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).

Minimal residual disease profiling predicts pathological complete response in esophageal squamous cell carcinoma.

Accurate presurgical prediction of pathological complete response (pCR) can guide treatment decisions, potentially avoiding unnecessary surgeries and improving the quality of life for cancer patients. We developed a minimal residual disease (MRD) profiling approach with enhanced sensitivity and specificity for detecting minimal tumor DNA from cell-free DNA (cfDNA). The approach was validated in two independent esophageal squamous cell carcinoma (ESCC) cohorts. In a cohort undergoing neoadjuvant, surgical, and adjuvant therapy (NAT cohort), presurgical MRD status precisely predicted pCR. All MRD-negative cases (10/10) were confirmed as pCR by pathological evaluation on the resected tissues. In contrast, MRD-positive cases included all the 27 non-pCR cases and only one pCR case (10/10 vs 1/28, P < 0.0001, Fisher's exact test). In a definitive radiotherapy cohort (dRT cohort), post-dRT MRD status was closely correlated with patient prognosis. All MRD-negative patients (25/25) remained progression-free during the follow-up period, while 23 of the 26 MRD-positive patients experienced disease progression (25/25 vs 3/26, P < 0.0001, Fisher's exact test; progression-free survival, P < 0.0001, log-rank test). The MRD profiling approach effectively predicted the ESCC patients who would achieve pCR with surgery and those likely to remain progression-free without surgery. This suggests that the cancer cells in these MRD-negative patients have been effectively eliminated and they could be suitable candidates for a watch-and-wait strategy, potentially avoiding unnecessary surgery.

Metastasis risk stratification and response prediction through dynamic viable circulating tumor cell counts for rectal cancer in a neoadjuvant setting.

PURPOSE: Distant metastasis (DM) and neoadjuvant treatment response prediction remain critical challenges in the management of locally advanced rectal cancer (LARC). The aim of this study was to investigate the clinical relevance of viable circulating tumor cells (CTCs) for DM or response in patients with LARC in a neoadjuvant setting. METHODS: The detection of viable CTCs at different stages of treatment was planned for consecutive patients from a prospective trial. The Kaplan-Meier method, Cox proportional hazards model, and logistic regression model were utilized to analyze factors associated with DM or pathological complete response (pCR) and clinical complete response (cCR). RESULTS: Between December 2016 and July 2018, peripheral blood samples from 83 patients were collected before any treatment (median follow-up time, 49.3 months). CTCs were present in 76 of 83 patients (91.6%) at baseline, and more than three CTCs detected in the blood sample was considered high risk. Only the CTC risk group was significantly associated with 3-year metastasis-free survival (MFS) (high risk vs. low risk, 57.1% (95% CI, 41.6-72.6) vs. 78.3% (95% CI, 65.8-90.8), p = 0.018, log-rank test). When all the important variables were entered into the Cox model, the CTC risk group remained the only significant independent factor for DM (hazard ratio (HR), 2.74; 95% CI, 1.17-6.45, p = 0.021). The pCR and continuous cCR rates were higher in patients with a decreased number of CTCs of more than one after radiotherapy (HR, 4.00; 95% CI, 1.09-14.71, P = 0.037). CONCLUSIONS: The dynamic detection of viable CTCs may strengthen pretreatment risk assessment and postradiotherapy decision making for LARC. This observation requires further validation in a prospective study.

The safety of an MRI simulation-guided boost after short-course preoperative radiotherapy for unresectable rectal cancer (SUNRISE): interim analysis of a randomized phase II trial.

PURPOSE: The safety of an MRI simulation-guided boost after short-course preoperative radiotherapy (SCPRT) for unresectable rectal cancer is assessed with a planned interim analysis. METHODS AND MATERIALS: Patients diagnosed with clinical stage T3-4 or regional lymph node-positive disease with positive mesorectal fascia or T4b disease evaluated by pelvic MRI were randomly assigned to the SCPRT-boost group (25 Gy in 5 fractions plus 4 Gy delivered to the gross tumor volume, followed by four cycles of chemotherapy) or preoperative chemoradiotherapy group (50 Gy in 25 fractions with concurrent chemotherapy). Then, patients received total mesorectal excision surgery after preoperative treatment. The primary endpoint was the R0 resection rate. The interim analysis was performed when 42 patients completed their assigned treatments. RESULTS: From October 2018 to November 2019, a total of 43 patients were enrolled, and 42 patients were included in the interim analysis. During preoperative therapy, grade 3 or above toxicities were observed in 10/21 (47.6%) patients in the experimental group, and 4/21 (19.0%) patients in the control group. A total of 17 (81.0%) and 13 (61.9%) patients in the experimental group and control group underwent surgery, respectively. Overall, 65.1% of the patients achieved R0 resection in the intention-to-treat analysis. Surgery-related adverse complications were observed in 2 patients (11.8%) in the experimental group and 1 patient (7.7%) in the control group. CONCLUSION: Our results show that the toxicity of an MRI simulation-guided boost after SCPRT for unresectable rectal cancer is acceptable. Thus, this clinical trial will be continued as planned.

Case report: Radiotherapy plus pneumococcal conjugate vaccine stimulates abscopal immune response in a patient with ALK+ NSCLC.

Most patients with anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer (NSCLC) could benefit from the treatment with selected tyrosine kinase inhibitors (TKIs) for a period of time, but almost inevitably progress due to drug resistance. It was reported that these patients were generally unresponsive to immune-based therapies. Here, we reported that stereotactic body radiotherapy (SBRT) combined with pneumococcal conjugate vaccine (PCV) produced excellent therapeutic outcomes in a patient after multiple lines of TKI treatment. The patient's metastasis lesion experienced regression after SBRT for lumbar spine. Unexpectedly, the patient also experienced an abscopal complete pathological response (CPR) just after combination use of SBRT and PCV. Biopsy analysis indicated that the primary lung lesion was map-like necrotic and infiltrated by tumor-infiltrating lymphocytes (TILs), and multifocal granulomas and early tertiary lymphoid structures (TLS) were formed. Our case reported that radiotherapy plus PCV could specifically stimulate immune response and remodel the tumor immune microenvironment in TKI-resistant NSCLC, which may provide a new perspective for future immunotherapy in this challenging clinical situation.

Preoperative Concurrent Chemoradiotherapy Versus Neoadjuvant Chemotherapy for Locally Advanced Gastric Cancer: Phase II Randomized Study.

Objective: We evaluated and compared the efficacy and safety of neoadjuvant chemoradiotherapy (NACRT) versus neoadjuvant chemotherapy (NACT) for locally advanced gastric cancer (LAGC) in a single-center randomized phase II trial. Methods: Patients with LAGC were enrolled and received either NACT or NACRT, followed by gastrectomy and adjuvant chemotherapy. The primary endpoint was an R0 resection rate. Results: We enrolled 75 patients: 75.7% (NACT, 28/37 patients) and 76.3% (NACRT, 29/38 patients) underwent surgery; R0 resection rates were 73.0% (27/37) and 73.7% (28/38), respectively. The NACRT group had significantly better major pathological response than the NACT group (37.9% vs 17.9%, p = 0.019). Between-group postoperative complications were not significantly different. The median follow-up was 59.6 months; 5-year overall survival (OS) rate was 50.1% (NACT) and 61.9% (NACRT); neither group reached the median OS; median progression-free survival was 37.3 and 63.4 months, respectively. Conclusions: S-1-based NACRT did not improve the R0 resection rate, although it presented better tumor regression with similar safety to NACT. Trial registration: ClinicalTrial.gov NCT02301481.

Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR).

PURPOSE: To ascertain if preoperative short-term radiotherapy followed by chemotherapy is not inferior to a standard schedule of long-term chemoradiotherapy in patients with locally advanced rectal cancer. MATERIALS AND METHODS: Patients with distal or middle-third, clinical primary tumor stage 3-4 and/or regional lymph node-positive rectal cancer were randomly assigned (1:1) to short-term radiotherapy (25 Gy in five fractions over 1 week) followed by four cycles of chemotherapy (total neoadjuvant therapy [TNT]) or chemoradiotherapy (50 Gy in 25 fractions over 5 weeks, concurrently with capecitabine [chemoradiotherapy; CRT]). Total mesorectal excision was undertaken 6-8 weeks after preoperative treatment, with two additional cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) in the TNT group and six cycles of CAPOX in the CRT group. The primary end point was 3-year disease-free survival (DFS). RESULTS: Between August 2015 and August 2018, a total of 599 patients were randomly assigned to receive TNT (n = 302) or CRT (n = 297). At a median follow-up of 35.0 months, 3-year DFS was 64.5% and 62.3% in TNT and CRT groups, respectively (hazard ratio, 0.883; one-sided 95% CI, not applicable to 1.11; P < .001 for noninferiority). There was no significant difference in metastasis-free survival or locoregional recurrence, but the TNT group had better 3-year overall survival than the CRT group (86.5% v 75.1%; P = .033). Treatment effects on DFS and overall survival were similar regardless of prognostic factors. The prevalence of acute grade III-V toxicities during preoperative treatment was 26.5% in the TNT group versus 12.6% in the CRT group (P < .001). CONCLUSION: Short-term radiotherapy with preoperative chemotherapy followed by surgery was efficacious with acceptable toxicity and could be used as an alternative to CRT for locally advanced rectal cancer.

Postoperative Chemoradiotherapy With Capecitabine and Oxaliplatin vs Capecitabine for Stage II to III Rectal Cancer: A Randomized Clinical Trial.

Importance: Several studies have explored the efficacy and toxic effects of concurrent 5-fluorouracil (5-FU)- or capecitabine-based chemoradiotherapy (CRT) with or without oxaliplatin in the neoadjuvant setting. Addition of oxaliplatin to 5-FU or capecitabine elicited similar outcomes but with significantly increased toxic effects; however, there is a need for randomized clinical trials comparing 2 CRT regimens for patients receiving CRT in the adjuvant setting. Objective: To explore the efficacy and toxic effects of oxaliplatin combined with postoperative concurrent capecitabine and radiotherapy (RT) for pathological stage II and III rectal cancer. Design, Setting, and Participants: This multicenter randomized clinical trial enrolled patients from 7 centers in China between April 1, 2008, and December 30, 2015. Patients with pathologically confirmed stage II and III rectal cancer were randomized (1:1) to receive concurrent CRT with capecitabine or capecitabine plus oxaliplatin. Analysis was conducted from December 31, 2019, to March 15, 2020. Interventions: RT comprised 45 to 50 Gy in 25 fractions of 1.8 to 2.0 Gy over 5 weeks. In the capecitabine with RT group, concurrent chemotherapy included 2 cycles of capecitabine (1600 mg/m2) on days 1 to 14 and 22 to 35. The capecitabine and oxaliplatin with RT group received identical postoperative RT to that in the capecitabine with RT group combined with capecitabine (1300 mg/m2) on days 1 to 14 and 22 to 35 and a 2-hour infusion of oxaliplatin (60 mg/m2) on weeks 1, 2, 4, and 5. Patients in both groups received adjuvant chemotherapy (capecitabine or fluorouracil and oxaliplatin) after CRT. Main Outcomes and Measures: The primary end point was 3-year disease-free survival (DFS). Results: A total of 589 patients (median [IQR] age, 55 [47-52] years; 375 [63.7%] men and 214 [36.3%] women) were enrolled, including 294 patients randomized to the capecitabine with RT group and 295 patients randomized to the capecitabine and oxaliplatin with RT group. Median (IQR) follow-up was 68 (45-96) months. Most patients had stage III disease (574 patients [75.9%]). Three-year DFS was 76.3% for the capecitabine with RT group and 74.1% for the capecitabine and oxaliplatin with RT group, and 5-year DFS was 72.0% for the capecitabine with RT group and 71.1% for the capecitabine and oxaliplatin with RT group (hazard ratio [HR], 1.07; 95% CI, 0.79-1.44; P = .68). There was no significant difference between groups in overall survival (HR, 0.93; 95% CI, 0.64-1.34; P = .70) or local recurrence (HR, 0.61; 95% CI, 0.31-1.22; P = .16). More grade 3 and 4 acute toxic effects were observed in the capecitabine and oxaliplatin with RT group than in the capecitabine with RT group (114 patients [38.6%] vs 84 patients [28.6%]; P = .01). Conclusions and Relevance: This randomized clinical trial found that addition of oxaliplatin to capecitabine-based postoperative CRT did not improve the efficacy of treatment but increased the risk of severe acute toxic effects. This finding highlights the basic role of postoperative capecitabine with RT for patients with locally advanced rectal cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT00714077.

Efficacy and toxicity of capecitabine combined with intensity-modulated radiotherapy after D1/D2 lymph node dissection in patients with gastric cancer.

BACKGROUND: Adjuvant chemoradiotherapy (ACRT) with oral capecitabine and intensity-modulated radiotherapy (IMRT) were well tolerated in a phase I study in patients who had undergone partial or total gastrectomy for locally advanced gastric cancer (GC). This phase II study aimed to further determine the efficacy and toxicity of this combination after radical resection and D1/D2 lymph node dissection (LND) for patients with locally advanced GC. AIM: To further determine the efficacy and toxicity of this combination after radical resection and D1/D2 LND for patients with locally advanced GC. METHODS: Forty patients (median age, 53 years; range, 24-71 years) with pathologically confirmed adenocarcinoma who underwent D1/D2 LND were included in this study. The patients received ACRT comprising IMRT (total irradiation dose: 45 Gy delivered in daily 1.8-Gy fractions on 5 d a week over 5 wk) and capecitabine chemotherapy (dose: 800 mg/m² twice daily throughout the duration of radiotherapy). The primary study endpoint was disease-free survival (DFS), and the secondary endpoints were overall survival (OS), toxic effects, and treatment compliance. RESULTS: The 3-year DFS and OS were 66.2% and 75%, respectively. The median time to recurrence was 19.5 mo (range, 6.1-68 mo). Peritoneal implantation (n = 10) was the most common recurrence pattern, and the lung was the most common site of extra-abdominal metastases (n = 5). Nine patients developed grade 3 or 4 toxicities during ACRT. Two patients discontinued ACRT, while eleven underwent ACRT without receiving the entire course of capecitabine. There were no treatment-related deaths. CONCLUSION: The ACRT protocol described herein showed acceptable safety and efficacy for patients with locally advanced GC who received radical gastrectomy and D1/2 LND.

Safety and efficacy of preoperative chemoradiotherapy in fit older patients with intermediate or locally advanced rectal cancer evaluated by comprehensive geriatric assessment: A planned interim analysis of a multicenter, phase II trial.

BACKGROUND AND PURPOSE: Comprehensive geriatric assessment (CGA) is a diagnostic method to assess the physical and mental health status of older patients. The purpose of this study was to assess the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for intermediate or locally advanced rectal cancer in older people who were classified as "fit" by CGA. The interim analysis focusing on safety was reported here as the first part of this trial. METHODS AND MATERIALS: This is a single arm, multicenter, phase II trial. The eligible patients for this study were aged 70 years or above that fulfilled the standard of intermediate or locally advanced risk category, and met the standard of fit (SIOG1) evaluated by CGA. All patients received preCRT (50 Gy) with Raltitrexed (3 mg/m2 on d1 and d22). Qualitative and quantitative variables were described using descriptive statistics. The surgery adherence predicting was analyzed by multivariate logistic regression. RESULTS: Thirty-nine fit patients were enrolled. All patients except one finished radiotherapy without dose reduction. Thirty-two patients finished the prescribed Raltitrexed therapy as scheduled. A serious toxicity was observed in 12 patients (30.8%), and only six patients (15.4%) experienced non-hematological side effects. CONCLUSION: Overall, our results showed that preCRT was feasible and safe in older patients with rectal cancer who were evaluated as fit based on CGA, supporting the use of CGA to tailor oncological treatment and predict the tolerance of a specific therapy. Completing this trial as planned would provide further valuable insights.

Tomotherapy as an adjuvant treatment for gastroesophageal junction and stomach cancer may reduce bowel and bone marrow toxicity compared to intensity-modulated radiotherapy and volumetric-modulated arc therapy.

PURPOSE: To compare dosimetric parameters of intensity-modulated radiotherapy (IMRT), volumetric-modulated arc therapy (VMAT) and tomotherapy (TOMO) in the adjuvant treatment of gastroesophageal junction (GEJ)/stomach cancer. The planning goal was to maintain high target coverage while keeping the dose to the bowel and bone marrow (BM) as low as possible. MATERIALS AND METHODS: After curative surgery, 16 patients with GEJ/stomach cancer were re-planned by coplanar IMRT (five fixed beam), VMAT (double-arc), and TOMO. The dose to the planning target volume (PTV) was 45 Gy in 25 fractions. The target parameters, including the homogeneity index (HI) and conformity index (CI), and doses to the organs at risk (OARs) were analyzed. RESULTS: Dosimetric parameters for PTV and OARs were comparable among the three techniques. However, TOMO provided improved conformity (CI = 0.92±0.03) and homogeneity (HI = 1.07±0.02) than IMRT (CI = 0.87±0.03; HI = 1.09±0.02; p < 0.05) and VMAT (CI = 0.86±0.03; HI = 1.09±0.02; p < 0.01). TOMO also improved dose sparing of the bowel (percentage of the volume receiving a dose of ≥ 30 Gy [V30] = 23.24±9.85) and BM (V30 = 71.66±6.15) compared with IMRT (bowel V30 = 30.02±11.74; BM V30 = 83.74±8.42; p < 0.01) and VMAT (bowel V30 = 31.88±11.59; BM V30 = 79.51±9.07; p < 0.01). CONCLUSIONS: TOMO is a good option for adjuvant treatment of GEJ/stomach cancer in patients undergoing radical surgery due to its superior bowel and BM dose sparing, dose conformity and dose homogeneity; however, future studies are required to validate its clinical efficacy.

Gefitinib for asymptomatic brain metastasis from advanced non-small cell lung cancer: Report of a favourable outcome.

Brain metastasis (BM) is common in patients with non-small cell lung cancer (NSCLC). Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have now been included as standard treatment options for NSCLC harboring EGFR-activating mutations, only a few prospective reports demonstrate the efficacy of these agents in a BM setting. We report a case of a patient with advanced NSCLC, in which oral gefitinib documented a significant antitumor effect on parallel progression of extracranial lesion and BM occurred during chemotherapy.

Adjuvant treatment may benefit patients with high-risk upper rectal cancer: A nomogram and recursive partitioning analysis of 547 patients.

PURPOSE: The role of adjuvant chemoradiotherapy (ACRT) or adjuvant chemotherapy (ACT) in treating patients with locally advanced upper rectal cancer (URC) after total mesorectal excision (TME) surgery remains unclear. We developed a clinical nomogram and a recursive partitioning analysis (RPA)-based risk stratification system for predicting 5-year cancer-specific survival (CSS) to determine whether these individuals require ACRT or ACT. MATERIALS AND METHODS: This retrospective analysis included 547 patients with primary URC. A nomogram was developed based on the Cox regression model. The performance of the model was assessed by concordance index (C-index) and calibration curve in internal validation with bootstrapping. RPA stratified patients into risk groups based on their tumor characteristics. RESULTS: Five independent prognostic factors (age, preoperative increased carcinoembryonic antigen and carcinoma antigen 19-9, positive lymph node [PLN] number, tumor deposit [TD], pathological T classification) were identified and entered into the predictive nomogram. The bootstrap-corrected C-index was 0.757. RPA stratification of the three prognostic groups showed obviously different prognosis. Only the high-risk group (patients with PLN ≤ 6 and TD, or PLN > 6) benefited from ACRT plus ACT when compared with surgery followed by ACRT or ACT, and surgery alone (5-year CSS: 70.8% vs. 57.8% vs. 15.6%, P < 0.001). CONCLUSIONS: Our nomogram predicts 5-year CSS after TME surgery for locally advanced rectal cancer and RPA-based stratification indicates that ACRT plus ACT post-surgery may be an important treatment plan with potentially ignificant survival advantages in high-risk URC. This may help to select candidates of adjuvant treatment in prospective studies.

Possible contribution of IMRT in postoperative radiochemotherapy for rectal cancer: analysis on 1798 patients by prediction model.

The evidence for adjuvant therapy in locally advanced rectal cancer after TME surgery is sparse. The aim of this study was to identify predicting factors of overall survival (OS) in these patients and combine them into a nomogram for individualized treatment. 1798 patients with pathologically staged II/III rectal adenocarcinoma treated by radical TME surgery from a single center's database were reviewed. The nomogram was derived by Cox proportional hazards regression. Its performance was assessed by concordance index and calibration curve in internal validation with bootstrapping. Pooled Cox model analysis identified age, sex, grade of histology, pathological T and N stage, residual tumor, concurrent radiochemotherapy (RTCT), adjuvant chemotherapy cycles (CT), radiotherapy (RT) unexpected interruption days and intensity-modulated radiation therapy (IMRT) as significant covariates for 5-year OS (P<0.05). Postoperative RTCT, CT and IMRT all improved OS. The proposed model can predict 5-year OS with a C-index of 0.7105. IMRT significantly benefited OS in multivariate analysis (p=0.0441).In conclusion, our nomogram can predict 5-year OS after TME surgery for locally advanced rectal cancer with simple and effective advantage. This model may provide not only baseline OS estimate but also a tool for candidates selecting of adjuvant treatment in prospective studies.