Multicenter phase II study of moderate low-dose radiotherapy in indolent non-Hodgkin lymphoma: CLCG-iNHL-01 protocol.

Background: Radiotherapy is an effective treatment for indolent non-Hodgkin lymphoma (iNHL); however, the optimal radiotherapy dose remains to be determined. We hypothesize that a suitable dose may exist between 4 and 24 Gy. Methods: This prospective multicenter phase II trial intends to recruit 73 sites of iNHL patients, who will receive involved-site radiotherapy of 12 Gy in four fractions. The primary objective is the 6-month clinical complete response rate. Tumor tissue, blood and conjunctival specimens will be collected to identify potential predictive biomarkers. Discussion: The CLCG-iNHL-01 trial will evaluate the efficacy and toxicity of 12 Gy in patients with iNHL and provide information on a novel hypofractionation regimen of low-dose radiotherapy. Clinical Trial Registration: NCT05543070 (ClinicalTrials.gov).

Preoperative chemoradiotherapy in older patients with rectal cancer guided by comprehensive geriatric assessment within a multidisciplinary team-a multicenter phase II trial.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older people who were classified as "fit" by comprehensive geriatric assessment (CGA). METHODS: A single-arm, multicenter, phase II trial was designed. Patients were eligible for this study if they were aged 70 years or above and met the standards of "fit" (SIOG1) as evaluated by CGA and of the locally advanced risk category. The primary endpoint was 2-year disease-free survival (DFS). Patients were scheduled to receive preCRT (50 Gy) with raltitrexed (3 mg/m2 on days 1 and 22). RESULTS: One hundred and nine patients were evaluated by CGA, of whom eighty-six, eleven and twelve were classified into the fit, intermediate and frail category. Sixty-eight fit patients with a median age of 74 years were enrolled. Sixty-four patients (94.1%) finished radiotherapy without dose reduction. Fifty-four (79.3%) patients finished the prescribed raltitrexed therapy as planned. Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced non-hematological side effects. Within a median follow-up time of 36.0 months (range: 5.9-63.1 months), the 2-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) rates were 89.6% (95% CI: 82.3-96.9), 92.4% (95% CI: 85.9-98.9) and 75.6% (95% CI: 65.2-86.0), respectively. Forty-eight patients (70.6%) underwent surgery (R0 resection 95.8%, R1 resection 4.2%), the corresponding R0 resection rate among the patients with positive mesorectal fascia status was 76.6% (36/47). CONCLUSION: This phase II trial suggests that preCRT is efficient with tolerable toxicities in older rectal cancer patients who were evaluated as fit based on CGA. TRIAL REGISTRATION: The registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016).

The prognostic value of tumour-infiltrating lymphocytes, programmed cell death protein-1 and programmed cell death ligand-1 in Stage I-III triple-negative breast cancer.

BACKGROUND: Tumour-infiltrating lymphocytes (TILs) represent a robust biological prognostic biomarker in triple-negative breast cancer (TNBC); however, the contribution of different subsets of immune cells is unclear. We investigated the prognostic value of immune markers, including stromal TILs (sTILs), CD8+T and FOPX3+T cells, PD-1 and PD-L1 in non-metastatic TNBC. METHODS: In total, 259 patients with Stage I-III TNBC were reviewed. The density of sTILs along with the presence of total (t), stromal (s), and intratumoral (i) CD8+T cells and FOPX3+T cells were evaluated by haematoxylin and eosin and immunohistochemical staining. Immunohistochemical staining of PD-1, PD-L1 was also conducted. RESULTS: All immune markers were positively correlated with each other (P < 0.05). In the multivariate analysis, sTILs (P = 0.046), tCD8+T cells (P = 0.024), iCD8+T cells (P = 0.050) and PD-1 (P = 0.039) were identified as independent prognostic factors for disease-free survival (DFS). Further analysis showed that tCD8+T cells (P = 0.026), iCD8+T cells (P = 0.017) and PD-1 (P = 0.037) increased the prognostic value for DFS beyond that of the classic clinicopathological factors and sTILs. CONCLUSIONS: In addition to sTILs, inclusion of tCD8+T, iCD8+T cells, or PD-1 may further refine the prognostic model for non-metastatic TNBC beyond that including classical factors alone.

Risk stratification and prognostic value of multi-modal MRI-based radiomics for extranodal nasal-type NK/T-cell lymphoma.

BACKGROUND: Magnetic resonance imaging (MRI) performs well in the locoregional assessment of extranodal nasal-type NK/T-cell lymphoma (ENKTCL). It's important to assess the value of multi-modal MRI-based radiomics for estimating overall survival (OS) in patients with ENKTCL. METHODS: Patients with ENKTCL in a prospectively cohort were systemically reviewed and all the pretreatment MRI were acquisitioned. An unsupervised spectral clustering method was used to identify risk groups of patients and radiomic features. A nomogram-revised risk index (NRI) plus MRI radiomics signature (NRI-M) was developed, and compared with the NRI. RESULTS: The 2 distinct type I and II groups of the MRI radiomics signatures were identified. The 5-year OS rates between the type I and type II groups were 87.2% versus 67.3% (P = 0.002) in all patients, and 88.8% versus 69.2% (P = 0.003) in early-stage patients. The discrimination and calibration of the NRI-M for OS prediction demonstrated a better performance than that of either MRI radiomics or NRI, with a mean area under curve (AUC) of 0.748 and 0.717 for predicting the 5-year OS in all-stages and early-stage patients. CONCLUSIONS: The NRI-M model has good performance for predicting the prognosis of ENKTCL and may help design clinical trials and improve clinical decision making.

Phase 2 Study of Adjuvant Radiotherapy Following Narrow-Margin Hepatectomy in Patients With HCC.

BACKGROUND AND AIMS: Surgical resection is the primary treatment for HCC; however, it is associated with a high rate of recurrence and death. We conducted this phase 2 study to investigate the efficacy and safety of postoperative intensity-modulated radiotherapy (IMRT) for HCC after narrow-margin hepatectomy. APPROACH AND RESULTS: We designed a single-arm, prospective phase 2 trial to evaluate overall survival (OS), disease-free survival (DFS), recurrence patterns, and toxicity in patients receiving adjuvant radiotherapy. The eligibility criteria included the following: pathological diagnosis of HCC after hepatectomy, with narrow pathological margins (< 1 cm); age > 18 years; and Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients received IMRT within 4-6 weeks after surgical resection. This trial was registered at ClinicalTrials.gov (NCT01456156). Between 2008 and 2016, a total of 76 eligible patients who underwent narrow-margin resection were enrolled. The median follow-up duration was 70 months; the 3-year OS and DFS rates were 88.2% and 68.1%, respectively; and the 5-year OS and DFS rates were 72.2% and 51.6%, respectively. Intrahepatic recurrence was the primary recurrence pattern. No marginal recurrence was found. Intrahepatic, extrahepatic, and combined recurrences at the first relapse were found in 33, 5, and 1 patient, respectively. The most common radiation-related grade-3 toxicities were leukopenia (7.9%), elevated alanine aminotransferase (3.9%) and aspartate aminotransferase (2.6%) levels, and thrombocytopenia (1.3%). Classical or nonclassical radiation-induced liver disease was not noted. CONCLUSIONS: Adjuvant radiotherapy is an effective, well-tolerated, and promising adjuvant regimen in patients with HCC who have undergone narrow-margin hepatectomy. Our trial provides evidence and a rationale for planning a future phase 3 trial.

Preoperative versus postoperative chemo-radiotherapy for locally advanced gastric cancer: a multicenter propensity score-matched analysis.

BACKGROUND: Peri-operative chemo-radiotherapyplayed important rolein locally advanced gastric cancer. Whether preoperative strategy can improve the long-term prognosis compared with postoperative treatment is unclear. The study purpose to compare oncologic outcomes in locally advanced gastric cancer patients treated with preoperative chemo-radiotherapy (pre-CRT) and postoperative chemo-radiotherapy (post-CRT). METHODS: From January 2009 to April 2019, 222 patients from 2 centers with stage T3/4 and/or N positive gastric cancer who received pre-CRT and post-CRT were included. After propensity score matching (PSM), comparisons of local regional control (LC), distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were performed using Kaplan-Meier analysis and log-rank test between pre- and post-CRT groups. RESULTS: The median follow-up period was 30 months. 120 matched cases were generated for analysis. Three-year LC, DMFS, DFS and OS for pre- vs. post-CRT groups were 93.8% vs. 97.2% (p = 0.244), 78.7% vs. 65.7% (p = 0.017), 74.9% vs. 65.3% (p = 0.042) and 74.4% vs. 61.2% (p = 0.055), respectively. Pre-CRT were significantly associated with DFS in uni- and multi-variate analysis. CONCLUSION: Preoperative CRT showed advantages of oncologic outcome compared with postoperative CRT. TRIAL REGISTRATION: ClinicalTrial.gov NCT01291407 , NCT03427684 and NCT04062058 , date of registration: Feb 8, 2011.

Total neoadjuvant therapy for locally advanced gastric cancer and esophagogastric junction adenocarcinoma: study protocol for a prospective, multicenter, single-arm, phase II clinical trial.

BACKGROUND: Gastric cancer ranks high in terms of morbidity and mortality worldwide. Multimodal therapy is therefore essential for locally advanced gastric cancer. Recent studies have demonstrated that both perioperative chemotherapy and neoadjuvant chemoradiotherapy can improve the prognosis of patients. However, the completion rate of chemotherapy after surgery remains low, which may affect survival. Thus, identifying the best way to combine radiotherapy, chemotherapy and surgery is important. The aim of this study was to explore the toxicity and efficacy of the total neoadjuvant therapy modality for locally advanced gastric cancer. METHODS: This study will be a prospective, multicenter, single-arm, phase II clinical trial. Patients diagnosed with locally advanced (stage cT3-4 and cN positive, AJCC 8th) gastric cancer and gastroesophageal junction adenocarcinoma will be enrolled. Patients will initially receive radiotherapy (95% planned target volume: 45 Gy/25 f) and concurrent chemotherapy (S-1: 40-60 mg twice a day) followed by six cycles of consolidated chemotherapy (SOX, consisting of S-1 and oxaliplatin) and surgery. The primary objective will assess pathological complete response; the secondary objectives will include toxicities assessing surgical complications, the tumor downstaging rate and the R0 resection rate. DISCUSSION: Investigation of total neoadjuvant therapy in gastric cancer is limited. The goal of this trial is to explore the efficacy and toxicity of total neoadjuvant therapy for locally advanced gastric cancer and gastroesophageal junction adenocarcinoma. TRIAL REGISTRATION: Clinicaltrials.gov (NCT04062058, August 20, 2019).

POstmastectomy radioThErapy in Node-posiTive breast cancer with or without Internal mAmmary nodaL irradiation (POTENTIAL): a study protocol for a multicenter prospective phase III randomized controlled trial.

BACKGROUND: Various randomized trials have demonstrated that postmastectomy radiotherapy (RT) to the chest wall and comprehensive regional nodal areas improves survival in patients with axillary node-positive breast cancer. Controversy exists as to whether the internal mammary node (IMN) region is an essential component of regional nodal irradiation. Available data on the survival benefit of IMN irradiation (IMNI) are conflicting. The patient populations enrolled in previous studies were heterogeneous and most studies were conducted before modern systemic treatment and three-dimensional (3D) radiotherapy (RT) techniques were introduced. This study aims to assess the efficacy and safety of IMNI in the context of modern systemic treatment and computed tomography (CT)-based RT planning techniques. METHODS: POTENTIAL is a prospective, multicenter, open-label, parallel, phase III, randomized controlled trial investigating whether IMNI improves disease-free survival (DFS) in high-risk breast cancer with positive axillary nodes (pN+) after mastectomy. A total of 1800 patients will be randomly assigned in a 1:1 ratio to receive IMNI or not. All patients are required to receive ≥ six cycles of anthracycline and/or taxane-based chemotherapy. Randomization will be stratified by institution, tumor location (medial/central vs. other quadrants), the number of positive axillary nodes (1-3 vs. 4-9 vs. ≥10), and neoadjuvant chemotherapy (yes vs. no). Treatment will be delivered with CT-based 3D RT techniques, including 3D conformal RT, intensity-modulated RT, or volumetric modulated arc therapy. The prescribed dose is 50 Gy in 25 fractions or 43.5 Gy in 15 fractions. Tiered RT quality assurance is required. After RT, patients will be followed up at regular intervals. Oncological and toxilogical outcomes, especially cardiac toxicities, will be assessed. DISCUSSION: This trial design is intended to overcome the limitations of previous prospective studies by recruiting patients with pN+ breast cancer, using DFS as the primary endpoint, and prospectively assessing cardiac toxicities and requiring RT quality assurance. The results of this study will provide high-level evidence for elective IMNI in patients with breast cancer after mastectomy. TRIAL REGISTRATION: ClinicalTrails.gov , NCT04320979 . Registered 25 Match 2020, https://clinicaltrials.gov/ct2/show/NCT04320979.

Down-staging depth score could be a survival predictor for locally advanced gastric cancer patients after preoperative chemoradiotherapy.

OBJECTIVE: The predictive effect of preoperative chemoradiotherapy (CRT) is low and difficult in guiding individualized treatment. We examined a surrogate endpoint for long-term outcomes in locally advanced gastric cancer patients after preoperative CRT. METHODS: From April 2012 to April 2019, 95 patients with locally advanced gastric cancer who received preoperative concurrent CRT and who were enrolled in three prospective studies were included. All patients were stage T3/4N+. Local control, distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were evaluated. Clinicopathological factors related to long-term prognosis were analyzed using univariate and multivariate analyses. The down-staging depth score (DDS), which is a novel method of evaluating CRT response, was used to predict long-term outcomes. RESULTS: The median follow-up period for survivors was 30 months. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve predicted by the DDS was 0.728, which was better than the pathological complete response (pCR), histological response and ypN0. Decision curve analysis further affirmed that DDS had the largest net benefit. The DDS cut-off value was 4. pCR and ypN0 were associated with OS (P=0.026 and 0.049). Surgery and DDS are correlated with DMFS, DFS and OS (surgery: P=0.001, <0.001 and <0.001, respectively; and DDS: P=0.009, 0.013 and 0.032, respectively). Multivariate analysis showed that DDS was an independent prognostic factor of DFS (P=0.021). CONCLUSIONS: DDS is a simple, short-term indicator that was a better surrogate endpoint than pCR, histological response and ypN0 for DFS.

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.

Effectiveness of the AJCC 8th edition staging system for selecting patients with T1-2N1 breast cancer for post-mastectomy radiotherapy: a joint analysis of 1986 patients from two institutions.

BACKGROUND: The role of post-mastectomy radiotherapy (PMRT) in the treatment of patients with T1-2N1 breast cancer is controversial. This study's purpose was to evaluate the risk of recurrence of T1-2N1 breast cancer and the efficacy of PMRT in low-, medium- and high-risk groups of patients. METHODS: Post-mastectomy patients with T1-2N1 breast cancer were restaged according to the American Joint Committee on Cancer Staging Manual, 8th edition (AJCC 8th ed.) staging system. Recurrence scores were generated using prognostic factors identified for loco-regional recurrence and distant metastasis in patients without PMRT, and three risk groups were identified. Rates of loco-regional recurrence and distant metastasis were calculated with a competing risk model and compared using Gray's test. Disease-free survival and overall survival were calculated using the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards regression model was used for the multivariate analysis. RESULTS: Data from 1986 patients (1521without PMRT; 465 with PMRT) were analyzed. Patients without PMRT were stratified into low-, intermediate- and high-risk groups by age, tumor location, AJCC 8th ed. stage, number of positive nodes and lympho-vascular invasion. The 5-year loco-regional recurrence rate and distant metastasis rates for the three risk groups were significant at 2.5, 5.4 and 16.2% (p <  0.001) respectively, and 4.9, 8.4 and 18.6% (p <  0.001) respectively. In the high-risk group, loco-regional recurrence (p <  0.001), and distant metastasis (p = 0.044) were significantly reduced, and disease free survival (p = 0.004), and overall survival (p = 0.029) were significantly improved after PMRT. In the low- and intermediate-risk groups, PMRT had no significant effect on loco-regional recurrence (p = 0.268), distant metastasis (p = 0.252), disease free survival (p = 0.608) or overall survival (p = 0.986). CONCLUSION: Our results showed no benefits of PMRT in the low-risk group, and thus, omitting PMRT radiotherapy in this population could be considered.

Risk stratification for prediction of locoregional recurrence in patients with pathologic T1-2N0 breast cancer after mastectomy.

BACKGROUND: Previous studies have revealed that nearly 15-20% of selected high-risk T1-2N0 breast cancers developed LRR after mastectomy. This study is aim to indentify the risk factors of locoregional recurrence (LRR) in patients with pathologic T1-2N0 breast cancer after mastectomy in a real-world and distinguish individuals who warrant postmastectomy radiotherapy (PMRT). METHODS: Female patients treated from 1999 to 2014 in National Cancer Center of China were retrospectively reviewed. A competing risk model was developed to estimate the cumulative incidence of LRR with death treated as a competing event. RESULTS: A total of 4841 patients were eligible. All underwent mastectomy plus axillary nodes dissection or sentinel node biopsy without PMRT. With a median follow-up of 56.4 months (range, 1-222 months), the 5-year LRR rate was 3.9%.Besides treatment era, age ≤ 40 years old (p < 0.001, hazard ratio [HR] = 2.262), tumor located in inner quadrant (p < 0.001, HR = 2.236), T2 stage (p = 0.020, HR = 1.419), and negative expressions of estrogen receptor (ER) and progesterone receptor (PR) (p = 0.032, HR = 1.485), were patients-related independent risk factors for LRR. The 5-year LRR rates were 1.7, 3.5, and 15.0% for patients with zero, 1-2, and 3-4 risk factors (p < 0.001). CONCLUSIONS: Risk Stratification based on age, T stage, ER/PR status and tumor location can stratify patients with pT1-2 N0 breast cancer into subgroups with different risk of LRR. PMRT might be suggested for patients with 3-4 risk factors.

Radiotherapy plays an important role in improving the survival outcome in patients with T1-2N1M0 breast cancer - a joint analysis of 4262 real world cases from two institutions.

BACKGROUND: To compare the survival outcomes between breast-conserving surgery (BCS) and modified radical mastectomy (MRM), and to investigate the role of radiotherapy (RT) in patients with pT1-2N1M0 breast cancer. METHODS: A total of 4262 women with T1-2N1M0 breast cancer treated at two institutions were retrospectively reviewed. A total of 3858 patients underwent MRM, and 832 (21.6%) of them received postoperative RT (MRM + RT). A total of 404 patients received BCS plus postoperative RT (BCS + RT). All patients received axillary lymph node dissection, while 3.8% of them had upfront sentinel node biopsy. The association of survival outcomes with different surgical modalities (BCS vs. MRM) and the role of RT were evaluated using multivariable proportional hazards regression and confirmed by the propensity score-matching (PSM) method. RESULTS: At a median follow-up of 71 months (range of 6-230 months), the 5-year overall survival (OS) rates of the BCS and MRM groups were 96.5 and 92.7%, respectively (P = .001), and the corresponding 5-year disease-free-survival (DFS) and locoregional recurrence (LRR) rates were 92.9 and 84.0%, and 2.0 and 7.0% (P = .001), respectively (P < .001). Multivariate analysis revealed that RT was an independent prognostic factor for improved OS (P = .001) and DFS (P = .009), and decreased LRR (P < .001). However, surgery procedure was not independently associated with either OS (P = .495), DFS (P = .204), or LRR (P = .996), which was confirmed by PSM analysis. CONCLUSION: Postoperative radiotherapy rather than the surgery procedures was associated with superior survival outcomes in patients with T1-2N1M0 breast cancer.

Abnormal pretreatment coagulation factor levels correlate with poor prognosis in patients with early-stage extranodal nasal-type natural/killer T cell lymphoma.

Coagulative dysfunction is frequently observed among patients with extranodal nasal-type natural killer/T cell lymphoma (NKTCL) in our clinical practice. However, the true prognostic value of coagulation factors in patients with NKTCL has not been evaluated systemically. Data for patients with stage I/II NKTCL who were treated in the Cancer Hospital, Chinese Academy of Medical Sciences, from January 2008 to January 2019 were collected retrospectively. The patients enrolled in this study were initially diagnosed as having early-stage disease. The patients' baseline characteristics and pretreatment laboratory tests for coagulation function, including fibrinogen (FIB) and D-dimer (D-D), were reviewed and analyzed. The influence of coagulative factors on the responses and prognosis of patients with early-stage NKTCL was evaluated. Among 394 patients assessed, 154 were included in this study. Abnormal coagulation function was found in nearly half of the patients (48.1%). Univariate analysis showed that reduced complete remission (CR) was associated with elevated D-D (P = 0.001) and elevated FIB levels (P = 0.006). The D-D level was demonstrated as associated with unfavorable progression-free survival (PFS) (P = 0.003) and overall survival (OS) (P = 0.002). Multivariate analysis indicated that an elevated D-D level was an independent factor for poor clinical response (P = 0.019), PFS (P = 0.046), and OS (P = 0.024). Elevated pretreatment levels of coagulation factors, especially D-D and plasma FIB, are unfavorable predictors for clinical response, OS, and PFS in early-stage NKTCL.

Hypofractionated versus conventional fractionated postmastectomy radiotherapy for patients with high-risk breast cancer: a randomised, non-inferiority, open-label, phase 3 trial.

BACKGROUND: To our knowledge, no randomised study has compared postmastectomy hypofractionated radiotherapy with conventional fractionated radiotherapy in patients with breast cancer. This study aimed to determine whether a 3-week schedule of postmastectomy hypofractionated radiotherapy is as efficacious and safe as a 5-week schedule of conventional fractionated radiotherapy. METHODS: This randomised, non-inferiority, open-label, phase 3 study was done in a single academic hospital in China. Patients aged 18-75 years who had undergone mastectomy and had at least four positive axillary lymph nodes or primary tumour stage T3-4 disease were eligible to participate. Patients were randomly assigned (1:1) according to a computer-generated central randomisation schedule, without stratification, to receive chest wall and nodal irradiation at a dose of 50 Gy in 25 fractions over 5 weeks (conventional fractionated radiotherapy) or 43·5 Gy in 15 fractions over 3 weeks (hypofractionated radiotherapy). The modified intention-to-treat population (including all eligible patients who underwent randomisation but excluding those who were considered ineligible or withdrew consent after randomisation) was used in primary and safety analyses. The primary endpoint was 5-year locoregional recurrence, and a 5% margin was used to establish non-inferiority (equivalent to a hazard ratio <1·883). This trial is registered at ClinicalTrials.gov, number NCT00793962. FINDINGS: Between June 12, 2008, and June 16, 2016, 820 patients were enrolled and randomly assigned to the conventional fractionated radiotherapy group (n=414) or hypofractionated radiotherapy group (n=406). 409 participants in the conventional fractionated radiotherapy group and 401 participants in the hypofractionated radiotherapy group were included in the modified intention-to-treat analyses. At a median follow-up of 58·5 months (IQR 39·2-81·8), 60 (7%) patients had developed locoregional recurrence (31 patients in the hypofractionated radiotherapy group and 29 in the conventional fractionated radiotherapy group); the 5-year cumulative incidence of locoregional recurrence was 8·3% (90% CI 5·8-10·7) in the hypofractionated radiotherapy group and 8·1% (90% CI 5·4-10·6) in the conventional fractionated radiotherapy group (absolute difference 0·2%, 90% CI -3·0 to 2·6; hazard ratio 1·10, 90% CI 0·72 to 1·69; p<0·0001 for non-inferiority). There were no significant differences between the groups in acute and late toxicities, except that fewer patients in the hypofractionated radiotherapy group had grade 3 acute skin toxicity than in the conventional fractionated radiotherapy group (14 [3%] of 401 patients vs 32 [8%] of 409 patients; p<0·0001). INTERPRETATION: Postmastectomy hypofractionated radiotherapy was non-inferior to and had similar toxicities to conventional fractionated radiotherapy in patients with high-risk breast cancer. Hypofractionated radiotherapy could provide more convenient treatment and allow providers to treat more patients. FUNDING: National Key Projects of Research and Development of China; the Chinese Academy of Medical Science Innovation Fund for Medical Sciences; and Beijing Marathon of Hope, Cancer Foundation of China.

LncRNA and mRNA signatures associated with neoadjuvant chemoradiotherapy downstaging effects in rectal cancer.

Radiotherapy plays a crucial role in combined treatment modality in local advanced rectal cancer (LARC). While neoadjuvant chemoradiotherapy responses were variable in LARC patients, so, it is important to identify genes that closely associated with short-term and long-term responses to radiotherapy. In this study, we profiled long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) expression values of LARC patients with different neoadjuvant chemoradiotherapy downstaging depth score based on Agilent Arraystar Human LncRNA V3.0 Array(Agilent, CA). LncRNAs and mRNAs with aberrant expression values between the two groups of LARC patients were identified and lncRNA-miRNA-mRNA regulation network was also obtained through the combination of miRcode and miRTarBase database. Gene interaction network and module analysis of differential expression mRNAs contained in the lncRNA-miRNA-mRNA network identified five hub genes, including KRAS, PDPK1, PPP2R5C, PPP2R1B, and YES1, that should be closely associated with LARC's response to chemoradiotherapy. Besides, Kaplan-Meier analysis based on the Cyber Research Center (CRC) data set from The Cancer Genome Atlas indicated that aberrant expression of the five hub genes is significantly associated with CRC overall survival. In conclusion, we obtained several biomarkers that should be associated with neoadjuvant chemoradiotherapy response in LARC, which should be helpful for individual treatment and prognosis improvement.

Prognostic Nomogram for Overall Survival in Patients with Diffuse Large B-Cell Lymphoma.

PURPOSE: This study aimed to develop a prognostic nomogram in diffuse large B-cell lymphoma (DLBCL) and compare it with traditional prognostic systems. MATERIALS AND METHODS: We included 1,070 consecutive and nonselected patients with DLBCL in the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, between 2006 and 2012. A nomogram based on the Cox proportional hazards model was developed. RESULTS: The entire group were divided into the primary (n = 748) and validation (n = 322) cohorts. The 5-year overall survival (OS) rate was 64.1% for the entire group. Based on a multivariate analysis of the primary cohort, seven independent prognostic factors including age, Ann Arbor stage, Eastern Cooperative Oncology Group performance status score, lactate dehydrogenase, ß2-microglobulin, CD5 expression, and Ki-67 index were identified and entered the nomogram. The calibration curve showed the optimal agreement between nomogram prediction and actual observation. In addition, the concordance index (C-index) of the nomogram for OS prediction was 0.77 (95% confidence interval [CI], 0.73-0.81) in the primary cohort and 0.76 (95% CI, 0.70-0.81) in the validation, superior to that of the international prognostic index (IPI), revised IPI (R-IPI), and National Comprehensive Cancer Network (NCCN)-IPI (range, 0.69-0.74, p<.0001). Moreover, in patients receiving rituximab plus CHOP (R-CHOP) or R-CHOP-like regimens, compared with IPI (C-index, 0.73; 95% CI, 0.69-0.77), R-IPI (C-index, 0.70; 95% CI, 0.66-0.74), or NCCN-IPI (C-index, 0.71; 95% CI, 0.66-0.75), the DLBCL-specific nomogram showed a better discrimination capability (p < .0001). CONCLUSIONS: The proposed nomogram provided an accurate estimate of survival of patients with DLBCL, especially for those receiving R-CHOP or R-CHOP-like regimens, allowing clinicians to optimized treatment plan based on individualized risk prediction. IMPLICATIONS FOR PRACTICE: A diffuse large B-cell lymphoma (DLBCL)-specific prognostic nomogram was developed based on Chinese patients with DLBCL. As a tertiary hospital, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences is the number 1 ranked cancer center in China, with more than 800,000 outpatients in 2018. Patients included in this study were nonselected and came from 29 different provinces, municipalities, and autonomous regions in China. Thus, the data is believed to be representative to an extent.

Outcomes after hypofractionated stereotactic radiotherapy for colorectal cancer oligometastases.

BACKGROUND AND OBJECTIVES: To assess the efficacy and the effect of biologic effective dose (BED) on outcomes treated by hypofractionated stereotactic radiotherapy for colorectal cancer (CRC) oligometastases. METHODS: Patients with CRC oligometastases treated at our hospital between 2009 and 2016 were included. The relationship between BED and risk of local recurrence was assessed. Recursive partitioning analysis (RPA) was used to evaluate the effect of BED on outcomes. RESULTS: A total of 48 patients were included in this study. Median follow-up time of surviving patient was 15 months (range, 3-82 months). The 1-year local control rate was 85%. The risk of local recurrence decreased sharply when BED was >90 Gy10 . RPA showed BED of 100 Gy 10 was the appropriate dose for recurrence risk stratification. BED ≥ 100 Gy 10 was significantly better than BED < 100 Gy 10 for achieving 1-year local control (94.4% vs 63.2%; P = 0.022) and 1-year OS (100% vs 73.4%; P = 0.028). One patient who received long-term antiangiogenic treatment died of massive intestinal hemorrhage; no other grade 3 or above early or late events were observed. CONCLUSIONS: Hypofractionated stereotactic radiotherapy provides favorable outcomes with acceptable toxicities in CRC oligometastases. BED ≥ 100 Gy is associated with better outcomes.

Clinical features and outcomes of diffuse large B-cell lymphoma based on nodal or extranodal primary sites of origin: Analysis of 1,085 WHO classified cases in a single institution in China.

OBJECTIVE: To explore the clinicobiologic features and outcomes of diffuse large B-cell lymphoma (DLBCL) patients in China according to the primary site. METHODS: A total of 1,085 patients diagnosed with DLBCL in National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College during a 6-year period were enrolled. Their clinical characteristics and outcomes were analyzed according to the primary site. RESULTS: In the 1,085 patients, 679 (62.6%) cases were nodal DLBCL (N-DLBCL) and 406 cases (37.4%) were extranodal DLBCL (EN-DLBCL). The most common sites of N-DLBCL were lymphonodus (64.8%), Waldeyer's ring (19.7%), mediastinum (12.8%) and spleen (2.7%), while in EN-DLBCL, stomach (22.4%), intestine (16.0%), nose and sinuses (8.9%), testis (8.4%), skin (7.9%), thyroid (6.9%), central nervous system (CNS) (6.4%), breast (5.7%), bone (3.4%), and salivary gland (2.7%) were most common. N-DLBCL patients tend to present B symptoms, bulky disease, and elevated LDH more often, while age >60 years, extranodal sites >1, Ann Arbor stage I or II, bone marrow involvement, and Ki-67 index >90% were usually seen in EN-DLBCL. The 5-year overall survival (OS) rate and progression-free survival (PFS) rate for all patients were 62.5% and 54.2%. The 5-year OS rate for patients with N-DLBCL and EN-DLBCL were 65.5% and 56.9% (P=0.008), and the 5-year PFS were 57.0% and 49.0% (P=0.020). Waldeyer's ring originated DLBCL possessed the highest 5-year OS rate (83.6%) and PFS rate (76.9%) in N-DLBCL. The top five EN-DLBCL subtypes with favorable prognosis were stomach, breast, nose and sinuses, lung, salivary gland, with 5-year OS rate: 70.3%, 69.6%, 69.4%, 66.7% and 63.6%, respectively. While CNS, testis, oral cavity and kidney originated EN-DLBCL faced miserable prognosis, with 5-year OS rate of 26.9%, 38.2%, and 42.9%. CONCLUSIONS: In our study, primary sites were associated with clinical characteristics and outcomes. Compared with EN-DLBCL, N-DLBCL had better prognosis.

A prospective phase I study of hypo-fractionated neoadjuvant radiotherapy for locally advanced gastric cancer.

BACKGROUND: Previous studies have reported that neoadjuvant chemoradiotherapy can downstage the advanced gastric cancer. However, no studies are available on the application of hypo-radiotherapy to neoadjuvant radiotherapy. This study sought to assess the maximum tolerated dose (MTD) and dose-limited toxicity (DLT) of hypo-fractionated chemoradiotherapy for local advanced gastric cancer. METHOD: Patients with cT3-4 and/or lymph node-positive locally advanced gastric cancer or Siewert II/III esophagogastric junction adenocarcinoma were enrolled. Preoperative chemoradiation was followed by 3 cycles of oxaliplatin + S-1 neoadjuvant chemotherapy with an interval duration of 3-4 weeks. D2 resection was performed 2-4 weeks after neoadjuvant therapy. Three cycles of adjuvant chemotherapy were planned after surgery. Intensity-modulated radiotherapy (IMRT) was used. The radiotherapy dose level was defined using three levels, namely, 40.0 Gy/2.5 Gy, 41.6 Gy/2.6 Gy, 43.2 Gy/2.7 Gy delivered concurrently with S-1 at 80 mg/m2. RESULTS: From May 2016 to Dec 2016, nine patients with a median age of 63 years were enrolled in this study. The most common grade I-III adverse events were leukopenia (88.9%), nausea (88.9%), vomiting (77.8%) and weight loss (66.7%). Grade III adverse events consisted of vomiting and weight loss. CONCLUSION: The MTD of hypo-fractionated radiotherapy for locally advanced gastric cancer was 40.0 Gy/2.5 Gy, and the DLTs were vomiting and weight loss. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT03427684 (Retrospectively registered on February 9, 2018).