Metronomic capecitabine as adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Patients with locoregionally advanced nasopharyngeal carcinoma have a high risk of disease relapse, despite a high proportion of patients attaining complete clinical remission after receiving standard-of-care treatment (ie, definitive concurrent chemoradiotherapy with or without induction chemotherapy). Additional adjuvant therapies are needed to further reduce the risk of recurrence and death. However, the benefit of adjuvant chemotherapy for nasopharyngeal carcinoma remains controversial, highlighting the need for more effective adjuvant treatment options. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was done at 14 hospitals in China. Patients (aged 18-65 years) with histologically confirmed, high-risk locoregionally advanced nasopharyngeal carcinoma (stage III-IVA, excluding T3-4N0 and T3N1 disease), no locoregional disease or distant metastasis after definitive chemoradiotherapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, sufficient haematological, renal, and hepatic function, and who had received their final radiotherapy dose 12-16 weeks before randomisation, were randomly assigned (1:1) to receive either oral metronomic capecitabine (650 mg/m2 body surface area twice daily for 1 year; metronomic capecitabine group) or observation (standard therapy group). Randomisation was done with a computer-generated sequence (block size of four), stratified by trial centre and receipt of induction chemotherapy (yes or no). The primary endpoint was failure-free survival, defined as the time from randomisation to disease recurrence (distant metastasis or locoregional recurrence) or death due to any cause, in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of capecitabine or who had commenced observation. This trial is registered with ClinicalTrials.gov, NCT02958111. FINDINGS: Between Jan 25, 2017, and Oct 25, 2018, 675 patients were screened, of whom 406 were enrolled and randomly assigned to the metronomic capecitabine group (n=204) or to the standard therapy group (n=202). After a median follow-up of 38 months (IQR 33-42), there were 29 (14%) events of recurrence or death in the metronomic capecitabine group and 53 (26%) events of recurrence or death in the standard therapy group. Failure-free survival at 3 years was significantly higher in the metronomic capecitabine group (85·3% [95% CI 80·4-90·6]) than in the standard therapy group (75·7% [69·9-81·9]), with a stratified hazard ratio of 0·50 (95% CI 0·32-0·79; p=0·0023). Grade 3 adverse events were reported in 35 (17%) of 201 patients in the metronomic capecitabine group and in 11 (6%) of 200 patients in the standard therapy group; hand-foot syndrome was the most common adverse event related to capecitabine (18 [9%] patients had grade 3 hand-foot syndrome). One (<1%) patient in the metronomic capecitabine group had grade 4 neutropenia. No treatment-related deaths were reported in either group. INTERPRETATION: The addition of metronomic adjuvant capecitabine to chemoradiotherapy significantly improved failure-free survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma, with a manageable safety profile. These results support a potential role for metronomic chemotherapy as an adjuvant therapy in the treatment of nasopharyngeal carcinoma. FUNDING: The National Natural Science Foundation of China, the Key-Area Research and Development Program of Guangdong Province, the Natural Science Foundation of Guangdong Province, the Innovation Team Development Plan of the Ministry of Education, and the Overseas Expertise Introduction Project for Discipline Innovation. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Nomogram predicting survival as a selection criterion for postmastectomy radiotherapy in patients with T1 to T2 breast cancer with 1 to 3 positive lymph nodes.

BACKGROUND: The role of postmastectomy radiotherapy (PMRT) in women with pT1-T2N1 breast cancer is controversial. The authors developed a nomogram that was predictive for overall survival (OS) and identified patients who derived no benefit from PMRT. METHODS: The authors retrospectively evaluated 4869 patients with pT1-T2N1 breast cancer who were treated with mastectomy between 2000 and 2014 in 11 Chinese hospitals. Rates of locoregional recurrence and distant metastasis were calculated using competing risk analysis, and disease-free survival and OS rates were calculated using the Kaplan-Meier method. Based on the risk factors identified from Cox regression analysis in 3298 unirradiated patients, a nomogram predicting OS was developed. The benefit of PMRT was evaluated in different risk groups stratified by the nomogram model. RESULTS: After a median follow-up of 65.9 months, the 5-year OS, disease-free survival, locoregional recurrence, and distant metastasis rates were 93.3%, 84.3%, 5.2%, and 8.3%, respectively. A total of 1571 patients (32.3%) underwent PMRT. On multivariable analyses, PMRT was found to increase OS significantly (hazard ratio, 0.61; P = .002). An OS prediction nomogram evaluated the effect of age; tumor location; tumor size; positive lymph node ratio; estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status; and treatment with trastuzumab. Based on nomogram scores, the entire patient cohort was classified into 3 risk groups. PMRT significantly improved the OS of patients in the intermediate-risk (P < .001) and high-risk groups (P = .004), but not in the low-risk group (P = .728). CONCLUSIONS: The authors developed a nomogram that is predictive of OS among women with pT1-T2N1 breast cancer after mastectomy. This nomogram may help to select a subgroup of patients with a good prognosis who will not benefit from PMRT.

Dose-Volume Predictors for Radiation Esophagitis in Patients With Breast Cancer Undergoing Hypofractionated Regional Nodal Radiation Therapy.

PURPOSE: Our objective was to assess the incidence and dose-volume predictors of radiation esophagitis (RE) in patients with breast cancer undergoing hypofractionated regional nodal irradiation. METHODS AND MATERIALS: Eligible patients who received intensity modulated radiation therapy (RT) at the chest wall, the supraclavicular/infraclavicular fossa, level II axilla, and/or the internal mammary chain after mastectomy were included. The prescribed dose was 43.5 Gy in 15 fractions. RE was evaluated weekly during RT and at 1 and 2 weeks, followed by 3 and 6 months after RT, and was graded according to National Cancer Institute Common Toxicity Criteria for Adverse Events, version 3.0. The esophagus was contoured from the lower border level of the cricoid cartilage to the lower margin of the aortic arch. Esophageal total volume, mean dose, maximum dose, and the relative volumes (RV) and absolute volumes (AV) receiving at least 5 to 45 Gy by 5-Gy increments (RV5-RV45 and AV5-AV45) were evaluated. Univariable and multivariable logistic regression analyses were performed to determine risk factors for RE, and receiver operating characteristic curves were obtained to identify the thresholds of esophageal dosimetric parameters. RESULTS: In total, 298 patients were included between May 8, 2020, and January 5, 2022 (minimum post-RT follow-up: 6 months). Grade 2 and 3 RE incidence was 40.9% (122/298) and 0.3% (1/298), respectively. No grade 4 or 5 RE was observed. Esophageal RV20-RV40 and AV35-AV40 were significantly associated with the risk of grade ≥2 RE after adjusting for tumor laterality and internal mammary nodal irradiation. RV25 and AV35 were optimum dose-volume predictors for grade ≥2 RE at thresholds 20% for RV25 (35.9% vs 60.9%; P = .04) and 0.27 mL for AV35 (31.0% vs 54.6%; P = .04). CONCLUSIONS: RE is common in patients with breast cancer undergoing hypofractionated regional nodal irradiation. Maintaining the upper esophageal V25 at <20% and V35 at <0.27 mL may decrease the risk of RE.

Quality assurance in a phase III, multicenter, randomized trial of POstmastectomy radioThErapy in Node posiTive breast cancer with or without Internal mAmmary nodaL irradiation (POTENTIAL): a planning benchmark case.

PURPOSE: To report the planning benchmark case results of the POTENTIAL trial-a multicenter, randomized, phase 3 trial-to evaluate the value of internal mammary nodal (IMN) irradiation for patients with high-risk breast cancer. METHODS: All participating institutions were provided the outlines of one benchmark case, and they generated radiation therapy plans per protocol. The plans were evaluated by a quality assurance team, after which the institutions resubmitted their revised plans. The information on beams arrangement, skin flash, inhomogeneity corrections, and protocol compliance was assessed in the first and final submission. RESULTS: The plans from 26 institutions were analyzed. Some major deviations were found in the first submission. The protocol compliance rates of dose coverage for the planning target volume of chest wall, supraclavicular fossa plus axilla, and IMN region (PTVim) were all significantly improved in the final submission, which were 96.2% vs. 69.2%, 100% vs. 76.9%, and 88.4% vs. 53.8%, respectively. For OARs, the compliance rates of heart Dmean, left anterior descending coronary artery V40Gy, ipsilateral lung V5Gy, and stomach V5Gy were significantly improved. In the first and final submission, the mean values of PTVim V100% were 79.9% vs. 92.7%; the mean values of heart Dmean were 11.5 Gy vs. 9.7 Gy for hypofractionated radiation therapy and 11.5 Gy vs. 11.0 Gy for conventional fractionated radiation therapy, respectively. CONCLUSION: The major deviations were corrected and protocol compliance was significantly improved after revision, which highlighted the importance of planning benchmark case to guarantee the planning quality for multicenter trials.

Influence of age as a continuous variable on the prognosis of patients with pT1-2N1 breast cancer.

PURPOSE: To assess the influence of age as a continuous variable on the prognosis of pT1-2N1 breast cancer and examine its decision-making value for postmastectomy radiotherapy (PMRT). METHODS: We retrospectively evaluated 5438 patients with pT1-2N1 breast cancer after mastectomy in 11 hospitals. A multivariable Cox proportional hazards regression model with penalized splines was used to examine the relationship between age and oncologic outcomes. RESULTS: The median follow-up was 67.0 months. After adjustments for confounding characteristics, nonsignificant downward trend in locoregional recurrence (LRR) risk was observed with increasing age (P-non-linear association = 0.640; P-linear association = 0.078). A significant non-linear association was found between age and disease-free survival (DFS) and overall survival (OS) (P-non-linear association <0.05; P-linear association >0.05, respectively). The DFS and OS exhibited U-shaped relationships, with the hazard ratios (HRs), reaching a nadir at 50 years old. A decreased risk of LRR with PMRT vs. no PMRT (HR = 0.304, 95% CI: 0.204-0.454) was maintained in all ages. The HR of PMRT vs. no PMRT for DFS and OS gradually increased with age. In patients ≤50 years old, PMRT was independently associated with favorable LRR, DFS, and OS, all P < 0.05). In patients >50 years old, PMRT was independently associated with reduced LRR (P = 0.004), but had no effect on DFS or OS. CONCLUSIONS: Age was an independent prognostic factor for pT1-2N1 breast cancer; PMRT provided survival benefits for patients ≤50 years old, but not for patients >50 years old.

Effect of postmastectomy radiotherapy on pT1-2N1 breast cancer patients with different molecular subtypes.

OBJECTIVE: To clarify the effect of postmastectomy radiotherapy (PMRT) on pT1-2N1 breast cancer patients with different molecular subtypes. METHODS: We retrospectively analyzed the data of 5442 patients with pT1-2N1 breast cancer treated using modified radical mastectomy in 11 hospitals in China. Univariate, multivariate, and propensity score matching (PSM) analyses were used to evaluate the effect of PMRT on locoregional recurrence (LRR). RESULTS: With a median follow-up duration of 63.8 months, the 5-year LRR rates were 4.0% and 7.7% among patients treated with and without PMRT, respectively (p < 0.001). PMRT was independently associated with reduced LRR after adjustments for confounders (p < 0.001). After grouping the patients according to the molecular subtype of cancer and conducting PSM, we found that the 5-year LRR rates among patients treated with and without PMRT (in that order) were as follows: luminal HER2-negative cancer, 1.9% and 6.5% (p < 0.001); luminal HER2-positive cancer, 3.8% and 13.7% (p = 0.041); HER2-overexpressing cancer, 10.2% and 15.5% (p = 0.236); and triple-negative cancer, 4.6% and 15.9% (p = 0.002). Among patients with HER2-overexpressing and triple-negative cancers, the LRR hazard rate displayed a dominant early peak, and was extremely low after 5 years. However, patients with luminal cancer continued to have a long-lasting high annual LRR hazard rate during follow-up. CONCLUSION: PMRT significantly reduced the LRR risk in patients with pT1-2N1 luminal and triple-negative breast cancers, but had no effect on the LRR risk in patients with HER2-overexpressing cancer. Patients with different molecular subtypes displayed different annual LRR patterns, and the late recurrence of the luminal subtype suggests the necessity of long-term follow-up to evaluate the efficacy of PMRT.

Variability of Target Volumes and Organs at Risk Delineation in Breast Cancer Radiation Therapy: Quality Assurance Results of the Pretrial Benchmark Case for the POTENTIAL Trial.

PURPOSE: To estimate the variations in clinical target volumes (CTVs) and organs at risk delineation within the quality assurance (QA) program of the POTENTIAL trial, which is a multicenter, randomized phase 3 trial evaluating postmastectomy radiation therapy (RT), with or without internal mammary nodal irradiation, for patients with high-risk breast cancer. METHODS AND MATERIALS: The simulating computed tomography scan data set of a benchmark case was sent to the participating centers, and the delineation of CTVs and organs at risk was required to be completed by the investigators following protocol guidelines. All submitted contours were reviewed and compared with the reference contours created by the QA team, using quantitative geometric analysis regarding volume and the Jaccard Index (JCI), Dice similarity coefficient, Geographic Miss Index, Discordance Index, and mean distance to agreement. In addition to the whole-volume analysis of all structures, the combination contour of the supraclavicular fossa and level III and II axilla (CTVsc + axIII + axII) was further analyzed on a slice-by-slice basis. RESULTS: The contours from 26 centers were reviewed and variations were observed between submission and reference. The variations of the CTV of the chest wall, contralateral breast, and heart were small, for which the mean JCI values were 0.62, 0.68, and 0.87, respectively. However, the mean JCI values of the CTV of the internal mammary nodal region, ipsilateral brachial plexus, left anterior descending coronary artery, and right coronary artery were 0.38, 0.21, 0.29, and 0.18, respectively, suggesting marked variations. In addition, marked under- and overoutlining variations were identified on 4 slices of CTVsc + axIII + axII on slice-by-slice analysis. CONCLUSIONS: There were residual contouring variations despite a detailed protocol being provided, confirming the importance of pretrial QA in RT and highlighting the need for education and consideration of a real-time central review of the target delineation before the trial participants begin RT.

A novel nomogram for predicting locoregional recurrence risk in breast cancer patients treated with neoadjuvant chemotherapy and mastectomy.

BACKGROUND: This study aimed to establish a nomogram for predicting locoregional recurrence (LRR) in breast cancer patients treated with neoadjuvant chemotherapy (NAC) and mastectomy. METHODS: A total of 2368 patients who received NAC and mastectomy between 2000 and 2014 from 12 grade A tertiary hospitals in China were analyzed retrospectively. The nomogram was developed based on the patients treated in three cancer hospitals (training set, n = 1629) and validated based on patients from the other nine general hospitals (validation set, n = 739). Factors identified from Fine and Gray's competing risk analysis were used to establish the nomogram. The predictive performance of the nomogram model was compared with the cTNM stage, ypTNM stage, and the Neo-Bioscore model by using the area under the time dependent receiver operating characteristic curves (tAUC), calibration curve, and decision curve analysis (DCA). RESULTS: The nomogram incorporated six risk factors derived from multivariable analysis of the training set including age, ypT stage, ypN stage, lymph node ratio, postmastectomy radiotherapy, and endocrine therapy. In the training set, the AUC of the nomogram was 0.792, which was higher than the values of the cTNM stage (0.582), ypTNM stage (0.737), and the Neo-Bioscore prognosis model (0.658). In the validation set, the AUC of the cTNM (0.619); ypTNM (0.636); and Neo-Bioscore staging system (0.584) were also significantly lower than the AUC of the nomogram (0.705). Both in the training and validation sets, the calibration curve showed good agreement between the nomogram-based predictions and the actual observations. CONCLUSION: The novel nomogram provides a more accurate evaluation of LRR for breast cancer patients treated with NAC and mastectomy.

The role of radiotherapy in pulmonary large cell neuroendocrine carcinoma: propensity score matching analysis.

The aim of the study was to investigate the survival advantage of radiotherapy (RT) in patients with pulmonary large cell neuroendocrine carcinoma (LCNEC). Patients with pulmonary LCNEC were extracted from the Surveillance, Epidemiology, and End Results (SEER) dataset between January 2004 and December 2013. Propensity score matching (PSM) analysis with 1:1 was used to ensure well-balanced characteristics of all comparison groups. A total of 1480 eligible cases were identified, with a median follow-up time of 11 months (0-131 months). After PSM, 980 patients were classified in no radiotherapy (No RT) and radiotherapy (RT) groups (n = 490 each). Patients in the RT group harbored significantly higher 3- and 5-year overall survival (OS) and cancer-specific survival (CSS) rates compared to those in the No RT group (both P < 0.05). Furthermore, RT was an independent favorable prognostic factor of OS as well as CSS in multivariate analysis, both before [OS: hazard ratio (HR) 0.840, 95% confidence interval (CI) 0.739-0.954, P = 0.007; CSS: HR 0.847, 95% CI 0.741-0.967, P = 0.014] and after (OS: HR 0.854, 95% CI 0.736-0.970, P = 0.016; CSS: HR 0.848, 95% CI 0.735-0.978, P = 0.023) PSM. In subgroup analysis, American Joint Committee on Cancer (AJCC) stage II and III, tumor size 5-10 cm, patients who underwent no surgery, or patients who received chemotherapy could significantly benefit from RT (all P < 0.05). To sum up, our findings suggested that RT could prolong the survival of patients with pulmonary LCNEC, especially those with stage II and III, tumor size 5-10 cm, those with no surgery, or those who received chemotherapy.

Postmastectomy Radiation Therapy Based on Pathologic Nodal Status in Clinical Node-Positive Stage II to III Breast Cancer Treated with Neoadjuvant Chemotherapy.

PURPOSE: The present study aimed to evaluate the effect of postmastectomy radiation therapy (PMRT) after neoadjuvant chemotherapy in patients with node-positive stage II to III (cT1-4N1-2M0) breast cancer. METHODS AND MATERIALS: A total of 1813 patients from 12 institutions were retrospectively reviewed. Patients were classified into 1 of 3 groups based on the pathologic lymph node status after neoadjuvant chemotherapy: ypN0, ypN1, and ypN2-3. The role of PMRT was separately evaluated in each group. Locoregional control, disease-free survival, and overall survival (OS) were estimated using the Kaplan-Meier method. The effect of PMRT was assessed by propensity score-matched analyses and multivariate Cox analyses. RESULTS: With a median follow-up of 72.9 months, 5-year locoregional control, disease-free survival, and OS rates were 86.3%, 68.4%, and 83.1% for the entire cohort, respectively. There were 490 (27.0%), 567 (31.3%), and 756 (41.7%) patients in the ypN0, ypN1, and ypN2-3 groups, respectively. PMRT significantly improved 5-year OS in the ypN2-3 group (74.2% vs 55.9%; P < .001) but had no effect on 5-year OS in the ypN0 group (93.1% vs 95.5%; P = .517) and ypN1 group (88.4% vs 87.8%; P = .549). CONCLUSIONS: With modern systemic therapy, PMRT significantly improved OS in the ypN2-3 group but not in the ypN0 and ypN1 groups. Whether PMRT can be safely omitted in the ypN0 and ypN1 groups should be addressed prospectively.

Combined use of intravenous and topical versus intravenous tranexamic acid in primary total knee and hip arthroplasty: a meta-analysis of randomised controlled trials.

BACKGROUND: This meta-analysis aimed to evaluate the efficiency and safety of combined intravenous and topical methods of application versus single intravenous of tranexamic acid in primary total knee and hip arthroplasty. METHODS: A systematic search was carried out in MEDLINE (from 1966 to 25 September 2016), PubMed (from 1966 to 25 September 2016), Embase (from 1980 to 25 September 2016), ScienceDirect (from 1985 to 25 September 2016) and the Cochrane Library. Only high-quality randomised controlled trials (RCT) were identified. Two authors independently performed data extraction and quality assessment of included studies. Meta-analysis was conducted using Review Manager 5.1 software. RESULTS: Six RCTs that included 687 patients met the inclusion criteria. The present meta-analysis indicated that there were significant differences in terms of total blood loss (MD = -193.59, 95% CI -338.06 to -49.13, P = 0.009), transfusion rate (RD = -0.07, 95% CI -0.12 to -0.03, P = 0.001), haemoglobin decline (MD = -0.51, 95% CI -0.83 to -0.18, P = 0.01) and length of stay (MD = -0.20, 95% CI -0.38 to -0.02, P = 0.03) between groups. CONCLUSIONS: Combined administration of tranexamic acid (TXA) in patients with total knee and hip arthroplasty was associated with significantly reduced total blood loss, transfusion requirements, postoperative haemoglobin decline and length of stay compared to single application alone but was not associated with prolonged operation time. Moreover, no adverse effects, such as superficial infection, deep vein thrombus (DVT) or pulmonary embolism (PE), were associated with TXA. We suggest that combined administration of TXA demonstrated excellent clinical efficacy and safety in patients with total knee and hip arthroplasty. More importantly, well-designed studies with larger sample size are needed to provide further reliable evidence for the combined use of TXA.

Moderate hypofractionated radiotherapy is more effective and safe for localized prostate cancer patients: a meta-analysis.

To compare the efficacy and safety of moderate hypofractionated radiotherapy (H-RT) with those of conventional radiotherapy (C-RT) in patients with localized prostate cancer, we conducted extensive literature searches of The Web of Science, Embase, Pubmed and Cochrane Library databases. We identified nine studies with 5969 patients for a meta-analysis. We calculated pooled risk ratios (RRs) and the 95% confidence intervals (CIs) for multiple parameters and performed statistical analysis using RevMan 5.3 software. Our analysis showed that the H-RT group obtained greater improvements in the 5-year biochemical or clinical failure-free survival (RR = 1.04, 95% CI:1.01-1.08; P = 0.01) and 5-year disease-free survival(RR = 1.04, 95% CI: 1.01-1.07, P = 0.02) than the C-RT group. However, the 5-year overall survival rates were comparable in the two groups (RR = 1.02, 95% CI: 0.99-1.04; P = 0.18). Comparison of multiple secondary parameters, including grade 2-4 acute/late gastrointestinal toxicity, grade 2-4 acute/late genitourinary toxicity, biochemical failure, local failure, distant failure and prostate cancer-specific mortality between the H-RT and the C-RT groups showed no statistical differences. This meta-analysis thus indicates that in patients with localized prostate cancer, moderate H-RT exerts a great beneficial effect on the primary parameters than C-RT without enhancing adverse events.

Fluorouracil-based neoadjuvant chemoradiotherapy with or without oxaliplatin for treatment of locally advanced rectal cancer: An updated systematic review and meta-analysis.

To measure the safety and efficacy of oxaliplatin (OX) application in neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC), EMBASE, PubMed, Cochrane Library, and Web of Science were used for a literature search. Cochrane's risk of bias tool of randomized controlled trials (RCTs) was used for quality evaluation. The statistical analyses were performed using RevMan 5.3. In addition, 95% confidence intervals (CIs) and pooled risk ratios (RRs) were calculated. Seven RCTs were included in our meta-analysis. After adding OX to fluoropyrimidine (FU), a marginal significant improvement in disease-free survival was noted compared with FU alone (RR = 0.89, 95% CI: 0.78-1.00; P = 0.05). Neoadjuvant CRT with OX significantly decreased the distant metastasis rate (RR = 0.79, 95% CI: 0.67-0.94, P = 0.007). However, no improvement in the local recurrence rate (RR = 0.86, 95% CI: 0.68-1.08; P = 0.19) was noted. In addition, neoadjuvant CRT with OX also significantly increased the pathologic complete response (RR = 1.24, 95% CI: 1.02-1.51; P = 0.03). Grade 3-4 acute toxicity and grade 3-4 diarrhea was considerably higher for OX/FU compared with FU alone. In conclusion, the use of OX on the basis of FU/capecitabine in preoperative CRT is feasible. LARC patients are likely to benefit from CRT regimens with OX.