Meta-analysis of stomatitis in clinical studies of everolimus: incidence and relationship with efficacy

Rugo, Hope S.; Hortobágyi, G. N.; Yao, James C.; Pavel, Marianne; Ravaud, Alain; Franz, David Neal; Ringeisen, François; Gallo, Jorge D.; Rouyrre, Nicolas; Anak, Oezlem; Motzer, Robert J.

doi:10.1093/annonc/mdv595

Cited by 73 publications

(63 citation statements)

References 12 publications

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“…There were 7 studies covering 2 topics each [3,13,14,15,16,17,18] and 7 meta-analyses [19,20,21,22,23,24,25]. 20 studies (29.4%) were from Europe [3,5,9,10,11,12,15,22,26,27,28,29,30,31,32,33,34,35,36,37,38,] 20 from the US [4,14,17,19,20,24,39,40,41,42,43,44,45,46,47,48,49,50,51,52], 3 studies (4.4%) from US plus Europe [23,53,54], 6 studies (8.8%) from Japan [16,55,56,57,58,59], 6 studies (8.8%) from China [18,25,60,61,62,63], 2 studies (3.0%) from Hong Kong [13,64,65], 3 studies (4.4%) from Canada [66,67,68], 3 studies (4.4%) from India [21,69,70] and 5 studies (7.4%) from other countries [7,71,72,73,74]. 21 studies (30.9%) used the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) scale for assessment of OM.…”

Section: Resultsmentioning

confidence: 99%

“…1 Studies on oral mucositis (OM). Incidence of OM was investigated in patients with hematopoietic stem cell transplantation (HSCT) in 14 studies (32.6%) [3,5,14,17,19,28,31,36,37,39,44,56,62,67], in head and neck cancer (HNC) patients in 13 studies (30.2%) [18,21,29,40,50,51,55,59,60,61,63,70,73], in patients with chemotherapy in 13 studies (30.2%) [15,16,22,23,24,25,30,34,38,46,48,58,71], with mixed tumor types and treatment in 1 study (2.3%) [13] and with palliative care in 2 studies (4.7%) [32,57]. Cost related to OM in patients undergoing HSCT was the focus in 4 studies [7,14,17,54], in HNC patients in 2 studies [43,47], in patients with chemotherapy in 6 studies [9,10,11,12,42,49,68], and in patients with mixed tumor types and treatment in 2 studies [20,45].…”

Section: Resultsmentioning

confidence: 99%

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Burden of Oral Mucositis: A Systematic Review and Implications for Future Research

et al. 2018

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Background: Surprisingly little is known about the burden of oral mucositis (OM). We provide a systematic review of studies on the burden of OM (incidence, economic impact, health-related quality of life (HRQoL)). Methods: Systematic literature searches were made in BIOSIS, EMBASE, and MEDLINE. Inclusion criteria were studies on OM in hematology/oncology patients of ≥ 18 years, journal articles, English language, and published between 2000 and 2016; OM treatment studies were excluded. Quality assessment was performed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results: We screened 4,996 hits, and identified 68 studies of which 13 were without transparency on OM grading. The evidence level of 65 studies was rated ‘low' or ‘very low' in 58.5%, ‘moderate' in 20% and ‘high' in 21.5%. Mean value of incidence (7 studies) was 83.5% for all grades of OM with hematopoietic stem cell transplantation. OM incidence for all grades in head and neck cancer patients was 59.4-100%. Considering the economic impact, 16 studies showed highly variable numbers. HRQoL was measured in 16 studies using 13 different instruments. Statistically significant changes in HRQoL scores were demonstrated. Conclusion: OM is common, burdensome, costly and imposes major reductions in HRQoL. However, from a quality standpoint, the level of current evidence in OM is disappointing. The field needs continued attention to address methodological challenges.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Burden of Oral Mucositis: A Systematic Review and Implications for Future Research

et al. 2018

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“…A recent meta-analysis observed that patients who experience stomatitis derive a clinical benefit from everolimus that is similar to the benefit derived by the overall trial population, suggesting that, with proactive management and dose adjustment according to the approved prescribing information, everolimus can be continued in most patients who experience stomatitis 30 . Interim analyses from a large German non-interventional study (brawo) of 3000 patients with advanced or metastatic hr-positive, her2-negative breast cancer treated with everolimus and exemestane suggest that physician experience, prophylactic measures, and close monitoring of patients can reduce the incidence of stomatitis.…”

Section: Early Recognition and Frequent Monitoringmentioning

confidence: 89%

Novel Agents and Associated Toxicities of Inhibitors of the PI3K/Akt/mTOR Pathway for the Treatment of Breast Cancer

et al. 2015

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The PI3K/Akt/mTOR (phosphatidylinositol 3 kinase/ Akt/mammalian target of rapamycin) signalling pathway is an established driver of oncogenic activity in human malignancies. Therapeutic targeting of this pathway holds significant promise as a treatment strategy. Everolimus, an mtor inhibitor, is the first of this class of agents approved for the treatment of hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer. Everolimus has been associated with significant improvements in progression-free survival; however, it is also associated with increased toxicity related to its specific mechanism of action. Methods: A comprehensive review of the literature conducted using a focused medline search was combined with a search of current trials at http://ClinicalTrials.gov/. Summary tables of the toxicities of the various classes of PI3K/Akt/mTOR inhibitors were created. A broad group of Canadian health care professionals was assembled to review the data and to produce expert opinion and summary recommendations for possible best practices in managing the adverse events associated with these pathway inhibitors. Results: Differing toxicities are associated with the various classes of PI3K/Akt/mTOR pathway inhibitors. The most common unique adverse events observed in everolimus clinical trials in breast cancer include stomatitis (all grades: approximately 60%), noninfectious pneumonitis (15%), rash (40%), hyperglycemia (15%), and immunosuppression (40%). To minimize grades 3 and 4 toxicities and to attempt to attain optimal outcomes, effective management of those adverse events is critical. Management should be interdisciplinary and should use approaches that include education, early recognition, active intervention, and potentially prophylactic strategies. Discussion: Everolimus likely represents the first of many complex oral targeted therapies for the treatment of breast cancer. Using this agent as a template, it is essential to establish best practices involving and integrating multiple disciplines for the management of future PI3K/Akt/mTOR signalling pathway inhibitors.

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“…Stomatitis is a known adverse effect of mTOR inhibitors, which was initially reported in the EXIST-1, RADIANT-3 and BOLERO-2 trials 8. A meta-analysis of the incidence of stomatitis with everolimus use reveals a rate of 67% in solid tumour trials and 70% in tuberous sclerosis trials 8.…”

Section: Discussionmentioning

confidence: 99%

“…mTOR inhibitor-associated stomatitis (mIAS) can significantly affect the treatment course and may contribute to discontinuation of therapy 6. mIAS has been reported to range from 43% to 70% 5 7 8. Other side effects of everolimus include nasopharyngitis, shortness of breath and acne-like lesions 7.…”

Section: Introductionmentioning

confidence: 99%

Everolimus-associated stomatitis in a patient who had renal transplant

Aboalela

Villa

2016

BMJ Case Reports

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Everolimus is used as an immunosuppressant in renal allograft transplant rejection and in metastatic breast cancer treatment. One side effect of everolimus is stomatitis, referred to as mammalian target of rapamycin inhibitor-associated stomatitis. This side effect can affect treatment course and contribute to discontinuation of therapy or dose reduction, previously reported in the treatment of metastatic breast cancer. Here, we present a case of everolimus-associated stomatitis with a novel management method with intralesional triamcinolone that allows for continuous course of everolimus.

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Meta-analysis of stomatitis in clinical studies of everolimus: incidence and relationship with efficacy

Cited by 73 publications

References 12 publications

Burden of Oral Mucositis: A Systematic Review and Implications for Future Research

Burden of Oral Mucositis: A Systematic Review and Implications for Future Research

Novel Agents and Associated Toxicities of Inhibitors of the PI3K/Akt/mTOR Pathway for the Treatment of Breast Cancer

Everolimus-associated stomatitis in a patient who had renal transplant

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