Severe Acute Mucositis Research Articles

XRCC1 (rs25487) polymorphism is associated with severe oral mucositis and poor treatment response after radiotherapy for oropharyngeal carcinoma

To investigate the association of Single Nucleotide Polymorphisms of DNA repair genes and patient-specific clinical characteristics with the risk of developing severe acute radiotoxicities and treatment response in Oropharyngeal Carcinoma. 179 cases of Oropharyngeal Carcinoma treated with 2-D radical radiotherapy were evaluated for acute radiotoxicity end-points viz; oral mucositis, dermatitis, dysphagia, and xerostomia; and the resultant requirement of nasogastric feeding tube, significant (> 10%) weight loss during treatment and treatment break(s). Eleven Single Nucleotide Polymorphisms of DNA repair genes were analyzed using Polymerase Chain Reaction and Restriction Fragment Length Polymorphism and correlated with the severity of these radiotoxicities (Common Toxicity Criteria for Adverse Events v4.0 grading) and the treatment response. Clinical parameters like age, Karnofsky Performance Status, smoking and tobacco chewing, etc. were also analysed in relation to the above. Homozygous AA genotype of XRCC1 (rs25487) (p = 0.024*, OR 2.629, 95% CI 1.136–6.087), Karnofsky Performance Status < 80 (p = 0.050*, OR 2.723, CI 1.000–7.418) and history of tobacco chewing (p = 0.030*, OR 2.615, 95% CI 1.099–6.222) were independent predictive factors for increased risk of severe (≥ grade 3) mucositis. Also, the presence of Homozygous AA genotype of XRCC1(rs25487) was significantly associated with poor response to radiotherapy in these patients (p = 0.014, OR 2.235, 95% CI 1.074–5.744). Our findings illustrate that patients with Homozygous AA genotype of XRCC1 (rs25487) and certain clinical characteristics are likely to develop severe acute mucositis after radiotherapy for Oropharyngeal Carcinoma and the presence of this polymorphism is also associated with poor response to treatment.

Intensity modulated radiation therapy and oral mucosa sparing in Head and neck cancer patients: A systematic review on behalf of Italian Association of Radiation Oncology - Head and neck working group.

Oral mucositis is a common dose-limiting toxicity during radiotherapy with or without chemotherapy in head and neck cancer patients. This potentially severe complication globally worsens quality of life and negatively impacts local control and survival's outcomes. Several studies have been published on feasibility and/or clinical benefit of intensity modulated radiotherapy (IMRT) mucosa-sparing technique. In 2017, the Italian Association of Radiation Oncology Head and Neck Cancer Working Group organized a study group to perform a systematic review. The aim was to verify if practical indications, including dose-constraints and demonstrated clinical benefit, could be proposed for oral mucosa (OM)-sparing IMRT in order to reduce the incidence of severe acute mucositis. Although dose to OM should be reduced as much as possible without compromising target volumes coverage, it is still tricky to firmly state that OM-sparing procedure should be considered the standard of care, especially due to high subjective variability in OM contour.

Intensity-modulated radiotherapy combined with sequential cisplatin and fluorouracil chemotherapy for locoregionally advanced nasopharyngeal carcinoma.

To investigate the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) combined with induction-adjuvant cisplatin and fluorouracil (PF) in locoregionally advanced nasopharyngeal carcinoma (NPC).A total of 91 biopsy-proven NPC patients treated with IMRT were retrospectively analyzed. All patients received induction chemotherapy (IC) consisting of cisplatin 25 mg/m2 on day 1 to 3, and 5-Fu 2500 mg/m2 as an intravenous infusion over 120 hours every 3 weeks for 2 cycles. Adjuvant chemotherapy of the same regime was given 28 days after the end of IMRT.A total of 87 patients completed 2 cycles of IC. During adjuvant chemotherapy phase, 74.7% patients received at least 1 cycle. With a median follow-up time of 45 months (10–123 months), the 5-year local control, regional control, distant metastasis-free (DMF) and overall survival (OS) rates were 84.1%, 86.9%, 81.3%, and 74.4%, respectively. The 5-year local control rates for patients with Stage T1-2 and T3-4 was 94.6% and 76.5%, respectively (P = .045). The 5-year DMF rates for patients with N0-1 and N2-3 diseases were 90.6% and 73.3%, respectively (P = .072). During radiotherapy (RT), 24.2% patients suffered severe acute mucositis (grade 3–4). Severe late toxicities included cranial nerve palsy in 1 patient and grade 3 hearing impairment in 1 patient.IMRT combined with induction-adjuvant chemotherapy consisting of PF regimen is well tolerated and provides satisfactory local-regional control for locoregionally advanced NPC. Further treatment strategies to control distant metastasis are needed in the future.

Normal Tissue Complication Probability (NTCP) Modelling of Severe Acute Mucositis using a Novel Oral Mucosal Surface Organ at Risk

AimsA normal tissue complication probability (NTCP) model of severe acute mucositis would be highly useful to guide clinical decision making and inform radiotherapy planning. We aimed to improve upon our previous model by using a novel oral mucosal surface organ at risk (OAR) in place of an oral cavity OAR. Materials and methodsPredictive models of severe acute mucositis were generated using radiotherapy dose to the oral cavity OAR or mucosal surface OAR and clinical data. Penalised logistic regression and random forest classification (RFC) models were generated for both OARs and compared. Internal validation was carried out with 100-iteration stratified shuffle split cross-validation, using multiple metrics to assess different aspects of model performance. Associations between treatment covariates and severe mucositis were explored using RFC feature importance. ResultsPenalised logistic regression and RFC models using the oral cavity OAR performed at least as well as the models using mucosal surface OAR. Associations between dose metrics and severe mucositis were similar between the mucosal surface and oral cavity models. The volumes of oral cavity or mucosal surface receiving intermediate and high doses were most strongly associated with severe mucositis. ConclusionsThe simpler oral cavity OAR should be preferred over the mucosal surface OAR for NTCP modelling of severe mucositis. We recommend minimising the volume of mucosa receiving intermediate and high doses, where possible.

Functional Data Analysis Applied to Modeling of Severe Acute Mucositis and Dysphagia Resulting From Head and Neck Radiation Therapy

PurposeCurrent normal tissue complication probability modeling using logistic regression suffers from bias and high uncertainty in the presence of highly correlated radiation therapy (RT) dose data. This hinders robust estimates of dose-response associations and, hence, optimal normal tissue—sparing strategies from being elucidated. Using functional data analysis (FDA) to reduce the dimensionality of the dose data could overcome this limitation.Methods and MaterialsFDA was applied to modeling of severe acute mucositis and dysphagia resulting from head and neck RT. Functional partial least squares regression (FPLS) and functional principal component analysis were used for dimensionality reduction of the dose-volume histogram data. The reduced dose data were input into functional logistic regression models (functional partial least squares—logistic regression [FPLS-LR] and functional principal component—logistic regression [FPC-LR]) along with clinical data. This approach was compared with penalized logistic regression (PLR) in terms of predictive performance and the significance of treatment covariate—response associations, assessed using bootstrapping.ResultsThe area under the receiver operating characteristic curve for the PLR, FPC-LR, and FPLS-LR models was 0.65, 0.69, and 0.67, respectively, for mucositis (internal validation) and 0.81, 0.83, and 0.83, respectively, for dysphagia (external validation). The calibration slopes/intercepts for the PLR, FPC-LR, and FPLS-LR models were 1.6/−0.67, 0.45/0.47, and 0.40/0.49, respectively, for mucositis (internal validation) and 2.5/−0.96, 0.79/−0.04, and 0.79/0.00, respectively, for dysphagia (external validation). The bootstrapped odds ratios indicated significant associations between RT dose and severe toxicity in the mucositis and dysphagia FDA models. Cisplatin was significantly associated with severe dysphagia in the FDA models. None of the covariates was significantly associated with severe toxicity in the PLR models. Dose levels greater than approximately 1.0 Gy/fraction were most strongly associated with severe acute mucositis and dysphagia in the FDA models.ConclusionsFPLS and functional principal component analysis marginally improved predictive performance compared with PLR and provided robust dose-response associations. FDA is recommended for use in normal tissue complication probability modeling.

Normal tissue complication probability (NTCP) modelling using spatial dose metrics and machine learning methods for severe acute oral mucositis resulting from head and neck radiotherapy

Background and purposeSevere acute mucositis commonly results from head and neck (chemo)radiotherapy. A predictive model of mucositis could guide clinical decision-making and inform treatment planning. We aimed to generate such a model using spatial dose metrics and machine learning. Materials and methodsPredictive models of severe acute mucositis were generated using radiotherapy dose (dose–volume and spatial dose metrics) and clinical data. Penalised logistic regression, support vector classification and random forest classification (RFC) models were generated and compared. Internal validation was performed (with 100-iteration cross-validation), using multiple metrics, including area under the receiver operating characteristic curve (AUC) and calibration slope, to assess performance. Associations between covariates and severe mucositis were explored using the models. ResultsThe dose–volume-based models (standard) performed equally to those incorporating spatial information. Discrimination was similar between models, but the RFCstandard had the best calibration. The mean AUC and calibration slope for this model were 0.71 (s.d.=0.09) and 3.9 (s.d.=2.2), respectively. The volumes of oral cavity receiving intermediate and high doses were associated with severe mucositis. ConclusionsThe RFCstandard model performance is modest-to-good, but should be improved, and requires external validation. Reducing the volumes of oral cavity receiving intermediate and high doses may reduce mucositis incidence.

The DAHANCA 6 randomized trial: Effect of 6 vs 5 weekly fractions of radiotherapy in patients with glottic squamous cell carcinoma

PurposeThe DAHANCA 6 trial evaluated tumor response and morbidity after moderate accelerated radiotherapy compared to conventional fractionated radiotherapy in patients treated for glottic squamous cell carcinoma (SCC). Further, the failure pattern and incidence of new primary tumors were explored. Patients and methodsSix hundred and ninety-four patients with non-metastatic glottic SCC were randomized between six or five weekly fractions (fx/w) of radiotherapy to the same total dose. The median treatment time was 38 and 46days, respectively. The primary endpoint was loco-regional failure. ResultsMedian follow-up time was 14.5years. Of the 177 failures, 167 involved T-site. The cumulative incidence of loco-regional failure (LRF) was 21.6% in the 6fx/w group and 29.3% in the 5fx/w group and the corresponding hazard rate (HR) of LRF was 0.72 (CI: 0.53–0.97, p=0.04). The effect of acceleration on LRF was especially evident in well differentiated tumors (HR=0.42 (CI: 0.23–0.75) and in T1–2 tumors (HR=0.60 (CI: 0.41–0.89)). The HR of laryngectomy was 0.72 (CI: 0.50–1.04) in the 6fx/w group compared to the 5fx/w group. The hazards of disease-specific death, event-free survival, and overall survival were comparable between the two groups. Significantly more patients experienced severe acute mucositis in the 6fx/w group but the incidence of late morbidity was comparable between the groups. New primary tumors occurred in 22.5% of the patients. ConclusionModerate accelerated radiotherapy significantly improved loco-regional control in patients with glottic SCC.

Immunonutrition before and during radiochemotherapy: improvement of inflammatory parameters in head and neck cancer patients

Inflammatory, angiogenic and oxidative stress markers have been explored in head and neck squamous cell carcinoma (HNSCC) patients before and during radiochemotherapy. Furthermore, the effects of an oral supplementation containing amino acids, ω-3 fatty acids, ribonucleic acids, vitamins, and antioxidants on biological markers and acute toxicities were investigated. Thirty-one patients with non-metastatic stage III or IV HNSCC treated with concomitant radiochemotherapy were recruited. A nutritional support (Oral Impact) was given during 5 days before each cycle of chemotherapy. Biological samples were collected at baseline, after 5 days of oral supplementation and before the last cycle of chemotherapy. Acute phase proteins levels, proteomic cytokines determination and urinary isoprostanes levels were used as inflammatory and oxidative stress biomarkers. Toxicities were followed up during radiochemotherapy. At baseline, median levels of inflammatory (CRP 9.8 mg/l [0.8-130.1], IL-6 4.2 pg/ml [0.7-126.5]), pro-angiogenic (VEGF 229.5 pg/ml [13.1-595.9]) and pro-oxidative stress (urinary isoprostanes 118 pmol/mmol creatinine [51-299]) markers were increased. Decrease in CRP (p = 0.002) and α-1 acid glycoprotein (p = 0.020) levels were observed after 5 days of oral supplementation. During radiochemotherapy, no significant variation of inflammatory markers was reported, and a low incidence of severe acute mucositis was noted. Stage III or IV HNSCC patients are characterised by a pro-inflammatory, pro-angiogenic and pro-oxidative status. Nutritional support could improve this inflammatory state and could prevent severe acute mucositis.

SMART (Simultaneous Modulated Accelerated RadioTherapy) for locally advanced nasopharyngeal carcinomas

Concurrent chemoradiotherapy is commonly used for locally advanced nasopharyngeal carcinoma (NPC). We retrospectively analyzed the clinical outcomes of simultaneous modulated accelerated radiotherapy (SMART) with concurrent chemotherapy. Between January 2003 and May 2005, 24 patients with stage IIB to IVB NPC underwent SMART encompassing 3 targets: gross tumor volume (GTV), high-risk subclinical disease (CTV1), and low-risk subclinical disease (CTV2). Daily fractions of 2.4, 2.15, and 1.9 Gy were delivered to GTV, CTV1, and CTV2 to a total dose of 64.8, 58.05, and 51.3 Gy in 27 fractions over 5.5 weeks, respectively. Fifteen patients received concurrent cisplatin (DDP group), and 9 received 5-fluorouracil plus cisplatin (FP group). With a median follow-up of 26 months (range, 17-45 months), 3-year overall and local-, regional-, and distant-progression-free survivals were 96% and 93%, 87%, and 88%, respectively. Grade 3 acute mucositis and pharyngitis were observed in 16 (67%) and 14 (59%) patients, respectively. Severe acute mucositis (100% vs 47%) and pharyngitis (100% vs 34%) were more frequently observed in the FP group than the DDP group (p < .01). Despite short follow-up with a small number of patients, our preliminary results demonstrated encouraging local-regional control and survival at the cost of modest increase in treatment related toxicities. The total dose and fractionation scheme of SMART used in our study is feasible with no life-threatening or fatal complications. However, the administration of fluorouracil in addition to cisplatin during SMART was associated with increased acute and late toxicities, and it should be administered with caution.

Relationship between clinical factors and the incidence of toxicity after intra-arterial chemoradiation for head and neck cancer

Background and purpose Concomitant chemoradiation is more and more used for advanced head and neck cancer. It improves local control and survival compared to radiotherapy alone, but goes along with serious toxicity. This study was set up to determine the relationship between patient-, tumour- and treatment-related factors and acute/late toxicity after concomitant chemoradiation. Patients and methods One hundred and twenty-five consecutive patients with newly diagnosed inoperable stage III and IV head and neck cancer were enrolled for intra-arterial chemoradiation. There were 28 women (22%) and 97 men (78%) and the mean age was 55 years (range 30–80). One hundred and nine patients had stage IV disease (87%), 16 patients (13%) had stage III disease. Statistical analyses were performed to identify an association between factors and acute/late toxicity. Results There were eight treatment-related deaths (6%). Severe acute toxicity (grade 3–4), mainly mucositis and dysphagia as categorized by the RTOG toxicity criteria, was recorded in 51% of the patients. Leucopenia (grade 3–4) occurred in 39% and aspiration pneumonia in 20% of patients. Tracheotomy was necessary in 15 (12%) patients. Neurological complications during treatment occurred in 3 (2%) patients. Severe late toxicity occurred in 34% of the patients. The most important of these were pneumonia (14%), osteoradionecrosis (9%) and swallowing problems with permanent percutaneous gastrostomy (20%). Statistical analysis did show a significant association between site and severe acute mucositis ( p = 0.007), site and osteoradionecrosis ( p = 0.014) and age and xerostomia ( p = 0.004). Conclusions Chemoradiation is frequently associated with serious toxicity. Oral cavity tumours and older age are related to acute mucositis/osteoradionecrosis and xerostomia, respectively.

Concurrent Radiation Chemotherapy for Locally Advanced Head and Neck Carcinoma: Are We Addressing Burning Subjects?

Improving the outcome for patients with locally advanced head and neck carcinomas (HNC) by rational modification of radiation fractionation regimens or combinations of radiation with chemotherapy has been the subject of intensive clinical investigations for more than three decades. The two prototypes of biologically sound-altered radiation fractionation regimens are hyperfractionation and accelerated fractionation. Hyperfractionation was based on preferential sparing of late-responding tissues when the radiation dose per fraction is reduced. Accelerated fractionation regimens emerged through the recognition that tumor clonogen proliferation occurring during radiotherapy has a detrimental effect on outcome. Results of large randomized trials addressing the optimization of radiation fractionation collectively show that a number of biologically sound altered fractionation schedules improve the locoregional (LR) control rate on the order of 10% to 15%, but have only a modest impact on overall survival. Although several altered fractionation regimens consistently induce more severe acute mucositis than standard 7-week radiotherapy, the general consensus is that late toxicities are not appreciably increased. Scores of clinical trials testing combined-modality therapy have also been published. Meta-analyses of studies completed before 1995 reveal that cytotoxic agents given before or after surgery or radiation do not significantly improve the therapeutic outcome over LR treatment alone. In contrast, chemotherapy given concurrently with radiation improves 2and 5-year overall survival rates by 8%. Although a variety of cytotoxic agents have been studied, cisplatin is the most extensively investigated, and will be the emphasis of this commentary. The data from four recent trials using standard radiation fractionation, with or without high-dose single-agent cisplatin given every 3 weeks, in the treatment of locally advanced non-nasopharyngeal HNC have been reported in the last 2 years. All four trials showed that the combined regimen was superior to radiation therapy alone in LR control or organ preservation; two trials also showed improvement in overall survival. A common finding, however, is that 100 mg/m of cisplatin given every 3 weeks during the course of radiotherapy substantially increases the severity of mucositis, apparently more so than altered fractionation regimens without chemotherapy. In addition, cisplatin induces systemic toxicity requiring intensive premedication and supportive care. Unfortunately, recording and reporting of the late morbidity of combined radiation-chemotherapy have not been sufficiently consistent and systematic. A thorough report of the long-term results of a French cooperative group (French Head and Neck Oncology and Radiotherapy Group [GORTEC]) trial revealed that the late complication rate of the combination of radiation with concurrent carboplatin and fluorouracil was significantly higher than that of radiation alone. Due to a lack of adequate reporting, there is controversy as to whether the late toxicity of the combination of standard radiation with 100 mg/m of cisplatin every 3 weeks might also be higher than radiation alone. Hopefully, longer and more complete follow-up data on late morbidities will be reported in the future. Although the collective data are strong in establishing the superiority of the combination of radiation with concurrent chemotherapy relative to standard radiation fractionation alone in the management of locally advanced HNC, there is variability of clinical trials in patient selection and regimens, leading to continuing debate as to which combined regimen should be considered standard. Furthermore, many questions remain to be answered, including whether the cisplatin dose can be altered to reduce acute JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 23 DECEMBER 1 2004