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Oral Medicine, Oral Surgery and Implantology Unit (MedOralRes), Faculty of Medicine and Dentistry, Universidade de Santiago de Compostela, Santiago de Compostela, A Coruña, SpainHealth Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, A Coruña, Spain
Oral Medicine, Oral Surgery and Implantology Unit (MedOralRes), Faculty of Medicine and Dentistry, Universidade de Santiago de Compostela, Santiago de Compostela, A Coruña, SpainHealth Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, A Coruña, Spain
Department of Nursing I, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, SpainBiocruces Bizkaia Health Research Institute, Barakaldo, Spain
Oral Medicine, Oral Surgery and Implantology Unit (MedOralRes), Faculty of Medicine and Dentistry, Universidade de Santiago de Compostela, Santiago de Compostela, A Coruña, SpainMedical Oncology Unit, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, A Coruña, Spain.
The aim of this study was to determine the prevalence of acute oral mucosal toxicities in non-irradiated patients treated with systemic antineoplastics agents. The secondary objective was to find out differences in its prevalence among the different types of systemic antineoplastics.
Study design
A systematic review and meta-analysis was performed. Articles from 2010 to July 2022 were retrieved and included if patients were adults undergoing oral assessment after administration of commercially available systemic antineoplastics. Data was extracted and pooled proportions were estimated using random-effect model method (Der Simonian and Lair).
Results
Eighty-two articles were included in the study. The overall prevalence of acute oral mucosal damage across studies was 38.2% (95% CI: 33.1%-43.3%). The prevalence was 42.9% (95% CI: 32.8%-53%) in patients treated with chemotherapy alone, 38% (95% CI: 29.1%-47%) in patients treated with a combination of chemotherapy and targeted therapies, and 32.1% (95% CI: 26.8%-37.5%) in targeted therapies alone-treated patients. No statistically significant differences were found in the prevalence of oral mucosal toxicities between the different types of systemic antineoplastic treatments.
Conclusions
Oral mucosal toxicity is a major side effect in non-irradiated cancer patients undergoing systemic antineoplastics.
Statement of Clinical Relevance
The prevalence of acute oral mucosal damage in non-irradiated patients treated with commercially available systemic antineoplastics is 38.2%. There is no significant difference according to the type of systemic antineoplastic regime administered.
Oral mucosal damage (OMD) is one of the most frequently reported adverse events in cancer therapy. It is described as oral coating injury, characterized by the presence of inflammation, erythema, atrophy, and/or ulceration that may develop acutely or be long-lasting in certain cases.
The pathophysiology of acute oral mucosal damage in patients with cancer has not been completely unveiled yet, which precludes the development of effective treatments or prophylactic measures and limits the clinical approach to symptomatic or palliative care.
Effectiveness of low-level laser therapy for oral mucositis prevention in patients undergoing chemoradiotherapy for the treatment of head and neck cancer: a systematic review and meta-analysis.
Patients who have these side effects often experience symptoms that may include xerostomia or localized acute pain that directly affect their quality of life up until recovery or death.
Patient-reported measurements of oral mucositis in head and neck cancer patients treated with radiotherapy with or without chemotherapy: demonstration of increased frequency, severity, resistance to palliation, and impact on quality of life.
Oral adverse events associated with tyrosine kinase and mammalian target of rapamycin inhibitors in renal cell carcinoma: a structured literature review.
Multiple clinical research articles have been published showing controversial results on the best clinical practice in oral mucositis. Antimicrobials, analgesia, anesthesia, or laser are some of the treatments that have been described so far.
The prevalence of acute oral mucositis varies according to the oncological treatment. Radiation therapy leads the ranking, causing oral mucositis to nearly every head and neck cancer patient receiving it. The incidence is slightly lower (60%-80%) in patients with hematologic malignancies that undergo hematopoietic cell transplantation, whereas cases in patients treated with chemotherapy account for 20% to 40% of the total.
From a medical oncology perspective, it is interesting to analyze the incidence of oral mucosal lesions caused by prescribed treatments. Over the last years, the management of patients with cancer has changed considerably, and the use of target drugs has increased remarkably, despite the significance of traditional chemotherapeutic agents.
The main objective of this study was to determine the frequency of acute oral mucosal damage development in non-irradiated cancer patients because it is a major side effect in oncology treatment. In addition, we also aimed to elucidate differences in the prevalence of this phenomenon in patients with cancer according to the type of systemic antineoplastic regime.
MATERIAL AND METHODS
Protocol design and registration
This systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines
and was as follows: ≥18-year-old patients diagnosed with cancer (P = Patient); whose oral mucosa was examined (I = intervention); after receiving systemic antineoplastics (C = Comparison); to assess the prevalence of oral mucositis (O = outcome).
Sources of information and search strategy
The bibliographic search was carried out in: PubMed/MEDLINE, Web of Knowledge, Cochrane, Directory of Open Access Journals, Literatura Latinoamericana y del Caribe en Ciencias de la Salud, and SciELO from 2010 to July 2022. A further electronic search was performed on databases of specific journals related to this topic.
The agreed search strategy was defined by the following algorithm with the aim of being applied in MEDLINE: (stomatitis OR "oral mucositis" OR "oral ulcer" AND cancer) AND ("Antineoplastic agent" OR Chemotherapy OR "targeted therapy" OR "Induction Chemotherapy" OR "Molecular Targeted Therapy"). The syntax was adapted specifically for each database; however, “oral mucositis” and “cancer therapy” were the main keywords. The human species filter was applied when available.
Eligibility criteria
The literature was retrieved from the databases, and the studies were included if they met the following inclusion criteria: original articles, cohort studies, clinical trials using approved drugs and case series, and with no language limitations. Participants in the included studies had to be ≥18 years of age and have undergone oral assessment after administration of systemic antineoplastics. The exclusion criteria included the following: letters, abstracts, literature reviews, systematic reviews, doctoral thesis, case reports, and original in vitro and in vivo articles. Studies that did not use grading scales for oral mucosa damage assessment were also excluded. Moreover, clinical trials using experimental drugs or other interventions that may potentially influence results, studies that included pediatric patients or pregnant women, as well as those involving patients who undergo/underwent radiotherapy alone or in combination with systemic antineoplastics were discarded.
Study selection and data extraction process
Two researchers (M.P.S. and M.E.R.F.) independently performed the selection of the studies in different phases, as follows: (1) reading the titles and abstracts and (2) fully reading the remaining articles and excluding those that did not meet eligibility. A third researcher (X.M.M.) intervened to deliver a verdict when discrepancies occurred about eligibility of specific articles. Later, a database was created including all the relevant available variables on each paper. Finally, the results were compared to ensure they matched.
The information extracted included first author, year of publication, country, sample size, sex, age, type of cancer, type of therapy, metastases, previous exposure to anticancer therapies, and number of patients with different grades of oral mucosal damage based on World Health Organization(WHO) Scores or National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE).
The risk of bias was assessed for each study by both researchers, following a similar pattern to study selection, using different tools for each specific paper type. For this research, and given our approach to it, it was agreed that most of the studies would be considered case series reports, although their initial design might have not been. Thus, the Joanna Briggs Institute Critical Appraisal Checklist for Case Series was the chosen tool for risk of bias assessment.
was chosen for risk of bias assessment in non-randomized clinical trials (NRCT). Moreover, in the case of randomized clinical trials, the Cochrane Risk of Bias 2.0 tool for Randomized Clinical Trials
A proportion meta-analysis was conducted using STATA version 17 (StataCorp, LLC, College Station, TX, USA). Pooled proportions were estimated using random-effect model method (Der Simonian and Lair) with the following variables: type of tumor, study type, and continent. To analyze the heterogeneity among the studies, the Q statistical test and the I2 were used as well as funnel plots for the publication bias. A P value of < .10 and I2 of >50% indicated that there was heterogeneity between the studies, meaning that a random-effects model would be used.
RESULTS
Study selection
The initial search generated 503 references. We excluded 421 at different stages of the process, as shown in Figure 1, which left us with 82 articles suitable for inclusion.
Fig. 1Preferred Reporting Items for Systematic reviews and Meta-Analyses flow diagram. From: Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021;372:n71.
Each type of article that met eligibility criteria was thoroughly evaluated (N = 82). Three out of 79 case series obtained an overall appraisal of “excluded,”
Dose intensity and efficacy of the combination of everolimus and exemestane (EVE/EXE) in a real-world population of hormone receptor-positive (ER+/PgR+), HER2-negative advanced breast cancer (ABC) patients: a multicenter Italian experience.
The choice of multiple myeloma induction therapy affects the frequency and severity of oral mucositis after melphalan-based autologous stem cell transplantation.
Dorocka-Bobkowska B. Oral mucositis in patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation in relation to the conditioning used prior to transplantation.
Safety and efficacy of sirolimus combined with endocrine therapy in patients with advanced hormone receptor-positive breast cancer and the exploration of biomarkers.
Thiotepa, busulfan, and cyclophosphamide or busulfan, cyclophosphamide, and etoposide high-dose chemotherapy followed by autologous stem cell transplantation for consolidation of primary central nervous system lymphoma.
Efficacy and safety of Everolimus and Exemestane in hormone-receptor positive (HR+) human-epidermal-growth-factor negative (HER2-) advanced breast cancer patients: new insights beyond clinical trials. The EVA study.
A prospective observational study on the evaluation of everolimus-related adverse events in metastatic renal cell carcinoma after first-line anti-vascular endothelial growth factor therapy: the AFINITE study in France.
A comparison of overall survival with 40 and 50mg/m2 pegylated liposomal doxorubicin treatment in patients with recurrent epithelial ovarian cancer: propensity score-matched analysis of real-world data.
Efficacy and toxicity of mammalian target rapamycin inhibitors in patients with metastatic renal cell carcinoma with renal insufficiency: the Korean Cancer Study Group GU 14-08.
The efficacy and safety of everolimus for the treatment of progressive gastroenteropancreatic neuroendocrine tumors: a multi-institution observational study in Taiwan.
Alemtuzumab-BEAM as conditioning for allogeneic hematopoietic stem cell transplantation in relapsed/refractory Hodgkin lymphoma: a single-center analysis.
Changes in microflora in dental plaque from cancer patients undergoing chemotherapy and the relationship of these changes with mucositis: a pilot study.
Differences in adverse event profiles between everolimus and temsirolimus and the risk factors for non-infectious pneumonitis in advanced renal cell carcinoma.
Effects of unidentified renal insufficiency on the safety and efficacy of chemotherapy for metastatic colorectal cancer patients: a prospective, observational study.
A prospective cohort study of the effects of adjuvant breast cancer chemotherapy on taste function, food liking, appetite and associated nutritional outcomes.
Comparison of 1-day vs 2-day dosing of high-dose melphalan followed by autologous hematopoietic cell transplantation in patients with multiple myeloma.
Sequential use of mammalian target of rapamycin inhibitors in patients with metastatic renal cell carcinoma following failure of tyrosine kinase inhibitors.
Assessment of efficacy, safety and quality of life of 55 patients with metastatic renal cell carcinoma treated with temsirolimus: a single-center experience in Japan.
Prognostic and predictive value of hematologic parameters in patients with metastatic renal cell carcinoma: second line sunitinib treatment following IFN-alpha.
The efficacy and toxicity of irinotecan with leucovorin and bolus and continuous infusional 5-fluorouracil (FOLFIRI) as salvage therapy for patients with advanced gastric cancer previously treated with platinum and taxane-based chemotherapy regimens.
Role of antioxidants in buccal mucosa cells and plasma on the incidence and severity of oral mucositis after allogeneic haematopoietic cell transplantation.
Efficacy and tolerability of biweekly bevacizumab, irinotecan, folinic acid and fluorouracil intravenous bolus (BIFF Regimen) in patients with metastatic colorectal cancer: the southern Italy cooperative oncology group experience.
Efficacy and safety of hepatic arterial infusion of fluorouracil with leucovorin as salvage treatment for refractory liver metastases from colorectal cancer.
Pharmacodynamic and pharmacokinetic study of pegylated liposomal doxorubicin combination (CCOP) chemotherapy in patients with peripheral T-cell lymphomas.
Practical use of capecitabine plus oxaliplatin (CAPEOX) with bevacizumab for patients with metastatic colorectal cancer that cannot expect conversion therapy.
(Supplemental Table S3; available at [URL/link*]).
Main characteristics of the studies and their samples
To maximize the information available and to allow data analysis in those scientific papers that passed the bias assessment, it was agreed that it would be appropriate to split 3 of them in 219-21. Subsequently, they were considered as independent articles, so we can state that a total of 82 have been included in our analysis.
Table I details that case series were the predominant type of article (96.3%), followed by NRCT (2.5%) and RCT (1.2%). Among the oral mucosa assessment tools, the CTCAE was the most frequently used in 71.6% of the articles, on any of its available versions (including the primary and its updates: 2.0, 3.0, 4.0, and 5.0). In 17.3% of the papers, authors chose the World Health Organization Oral Toxic Scale, whereas in 11.1% of the articles it was not specified. The most recurrent type of primary cancer among the studies was hematologic (20.7%), followed by kidney (18.3%), digestive system (18.3%), breast (12.2%), and lung (12.2%). In terms of location, 47.6% of the studies were carried out in Asia, 32.9% in Europe, and 12.2% in North America.
Table IMain characteristics of the included literature
The sample size obtained from the 82 studies was 10104 patients (Table I). The mean number of patients in each one was 123 ± 227, with 9 being the smallest group of participants and 1790 the largest. Of these, ≥4064 were male and ≥5465 female. The included population had a mean age of 58 ± 8.5 years, and across the articles it ranged from 29 to 75. Patients treated with traditional chemotherapy drugs integrated the largest group with 5678 patients, those receiving targeted therapies alone summed 3184, whereas only 1165 patients were prescribed a combination of chemotherapy and targeted therapies. Overall, 3668 cases of oral mucosal toxicities were reported and at least 3447 cases of metastases were reported. Further information about all the included articles is displayed on Supplemental Table S4 (available at [URL/link*]).
Meta-analysis
The prevalence of acute oral mucosal damage was 38.2% (95% CI: 33.1%-43.3%) across all studies. Despite finding relevant heterogeneity (I2 = 97.7%; P < .001; Figure 2), no publication risk of bias was identified using a funnel plot (P = .215; Figure 3).
Fig. 2Forest plot for the prevalence of acute oral mucosal damage.
Chemotherapy alone had the highest prevalence of oral mucosal damage prevalence at 42.9% (95% CI: 32.8%-53%), followed by the combination of conventional chemotherapy and targeted therapies at 38% (95% CI: 29.1%-47%), and the lowest prevalence showed on the targeted therapies at 32.1% (95% CI: 26.8%-37.5%). However, heterogeneity was very high overall (I2 = 97.8%; P = .00; Figure 4), no statistically significant differences were found among them (P = .15).
Fig. 4Forest plot for the prevalence of acute oral mucosal damage by type of systemic antineoplastic.
Regarding the type of cancer, articles including patients suffering various types of cancer presented the higher prevalence of oral mucosal toxicities with 62.3% (95% CI: 33.1%-91.4%), followed by hematologic with 47.5% (95% CI: 32.4%-62.6%), lymphoma with 38.3% (95% CI: 8%-68.6%), ovarian with 39.1% (95% CI: 36.8%-41.3%), kidney with 33.6% (95% CI: 26.7%-40.5%), and breast with 33.1% (95% CI: 22.8%-43.4%). Among them no significant differences were noted (P = .19). The heterogeneity was I2 > 50% to all groups except for ovarian cancer (I2 = 0%), which was overall significant (P = .00; Figure 5).
Fig. 5Forest plot for the prevalence of acute oral mucosal damage according to cancer type.
According to study design, the prevalence was very similar; 38.2% (95% CI: 33%-43.4%) in observational studies and 39.4% (95% CI: 10.1%-68.8%) in experimental studies without statistically significant differences (P = .93). Both groups showed high heterogeneity (I2 = 97.7%; P = .00; Figure 6).
Fig. 6Forest plot for the prevalence of acute oral mucosal damage categorized by study design.
With regards to the locations where the studies had been carried out, the highest prevalence of oral mucosal appeared in studies developed in North America 48.6% (95% CI: 28.1%-69%), the second location was Europe with 42% (95% CI: 32.7%-51.2%), and the third location was Asia with 34.1% (95% CI: 27.8%-40.3%). Oral mucosal prevalence was not statistically different among the locations (P = .24). Similarly to what has been observed for all previous parameters, heterogeneity was significantly elevated (I2 = 97.7%; P = .00; Supplemental Figure S1; available at [URL/link*]).
Supplemental Figure S2 (available at [URL/link*]) shows how each new study has chronologically contributed to the estimate of the prevalence of oral mucosal damage in patients receiving systemic antineoplastics since year 2010.
Meta-regression
We ran meta-regressions to investigate possible sources of heterogeneity in our covariates. No differences were found in the prevalence of oral mucosal toxicities according to the study design and the type of therapy (P = .663) or cancer type and type of therapy (P = .340). Similar results were found when considering location and year of publication (P = .569; location and type of therapy (P = .523); location and cancer type (P = .424); and study design, location, cancer type, type of therapy, and year of publication (P = .660).
DISCUSSION
Oral mucositis is a side effect of systemic antineoplastics with a noteworthy prevalence in cancer patients.
This statement is consistent with our finding that estimates the prevalence of acute oral mucosal damage to be 38.2% in non-irradiated patients treated with systemic antineoplastics. Despite all the scientific discoveries on cancer pathophysiology, as well as in research and development of new therapeutic strategies in recent years, which seem to be more specific for each type of cancer, side effects are common.
Therefore, knowing prevalence data could encourage further research focus into the biological basis that triggers oral mucosal damage, which could lead to the discovery of possible therapeutic targets. Hence, our results suggest that differences in oral mucosal damage prevalence in conventional chemotherapy, targeted therapies, or a combination of both are not significant. The clinical implication of this finding supports the need to approach all cancer patients equally, regardless of the therapy of choice, promoting the multidisciplinary team to collaborate on the patient's behalf. This means that medical oncologists should be supported by other professionals such as odontologists, maxillofacial surgeons, dermatologists, palliative care providers, and nurses, aiming for preventive or curative treatments.
Non-randomized clinical trials, large cohort studies, or case-control studies have traditionally been considered optimal to determine the incidence or prevalence of adverse events in pharmacovigilance.
in: Higgins JPT Thomas J Chandler J Cumpston M Li T Page MJ Welch VA Cochrane Handbook for Systematic Reviews of Interventions, version 6.3. Wiley-Blackwell,
Hoboken, New Jersey2022
The nature of the present study to assess the prevalence of oral mucosal damage considering only commercially available systemic antineoplastics was decisive when designing how to tackle our topic and led us to perform a systematic review of the available data to achieve representative measures, and research has proven its reliability.
Moreover, we decided to establish a timeframe for inclusion that starts in 2010, coinciding with the development of new monoclonal antibodies directed toward tumor antigens or T-cell receptors and the growth of other targeted therapies use worldwide.
Throughout our research, we encountered several challenges. For example, the method of assessment of oral mucosa involvement was not homogeneous in all articles because some used the WHO scale, whereas others used the CTCAE in its consecutive versions, and, in some cases, the tool used was not even reported. This discrepancy has been remedied by taking into account only reported cases of oral mucosal injuries in general, which means scoring >0 for the WHO scale or ≥1 for the CTCAE. Conversely, many of the articles only reported those cases in which the involvement was ≥3, or ≥2, thus ignoring mild cases of oral damage. The fact of not precisely reporting the number of patients that developed each certain severity degree of their lesions could influence the results obtained. Likewise, this lack of detail has prevented us from studying and determining possible associations between the type of systemic antineoplastics and the severity of the oral lesions. Note that the wide variety of treatments, doses, routes of administrations, and adjuvant therapies within the included articles may have influenced the results.
Data analysis based on sociodemographic features (e.g., sex and age) was not feasible due to differences in samples of each study. Some articles did not describe certain characteristics of their sample and others included a population that was completely female, given that they had breast or ovarian cancer.
Lastly, although it could be thought that patients with hematologic cancer might show different prevalence data for oral mucosal damage than other solid tumors, due to the peculiarities in the approach to the disease and the therapies used (including transplants), no statistically significant differences have been observed.
The present study may lead researchers to further work on this highly prevalent side effect in patients with cancer treated with systemic antineoplastics, whether it be discovering effective treatments for this condition, preventive therapies, or developing innovative cancer therapies that do not produce this side effect.
CONCLUSIONS
Oral mucosal damage has a prevalence of 38.2% in patients receiving systemic antineoplastics. No significant differences were found among traditional chemotherapy alone, targeted therapies, or their combination. This finding supports the need to assess oral mucosa of all patients receiving any type of systemic antineoplastics in the same manner to avoid under-diagnosis because it is a highly prevalent side effect.
Effectiveness of low-level laser therapy for oral mucositis prevention in patients undergoing chemoradiotherapy for the treatment of head and neck cancer: a systematic review and meta-analysis.
Patient-reported measurements of oral mucositis in head and neck cancer patients treated with radiotherapy with or without chemotherapy: demonstration of increased frequency, severity, resistance to palliation, and impact on quality of life.
Oral adverse events associated with tyrosine kinase and mammalian target of rapamycin inhibitors in renal cell carcinoma: a structured literature review.
Dose intensity and efficacy of the combination of everolimus and exemestane (EVE/EXE) in a real-world population of hormone receptor-positive (ER+/PgR+), HER2-negative advanced breast cancer (ABC) patients: a multicenter Italian experience.
The choice of multiple myeloma induction therapy affects the frequency and severity of oral mucositis after melphalan-based autologous stem cell transplantation.
Dorocka-Bobkowska B. Oral mucositis in patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation in relation to the conditioning used prior to transplantation.
Safety and efficacy of sirolimus combined with endocrine therapy in patients with advanced hormone receptor-positive breast cancer and the exploration of biomarkers.
Thiotepa, busulfan, and cyclophosphamide or busulfan, cyclophosphamide, and etoposide high-dose chemotherapy followed by autologous stem cell transplantation for consolidation of primary central nervous system lymphoma.
Efficacy and safety of Everolimus and Exemestane in hormone-receptor positive (HR+) human-epidermal-growth-factor negative (HER2-) advanced breast cancer patients: new insights beyond clinical trials. The EVA study.
A prospective observational study on the evaluation of everolimus-related adverse events in metastatic renal cell carcinoma after first-line anti-vascular endothelial growth factor therapy: the AFINITE study in France.
A comparison of overall survival with 40 and 50mg/m2 pegylated liposomal doxorubicin treatment in patients with recurrent epithelial ovarian cancer: propensity score-matched analysis of real-world data.
Efficacy and toxicity of mammalian target rapamycin inhibitors in patients with metastatic renal cell carcinoma with renal insufficiency: the Korean Cancer Study Group GU 14-08.
The efficacy and safety of everolimus for the treatment of progressive gastroenteropancreatic neuroendocrine tumors: a multi-institution observational study in Taiwan.
Alemtuzumab-BEAM as conditioning for allogeneic hematopoietic stem cell transplantation in relapsed/refractory Hodgkin lymphoma: a single-center analysis.
Changes in microflora in dental plaque from cancer patients undergoing chemotherapy and the relationship of these changes with mucositis: a pilot study.
Differences in adverse event profiles between everolimus and temsirolimus and the risk factors for non-infectious pneumonitis in advanced renal cell carcinoma.
Effects of unidentified renal insufficiency on the safety and efficacy of chemotherapy for metastatic colorectal cancer patients: a prospective, observational study.
A prospective cohort study of the effects of adjuvant breast cancer chemotherapy on taste function, food liking, appetite and associated nutritional outcomes.
Comparison of 1-day vs 2-day dosing of high-dose melphalan followed by autologous hematopoietic cell transplantation in patients with multiple myeloma.
Sequential use of mammalian target of rapamycin inhibitors in patients with metastatic renal cell carcinoma following failure of tyrosine kinase inhibitors.
Assessment of efficacy, safety and quality of life of 55 patients with metastatic renal cell carcinoma treated with temsirolimus: a single-center experience in Japan.
Prognostic and predictive value of hematologic parameters in patients with metastatic renal cell carcinoma: second line sunitinib treatment following IFN-alpha.
The efficacy and toxicity of irinotecan with leucovorin and bolus and continuous infusional 5-fluorouracil (FOLFIRI) as salvage therapy for patients with advanced gastric cancer previously treated with platinum and taxane-based chemotherapy regimens.
Role of antioxidants in buccal mucosa cells and plasma on the incidence and severity of oral mucositis after allogeneic haematopoietic cell transplantation.
Efficacy and tolerability of biweekly bevacizumab, irinotecan, folinic acid and fluorouracil intravenous bolus (BIFF Regimen) in patients with metastatic colorectal cancer: the southern Italy cooperative oncology group experience.
Efficacy and safety of hepatic arterial infusion of fluorouracil with leucovorin as salvage treatment for refractory liver metastases from colorectal cancer.
Pharmacodynamic and pharmacokinetic study of pegylated liposomal doxorubicin combination (CCOP) chemotherapy in patients with peripheral T-cell lymphomas.
Practical use of capecitabine plus oxaliplatin (CAPEOX) with bevacizumab for patients with metastatic colorectal cancer that cannot expect conversion therapy.
in: Higgins JPT Thomas J Chandler J Cumpston M Li T Page MJ Welch VA Cochrane Handbook for Systematic Reviews of Interventions, version 6.3. Wiley-Blackwell,
Hoboken, New Jersey2022
No. of patients differs from meta-analysis due to 3 patients’ loss.
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