breast cancer.

Prevention of everolimus/exemestane (EVE/EXE) stomatitis in postmenopausal (PM) women with hormone receptor-positive (HR+) metastatic breast cancer (MBC) using a dexamethasone-based mouthwash (MW): Results of the SWISH trial.

189 Background: Stomatitis is a frequent adverse event (AE) associated with mTOR inhibition. In BOLERO-2 patients (pts) receiving EVE/EXE, all grade (Gr) stomatitis was 67%; 33% had Gr ≥ 2 and 8% Gr 3. Median time to ≥ Gr 2 onset was 15.5 days; incidence of new stomatitis (Gr ≥ 2) plateaued at 6 wks. In a meta-analysis, 89% of first stomatitis events occurred within 8 wks. Topical steroids are used to treat aphthous ulcers; anecdotal use as prophylaxis has been reported. Methods: Eligibility included PM women with HR+ MBC prescribed EVE/EXE. Treatment included EVE 10 mg and EXE 25 mg QD, with 10 mL of commercially available 0.5 mg/5 mL dexamethasone oral solution to swish x 2 min and spit QID for 8 wks starting day 1. Pts completed a daily adherence log, including an oral pain (range 0-10) and normalcy of diet score. The primary endpoint was to compare the incidence of Gr ≥ 2 stomatitis at 8 wks with BOLERO-2 results. Secondary endpoints included MW use by average times/day, EVE/EXE dose intensity, incidence of all Gr stomatitis and time to resolution to Gr ≤ 1. Results: 92 women were enrolled; 86 were evaluable for efficacy. Median age was 61 yrs (range 34-87); median dose intensity was 10 (range 3-10) and 25 mg (range 8-25) for EVE and EXE, respectively. 95% of pts used the MW 3-4 times/day (median MW use/day = 3.95, range 1.9-4). At 8 wks, the rate of ≥ Gr 2 stomatitis was 2.4% (2 pts) with a Gr 1 rate of 18.8%. A comparison of stomatitis incidence by grade between BOLERO-2 and SWISH is shown in the table. In the 75 patients with complete ECOG scores, 88% maintained/improved ECOG status. Mean pain scale score was < 1 at all visits; 88% of pts reported a normal diet at 8 wks. 13% discontinued EVE/EXE due to suspected related AEs (most common: rash, 2%; hyperglycemia, 2%; stomatitis, 2%; and pneumonitis, 1%). Conclusions: Prophylactic use of 0.5 mg/5 mL dexamethasone oral solution markedly decreases the incidence and severity of stomatitis in patients receiving EVE/EXE for MBC and should be considered a new standard of oral care in this setting. Clinical trial information: NCT02069093. [Table: see text]

Abstract P1-15-06: Evaluation of miracle mouthwash (MMW) plus hydrocortisone versus prednisolone mouth rinses as prophylaxis for everolimus-associated stomatitis: Preliminary results of a randomized phase II study

Abstract Background: Oral stomatitis is a frequent adverse event (AE) associated with mTOR-inhibitor therapy, and can impact treatment adherence. In the BOLERO-2 trial in patients (pts) with hormone receptor-positive (HR+) metastatic breast cancer (MBC) treated with exemestane (EXE) plus everolimus (EVE), the incidence of all-grade stomatitis or related AEs was 67%, with 24% and 8% of pts developing Grade (G) 2 and G3 stomatitis or related AEs, respectively (Perez et al ASCO 2013 Abst 7029). In BOLERO-2, 24% of pts required EVE dose reduction for stomatitis (Rugo et al Ann Oncol 2014;25:808). The current study evaluated 2 different steroid-based mouth rinses for the prevention or amelioration of oral stomatitis in pts with MBC treated with EVE. Methods: This prospective randomized phase II study enrolled postmenopausal pts (planned accrual=100) with HR+ MBC within the US Oncology Network who were initiating therapy with an aromatase inhibitor plus EVE (10 mg/day). Eligible pts were randomized, blinded, 1:1 to prophylactic treatment with 1 of 2 oral rinses (ARM 1: MMW 480 ml recipe: 320 mL oral Benadryl, 2 g Tetracycline, 80 mg Hydrocortisone, 40 mL Nystatin suspension, water; or ARM 2: Prednisolone 15mg/5mL oral solution). Pts were instructed to swish/expectorate 10 ml of the assigned rinse 4 x daily starting with Day 1 of EVE treatment, for a total of 12 wks. The primary objective was to determine the incidence of G≥2 stomatitis during the first 12 wks of treatment. Secondary objectives included assessment of AEs (all grades), determination of the percentage of pts requiring dose interruption and/or dose reduction of EVE or discontinuation of therapy due to toxicity, and evaluation of the impact of the oral rinses on the duration and severity of stomatitis. Results: As of April 16, 2015, a total of 48 pts have been randomized and 47 pts have received treatment, with a mean time on mouth rinse of 68 days (range 2-84 days). Median age was 65 yrs (range 31-82 yrs). Twelve patients developed an oral AE and the incidence of all-grade stomatitis was 25% (n=12/48). The incidence of G1 stomatitis was 17% (8/48), G2 stomatitis was 8% (4/48) and there were no G3 events. The 4 G2 stomatitis AEs occurred within the first 30 days of treatment. One pt (1/48; 2%) required EVE dose delay. One pt developed oral candidiasis while on the steroid mouth rinse and no pts have stopped the steroid mouth rinse therapy due to mouth rinse-related toxicity. Conclusion: These preliminary data are the first from a prospective trial to provide evidence of a reduced incidence of mTOR-associated stomatitis with prophylactic use of a steroid mouth rinse. The 25% incidence of all-grade and 8%/0% incidence of G2/3 stomatitis compare favorably with the 67% and 24%/8% incidence of all-grade and G2/3 stomatitis, respectively, in BOLERO-2. These preliminary data also demonstrated the safety and tolerability of these 2 steroid mouth rinses. The incidence of stomatitis on each study arm will be available when accrual is completed. The prophylactic use of steroid mouth rinses substantially decreases the incidence of G2/3 stomatitis and the need for EVE dose interruption/reduction. Citation Format: Jones VL, Jensen LL, McIntyre KJ, Oommen SP, Patt DA, Cortas TE, Harris RP, Wilks ST, Fox P, O'Shaughnessy JA. Evaluation of miracle mouthwash (MMW) plus hydrocortisone versus prednisolone mouth rinses as prophylaxis for everolimus-associated stomatitis: Preliminary results of a randomized phase II study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-15-06.

Abstract P4-13-10: Stomatitis following everolimus (EVE) plus exemestane (EXE) in patients with hormone receptor-positive (HR+), HER2– advanced breast cancer (ABC) in the BALLET trial (CRAD001YIC04)

Abstract Background Stomatitis is the most common adverse event (AE) associated with mTOR inhibitors, including EVE. In the pivotal BOLERO-2 trial, stomatitis was reported for 59% vs 12% (Gr3, 8% vs <1%) of pts with HR+, HER2– ABC who received EVE + EXE vs EXE alone. Of the limited real world evidence available, the BRAWO trial showed a stomatitis incidence of 39.8% (Gr3, 3.4%) in a similar pt population. Additional data are warranted to better understand the stomatitis incidence and time-course in order to minimize treatment discontinuations. Methods BALLET is a Phase 3b, European, multi-center, open-label, single-arm, expanded-access study that evaluated safety of EVE (10 mg/d) and EXE (25 mg/d) in 2131 postmenopausal women with HR+, HER2– ABC that progressed on prior NSAI treatment. Primary endpoint was safety; secondary endpoint was characterization of grade 3/4 AEs. In this exploratory analysis, we split the pts in two groups based on having experienced at least one all grade stomatitis event in the first 8 wks (cut-off chosen based on reports that 89.4% of stomatitis events occurred within 8 wks of EVE initiation [Rugo, ASCO 2014]) vs none. Results This subgroup analysis included 919 pts with stomatitis (43.1% of the full population). Baseline pt characteristics were comparable to the overall study population, except for more comorbidity (cardiovascular and metabolic disorder) in stomatitis subset. Pts with stomatitis had a longer EVE treatment duration vs pts who didn't (5.8 mo [95%CI, 5.0-6.2] vs 4.7 mo [95%CI, 4.4-5.3]; hazard ratio, 1.121 [95%CI, 0.97-1.28] censored by pts who switched to commercial drug). The relative risk of initial onset of stomatitis at 6 wks was ∼40%; median time to onset was 28 days. Majority of stomatitis events were of grade 1/2 severity (80%); grade 3/4 stomatitis was reported for 20% of pts. Most frequent reasons for treatment discontinuation in pts with stomatitis were reimbursement (37.6%), disease progression (35.0%), and AEs (16.2%). Most frequent AEs which led to treatment discontinuation in these pts were stomatitis in 3.7% (Grade 3/4, 2%), pneumonitis in 2.9% (Grade 3/4, 1.3%) and asthenia in 1.8% (Grade 3/4, 1%). Median EVE relative dose intensity in pts with stomatitis was 0.92. In the stomatitis subset, dose interruptions and reductions were required for 66.7% and 37.6% of pts, respectively; most frequent reasons for dose adjustments were AEs (65.9%) which included stomatitis (46.8%), asthenia (6.3%), and pneumonitis (5.3%). Median time to first dose modification in pts with stomatitis was 30 days; median duration of dose interruptions was 16 days. On-treatment deaths (4.4%) were due to progressive disease (2.1%), AEs (1.7%), and other reasons (0.5%). Conclusions These results confirmed the stomatitis time-course observed previously and that the majority of these events are of low grade. Stomatitis was the most common cause of dose reductions and interruptions due to AEs and was manageable with dose adjustments; there was a positive association between stomatitis and longer treatment duration. Therefore, proactive management, diligent monitoring and appropriate dose modifications, are recommended to keep pts on treatment. Citation Format: Ciruelos EM, Jerusalem G, Generali D, Lang I, Gavila JG, Michelotti A, Tjan-Heijnn VCG, Mariani G, Conte P, Beliera A, Camozzi M, Lorizzo K, Martin M. Stomatitis following everolimus (EVE) plus exemestane (EXE) in patients with hormone receptor-positive (HR+), HER2– advanced breast cancer (ABC) in the BALLET trial (CRAD001YIC04). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-10.

Abstract P4-13-08: Stomatitis in patients treated with everolimus and exemestane - Results of the 3rd interim analysis of the non-interventional trial BRAWO

Abstract Background BRAWO is a German non-interventional study of 3000 patients (pts) with advanced/metastatic, hormone receptor positive and HER2 negative breast cancer treated with everolimus and exemestane (EVE+EXE). One of the objectives was the documentation of how stomatitis was managed and prevented in clinical routine. We report data of the 3rd preplanned interim analysis (IA) focusing on prophylaxis and management of stomatitis in daily clinical routine. Methods Here we report data of the first 1300 documented pts on efficacy and safety with focus on the adverse event stomatitis. Patient and treatment characteristics were associated with the occurrence of stomatitis. Furthermore chosen treatments for the management of stomatitis are described. Results At time of data cut-off 71% pts had discontinued the study, 29% were still under therapy. Patient and tumor characteristics were reported previously. The most commonly reported AEs of any grade were stomatitis (41.5%), fatigue (14.6%), nausea (12.2%), diarrhea (12.1%), dyspnea (11.3%). 75.2% of stomatitis events occurred during the first 5 weeks of treatment, regardless of the chosen starting dose 5 mg or 10 mg EVE per day. Median duration of a stomatitis episode was 28 days for 5 mg EVE start dose and 23 days for 10mg. However, there was a numerically lower stomatitis incidence and less severe intensity of stomatitis for a start dose of 5 mg vs 10 mg (Table 1). Table 1: Stomatitis incidence and severity by EVE start dose: Worst intensitiy of stomatitisTotal (n=1300)Start dose 5mg (n=316)Start dose 10mg (n=975)Other* (n=9)Number (%) of pts with at least one stomatitis event (any grade)513 (41.5)115 (36.4)421 (43.2)3 (33.3)Grade 1276 (21.2)73 (23.1)202 (20.7)1 (11.1)Grade 2198 (15.2)31 (9.8)165 (16.9)2 (22.2)Grade 330 (2.3)3 (0.9)27 (2.8)0Unknown35 (2.7)8 (2.5)27 (2.8)0*Other includes 2.5mg (n=3), 7.5mg (n=2), 15mg (n=1), 20mg(n=2), 30mg (n=1) 86.5% of pts received recommendations regarding stomatitis prophylaxis. The most frequent recommendations were: mild dental hygiene (e.g. soft toothbrush) (74.8%), avoidance of hot, sour or salty food (70.9%), rinsing with tea (61.7%), and cooling (e.g. sucking ice or frozen pineapple) (56,6%). At least one therapeutic measure was documented for 85.5% of stomatitis events. The most common therapeutic measures were non-drug mouthwash solution (58.3%), cooling (34.7%) or drug intervention (31.9%). Temporary EVE dose adjustments due to stomatitis were done in 11.6% of stomatitis events, temporary dose interruptions in 21.8%, respectively. Efficacy of EVE+EXE seemed to be independent of stomatitis occurrence within 8 weeks after therapy start: mPFS 6.9 months (95%CI, 6.4-8.0) without stomatitis, mPFS 7.4 months (95%CI, 6.3-8.6) with stomatitis. Discussion The percentage of patients with any grade stomatitis was lower in BRAWO (41.5%) than in the pivotal BOLERO-2 trial (59%), which might be explained by increased awareness and experience of treating physicians for prophylaxis and management of this type of adverse event under treatment with EVE+EXE. Most stomatitis events occurred during the first 5 weeks of treatment, which is consistent with data from BOLERO-2. Citation Format: Schütz F, Grischke E-M, Decker T, Uleer C, Schneeweiss A, Salat C, Wimberger P, Mundhenke C, Förster F, Kluth-Pepper B, Schubert J, Bloch W, Tesch H, Jackisch C, Lüftner D, Fasching PA. Stomatitis in patients treated with everolimus and exemestane - Results of the 3rd interim analysis of the non-interventional trial BRAWO. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-08.

RandomizEd phase II trial of Sunitinib four weeks on and two weeks off versus Two weeks on and One week off in metastatic clear-cell type REnal cell carcinoma: RESTORE trial

BackgroundThe standard sunitinib schedule, 4 weeks on, followed by 2 weeks off (4/2 schedule), is associated with troublesome toxicities, and maintenance of adequate sunitinib dosing and drug levels, which are essential for achieving an optimal treatment outcome, is challenging. The objective of this study was to investigate the efficacy and safety of an alternative sunitinib dosing schedule of 2 weeks on and 1 week off (2/1 schedule) compared with the standard sunitinib schedule of 4 weeks on and 2 weeks off (4/2 schedule). Patients and methodsIn this multicenter, randomized, open-label, phase II trial, treatment-naïve patients with clear-cell type metastatic renal cell carcinoma (mRCC) were randomly assigned to 4/2 or 2/1 schedules after stratification by Memorial Sloan Kettering Cancer Center risk group and the presence or absence of measurable lesions. The primary end point was the 6-month failure-free survival (FFS) rate, determined by intention-to-treat analysis. ResultsFrom November 2007 to February 2014, 76 patients were accrued, and 74 were eligible. FFS rates at 6 months were 44% with the 4/2 schedule (N = 36) and 63% with the 2/1 schedule (N = 38). Neutropenia (all grades, 61% versus 37%; grade 3–4, 28% versus 11%) and fatigue (all grades, 83% versus 58%) were more frequently observed with schedule 4/2. There was a strong tendency toward a lower incidence of stomatitis, hand–foot syndrome, and rash with schedule 2/1. Objective response rates (ORRs) were 47% in schedule 2/1 and 36% in schedule 4/2. With a median follow-up of 30.0 months, the median time to progression (TTP) was 12.1 months in schedule 2/1 and 10.1 months in schedule 4/2. ConclusionSunitinib administered with a 2/1 schedule is associated with less toxicity and higher FFS at 6 months than a 4/2 schedule, without compromising the efficacy in terms of ORR and TTP (NCT00570882).

Metastatic Nasopharyngeal Carcinoma Outcomes in Patients on Cisplatin with Nolatrexed or 5-Fluorouracil

SummaryBackground: Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors in southern China. In this study, we compared the clinical efficacy and toxicity of cisplatin with nolatrexed (LP) or 5-fluorouracil (FP) for NPC. Patients and Methods: 33 patients with metastatic NPC were randomized to the LP and FP regimens. The LP regimen consisted of continuous intravenous infusions of 740 mg/m² nolatrexed on days 1-5 and 25 mg/m² intravenous cisplatin on days 2-4. The FP regimen consisted of continuous intravenous infusions of 600 mg/m² 5-fluorouracil on days 1-5 and 25 mg/m² intravenous cisplatin on days 2-4. Cycles were repeated every 3 weeks until disease progression or completion of a total of 6 courses. Results: There were no significant differences in the response rates (RR), disease control rates (DCR), times to progression (TTP), and median survival times (MST) between the regimens. The toxicities of the two regimens were mostly grade I/II, but the stomatitis incidence in the patients on the LP regimen was significantly lower than that on the FP regimen. Conclusions: The efficacy of the LP regimen was similar to that of the FP regimen. The LP regimen had lower toxicity.

Stomatitis incidence and its relationship with efficacy: A meta-analysis of everolimus clinical studies.

151 Background: The most common adverse event (AE) with everolimus (EVE) is stomatitis. This meta-analysis evaluated the incidence, severity, and possible impact of stomatitis on efficacy in patients (pts) with cancer or tuberous sclerosis complex (TSC) who received EVE. Methods: Stomatitis events from 7 randomized, double-blind, phase 3 EVE studies included: RECORD-1 (RCC), RADIANT-2 (NET), RADIANT-3 (pNET), BOLERO-2 (HR+/HER2- breast cancer [BC]), BOLERO-3 (HER2+BC), and EXIST-1 and -2 (TSC). Time to first stomatitis occurrence and recurrence were analyzed using Kaplan-Meier (KM) methods. Stratified Cox regression analysis adjusted for baseline prognostic factors and corrected for confounding effect of duration of exposure was used to analyze association between stomatitis occurrence (≤ 8 wks of EVE start) and PFS in pts with cancer and response rate in pts with TSC. Results: This evaluation included EVE-treated pts with cancer (n = 1,455) and TSC (n = 157). Pts with cancer had stomatitis incidence of 66.9%, which occurred early, median 0.82 mo (95% CI, 0.7-1.0; 2-mo KM estimate 60.8%). 8.6% were grade 3/4 events. 1.7% of pts discontinued due to stomatitis. Stomatitis recurred in 40% of pts and appeared gradually. In pts with TSC similar results were observed. In EVE-treated pts, development of stomatitis was associated with longer PFS (corrected HR [95% CI]) in BOLERO-2 (0.78 [0.62-1.00]) and RADIANT-3 (0.70 [0.48-1.01]), and similar trend was observed in RECORD-1 (0.90 [0.66-1.22]) and RADIANT-2 (0.87 [0.61-1.22]), but not in BOLERO-3. In TSC, probably due to few pts, relationship between stomatitis and response was not conclusive. In all trials, pts on EVE had longer PFS vs placebo irrespective of stomatitis incidence. Conclusions: Stomatitis is observed frequently in initial wks of EVE therapy. Most AEs were grade 1/2 and manageable, rarely led to pt discontinuation. Stomatitis recurred in < 50% of pts. EVE-treated pts with cancer who had stomatitis achieved stable benefit similar to overall population, suggesting that continuing EVE is helpful. The importance of prophylactic measures in reducing EVE-induced stomatitis incidence and improving its management is being determined by ongoing studies.

Meta-analysis of stomatitis incidence in everolimus (EVE) clinical studies and its relationship with efficacy.

645 Background: Stomatitis is a common adverse event with EVE. This meta-analysis of individual patient (pt) data assessed the incidence, severity, and potential impact on outcomes of stomatitis an...

Assessing the effectiveness of Gelclair® in the prevention and therapy of stomatitis in patients undergoing hematopoietic stem-cell transplantation: a randomized trial

Chemotherapy-induced stomatitis is a major side effect of the treatment. Numerous approaches are described in the literature for the prevention and treatment of this complication. the aim was assess the effectiveness of Gelclair® in patients undergoing hematopoietic stem-cell transplantation in terms of reducing the incidence of stomatitis, stomatitis-pain and the severity of stomatitis Fifty-seven patients (28 control group and 29 experimental group) used a mouthwash 3 times a day and were evaluated by means of a specially-tailored form containing the following assessment items:stomatitis evaluation scale (WHO), VAS for pain and Likert-Scale for agreement. 61% of patients presented with stomatitis. No difference was observed between the two groups with regard to stomatitis grade throughout the observation period. Painful symptoms were observed in 54% subjects. No differences were observed in terms of average pain perception before the use of mouthwashes throughout the period of observation p=0.06. RESULTS showed a pain-relieving effect in the experimental group after using the mouthwash p=0.04. Although Gelclair® had no influence on the onset and severity of stomatitis in transplanted patients, a significant benefit was observed in terms of pain control. Our study suggest the possibility to implementation the use of Gelclair® in clinical practice. However, further multicenter trials are needed to provide stronger evidence on the real usefulness of this product.

Impact of oral care protocol on the incidence and severity of stomatitis induced by radiotherapy

Background: Oral stomatitis is a common debilitating complication of cancer radiotherapy. It results from local effects of radiation on the oral mucosa. The impact of oral stomatitis is far-reaching for patients, caregivers and the medical system. Objective: the aim of the study was to assess impact of oral care protocol to radiotherapy induced stomatitis in cancer patients. Methods: Quasi-experimental research design was conducted in the Clinical Oncology and Nuclear Medicine Department at Main Mansoura University Hospital. The data were collected from two hundred adult patients of both sex randomized selected who corresponded to inclusion criteria and divided into two groups. Results: the result indicates increased total knowledge score for patients at immediate post more than post tests 1 and post test 2. Also it was found decreased incidence and severity of stomatitis after oral care protocol. There were a positive relation between severity and incidence of stomatitis of studied patients in relation to their knowledge. Conclusion: The implementation of oral care protocol had a positive effect on the studied patients' total knowledge scores and decrease incidence and severity of stomatitis in the study group. It was recommended that, Cancer patients should be given a written instruction plan for their radiotherapy steps and selfmanagement measures to radiotherapy.

Abstract OT2-6-14: Phase 2, single arm study of a steroid-based mouthwash to prevent stomatitis in women with hormone receptor–positive advanced breast cancer treated with everolimus plus exemestane

Abstract BACKGROUND: Stomatitis, the inflammation of mucous membranes lining the mouth and throat, is a frequent adverse event that is associated with the oral mTOR inhibitor everolimus and can significantly impact treatment adherence. Specific strategies to prevent and/or lessen the severity of everolimus-associated stomatitis are not well documented. Steroid mouthwashes and steroid gels or pastes used to treat recurrent aphthous stomatitis may be effective for stomatitis associated with everolimus. This phase 2, single-arm study will evaluate a steroid-based therapeutic intervention to prevent stomatitis (Grade ≥2) in breast cancer patients taking everolimus + exemestane. METHODS: Eligible participants will be patients with HR-positive, HER2-negative advanced breast cancer with no evidence of oral stomatitis or other oral pathology who have been prescribed everolimus + exemestane but have not yet started treatment. A baseline oral assessment will be conducted, and patients will be provided instructions on how to self-monitor for stomatitis, along with instructions to contact the study site at the first sign of oral pain or changes to the oral mucosa. All patients will be instructed to perform routine good oral care. Eligible patients will receive a steroid-based mouthwash (alcohol-free 0.5mg/5ml dexamethasone solution) prophylactically. Patients will be instructed to perform the mouthwash regimen four times per day and swish the mouthwash in mouth for a minimum of 120 seconds before spitting it out. Patients will be instructed to abstain from eating or drinking for at least an hour after taking the mouthwash. Mouthwash regimen will begin on the first day of everolimus after administration of the dose and patients will continue the regimen for the first 4 months of everolimus therapy. Primary endpoint is the incidence of stomatitis (Grade ≥2) at 2 months defined as meeting at least one of the following criteria: ≤50 on Normalcy of Diet Scale to assess oral intake and a rating of 7 on two consecutive days or a rating of 8, 9 or 10 on any one day using Visual Analog Scale to assess oral pain. Evidence of stomatitis must be confirmed by investigator on physical exam and/or phone call assessment. Secondary endpoints include average number of times per day the mouthwash regimen was performed and time to resolution of stomatitis (Grade ≥2) that occurs during the trial. Assuming a 13% absolute reduction in the rate of grade ≥ stomatitis from the historical control rate of 33% and one sided Type 1 error = 0.05 and power = 80%,73 evaluable patients will be needed. To account for 25% of the total patient population being non-evaluable, 97 patients will be enrolled for this study. Supported by funding from Novartis Pharmaceuticals Corporation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-14.

Randomized study of sinusoidal chronomodulated versus flat intermittent induction chemotherapy with cisplatin and 5-fluorouracil followed by traditional radiotherapy for locoregionally advanced nasopharyngeal carcinoma

Neoadjuvant chemotherapy plus radiotherapy is the most common treatment regimen for advanced nasopharyngeal carcinoma (NPC). Whether chronomodulated infusion of chemotherapy can reduce its toxicity is unclear. This study aimed to evaluate the toxic and therapeutic effects of sinusoidal chronomodulated infusion versus flat intermittent infusion of cisplatin (DDP) and 5-fluorouracil (5-FU) followed by radiotherapy in patients with locoregionally advanced NPC. Patients with biopsy-diagnosed untreated stages III and IV NPC (according to the 2002 UICC staging system) were randomized to undergo 2 cycles of sinusoidal chronomodulated infusion (Arm A) or flat intermittent constant rate infusion (Arm B) of DDP and 5-FU followed by radical radiotherapy. Using a “MELODIE” multi-channel programmed pump, the patients were given 12-hour continuous infusions of DDP (20 mg/m2) and 5-FU (750 mg/m2) for 5 days, repeated every 3 weeks for 2 cycles. DDP was administered from 10:00 am to 10:00 pm, and 5-FU was administered from 10:00 pm to 10:00 am each day. Chronomodulated infusion was performed in Arm A, with the peak deliveries of 5-FU at 4:00 am and DDP at 4:00 pm. The patients in Arm B underwent a constant rate of infusion. Radiotherapy was initiated in the fifth week, and both arms were treated with the same radiotherapy techniques and dose fractions. Between June 2004 and June 2006, 125 patients were registered, and 124 were eligible for analysis of response and toxicity. The major toxicity observed during neoadjuvant chemotherapy was neutropenia. The incidence of acute toxicity was similar in both arms. During radiotherapy, the incidence of stomatitis was significantly lower in Arm A than in Arm B (38.1% vs. 59.0%, P = 0.020). No significant differences were observed for other toxicities. The 1-, 3-, and 5-year overall survival rates were 88.9%, 82.4%, and 74.8% for Arm A and 91.8%, 90.2%, and 82.1% for Arm B. The 1-, 3-, and 5-year progression-free survival rates were 91.7%, 88.1%, and 85.2% for Arm A and 100%, 94.5%, and 86.9% for Arm B. The 1-, 3-, and 5-year distant metastasis-free survival rates were 82.5%, 79.1%, and 79.1% for Arm A and 90.2%, 85.2%, and 81.7% for Arm B. Chronochemotherapy significantly reduced stomatitis but was not superior to standard chemotherapy in terms of hematologic toxicities and therapeutic response.

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis.

Methotrexate (MTX) is a disease modifying antirheumatic drug (DMARD) used as a first line agent for treating rheumatoid arthritis (RA). Pharmacologically, it is classified as an antimetabolite due to its antagonistic effect on folic acid metabolism. Many patients treated with MTX experience mucosal, gastrointestinal, hepatic or haematologic side effects. Supplementation with folic or folinic acid during treatment with MTX may ameliorate these side effects. To identify trials of supplementation with folic acid or folinic acid during MTX therapy for rheumatoid arthritis and to assess the benefits and harms of folic acid and folinic acid (a) in reducing the mucosal, gastrointestinal (GI), hepatic and haematologic side effects of MTX, and (b) whether or not folic or folinic acid supplementation has any effect on MTX benefit. We originally performed MEDLINE searches, from January 1966 to June 1999. During the update of this review, we searched additional databases and used a sensitive search strategy designed to retrieve all trials on folic acid or folinic acid for rheumatoid arthritis from 1999 up to 2 March 2012. We selected all double-blind, randomised, placebo-controlled clinical trials (RCTs) in which adult patients with rheumatoid arthritis were treated with MTX (at a dose equal to or less than 25 mg/week) concurrently with folate supplementation. In this update of the review we only included trials using 'low dose' folic or folinic acid (a starting dose of ≤ 7 mg weekly). Data were extracted from the trials, and the trials were independently assessed for risk of bias using a predetermined set of criteria. Six trials with 624 patients were eligible for inclusion. Most studies had low or unclear risk of bias for key domains. The quality of the evidence was rated as 'moderate' for each outcome as assessed by GRADE, with the exception of haematologic side effects which were rated as 'low'. There was no significant heterogeneity between trials, including where folic acid and folinic acid studies were pooled.For patients supplemented with any form of exogenous folate (either folic or folinic acid) whilst on MTX therapy for rheumatoid arthritis, a 26% relative (9% absolute) risk reduction was seen for the incidence of GI side effects such as nausea, vomiting or abdominal pain (RR 0.74, 95% CI 0.59 to 0.92; P = 0.008). Folic and folinic acid also appear to be protective against abnormal serum transaminase elevation caused by MTX, with a 76.9% relative (16% absolute) risk reduction (RR 0.23, 95% CI 0.15 to 0.34; P < 0.00001), as well as reducing patient withdrawal from MTX for any reason (60.8% relative (15.2% absolute) risk reduction, RR 0.39, 95% CI 0.28 to 0.53; P < 0.00001).We analysed the effect of folic or folinic acid on the incidence of stomatitis / mouth sores, and whilst showing a trend towards reduction in risk, the results were not statistically significant (RR 0.72, 95% CI 0.49 to 1.06)It was not possible to draw meaningful conclusions on the effect of folic or folinic acid on haematologic side effects of methotrexate due to small numbers of events and poor reporting of this outcome in included trials.It does not appear that supplementation with either folic or folinic acid has a statistically significant effect on the efficacy of MTX in treating RA (as measured by RA disease activity parameters such as tender and swollen joint counts, or physician's global assessment scores). The results support a protective effect of supplementation with either folic or folinic acid for patients with rheumatoid arthritis during treatment with MTX.There was a significant reduction shown in the incidence of GI side effects, hepatic dysfunction (asmeasured by elevated serum transaminase levels) as well as a significant reduction in discontinuation of MTX treatment for any reason. A trend towards a reduction in stomatitis was demonstrated however this did not reach statistical significance.This updated review with its focus on lower doses of folic acid and folinic acid and updated assessment of risk of bias aimed to give a more precise and more clinically relevant estimate of the benefit of folate supplementation for patients with rheumatoid arthritis receiving methotrexate.