Impact of adaptive radiotherapy on survival in locally advanced nasopharyngeal carcinoma treated with concurrent chemoradiotherapy.

PURPOSE: To investigate the clinical significance of adaptive radiotherapy (ART) in locally advanced nasopharyngeal carcinoma treated with intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: Eligible patients were treated with concurrent chemoradiotherapy using IMRT. Planning computed tomography in ART was performed during radiotherapy, and replanning was performed. Since ART was started in May 2011 (ART group), patients who were treated without ART up to April 2011 (non-ART group) were used as the historical control. The Kaplan-Meier method was used to calculate overall survival (OS), locoregional recurrence-free survival (LRFS), progression-free survival (PFS), and distant metastasis-free survival (DMFS). LRFS for the primary tumor (LRFS_P) and regional lymph node (LRFS_LN) were also studied for more detailed analysis. Statistical significance was evaluated using the log-rank test for survival. RESULTS: The ART group tended to have higher radiation doses. The median follow-up period was 127 months (range, 10 to 211 months) in the non-ART group and 61.5 months (range, 5 to 129 months) in the ART group. Compared to the non-ART group, the ART group showed significantly higher 5-year PFS (53.8% vs. 81.3%, p = 0.015) and LRFS (61.2% vs. 85.3%, p = 0.024), but not OS (80.7% vs. 80.8%, p = 0.941) and DMFS (84.6% vs. 92.7%, p = 0.255). Five-year LRFS_P was higher in the ART group (61.3% vs. 90.6%, p = 0.005), but LRFS_LN did not show a significant difference (91.9% vs. 96.2%, p = 0.541). CONCLUSION: Although there were differences in the patient backgrounds between the two groups, this study suggests the potential effectiveness of ART in improving locoregional control, especially in the primary tumor.

Daily fraction dose-adjusted radiotherapy policy to avoid prolonging the overall treatment time for early glottic squamous cell carcinoma: a single-institutional retrospective study.

The objective of this study was to determine the outcomes of radical radiotherapy for early glottic squamous cell carcinoma (EGSCC) with the policy of increasing the fraction size during radiotherapy when the overall treatment time (OTT) was expected to be prolonged. Patients diagnosed with clinical T1-2N0M0 EGSCC, who were treated with radical radiotherapy between 2008 and 2019 at Hokkaido University Hospital, were included. Patients received 66 Gy in 33 fractions for T1 disease and 70 Gy in 35 fractions for T2 disease as our standard regimen (usual group [UG]). If the OTT was expected to extend for >1 week, the dose fraction size was increased from 2.0 to 2.5 Gy from the beginning or during radiotherapy (adjusted group [AG]). At this time, we performed a statistical analysis between UG and AG. In total, 116 patients were identified, and the treatment schedules of 29 patients were adjusted. The median follow-up was 60.9 months. In the T1 group, the cumulative 5-year local failure rate was 12.0% in the AG and 15.4% in the UG, and in the T2 group, the rate was 40.7% in the AG and 25.3% in the UG. There were no significant differences between the AG and UG. Similarly, no significant differences were observed for overall survival and progression-free survival rates. Our single-institutional retrospective analysis of EGSCC patients suggested that a method of adjusting the radiotherapy schedule to increase fraction size from the beginning or during the course may be effective in maintaining treatment outcomes.

Detailed analysis of failure patterns using deformable image registration in hypopharyngeal cancer patients treated with sequential boost intensity-modulated radiotherapy.

INTRODUCTION: Sequential boost intensity-modulated radiotherapy (SQB-IMRT) uses two different planning CTs (pCTs) and treatment plans. SQB-IMRT is a form of adaptive radiotherapy that allows for responses to changes in the shape of the tumour and organs at risk (OAR). On the other hand, dose accumulation with the two plans can be difficult to evaluate. The purpose of this study was to analyse patterns of loco-regional failure using deformable image registration (DIR) in hypopharyngeal cancer patients treated with SQB-IMRT. METHODS: Between 2013 and 2019, 102 patients with hypopharyngeal cancer were treated with definitive SQB-IMRT at our institution. Dose accumulation with the 1st and 2nd plans was performed, and the dose to the loco-regional recurrent tumour volume was calculated using the DIR workflow. Failure was classified as follows: (i) in-field (≥95% of the recurrent tumour volume received 95% of the prescribed dose); (ii) marginal (20-95%); or (iii) out-of-field (<20%). RESULTS: After a median follow-up period of 25 months, loco-regional failure occurred in 34 patients. Dose-volume histogram analysis showed that all loco-regional failures occurred in the field within 95% of the prescribed dose, with no marginal or out-of-field recurrences observed. CONCLUSION: The dosimetric analysis using DIR showed that all loco-regional failures were within the high-dose region. More aggressive treatment may be required for gross tumours.

Visualizing the urethra by magnetic resonance imaging without usage of a catheter for radiotherapy of prostate cancer.

The urethra position may shift due to the presence/absence of the catheter. Our proposed post-urination-magnetic resonance imaging (PU-MRI) technique is possible to identify the urethra without catheter. We aimed to verify the inter-operator difference in contouring the urethra by PU-MRI. The mean values of the evaluation indices of dice similarity coefficient, mean slice-wise Hausdorff distance, and center coordinates were 0.93, 0.17 mm, and 0.36 mm for computed tomography, and 0.75, 0.44 mm, and 1.00 mm for PU-MRI. Therefore, PU-MRI might be useful for identifying the prostatic urinary tract without using a urethral catheter. Clinical trial registration: Hokkaido University Hospital for Clinical Research (018-0221).

Predictors of the need for prophylactic percutaneous endoscopic gastrostomy in head and neck cancer patients treated with concurrent chemoradiotherapy.

BACKGROUND: We investigated whether prophylactic percutaneous endoscopic gastrostomy (PEG) is used effectively for patients treated with definitive concurrent chemoradiotherapy (CCRT) and the predictors of the need for PEG. METHODS: 326 patients with laryngeal, oropharyngeal or hypopharyngeal cancers were retrospectively reviewed. RESULTS: The PEG tube use group had more favorable results than the total parenteral nutrition and nasogastric tube groups in terms of rate of serum albumin loss, incidence of severe fever and aspiration pneumonia, CCRT completion rate and hospitalization period. However, it was inferior to oral intake. Analysis of the relative risk of requiring enteral or parenteral nutrition revealed that performance status (PS) 2, primary site (supraglottis, oropharynx, or hypopharynx), N3 disease, and cisplatin were predictors of the need for nutritional support. CONCLUSIONS: Prophylactic PEG is effective for patients treated with definitive CCRT and is especially required for patients with PS2 or oropharyngeal cancer.

Assessment of the confidence interval in the multivariable normal tissue complication probability model for predicting radiation-induced liver disease in primary liver cancer.

We developed a confidence interval-(CI) assessing model in multivariable normal tissue complication probability (NTCP) modeling for predicting radiation-induced liver disease (RILD) in primary liver cancer patients using clinical and dosimetric data. Both the mean NTCP and difference in the mean NTCP (ΔNTCP) between two treatment plans of different radiotherapy modalities were further evaluated and their CIs were assessed. Clinical data were retrospectively reviewed in 322 patients with hepatocellular carcinoma (n = 215) and intrahepatic cholangiocarcinoma (n = 107) treated with photon therapy. Dose-volume histograms of normal liver were reduced to mean liver dose (MLD) based on the fraction size-adjusted equivalent uniform dose. The most predictive variables were used to build the model based on multivariable logistic regression analysis with bootstrapping. Internal validation was performed using the cross-validation leave-one-out method. Both the mean NTCP and the mean ΔNTCP with 95% CIs were calculated from computationally generated multivariate random sets of NTCP model parameters using variance-covariance matrix information. RILD occurred in 108/322 patients (33.5%). The NTCP model with three clinical and one dosimetric parameter (tumor type, Child-Pugh class, hepatitis infection status and MLD) was most predictive, with an area under the receiver operative characteristics curve (AUC) of 0.79 (95% CI 0.74-0.84). In eight clinical subgroups based on the three clinical parameters, both the mean NTCP and the mean ΔNTCP with 95% CIs were able to be estimated computationally. The multivariable NTCP model with the assessment of 95% CIs has potential to improve the reliability of the NTCP model-based approach to select the appropriate radiotherapy modality for each patient.

Potential benefits of adaptive intensity-modulated proton therapy in nasopharyngeal carcinomas.

PURPOSE: To investigate potential advantages of adaptive intensity-modulated proton beam therapy (A-IMPT) by comparing it to adaptive intensity-modulated X-ray therapy (A-IMXT) for nasopharyngeal carcinomas (NPC). METHODS: Ten patients with NPC treated with A-IMXT (step and shoot approach) and concomitant chemotherapy between 2014 and 2016 were selected. In the actual treatment, 46 Gy in 23 fractions (46Gy/23Fx.) was prescribed using the initial plan and 24Gy/12Fx was prescribed using an adapted plan thereafter. New treatment planning of A-IMPT was made for the same patients using equivalent dose fractionation schedule and dose constraints. The dose volume statistics based on deformable images and dose accumulation was used in the comparison of A-IMXT with A-IMPT. RESULTS: The means of the Dmean of the right parotid gland (P < 0.001), right TM joint (P < 0.001), left TM joint (P < 0.001), oral cavity (P < 0.001), supraglottic larynx (P = 0.001), glottic larynx (P < 0.001), , middle PCM (P = 0.0371), interior PCM (P < 0.001), cricopharyngeal muscle (P = 0.03643), and thyroid gland (P = 0.00216), in A-IMPT are lower than those of A-IMXT, with statistical significance. The means of, D0.03cc , and Dmean of each sub portion of auditory apparatus and D30% for Eustachian tube and D0.5cc for mastoid volume in A-IMPT are significantly lower than those of A-IMXT. The mean doses to the oral cavity, supraglottic larynx, and glottic larynx were all reduced by more than 20 Gy (RBE = 1.1). CONCLUSIONS: An adaptive approach is suggested to enhance the potential benefit of IMPT compared to IMXT to reduce adverse effects for patients with NPC.

Analysis of acute-phase toxicities of intensity-modulated proton therapy using a model-based approach in pharyngeal cancer patients.

Pharyngeal cancer patients treated with intensity-modulated proton therapy (IMPT) using a model-based approach were retrospectively reviewed, and acute toxicities were analyzed. From June 2016 to March 2019, 15 pharyngeal (7 naso-, 5 oro- and 3 hypo-pharyngeal) cancer patients received IMPT with robust optimization. Simulation plans for IMPT and intensity-modulated X-ray therapy (IMXT) were generated before treatment. We also reviewed 127 pharyngeal cancer patients with IMXT in the same treatment period. In the simulation planning comparison, all of the normal-tissue complication probability values for dysphagia, dysgeusia, tube-feeding dependence and xerostomia were lower for IMPT than for IMXT in the 15 patients. After completing IMPT, 13 patients completed the evaluation, and 12 of these patients had a complete response. The proportions of patients who experienced grade 2 or worse acute toxicities in the IMPT and IMXT cohorts were 21.4 and 56.5% for dysphagia (P < 0.05), 46.7 and 76.3% for dysgeusia (P < 0.05), 73.3 and 62.8% for xerostomia (P = 0.43), 73.3 and 90.6% for mucositis (P = 0.08) and 66.7 and 76.4% for dermatitis (P = 0.42), respectively. Multivariate analysis revealed that IMPT was independently associated with a lower rate of grade 2 or worse dysphagia and dysgeusia. After propensity score matching, 12 pairs of IMPT and IMXT patients were selected. Dysphagia was also statistically lower in IMPT than in IMXT (P < 0.05). IMPT using a model-based approach may have clinical benefits for acute dysphagia.

Factors related to primary cancer death and non-primary cancer death in patients treated with stereotactic body radiotherapy for pulmonary oligometastases.

Cancer-specific death (CSD) and non-cancer-specific death (non-CSD) after stereotactic body radiotherapy (SBRT) for pulmonary oligometastases have not been studied in detail. The aim of this study was to determine the cumulative incidences of CSD and non-CSD and to reveal prognostic factors. Data from a large survey of SBRT for pulmonary oligometastases were used for analyses, and patients with unknown cause of death were excluded from current analyses. CSD was primary cancer death and non-CSD was non-primary cancer death including a series of cancer treatment-related deaths. Cumulative incidences were calculated using the Kaplan-Meier method and a stratified Cox regression model was used for multivariate analyses (MVA). Fifty-two patients with an unknown death were excluded and a total of 1326 patients was selected. CSD and non-CSD occurred in 375 and 109 patients, respectively. The median OS period was 53.2 months and the cumulative incidences of 1-, 3-, and 5-year CSD vs. non-CSD rates were 6.5% vs. 2.3%, 29.5% vs. 8.6%, and 41.2% vs. 11.0%, respectively. In MVA, the incidence of CSD was related to performance status (1 vs. 0; p < 0.001, 2-3 vs. 0; p = 0.011), oligometastatic state (sync-oligometastases vs. oligo-recurrence, p = 0.026) and maximum tumor diameter (p = 0.009), and the incidence of non-CSD was related to age (p = 0.001), sex (p = 0.030), performance status (2-3 vs. 0; p = 0.002), and irradiated tumor-located lung lobe (left lower lobe vs. other lobes, p = 0.036). CSD was main cause of death, but non-CSD was not rare after SBRT. Prognostic factors for CSD and non-CSD were different, and an understanding of the factors would help in treatment.

Significant reduction of oncologic pulmonary death by local control for pulmonary oligometastases treated with stereotactic body radiotherapy.

BACKGROUND AND PURPOSE: The rate of oncologic pulmonary death after stereotactic body radiotherapy for pulmonary oligometastases has never been reported. The purpose of current study was to investigate the rate of freedom from oncologic pulmonary death (FOPD) and to analyze factors affecting for FOPD. MATERIALS AND METHODS: The inclusion criteria for this retrospective study were that SBRT was performed between 2004 and 2015, the number of metastases was 5 or less, the primary lesion and extrathoracic metastases needed to be controlled before SBRT and a biological effective dose (BED10) of 75 Gy or more was needed. The Kaplan-Meier estimator and the log-rank test were used to calculate and compare the stratified rates of FOPD. The Cox proportional hazards model was used for multivariate analyses (MVA). Primary disease death from a non-oncologic pulmonary cause was censored in model 1 and was excluded in model 2. RESULTS: A total of 1172 patients with 1315 tumors were enrolled. During a median follow-up period of 24.5 months, oncologic pulmonary deaths accounted for 101 of 221 primary disease deaths. The 1-year, 3-year and 5-year FOPD rates in model 1 were 98.2%, 89.4% and 84.0%, respectively. MVA for FOPD revealed that local failure of the irradiated tumor, squamous cell carcinoma pathology, and chemotherapy after SBRT had significant relationships with lower FOPD rates in both model 1 and model 2. CONCLUSIONS: Successful local control of pulmonary oligometastases by SBRT contributed to a higher FOPD rate.

Stereotactic Body Radiotherapy for Pulmonary Oligometastases from Esophageal Cancer: Results and Prognostic Factors.

BACKGROUND/AIM: The aim of this multi-center retrospective study was to investigate the results of stereotactic body radiotherapy (SBRT) for pulmonary oligometastases from esophageal cancer. PATIENTS AND METHODS: Oligometastases from the esophagus were identified from a dataset of a Japanese survey. The Kaplan-Meier method and Cox regression were applied to perform analyses. RESULTS: A total of 114 patients with 132 pulmonary oligometastases were collected. The 3-year local control rate, freedom from further metastasis (FFFM) rate and overall survival (OS) rate were 70.2%, 25.3% and 37.5%, respectively. Performance status (PS) (PS 1 vs. PS 0, p<0.01), disease-free interval (p=0.03) and history of local therapy for metastasis (p=0.01) had significant relationships with FFFM and only PS was an independent prognostic factor for OS (PS 1 vs. PS 0, p=0.02; PS 2-3 vs. PS 0, p=0.04). CONCLUSION: SBRT for pulmonary oligometastases from esophageal cancer provided good local control and survival.

The urethral position may shift due to urethral catheter placement in the treatment planning for prostate radiation therapy.

PURPOSE: To determine the best method to contour the planning organ at risk volume (PRV) for the urethra, this study aimed to investigate the displacement of a Foley catheter in the urethra with a soft and thin guide-wire. METHODS: For each patient, the study used two sets of computed tomography (CT) images for radiation treatment planning (RT-CT): (1) set with a Foley urethral catheter (4.0 mm diameter) plus a guide-wire (0.46 mm diameter) in the first RT-CT and (2) set with a guide-wire alone in the second CT recorded 2 min after the first RT-CT. Using three fiducial markers in the prostate for image fusion, the displacement between the catheter and the guide-wire in the prostatic urethra was calculated. In 155 consecutive patients treated between 2011 and 2017, 5531 slices of RT-CT were evaluated. RESULTS: Assuming that ≥3.0 mm of difference between the catheter and the guide-wire position was a significant displacement, the urethra with the catheter was displaced significantly from the urethra with the guide-wire alone in > 20% of the RT-CT slices in 23.2% (36/155) of the patients. The number of patients who showed ≥3.0 mm anterior displacement with the catheter in ≥20% RT-CT slices was significantly larger at the superior segment (38/155) than at the middle (14/155) and inferior segments (18/155) of the prostatic urethra (p < 0.0167). CONCLUSIONS: The urethral position with a Foley catheter is different from the urethral position with a thin and soft guide-wire in a significant proportion of the patients. This should be taken into account for the PRV of the urethra to ensure precise radiotherapy such as in urethra-sparing radiotherapy.

[A Nutritional Supplement with a High Blend Ratio of ω-3 Fatty Acids(Prosure®) Reduces Severe Oral Mucositis and Body Weight Loss for Head and Neck Cancer Patients Treated with Chemoradiotherapy].

BACKGROUND: Oral mucositis and body weight loss are the most critical conditions known to lead to the discontinuation of chemoradiotherapy for head and neck cancer. We investigated the effect of a nutritional supplement with a high blend ratio of w-3 fatty acids(Prosure®)on body weight loss, oral mucositis, and the completion rate of chemoradiotherapy in patients with oropharyngeal and hypopharyngeal cancer. PATIENTS AND METHODS: The study group comprised patients with oropharyngeal and hypopharyngeal cancer who were treated with concomitant cisplatin and 70 Gy of radiotherapy. These patients received 2 packs of Prosure®per day during chemoradiotherapy. RESULTS: A total of 17 patients were included in this study. The reduction in body weight was significantly improved compared with that in the historical control group that did not receive Prosure®(7.3% vs 10.3%, p<0.01), and the rate of Grade 3-4 oral mucositis was significantly reduced for the patient groups that received Prosure®(CTCAE v3.0 GradeB3; 24% vs 58%, p<0.05). The completion rate of chemoradiotherapy was not significantly different between both groups(77% vs 60%, NS). CONCLUSIONS: A nutritional supplement with a high blend ratio of w-3 fatty acids(Prosure®)had effects on oral mucositis and body weight loss in head and neck cancer patients treated with chemoradiotherapy.

The normal tissue complication probability model-based approach considering uncertainties for the selective use of radiation modality in primary liver cancer patients.

PURPOSE: To predict the probability of radiation-induced liver toxicity (RILT) and implement the normal tissue complication probability (NTCP) model-based approach considering confidence intervals (CIs) to select patients for new treatment techniques, such as proton beam therapy, based on a certain NTCP reduction (ΔNTCP) threshold for primary liver cancer patients. METHODS AND MATERIALS: Common Toxicity Criteria for Adverse Events (CTCAE) grade ≥2 RILT was scored. The Lyman NTCP models predicting the probability of CTCAE grade ≥2 RILT as a function of the fraction-size adjusted mean liver dose (MLD), using reference fraction size = 2 Gy/fraction and α/ß ratio = 2 Gy, were fitted using the maximum likelihood method. At certain combinations of MLDs, ΔNTCP with a CI was evaluated by the delta method. RESULTS: Of the 239 patients, the incidence of CTCAE grade ≥2 RILT was 55% (46% in the Child-Pugh (CP)-A vs. 81% in the CP-B/C, p < 0.001). Among 180 CP-A patients, 40% who had viral hepatitis infections experienced toxicity vs. 32% in the nonhepatitis subgroup. The MLD was 18 Gy in the toxicity group vs. 16.1 Gy in the nontoxicity group (p = 0.002). The estimated NTCP model parameters specific to the patient subgroups and the ΔNTCP with CI assuming a particular CP classification and viral hepatitis infection status were considerably different which possible changed treatment decision. CONCLUSIONS: Patients with CP-A and viral hepatitis infection or CP-B/C cirrhosis had greater susceptibility to CTCAE grade ≥2 RILT. The estimated NTCP and ΔNTCP for individual patients along with a consideration of uncertainties improve the reliability of the NTCP model-based approach.

Assessing the uncertainty in a normal tissue complication probability difference (∆NTCP): radiation-induced liver disease (RILD) in liver tumour patients treated with proton vs X-ray therapy.

Modern radiotherapy technologies such as proton beam therapy (PBT) permit dose escalation to the tumour and minimize unnecessary doses to normal tissues. To achieve appropriate patient selection for PBT, a normal tissue complication probability (NTCP) model can be applied to estimate the risk of treatment-related toxicity relative to X-ray therapy (XRT). A methodology for estimating the difference in NTCP (∆NTCP), including its uncertainty as a function of dose to normal tissue, is described in this study using the Delta method, a statistical method for evaluating the variance of functions, considering the variance-covariance matrix. We used a virtual individual patient dataset of radiation-induced liver disease (RILD) in liver tumour patients who were treated with XRT as a study model. As an alternative option for individual patient data, dose-bin data, which consists of the number of patients who developed toxicity in each dose level/bin and the total number of patients in that dose level/bin, are useful for multi-institutional data sharing. It provides comparable accuracy with individual patient data when using the Delta method. With reliable NTCP models, the ∆NTCP with uncertainty might potentially guide the use of PBT; however, clinical validation and a cost-effectiveness study are needed to determine the appropriate ∆NTCP threshold.

Present developments in reaching an international consensus for a model-based approach to particle beam therapy.

Particle beam therapy (PBT), including proton and carbon ion therapy, is an emerging innovative treatment for cancer patients. Due to the high cost of and limited access to treatment, meticulous selection of patients who would benefit most from PBT, when compared with standard X-ray therapy (XRT), is necessary. Due to the cost and labor involved in randomized controlled trials, the model-based approach (MBA) is used as an alternative means of establishing scientific evidence in medicine, and it can be improved continuously. Good databases and reasonable models are crucial for the reliability of this approach. The tumor control probability and normal tissue complication probability models are good illustrations of the advantages of PBT, but pre-existing NTCP models have been derived from historical patient treatments from the XRT era. This highlights the necessity of prospectively analyzing specific treatment-related toxicities in order to develop PBT-compatible models. An international consensus has been reached at the Global Institution for Collaborative Research and Education (GI-CoRE) joint symposium, concluding that a systematically developed model is required for model accuracy and performance. Six important steps that need to be observed in these considerations include patient selection, treatment planning, beam delivery, dose verification, response assessment, and data analysis. Advanced technologies in radiotherapy and computer science can be integrated to improve the efficacy of a treatment. Model validation and appropriately defined thresholds in a cost-effectiveness centered manner, together with quality assurance in the treatment planning, have to be achieved prior to clinical implementation.