Neoadjuvant Concurrent Chemoradiotherapy Research Articles

NEOSPACE trial: Neoadjuvant pembrolizumab-gemcitabine-cisplatin followed by concurrent pembrolizumab-chemoradiation and maintenance pembrolizumab for stage IVA nasopharyngeal cancer (NPC).

6010 Background: Stage IVA NPC had the worst prognosis despite the current standard of neoadjuvant chemotherapy and concurrent chemoradiation (CRT). There is no safety and efficacy data combining immune checkpoint inhibitor (ICI) and CRT in NPC. Methods: We conducted an open label, single arm, multi-site, phase 2 clinical trial in AJCC 8th Edition Stage IVA (T4 and/or N3, M0) WHO type 2/3 Epstein Barr virus (EBV) +ve NPC (Clinical trial register NCT03734809). The experimental treatment consisted of neoadjuvant pembrolizumab (200 mg D1), gemcitabine (1000 mg/m2 D1+8) and cisplatin (80 mg/m2 D1) q3w x2 followed by concurrent pembrolizumab (200 mg x3 week 1, 4 and 7) and cisplatin (40 mg/m2 weekly x7) during intensity-modulated radiation (IMRT), and maintenance pembrolizumab 200 mg q3w x12 from 4 weeks post-RT. By Fleming one-stage design (type I error 0.05, power 0.80, 10% drop out), planned sample size is 46. Primary endpoint is 2-year (yr) progression free survival (PFS). Secondary endpoints include safety and tolerability. Plasma EBV DNA (pEBV DNA) was monitored. Results: Accrual was completed with 46 subjects recruited at two study sites from May 2019 to June 2022 in Hong Kong (n=31) and Singapore (n=15). This protocol specified analysis included 37 subjects with >12 months post-treatment follow up (median 26.8 months, 95% CI 21.3-32.9). Patient demographics: mean age 52 (range 27 - 84); M:F 31:6; ECOG 0=23, 1=14; stages: T4N1-2 (16), T1-3N3 (18), T4N3 (3). Overall compliance rate: neoadjuvant cisplatin 98.6%, gemcitabine 97.7%, concurrent cisplatin 73.7%, pembrolizumab 100% (neoadjuvant), 77.5% (concurrent), 77% (maintenance), IMRT 99.7% (69.96 Gy). Treatment related adverse events (≥ grade 3, >10%): dysphagia (32.4%), mucositis (29.7%), neutropenia (29.7%), radiation dermatitis (24.3%), anemia (18.9%), hyponatremia (13.5%), thrombocytopenia (10.8%). No ≥ grade 4 mucositis/dermatitis. The 2-yr PFS was 69.6% (95% CI 53.8 - 88.5%). At the end of neoadjuvant, CRT and maintenance phases, molecular remission (pEBV DNA = 0) was achieved in 24.3%, 70.3% and 70.3% of patients respectively, which strongly correlated with PFS (p=0.0253, 0.0007 and <0.0001 respectively, Table). Conclusions: Pembrolizumab incorporated into neoadjuvant, CRT and maintenance protocol is safe with promising results. This strategy of combining ICI with neoadjuvant chemotherapy and CRT is being tested in several ongoing phase 3 trials in advanced NPC. Clinical trial information: NCT03734809 . [Table: see text]

Phase Ib study of neoadjuvant concurrent chemoradiation plus durvalumab followed by surgery and adjuvant durvalumab for resectable stage III NSCLC.

8556 Background: The use of neoadjuvant and adjuvant immunotherapy in resectable non-small cell lung cancer (NSCLC) has become a standard of care. However, the integration of immunotherapy into a trimodality treatment regimen has not been widely explored. We hypothesized that adding durvalumab to neoadjuvant concurrent chemoradiation and surgery would not increase treatment-related adverse events (TRAE) during neoadjuvant period. Methods: This was a prospective, single center, single-arm, open-label phase Ib study. Patients with resectable, stage III N2 NSCLC received concurrent chemoradiation [weekly paclitaxel (45mg/m2)/carboplatin (AUC 2.0) for 5 weeks with radiotherapy 45Gy] and durvalumab 1,500mg Q4W for 2 cycles followed by surgical resection and adjuvant durvalumab for 1 year. The primary endpoint was the frequency of patients who experience grade 3 or more TRAE during neoadjuvant therapy based on CTCAE 4.03. Results: Of 30 patients (median age 65.5 years; 67% male), 56.7% had squamous histology and 60.0% had stage IIIA. Any grade AEs and TRAEs (neoadjuvant/adjuvant) were reported in 83.3%/76.7% and 70.0%/63.3% of patients, respectively. Grade 3 or more AEs and TRAEs (neoadjuvant/adjuvant) were reported in 10.0/3.3% and 10.0%/0.0%, respectively. Grade 3 or more TRAE reported during neoadjuvant treatment were neutropenia, anemia, and nausea, one each; no Grade 5 AEs occurred. Surgical resection was not performed in three patients: two due to treatment-related adverse events (AEs) and one due to patient refusal. Among 27 patients who received complete resection, the pathologic complete response (pCR) rate and major pathologic response (MPR) rate were 40.7% (95% CI, 22.4 – 61.2) and 74.1% (95% CI, 53.7 – 88.9), respectively. Excluding four patients with EGFR, ALK, KRAS G12C, or MET ex14skipping mutations, the pCR rate was 47.8% (95% CI, 26.8 – 69.4) and MPR rate was 87.0% (95% CI, 66.4 – 97.2). Overall, pathologic downstaging was achieved in 70.4% (95% CI, 49.8 – 86.2). Objective response rate according to RECIST v1.1 was 50.0% (95% CI, 31.3 – 68.7). One patient delayed the schedule for surgical resection due to radiation pneumonitis (G2), unrelated to the drug administered. Otherwise, there were no peri-operative mortality or morbidity. All patients who underwent surgery, except one whose disease progressed immediately after resection, received at least one dose of adjuvant durvalumab; 61.5% completed 1-year treatment, 11.5% were continuing treatment, 11.5% discontinued due to AE, and 11.5% discontinued due to disease progression at the time of data cutoff. Grade 3 or more TRAE reported during adjuvant treatment were radiation pneumonitis and proteinuria, one each. Conclusions: This study confirms the manageable safety profile of adding durvalumab to neoadjuvant concurrent chemoradiation for treatment of resectable stage III NSCLC. Clinical trial information: NCT03694236 .

A retrospective analysis of tislelizumab and GP regimen neoadjuvant therapy followed by concurrent chemoradiotherapy plus nimotuzumab in patients with high-risk nasopharyngeal carcinoma.

e18060 Background: Efficacy of nasopharyngeal carcinoma (NPC) with T4 or N3 remains unsatisfactory due to high-risk of distant metastasis or recurrence, indicating the need of more comprehensive treatment. We aim to analysis the efficacy and safety of tislelizumab and GP regimen in combination with neoadjuvant therapy and concurrent chemoradiotherapy (CCRT) plus nimotuzumab in patients with high-risk NPC. Methods: Our team conducted a retrospective analysis of 44 adult patients with high-risk locally advanced (T4 or N3; M0) nasopharyngeal carcinoma between March 2021 and January 2022, the median follow-up time was 599 days. The patients had received neoadjuvant chemotherapy (gemcitabine,1000 mg/m2, days 1 and 8, cisplatin,80 mg/m2, day 1), and tislelizumab (200mg) on day 1 every 3 weeks for 4 cycles followed by chemoradiotherapy including intensity modulated radiotherapy (IMRT), lobaplatin and nimotuzumab. Lobaplatin was intravenously administered at a dose of 30 mg/m2 on days 1 and 22. Nimotuzumab was intravenously administered at a dose of 200 mg on day 1 every week for 6 weeks. All patients underwent response assessments during neoadjuvant therapy, chemoradiotherapy and follow-up at regular intervals. Results: 44 patients were identified with the median age being 50y(24y-70y). At neoadjuvant treatment period, 44 patients completed 170 cycles of the combination of tislelizumab and GP regimen. During concurrent chemo-radiotherapy period, 42 (95.45%) of 44 patients completed 6 weeks of nimotuzumab treatment and 41 (93.18%) of 44 patients completed 2 cycles of lobaplatin treatment. Overall, 20 patients (45.5%) had a complete response, and 24 (54.5%) had a partial response after neoadjuvant therapy before the start of chemoradiotherapy. At 3 months and 6 months after radiotherapy, 90.9% (40 of 44) and 97.7% (43 of 44) of the patients had a complete response. 42 of the 44 patients were alive (95.5%). 3 events of recurrence(1) or death(2) were recorded. 19 (43.2%) of 44 patients had grade 3-4 treatment-related adverse events, and grade 3-4 immune-related adverse events(irAE) was recorded in 3 patients (6.8%) in the entire treatment. Grade 3-4 irAEs were rash(2) and hypothyroidism(1). Conclusions: Neoadjuvant therapy with tislelizumab and GP regimen followed by concurrent chemoradiotherapy plus nimotuzumab seems to have promising efficacy, lower toxic effects and better treatment compliance, which is a new treatment strategy for high-risk NPC.

Efficacy and safety of camrelizumab and apatinib combined with neoadjuvant concurrent chemoradiation for MSS locally advanced rectal cancer.

e15647 Background: Long-term neoadjuvant concurrent chemoradiotherapy (CRT) is the standard therapy for local advanced rectal cancer (LARC).However, the pCR rate is only about 15 %. Immune checkpoint inhibitors (ICIs) and antiangiogenic agents have shown activity in advanced rectal cancer, but their efficacy in the neoadjuvant setting is unclear. In this exploratory trial, we evaluate the efficacy and safety of a combination of ICI (Camrelizumab), anti-angiogenesis (Apatinib) and CRT for neoadjuvant treatment of microsatellite-stable (MSS) LARC. Methods: Patients in experimental group received Camrelizumab injection combined with Apatinib tablets and concurrent CRT. Radiotherapy dose: 5040cGy/28f/180cGy; Capecitabine 825 mg/m2 bid on the radiotherapy day; Apatinib 250mg qd d1-d60; Camrelizumab 200 mg q3w, d22, d43, d64. Surgery with total mesorectal excision was performed 7-9 weeks after the end of CRT. The primary endpoint was pCR rate and the secondary endpoints included major pathological response (MPR) rate, R0 resection rate, 2-year DFS rate, 3-year OS rate and safety. Results: From July/2022 to October/2022, a total of 11 patients were recruited and assessed, 90.91% (10/11) of which is at high-risk (cT3 with any MRF involved, any cT4a/b, lateral node +, HLARC). Out of the 11 patients evaluable for pathological response, 4 (36.36%) patients achieved a pCR (AJCC grade 0) and 7 (63.64%) obtained a MPR(AJCC grade 0+1)(table). All patients achieved R0 resection and downstaging. Treatment-related severe adverse events were observed in 3 patients (grade 3-4 transaminase elevations); all fully recovered and received radical surgery. No treatment-related deaths were observed. Conclusions: A promising pCR rate of 36.36%, with mild toxicities, was shown in MSS LARC patients treated with neoadjuvant Camrelizumab combined with Apatinib and long-term CRT plus radical surgery, suggesting the candidate therapy for the future non-surgical approach. Clinical trial information: ChiCTR2100053040 . [Table: see text]

Advantages of nasogastric tube feeding during neoadjuvant concurrent chemoradiotherapy for esophageal cancer: A retrospective study

ObjectiveTo compare the effects of oral intake and nasogastric tube (NG) feeding on nutritional status, complications and survival during neoadjuvant chemoradiotherapy for esophageal squamous-cell carcinoma (ESCC) patients. MethodsA total of 61 ​ESCC cases treated with neoadjuvant chemoradiotherapy from December 2018 to March 2020 were enrolled, including (38 in oral intake group, and 22 in NG feeding group. Disease characteristics and baseline nutritional markers were collected in both groups. Nutritional status, complication and completion rate of chemoradiotherapy in both groups were evaluated. ResultsCompared with the oral intake group, patients in the NG feeding group had a later T stage (P ​= ​0.027) and clinical stage (P ​= ​0.014). The levels of energy intake (P ​= ​0.033), serum prealbumin (P ​< ​0.001), albumin (P ​= ​0.017) and hemoglobin (P ​= ​0.015) before treatment in NG group were significantly lower than those in oral intake group. Furthermore, patient-generated subjective global assessment (PG-SGA) score (P ​= ​0.016) and the levels of serum C-reactive protein (P ​= ​0.014) of NG feeding group were significantly higher than those of oral intake group. However, at the end of treatment, PG-SGA scores were increased in oral intake group and decreased in NG feeding group. In addition, the NG feeding group had a lower incidence of grade ≥2 esophagitis (P ​= ​0.037), and higher completion rate of chemotherapy compared with oral intake group (P ​= ​0.034). Meanwhile, the proportion of parenteral nutrition (P ​= ​0.008) and anti-inflammatory (P ​= ​0.022) treatment in NG feeding group was significantly lower than that in oral intake group. Although patients in the NG feeding group had a worse prognosis, there were no statistically significant differences in overall survival (OS) and progression-free survival (PFS) between the two groups (P ​> ​0.05). ConclusionsAs a safe and effective enteral nutrition approach to improving nutrition, nasogastric tube feeding could increase treatment completion rate and reduce the incidence of ≥ grade 2 esophagitis reaction during neoadjuvant chemoradiotherapy.

Radiomics Analysis of 18F-FDG PET/CT for Prognosis Prediction in Patients with Stage III Non-Small Cell Lung Cancer Undergoing Neoadjuvant Chemoradiation Therapy Followed by Surgery

We investigated the prognostic significance of radiomic features from 18F-FDG PET/CT to predict overall survival (OS) in patients with stage III NSCLC undergoing neoadjuvant chemoradiation therapy followed by surgery. We enrolled 300 patients with stage III NSCLC who underwent PET/CT at the initial work-up (PET1) and after neoadjuvant concurrent chemoradiotherapy (PET2). Radiomic primary tumor features were subjected to LASSO regression to select the most useful prognostic features of OS. The prognostic significance of the LASSO score and conventional PET parameters was assessed by Cox proportional hazards regression analysis. In conventional PET parameters, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) of each PET1 and PET2 were significantly associated with OS. In addition, both the PET1-LASSO score and the PET2-LASSO score were significantly associated with OS. In multivariate Cox regression analysis, only the PET2-LASSO score was an independently significant factor for OS. The LASSO score showed better predictive performance for OS regarding the time-dependent receiver operating characteristic curve and decision curve analysis than conventional PET parameters. Radiomic features from PET/CT were an independent prognostic factor for the estimation of OS in stage III NSCLC. The newly developed LASSO score using radiomic features showed better prognostic results for individualized OS estimation than conventional PET parameters.

Prospective, longitudinal analysis of the gut microbiome in patients with locally advanced rectal cancer predicts response to neoadjuvant concurrent chemoradiotherapy

BackgroundNeoadjuvant concurrent chemoradiotherapy (nCCRT) is a standard treatment for locally advanced rectal cancer (LARC). The gut microbiome may be reshaped by radiotherapy through its effects on microbial composition, mucosal immunity, and the systemic immune system. We sought to clarify dynamic, longitudinal changes in the gut microbiome and blood immunomodulators throughout nCCRT and to explore the relationship of such changes with outcomes after nCCRT.MethodsA total of 39 patients with LARC were recruited for this study. Fecal samples and peripheral blood samples were collected from all 39 patients before nCCRT, during nCCRT (at week 3), and after nCCRT (at week 5). The gut microbiota and the microbial community structure were analyzed by 16S rRNA sequencing of the V3–V4 region. Levels of blood immunomodulatory proteins were measured with a Millipore HCKPMAG-11 K kit and Luminex 200 platform (Luminex, USA).ResultsCross-sectional and longitudinal analyses revealed that the gut microbiome profile and enterotype exhibited characteristic variations that could distinguish patients with good response (AJCC TRG classification 0–1) vs poor response (TRG 2–3) to nCCRT. Sparse partial least squares regression and canonical correspondence analyses showed multivariate associations between specific microbial taxa, host immunomodulatory proteins, immune cells, and outcomes after nCCRT. An integrated model consisting of baseline Clostridium sensu stricto 1 levels, fold changes in Intestinimonas, blood levels of the herpesvirus entry mediator (HVEM/CD270), and lymphocyte counts could predict good vs poor outcome after nCCRT [area under the receiver-operating characteristics curve (AUC)= 0.821; area under the precision-recall curve [AUPR] = 0.911].ConclusionsOur results showed that longitudinal variations in specific gut taxa, associated host immune cells, and immunomodulatory proteins before and during nCCRT could be useful for early predictions of the efficacy of nCCRT, which could guide the choice of individualized treatment for patients with LARC.

Randomized controlled trial of intravenous sedation vs general anesthesia for esophageal dilation with percutaneous endoscopic gastrostomy in esophageal cancer patients.

Esophageal squamous cell cancer (ESCC) is mostly diagnosed in its later stages, when patients present with dysphagia and weight loss. Esophageal dilation with percutaneous endoscopic gastrostomy (PEG) is a common surgical procedure in patients with locally advanced ESCC because of tumor obstruction and enteral nutrition support during neoadjuvant or definitive concurrent chemoradiotherapy (CCRT). Esophageal dilation with PEG is widely performed under general anesthesia (GA) with endotracheal intubation. To determine the overall success rate of completing this procedure using intravenous (IV) sedation with dexmedetomidine (DEX) relative to GA and to compare its perioperative conditions, including procedure times, pain scores (visual analog scale), adverse events, and costs. SongklanagarindHospital, Faculty of Medicine, Prince of Songkla University, Thailand. Prospective randomized controlled trial (RCT) of locally advanced ESCC patients who had dysphagia and needed esophageal dilation with PEG between January 2020 and December 2021. Esophageal dilation (using a Savary-Gilliard dilator) and PEG were performed using the pull technique. Seventy patients were randomly assigned to either the DEX group (n = 34) or the GA group (n = 36). All patients in both groups underwent successful surgery. The DEX group had a significantly shorter procedure time, lower procedure cost, and lower total hospital cost than the GA group. However, there were no significant between-group differences in pain scores or length of hospital stay. There were no serious adverse events in either group; however, the GA group had some incidences of sore throat, transient hoarseness, and atelectasis. This study found that IV sedation with DEX during esophageal dilation with PEG was as effective and safe as using GA.

A double-blind, randomized, placebo-controlled, parallel study to investigate the auxiliary effects of fucoidan in patients with locally advanced rectal cancer who receive neoadjuvant concurrent chemoradiotherapy before surgery.

12 Background: Preoperative concurrent chemoradiotherapy (CCRT) is the standard treatment for patients with locally advanced rectal cancer (LARC). Low molecular weight fucoidan (LMF) is widely used as food supplements in cancer patients. This study is aimed to evaluate the efficacy of LMF as supplemental therapy to CCRT in LARC patients. Methods: We conducted a double-blind, prospective, randomized, placeo-controlled study to investigate the auxiliary effects of fucoidan in 107 patients with LARC who receive neoadjuvant CCRT before surgery. Finally, 87 patients were enrolled, of whom 44 were included in the study (fucodin) group and 43 in the control (placebo) group. The primary endpoint was the EORTC QLQ-C30 and FACT-C quality of life (QoL), and secondary endpoints included the overall response rate (ORR), disease control rate (DCR) and adverse events (AEs). Results: The physical well-being (PWB) was much improved after 2-month administration in the study (fucodin) group when compared with placebo group ( P= 0.007), whereas colorectal cancer subscale (CCS) was also better after 3-month administration when compared with placebo group ( P= 0.034). ORR and DCR were not significantly different between 2 groups (both P &gt; 0.05). Moreover, skin rash ( P= 0.038) and fatigue ( P= 0.008) was less common in the fucodin group. Conclusions: This is the first clinical trial evaluating the efficacy of LMF as a supplemental therapy in the management of patients with LARC who undergoing CCRT. The results indicate that LMF would significantly improve QoL and decrease AEs of skin rash/fatigue; however, a long-term follow up is mandatory for the confirmation of oncological outcomes by LMF. Clinical trial information: NCT04342949 .

Radiomic features derived from pretherapeutic MRI predict chemoradiation response in locally advanced rectal cancer.

The standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant concurrent chemoradiotherapy (CRT) followed by surgical excision. Current evidence suggests a favorable prognosis for those with pathological complete response (pCR), and surgery may be spared for them. We trained and validated regression models for CRT response prediction with selected radiomic features extracted from pretreatment magnetic resonance (MR) images to recruit potential candidates for this watch-and-wait strategy. We retrospectively enrolled patients with LARC who underwent pre-CRT MR imaging between 2010 and 2019. Pathological complete response in surgical specimens after CRT was defined as the ground truth. Quantitative features derived from both unfiltered and filtered images were extracted from manually segmented region of interests on T2-weighted images and selected using variance threshold, univariate statistical tests, and cross-validation least absolute shrinkage and selection operator (Lasso) regression. Finally, a regression model using selected features with high coefficients was optimized and evaluated. Model performance was measured by classification accuracies and area under the receiver operating characteristic (AUROC). We extracted 1223 radiomic features from each MRI study of 133 enrolled patients. After tumor excision, 34 (26 %) of 133 patients had pCR in resected specimens. When 25 image-derived features were selected from univariate analysis, classification AUROC was 0.86 and 0.79 with the addition of six clinical features on the hold-out internal validation dataset. When 11 image-derived features were used, the optimized linear regression model had an AUROC value of 0.79 and 0.65 with the addition of six clinical features on the hold-out dataset. Among the radiomic features, texture features including gray level variance, strength, and cluster prominence had the highest coefficient by Lasso regression. Radiomic features derived from pretreatment MR images demonstrated promising efficacy in predicting pCR after CRT. However, radiomic features combined with clinical features did not result in remarkable improvement in model performance.

The Auxiliary Effects of Low-Molecular-Weight Fucoidan in Locally Advanced Rectal Cancer Patients Receiving Neoadjuvant Concurrent Chemoradiotherapy Before Surgery: A Double-Blind, Randomized, Placebo-Controlled Study.

Patients with cancer use low-molecular-weight fucoidan (LMF) as a supplement to therapy. However, most studies of LMF are in vitro or conducted using animals. Concurrent chemoradiotherapy (CCRT) is the gold standard for locally advanced rectal cancer (LARC). This study investigated the quality of life (QoL) and clinical outcomes of patients with LARC taking LMF as a supplement to neoadjuvant CCRT. This was a double-blind, randomized, placebo-controlled study. The sample comprised 87 patients, of whom 44 were included in a fucoidan group and 43 were included in a placebo group. We compared their QoL scores and clinical outcomes before treatment, and at 1 month, 2 months, and 3 months posttreatment. Pretreatment and posttreatment gut microbiota differences were also compared. Although enhanced physical well-being (PWB) at 2 months and 3 months posttreatment in the fucoidan group were observed (both P < .0125), the improvements of the Functional Assessment of Cancer Therapy for Patients with Colorectal Cancer (FACT-C) were nonsignificant (all P > .0125). Skin rash and itching and fatigue were less common in the fucoidan group (both P < .05). Posttreatment, the genus Parabacteroides was significantly more common in the gut microbiota of the fucoidan group. LMF administration improved the QoL, skin rash and itching, fatigue, and gut microbiota composition of the patients with LARC receiving CCRT.Clinical Trial Registration: NCT04342949.

Tumor Microenvironment before and after Chemoradiation in Locally Advanced Rectal Cancer: Beyond PD-L1.

In locally advanced rectal cancer treatment, neoadjuvant concurrent chemoradiation therapy (cCRT) is the standard of care. The tumor microenvironment (TME) is a complex entity comprising of tumor cells, immune cells and surrounding stroma and is closely associated with tumor growth and survival, response to antitumor therapies and also resistance to treatment. We aimed to assess the change in biomarkers associated with TME following standard neoadjuvant cCRT in rectal cancer. We accessed archival tissue from rectal cancer patients treated with neoadjuvant cCRT at Allegheny Health Network (AHN) facilities over the past 14 years. Pre-treatment and post-treatment biopsies were assayed for PD-L1, CD8+ T-cells, CXCL9, TIM-3, IDO-1, IFN-G, IL17RE, LAG-3, and OX40 in 41 patients. We found statistically significant upregulation in multiple biomarkers namely CD8, IL17RE, LAG3 and OX40 post neoadjuvant cCRT and a trend towards upregulation, although not statistically significant, in biomarkers PD-L1, CXCL9, TIM-3, IDO-1 and IFN-G expression. This provides a glimpse into the TME before and after neoadjuvant cCRT. We suggest that the biomarkers noted to be upregulated could be used for designing appropriate clinical trials and development of therapeutic targeted drug therapy in an effort to achieve better response to neoadjuvant therapy, increasing clinical and pathological complete response rates and improved overall outcomes.

Strategies to Optimize Treatment for Locally Advanced Rectal Cancer

Neoadjuvant long-course concurrent chemoradiation plus surgery, followed by optional adjuvant chemotherapy, is a standard of care for locally advanced rectal cancer (LARC). However, this traditional approach has several limitations, including low pathological complete response (pCR) (10-25%), high metastasis rate (30-35%), and highly inconsistent compliance with adjuvant chemotherapy (25-75%). Treatment modalities for LARC have dramatically evolved in recent years. Multiple clinical trials have focused on optimizing strategies to achieve a win-win situation for oncologic outcomes and functions. Here, we review the latest studies into optimizing neoadjuvant treatment for LARC.

Racial disparities and standard treatment in locally advanced rectal cancer: a National Cancer Database study

Mortality rates in colorectal cancer (CRC) continue to be higher in Black compared to White patients. While standard treatment modalities for locally advanced rectal cancer have been shown to improve outcomes, there are limited studies assessing the receipt of standard treatment in rectal cancer based on race. Therefore, we sought to evaluate the use of standard treatment across racial groups in locally advanced rectal cancer and its effect on survival. The National Cancer Database (NCDB) was queried for patients ≥18 years old with clinical and pathologic stage II-III rectal adenocarcinoma who received treatment from 2004 to 2014. Standard treatment was defined as complete surgical excision with either neoadjuvant or adjuvant concurrent chemoradiation. Multivariable logistic regressions were used to identify racial differences in receiving standard treatment. Cox proportional hazards were used to estimate the effects of standard vs. nonstandard treatment on survival differences based on race. A total of 70,677 patients with stage II (n=35,079) or stage III (n=35,598) rectal adenocarcinoma met the inclusion criteria. On multivariate analysis, Black [odds ratio (OR): 0.75; 95% confidence interval (CI): 0.71-0.79; P<0.001] and Hispanic White (OR: 0.86; 95% CI: 0.80-0.92; P>0.001) patients were less likely to receive standard treatment compared to non-Hispanic White patients. On multivariable Cox regression, nonstandard treatment was significantly associated with worse survival [hazard ratio (HR): 1.69; 95% CI: 1.65-1.73; P<0.001] compared to standard treatment. Even after adjusting for patient, demographic, and facility characteristics, Black patients had higher mortality rates compared to White patients in the whole population (HR: 1.15; 95% CI: 1.09-1.20; P<0.0001). This survival difference between Black and non-Hispanic White patients persisted in both the standard (HR: 1.10; 95% CI: 1.03-1.19; P=0.008) and nonstandard (HR: 1.17; 95% CI: 1.10-1.25; P<0.0001) treatment subgroups. Decreased survival outcomes in Black patients were more pronounced for those who underwent nonstandard treatment, particularly when treating stage III disease (HR: 1.30; 95% CI: 1.19-1.42; P<0.0001). Nonstandard treatment in stage II and III rectal cancer is associated with worse survival compared to standard treatment regimens. Black patients are more likely to receive nonstandard treatment and have worse survival outcomes compared to White patients.

High vs. low radiotherapy dose in locally advanced esophageal squamous cell carcinoma patients treated with neoadjuvant concurrent chemoradiotherapy: an endemic area population-based study

BackgroundThe optimal radiotherapy dose for locally advanced esophageal squamous cell carcinoma in endemic areas treated with neoadjuvant concurrent chemoradiotherapy is unclear.MethodsEligible patients diagnosed between 2010 and 2019 were identified via the Taiwan Cancer Registry. We used propensity score (PS) weighting to balance observable potential confounders. The hazard ratio (HR) of death was compared between high dose (50–50.4 Gy) and low dose (40–41.4 Gy) radiotherapy. We also evaluated other outcomes and performed supplementary analyses via an alternative approach.ResultsOur study population consisted of 644 patients. The PS weight-adjusted HR of death was 0.92 (95% confidence interval: 0.7–1.19, p = 0.51). There were no statistically significant differences for other outcomes or supplementary analyses.ConclusionsIn this population-based study from an endemic area, we found no significant difference in overall survival between high vs. low radiotherapy doses.

The Neo-PLANET phase II trial of neoadjuvant camrelizumab plus concurrent chemoradiotherapy in locally advanced adenocarcinoma of stomach or gastroesophageal junction

The synergistic effect of neoadjuvant immunotherapy and chemoradiotherapy in gastric adenocarcinoma is unclear. This phase II trial (NCT03631615) investigated this neoadjuvant combination in locally advanced adenocarcinoma of stomach or gastroesophageal junction. Thirty-six patients received capecitabine 850 mg/m2 twice daily and simultaneous radiotherapy for 5 weeks, sandwiched by a 21-day cycle of oxaliplatin 130 mg/m2 (day 1) plus capecitabine 1000 mg/m2 twice daily (days 1–14), respectively, followed by surgery. Camrelizumab 200 mg (day 1) was given for 5 cycles since initiating chemotherapy. Primary endpoint was pathological complete response (pCR, ypT0) rate. Secondary endpoints included total pCR (tpCR, ypT0N0) rate, major pathological response (MPR, < 10% residual tumor cells) rate, margin-free (R0) resection rate, downstaging, progression-free survival (PFS), overall survival (OS), and safety. The pCR rate was 33.3% (95% CI, 18.6–51.0), meeting pre-specified endpoint. TpCR, MPR, and R0 resection rates were 33.3%, 44.4%, and 91.7%, respectively. Twenty-eight (77.8%) patients reached ypN0. Two-year PFS and OS rates were 66.9% and 76.1%, respectively. The most common grade 3–4 adverse event was decreased lymphocyte count (27 [75.0%]). Neoadjuvant camrelizumab plus concurrent chemoradiotherapy exhibits promising pathological response in patients with locally advanced gastric adenocarcinoma, with an acceptable safety profile.

High SLC28A2 expression endows an inferior survival for rectal cancer patients managed by neoadjuvant CCRT.

For rectal cancer patients with stage T3-4 disease or positive lymph node, neoadjuvant concurrent chemoradiotherapy (CCRT) has become the standard treatment, but the clinical outcomes are still far from satisfactory. Accordingly, a more precise predictive tool such as genetic biomarkers is urgently required to optimize therapy decisions. Colorectal cancer (CRC) development has been considerably correlated with cellular metabolic process involving nucleotides, but the underlying molecular mechanisms remain unclear. In this study, we employed a transcriptome dataset comprising 46 rectal adenocarcinoma patients undergoing preoperative CCRT and focused on nucleobase-containing compound metabolic process (GO: 0055134) for data mining. We identified solute carrier family 28 member 2 (SLC28A2) as the most considerably upregulated gene among rectal cancer patients with CCRT resistance. Afterwards, there were a total of 172 rectal cancer tissue blocks procuring from our biobank, and the immunointensity of SLC28A2 was appraised utilizing immunohistochemical staining. Strong SLC28A2 immunointensity was significantly linked to female patients (p=0.032), vascular invasion (p=0.021), and post-CCRT tumor invasion and regional lymph node involvement (p<0.001 and p=0.005). Notably, patients with strong SLC28A2 immunointensity had no tumor downstaging (p<0.001). Univariate analysis revealed that high SLC28A2 immunoexpression was considerably unfavorably linked to all three endpoints: local recurrence-free survival (LRFS), metastasis-free survival (MeFS), and disease-specific survival (DSS) (all p≤0.0333). Moreover, both high SLC28A2 immunoexpression and low tumor regression grade were independently unfavorable prognostic factors for all three endpoints (all p≤0.013) in the multivariate analysis. Utilizing function prediction analysis, SLC28A2 upregulation was more likely to be linked with stem cell homeostasis in rectal cancer. In brief, we demonstrated that high SLC28A2 immunoexpression is substantially linked to an advanced stage, poor response to CCRT, and worse patient survival. Consequently, SLC28A2 expression can be a valuable predictive and prognostic marker for rectal cancer patients and be an encouraging therapeutic target for those with CCRT resistance.

Feasibility of Pretreatment FDG PET Radiomics in Predicting Complete Pathological Response after Neoadjuvant Concurrent Chemoradiotherapy for Esophageal Cancer

<h3>Purpose/Objective(s)</h3> To investigate the feasibility in predicting the pathological complete pathological response (pCR) of esophageal tumors after neoadjuvant concurrent chemoradiotherapy (CCRT) using pretreatment 18-fluorodeoxyglucose positron emission tomography (FDG PET) images. <h3>Materials/Methods</h3> This study retrospectively included 60 esophageal tumors of 59 patients from November 2012 to August 2021. All patients received neoadjuvant CCRT followed by radical surgery. The FDG PET examination before CCRT was used for evaluation. First, the maximum standardized uptake value (SUVmax) within a tumor was identified and then utilized to form a metabolic tumor volume (MTV) by grouping a set of voxels connecting to the SUVmax and with SUV not less than SUVmax * 0.5. Next, the texture indices were further calculated to describe the heterogeneity of the FDG uptakes discretized as gray level (GL) within MTV. Finally, receiver operating characteristic (ROC) curves analysis assessed the predictive performance of each index. In the analysis, pCR was defined as a positive event. <h3>Results</h3> Fifty-seven out of 59 patients were men (57/59, 96.6%). The number of tumors located at the upper, middle, and lower third of the esophagus were 9, 12, and 39, respectively. Ninety-five percent of the tumors were squamous cell carcinomas (57/60, 95%). Seventeen tumors of 17 patients were proved as pCR (17/60, 28.3%). The Chi-square test demonstrated that the associations between treatment response (pCR and non-pCR) and tumor location, clinical T, and N stage were insignificant (p=.16, .193, and .254). The SUVmax demonstrated a significant ability in identifying pCR tumors (AUC=.694, p=.013), whereas MTV was nonsignificant. The tumors with high metabolic uptake corresponded to a high probability of pCR. The texture indices, including GL nonuniformity normalized, low GL zone emphasis, and small area low GL emphasis of zones, GL nonuniformity normalized, long run low GL emphasis, low GL run emphasis, and short run low GL emphasis of runs, and low GL emphasis and small dependence low GL emphasis of GL dependencies, exhibited a significant ability to differentiate pCR from non-pCR tumors (AUC=.331, .289, .298, .339, .311, .311, .316, .312, and .302). These texture indices reflected that a low evaluation corresponded to a high likelihood of pCR. The tumors with a low or low uptake associated with small areas demonstrated a high probability of non-pCR. <h3>Conclusion</h3> This study revealed that pCR for esophageal cancer tumors could be predicted using metabolic and texture indices. Future studies are warranted for clinical application.

Impact of Induction Chemotherapy Antecedent to Long Course Neoadjuvant Concurrent Chemo-Radiotherapy on Clinical Outcomes of Patients with Carcinoma Rectum: Retrospective Audit from a Tertiary Cancer Center

<h3>Purpose/Objective(s)</h3> The paradigm of management of locally advanced rectal (T3/4; T1-4N1-2) cancers (LARC) have been shifting to induction chemotherapy (NACT) with long course neoadjuvant chemo-radiotherapy (NACRT) followed by total mesorectal excision (TME) inching towards total neoadjuvant therapy approach. We aimed to evaluate the outcomes of NACRT alone (Arm A) versus NACT followed by NACRT (Arm B) in LARC treated at our center. <h3>Materials/Methods</h3> Data of 101 patients of LARC (March 2013 – Jan 2021) were retrieved for this retrospective analysis. NACT in Arm B consisted of 2 cycles of CAPOX [oxaliplatin (130 mg/m² day 1) and capecitabine (1000 mg/m² twice daily for 14 days) repeated every 3 weeks]. Radiotherapy (RT) in both the arms was 50.4 Gray in 28 fractions with capecitabine 825 mg/m² twice daily on days of RT. All patients underwent TME. Adjuvant chemotherapy (ACT) consisted of CAPOX regimen. Pathological complete response (pCR) and overall complete response OCR (pCR plus near complete response) were defined as per modified Ryan grading system. Disease-free survival (DFS) and overall survival (OS) were assessed with Kaplan Meier method. <h3>Results</h3> Patient characteristics are summarized in Table 1. Median number of NACT cycles in Arm B was two (range 2-4). Median radiotherapy dose was 50.4 Gray. pCR rates were 12.7% in arm B and 7.3% (3/41) in arm A (p=0.516). OCR rates were 28.3% (17/60) in Arm B vs 12.1% (5/41) in Arm A (p=0.044). 2-Year DFS and OS in Arm A versus B were 47.5% vs. 73.9% (p=0.781) and 54.3% vs 67.3% (p= 0.371) respectively. Patients with pCR vs no pCR had better 2-year DFS and OS 88.9% vs 50.1% (p = 0.009) and 83.3% vs 55.4% (p = 0.015) respectively. Patients with OCR vs no OCR had better 2-year DFS and OS 88.5% vs 45.2% (p = 0.009) and 94.4% vs 51% (p = 0.015) respectively. Patients with positive circumferential margin (CRM) and regional node at presentation had poorer DFS 18.6% vs 83.6% (p=0.03) and 42.7% vs 54.9% (p=0.004) respectively. <h3>Conclusion</h3> NACT prior to NACTRT leads to higher OCR rates in LARC. pCR and OCR predicted better DFS and OS and positive CRM and node positivity at presentation portended poorer outcome in our cohort of patients.

Effect of Pelvic Bone Marrow Dose-Volume Parameters on Acute Hematologic Toxicity in Neoadjuvant Pelvic Intensity-Modulated Radiotherapy for Local Advance Rectal Cancer

<h3>Purpose/Objective(s)</h3> Neoadjuvant concurrent chemoradiotherapy effectively improves survival and local control of locally advanced rectal cancer (LARC). However, because the pelvic bone marrow is inevitably irradiated, pelvic radiotherapy often results in varying degrees of acute hematologic toxicity (HT). To effectively control the risk of acute HT, this study analyzed the correlation between the volume of irradiated pelvic bone marrow and acute HT based on clinical cases, and identified the corresponding risk threshold. <h3>Materials/Methods</h3> From October 2017 to May 2019, 41 LARC patients who received neoadjuvant CRT were retrospectively reviewed in our center. All patients were treated with 5-field intensity-modulated radiotherapy (IMRT), and the prescription dose delivered to PTV was 45∼50.4 Gy in 25∼28 fractions. Capecitabine or 5-fluorouracil were administered daily 5 days a week during radiotherapy. Different HT were recorded according to National Cancer Institute Common Toxicity Criteria Version 3.0 (NCI‐CTC.V3.0) based on laboratory tests. Multivariable logistic regression was performed to evaluate the association between the volume of irradiated pelvic bone marrow and different HT. Generalized additive model (GAM) and piecewise linear regression were used to further analyze the possible non-linear relationship and threshold effect between them. <h3>Results</h3> Multivariate Logistic regression analysis showed that low-dose (5,10,15,20 Gy) of irradiated total pelvic bone marrow volume (TVx) and coxal bone marrow volume (CVx) were significantly correlated with ≥I grade hemoglobin decreased, ≥I grade neutropenia and ≥II grade leukopenia. There was a significant negative correlation between the irradiated sacrum bone marrow volume (SVx) and ≥I grade hemoglobin decreased, ≥II grade leukopenia. Threshold effect has been observed between CV₅, CV₁₀, CV₁₅ and ≥I grade neutropenia by Generalized additive model (GAM) and piecewise linear regression, and the thresholds were 597ml, 575ml, 518ml, OR (95%CI) were 1.86 (1.04, 3.33), 2.36 (1.13, 4.94), 1.57 (1.08, 2.29), respectively. The thresholds between CV₅, CV₁₀ and ≥II grade leukopenia was 595ml, 575ml, OR (95%CI) was 1.86 (1.06, 3.25), 1.85(1.08, 3.16), respectively. <h3>Conclusion</h3> In neoadjuvant IMRT of rectal cancer, CV is a better predictor of acute HT induced by concurrent chemoradiotherapy than TV. The irradiated volume of CV associated with acute HT was mainly low dose levels (CV₅, CV₁₀, CV₁₅, CV₂₀). In order to effectively reduce the risk of acute HT, keeping CV₁₀ within 575ml may be a good choice.