Preoperative Concurrent Chemoradiotherapy Research Articles

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

BackgroundThe 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).MethodsA 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).ResultsOne 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).ConclusionThis 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 registrationThe registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016).

Total neoadjuvant treatment without surgery for locally advanced rectal cancer: Prospective study to assess tumor response, circulating genetic, and epigenetic biomarkers, and stromal transcriptome to interpret clinical outcome (NO-CUT trial).

TPS3633 Background: Total neoadjuvant therapy (TNT) has recently become a standard therapy for locally advanced rectal cancer (LARC). All nonsurgical interventions, including chemotherapy and concurrent chemoradiotherapy (CRT), are administered before either surgical resection of the rectum or non-operative management (NOM), depending on response to TNT. In the case of NOM, the impact of distant relapse on survival remains to be elucidated and circulating tumor DNA (ctDNA) monitoring has been proposed as a tool for early detection of relapse. Furthermore, predictive biomarkers of response to TNT are warranted for the early identification of patient candidates for NOM. In this regard, stromal contribution to sensitivity to pre-operative CRT is investigated by a transcriptomic signature on baseline tumor samples, as previously proposed by Isella C et al., Nature Genet, 2015. Methods: NO-CUT is a multicenter one-stage phase II trial aimed at assessing if a TNT approach with CAPOX followed by CRT can safely spare demolitive surgery in patients with LARC achieving a clinical complete response without increasing the risk of distant metastatic relapse. A Brookmeyer and Crowley approach was chosen to test the null hypothesis that the true distant relapse-free survival at 2.5 years rate is ≤75% against a one-sided alternative. The NOM cohort of the trial needs to accrue 44 evaluable patients and to be followed for at least 2.5 years. Such design yields a type I error rate of 10% and power of 80% when the true 2.5 years distant RFS proportion is 87%. Since it is assumed that the proportion of patients entering in the NOM cohort of the trial is at least 25%, a total of 180 patients are to be enrolled in NO-CUT study. Patients with medium-low LARC undergo TNT (4 cycles of CAPOX: capecitabine 1000 mg/m2 bid days 1-14 q 3 weeks; oxaliplatin 130 mg/m2 day 1 q 3 weeks) and 5 weeks of standard pelvic CT-RT, then restaging with imaging (MRI, CT-scan, and ultrasound endoscopy), and tumor biopsy. According to an algorithm defined for assessing tumor response, patients enter either NOM or surgery cohorts. During the follow-up phase of the trial, the NOM cohort is followed with intensive pelvic imaging and periodic blood samplings for 5 years. Tumor samples and ctDNA are studied at baseline, after TNT, and during follow-up. As of January 2023, 161 of planned 180 patients in 4 centers have been enrolled. Supported by grants from Associazione Italiana Ricerca Cancro (AIRC IG 2017-20685) and Fondazione Oncologia Niguarda. Clinical trial information: EudraCT 2017-003671-60 .

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 > 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 .

Prospective evaluation of dose-escalated preoperative concurrent chemo-radiation with image-guided intensity modulated radiation therapy in locally advanced rectal cancers.

155 Background: The paradigm of locally advanced (T3/4; T1-4N1-2) rectal cancers (LARC) requires an intensified treatment for better pathological outcomes. Treatment intensification may be done by radiation dose escalation of long course neoadjuvant chemoradiation therapy (NACRT) by image guided Intensity Modulated Radiation Therapy (IG-IMRT) to increase downstaging with potentially higher local control rates. We aimed to analyze the efficacy and safety of NACRT with dose escalated IG-IMRT in LARC. Methods: 20 patients of LARC were recruited in this prospective interventional phase-II study treated by IG-IMRT with 45 Gray/25 fractions to elective nodal volumes and concomitant boost of 55 Gray/25 fractions to gross primary and nodal disease with concurrent capecitabine (825 mg/m2 twice a day on radiation days). All were planned to undergo definitive surgery 6-8 weeks post completion of NACRT with Total mesorectal excision by Low anterior resection (LAR) or Abdominoperineal resection (APR) followed by 6-8 cycles of adjuvant chemotherapy. Post operative response assessment was assessed by Modified Ryan’s scheme for regression and by tumor downstaging. Primary end point was acute toxicity assessment and secondary end points were pathological complete response (pCR) and loco-regional control (LRC). Results: Of 20 patients, 18 underwent definitive surgery and received full course adjuvant chemotherapy (90%). Median follow up was 15.1 months. 2 patients refused surgery, had complete clinical response (cCR) on assessment and were on follow up. Tumor downstaging was achieved in 14 (77.7%) patients and nodal downstaging was achieved in 15/18 (83.3%) patients. In 4 patients (22.2%) pCR was achieved and overall complete response (OCR defined as pCR and nearCR, including 2 patients with cCR) in 10 patients (50%). 4 patients planned for APR underwent LAR achieving a sphincter preservation rate of 22%. Grade 3 toxicities were observed in 2 patients which resolved on first follow up. No Grade 4 acute toxicities were reported. No loco-regional relapses were found and all patients are disease free at the time of last follow up. Conclusions: Dose escalation with IG-IMRT offers higher rates of pCR and OCR with acceptable toxicity profile and excellent short term locoregional control. [Table: see text]

3D-CRT Versus SIB IMRT Acute Toxicity Outcomes in Preoperative Concurrent Chemo-Radiotherapy for Locally Advanced Rectal Cancer

3D-CRT Versus SIB IMRT Acute Toxicity Outcomes in Preoperative Concurrent Chemo-Radiotherapy for Locally Advanced Rectal Cancer

Retrospective Evaluation of the Impact of Dose Escalation Using Pre-operative Simultaneous Integrated Boost Volumetric Modulated Arc Therapy on the Outcome of Locally Advanced Rectal Cancer Patients.

Evaluating the outcome of pre-operative simultaneous integrated boost volumetric modulated arc therapy (SIB-VMAT) concomitant with capecitabine in patients diagnosed with locally advanced rectal cancer (LARC) at King Faisal Specialist Hospital and Research Centre (KFSH&RC), Riyadh, Saudi Arabia, during the period January 2013-December 2019. A total of 134 patients were enrolled. The median age at diagnosis was 59years. All patients received pre-operative concurrent chemo-radiation therapy (CCRT) using SIB-VMAT with oral capecitabine. Neoadjuvant chemotherapy was administered prior to CCRT in 32 patients (23.9%). The dose of radiation was 55Gy in 94 patients (70.1%), while 40 patients (29.9%) received 50Gy. All patients completed the CCRT treatment without breaks. No records of acute and late grade III and IV toxicities. Curative surgery was performed in all patients with a median interval of 11 (6-52) weeks between the end of CCRT and the date of surgery. No reported 30-day postoperative mortality and no grade III and IV Clavien-Dindo complications. PCR was reported in 26 patients (19.4%), while pathologically negative nodes (pN0) were achieved in 103 patients (76.9%). Adjuvant chemotherapy was utilized in 57 patients (42.5%). The 5-year local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS) were 93.2%, 67.1%, and 87.3%, respectively. Only tumor regression grade (TRG) was significantly correlated with LRFS, (p value 0.043). On multivariate analysis, only TRG and achievement of pN0 were significantly correlated with DFS (p value < 0.001). Dose escalation utilization (SIB-VMAT) in the pre-operative treatment of LARC is well tolerated and provides effective local control.

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.

Tumor Volume Regression of Rectal Cancer in Daily MRI during Preoperative Chemoradiotherapy with Capecitabine

<h3>Purpose/Objective(s)</h3> Although cone beam computed tomography (CBCT) has been available for over a decade, the pattern of tumor volume change in rectal cancer during preoperative concurrent chemoradiotherapy (CCRT) has been under the veil due to poor soft tissue contrast of registration CBCT. This study was conducted to investigate daily rectal tumor volume change using registration magnetic resonance imaging (MRI). <h3>Materials/Methods</h3> Patients diagnosed with cT3-4 and/or cN+ rectal adenocarcinoma undergoing preoperative CCRT with capecitabine on the pelvis up to 50 Gy in 25 daily fractions from November 2018 to June 2019 were consecutively included. Rectal tumor volume was uniformly measured by single physician (YKK) in daily 0.35T MRI obtained with MR-guided linear accelerator. The mean +/- standard deviation (SD) of daily tumor volume (cc), difference of tumor volume between first fraction and daily fraction (baseline tumor volume at first fraction – daily tumor volume), and tumor volume reduction rate (%, [baseline tumor volume at first fraction – daily tumor volume]/baseline tumor volume at first fraction x 100) were calculated. Statistical significance of differences were tested using the Wilcoxon's signed rank test and paired t-test. <h3>Results</h3> Twenty patients were included. Median age was 64 and majority of the patients were male (90%). Most tumors were T3 (70%) and N1-2 (95%). Tumors were located median 6.9 cm (range: 1 – 12) above anal verge. Median follow-up was 32 months (range: 2.5 – 36.8) and 4 patients had recurred at the time of analysis (2 local and 2 distant). Tumor volume steadily regressed with daily administration of CCRT (mean 2.47 +/- 4.46 cc; Figure 1). Significant tumor volume reduction compared to baseline was observed from 4^th fraction (mean 13.95 +/- 17.78 cc; <i>P</i> < 0.0001). The difference of tumor volume between baseline and the last fraction was mean 46.62 +/- 56.01 cc (<i>P</i> < 0.0001). The tumor volume reduction rate was significantly increased since 4^th fraction (mean 16.64 +/- 10.9 %; <i>P</i> < 0.0001). The tumor volume reduction rate at the last fraction was – 68.18 +/- 15.68 % (<i>P</i> < 0.0001). <h3>Conclusion</h3> For the first time, this study demonstrated daily tumor volume regression in preoperative rectal CCRT with capecitabine using daily MRI. Steady pattern of tumor regression may be explained in part by daily administration of capecitabine. Based on the hypothesis-generating observation, this study may warrant initiation of further investigations on rectal tumor volume change with CCRT using daily MRI.

Upregulated Ubiquitin D is a Favorable Prognostic Indicator for Rectal Cancer Patients Undergoing Preoperative Concurrent Chemoradiotherapy.

PurposeFor locally advanced rectal cancer, neoadjuvant concurrent chemoradiotherapy (CCRT) allows tumor downstaging and makes curative radical proctectomy possible. However, we lack a genetic biomarker to predict cancer prognosis or treatment response. We investigated the association between ubiquitin D (UBD) expression and clinical outcomes in rectal cancer patients receiving CCRT.Patients and MethodsWe analyzed the genes associated with the protein modification process (GO:0036211) and identified the UBD gene as the most relevant among the top 7 differentially expressed genes associated with CCRT resistance. We collected tissue specimens from 172 rectal cancer patients who had received CCRT followed by a curative proctectomy. We examine the relationship between UBD expression and patient characteristics, pathological findings, and patient survival, such as metastasis-free survival (MeFS) and disease-specific survival.ResultsUpregulated UBD expression was associated with lower pre-CCRT tumor T stage (P = 0.009), lower post-CCRT tumor T stage (P < 0.001), lower post-CCRT nodal stage (P < 0.001), less vascular invasion (P = 0.015), and better tumor regression (P < 0.001). Using univariate analysis, we found that high UBD expression was correlated with better disease-free survival (DFS) (P < 0.0001), local recurrence-free survival (LRFS) (P < 0.0001) and MeFS (P < 0.0001). Moreover, multivariate analysis demonstrated that high UBD expression was associated with superior DFS (P < 0.001), LRFS (P = 0.01), and MeFS (P = 0.004).ConclusionUBD upregulation was linked to better clinical prognosis, favorable pathological features, and good treatment response in rectal cancer patients undergoing CCRT. These results suggest UBD is a biomarker for rectal cancer.

ERCC1 Overexpression Increases Radioresistance in Colorectal Cancer Cells.

Simple SummaryThe 20–30% of locally advanced rectal cancer patients undergoing preoperative concurrent chemoradiotherapy had no expected efficacy, and ERCC1 overexpression was found in these tumor tissue patients. In the interest of confirming and adding details to our understanding of that correlation, The Tet-on gene expression system was used to examine ERCC1 functionality and stability. Our data from regulatable HCT116-Tet-on and COLO205-Tet-on cell lines verified the increased radioresistance in colorectal cancer cells that are associated with ERCC1 overexpression, and they confirmed a high correlation between ERCC1 levels and radiotherapeutic efficiency. Furthermore, overexpression of ERCC1 also increases cell migration under radiation exposure. Additional data from ERCC1 expression regulation in vivo confirmed that the overexpression of increased cancer radiation resistance suggests that ERCC1 expression plays a key role.Preoperative concurrent chemoradiotherapy (CCRT) is a standard treatment for locally advanced rectal cancer patients, but 20–30% do not benefit from the desired therapeutic effects. Previous reports indicate that high levels of ERCC1 reduce the effectiveness of cisplatin-based CCRT; however, it remains unclear as to whether ERCC1 overexpression increases radiation resistance. To clarify the correlation between ERCC1 levels and radiation (RT) resistance, we established two cell lines (HCT116-Tet-on and COLO205-Tet-on), induced them to overexpress ERCC1, detected cell survival following exposure to radiation, established HCT116-Tet-on and COLO205-Tet-on heterotopic cancer animal models, and detected tumor volume following exposure to radiation. We found that ERCC1 overexpression increased radiation resistance. After regulating ERCC1 levels and radiation exposure to verify the correlation, we noted that increased radiation resistance was dependent on ERCC1 upregulation in both cell lines. For further verification, we exposed HCT116-Tet-on and COLO205-Tet-on heterotopic cancer animal models to radiation and observed that ERCC1 overexpression increased colorectal cancer tumor radioresistance in both. Combined, our results suggest that ERCC1 overexpression may serve as a suitable CCRT prognostic marker for colorectal cancer patients.

Serine protease inhibitor Kazal type 1 (SPINK1) promotes proliferation, migration, invasion and radiation resistance in rectal cancer patients receiving concurrent chemoradiotherapy: a potential target for precision medicine

Serine peptidase inhibitor Kazal type-1 (SPINK1), a trypsin kinase inhibitor, is known to be associated with inflammation and pathogenesis. The aim in this study was to demonstrate the clinicopathological role and progression of SPINK1 in rectal cancer (RC) patients undergoing concurrent chemoradiotherapy (CCRT). Immunohistochemical staining for SPINK1 protein expression in 111 RC cases revealed high SPINK1 expression was significantly associated with perineural invasion and poor CCRT response in pre-CCRT specimens. In addition, multivariable analyses showed that pre-CCRT SPINK1 expression was a significant prognostic marker of both overall and disease-free survival in RC patients receiving pre-operative CCRT; furthermore, in vitro studies demonstrated SPINK1 interacted with EGFR to promote the abilities of proliferation, migration and invasion attenuated by SPINK1 si-RNA via ERK, p38, and JNK pathways. SPINK1 was also found to regulate radio-resistance in CRC cell lines. In conclusion, SPINK1 expression is an independent prognostic marker in patients receiving pre-operative CCRT, and SPINK1 regulates proliferation, migration and invasion via EGFR-downstream ERK, p38 and JNK pathways. The phenotypes of radiosensitivity that could be reversed with attenuation of SPINK1 levels suggest that targeting SPINK1 might offer a strategy for optimal precision medicine.

HIF-1α Expression Increases Preoperative Concurrent Chemoradiotherapy Resistance in Hyperglycemic Rectal Cancer.

Simple SummaryPreoperative Concurrent Chemoradiotherapy (CCRT) is one of the standard treatments for patients with locally advanced rectal cancer. However, the efficacy of CCRT in hyperglycemic rectal cancer patients does not seem to be as expected. Therefore, we used clinical specimens, ectopic hyperglycemia animal models, and rectal cancer cells in a high-glucose environment to confirm how the high-glucose environment causes radiation resistance. The results confirmed that the high-glycemic environment could induce the overexpression of HIF-1α to cause CCRT tolerance in rectal cancer and suggest that combining HIF-1α inhibitors could reverse radioresistance in a high glucose environment. In future, HIF-1α inhibitors might be used as sensitizers to improve the efficacy of hyperglycemic rectal cancer patients receiving CCRT.Purpose: Preoperative concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced rectal cancer patients. However, the poor therapeutic efficacy of CCRT was found in rectal cancer patients with hyperglycemia. This study investigated how hyperglycemia affects radiochemotherapy resistance in rectal cancer. Methods and Materials: We analyzed the correlation between prognosis indexes with hypoxia-inducible factor-1 alpha (HIF-1α) in rectal cancer patients with preoperative CCRT. In vitro, we investigated the effect of different concentrated glucose of environments on the radiation tolerance of rectal cancers. Further, we analyzed the combined HIF-1α inhibitor with radiation therapy in hyperglycemic rectal cancers. Results: The prognosis indexes of euglycemic or hyperglycemic rectal cancer patients after receiving CCRT treatment were investigated. The hyperglycemic rectal cancer patients (n = 13, glycosylated hemoglobin, HbA1c > 6.5%) had poorer prognosis indexes. In addition, a positive correlation was observed between HIF-1α expression and HbA1c levels (p = 0.046). Therefore, it is very important to clarify the relationship between HIF-1α and poor response in patients with hyperglycemia receiving pre-operative CCRT. Under a high glucose environment, rectal cancer cells express higher levels of glucose transport 1 (GLUT1), O-GlcNAc transferase (OGT), and HIF-1α, suggesting that the high glucose environment might stimulate HIF-1α expression through the GLUT1-OGT-HIF-1α pathway promoting tolerance to Fluorouracil (5-FU) and radiation. In the hyperglycemic rectal cancer animal model, rectal cancer cells confirmed that radiation exposure reduces apoptosis by overexpressing HIF-1α. Combining HIF-1α inhibitors was able to reverse radioresistance in a high glucose environment. Lower HIF-1α levels increased DNA damage in tumors leading to apoptosis. Conclusions: The findings here show that hyperglycemia induces the expression of GLUT1, OGT, and HIF-1α to cause CCRT tolerance in rectal cancer and suggest that combining HIF-1α inhibitors could reverse radioresistance in a high glucose environment. HIF-1α inhibitors may be useful for development as CCRT sensitizers in patients with hyperglycemic rectal cancer.

MO41-5 PD-L1 promoter methylation predicts survival in advanced colorectal cancer patients who received preoperative CCRT

Radiotherapy can boost the therapeutic response to immune checkpoint inhibitors (ICIs) by recruiting T lymphocytes and upregulating PD-L1 expression within the tumor microenvironment (TME). Our previous studies found that tumor PD-L1 expression cannot be induced in some locally advanced colorectal cancer (CRC) patients who receive preoperative concurrent chemoradiotherapy (CCRT) even in the presence of abundant T lymphocytes. We aimed to evaluate whether PD-L1 promoter methylation impacted the response to CCRT and acted as an independent biomarker for locally advanced CRC patients.

Association of neutrophil-to-lymphocyte ratio, radiotherapy fractionation/technique, and risk of development of distant metastasis among patients with locally advanced rectal cancer

BackgroundWe investigated the prognostic impact of the neutrophil-to-lymphocyte ratio (NLR) in patients with locally advanced rectal cancer (LARC) and whether modifiable factors in radiotherapy (RT) influenced the NLR.MethodsData of 1386 patients who were treated with neoadjuvant RT and concurrent or sequential chemotherapy for LARC between 2006 and 2019 were evaluated. Most patients (97.8%) were treated with long-course RT (LCRT; 50–50.4 Gy in 25–28 fractions) using three-dimensional conformal radiotherapy (3D-CRT) (n = 851) or helical tomotherapy (n = 504), and 30 patients underwent short-course RT (SCRT; 25 Gy in 5 fractions, followed by XELOX administration for 6 weeks). Absolute neutrophil and lymphocyte counts were obtained at initial diagnosis, before and during the preoperative RT course, and after preoperative concurrent chemoradiotherapy. The primary endpoint was distant metastasis-free survival (DMFS).ResultsThe median follow-up time was 61.3 (4.1–173.7) months; the 5-year DMFS was 80.1% and was significantly associated with the NLR after RT but not before. A post-RT NLR ≥ 4 independently correlated with worse DMFS (hazard ratio, 1.42; 95% confidence interval, 1.12–1.80), along with higher ypT and ypN stages. Post-RT NLR (≥ 4) more frequently increased following LCRT (vs. SCRT, odds ratio [OR] 2.77, p = 0.012) or helical tomotherapy (vs. 3D-CRT, OR 1.29, p < 0.001).ConclusionsIncreased NLR after neoadjuvant RT is associated with increased distant metastasis risk and poor survival outcome in patients with LARC. Moreover, high NLR following RT is directly related to RT fractionation, delivery modality, and tumor characteristics. These results are hypothesis-generating only, and confirmatory studies are required.

Biomarkers of Favorable vs. Unfavorable Responses in Locally Advanced Rectal Cancer Patients Receiving Neoadjuvant Concurrent Chemoradiotherapy.

Colorectal cancer is the second leading cause of cancer death globally. The gold standard for locally advanced rectal cancer (LARC) nowadays is preoperative concurrent chemoradiation (CCRT). Approximately three quarters of LARC patients do not achieve pathological complete response and hence suffer from relapse, metastases and inevitable death. The exploration of trustworthy and timely biomarkers for CCRT response is urgently called for. This review focused upon a broad spectrum of biomarkers, including circulating tumor cells, DNA, RNA, oncogenes, tumor suppressor genes, epigenetics, impaired DNA mismatch repair, patient-derived xenografts, in vitro tumor organoids, immunity and microbiomes. Utilizing proper biomarkers can assist in categorizing appropriate patients by the most efficient treatment modality with the best outcome and accompanied by minimal side effects. The purpose of this review is to inspect and analyze accessible data in order to fully realize the promise of precision oncology for rectal cancer patients.

The Radiation Dose to the Left Supraclavicular Fossa is Critical for Anastomotic Leak Following Esophagectomy - A Dosimetric Outcome Analysis.

PurposeFor locally advanced esophageal cancer, definitive concurrent chemoradiotherapy (CCRT) with a radiation dose of 50–50.4 Gy/25-28 Fx is prescribed, followed by adjuvant esophagectomy for better local control or salvage treatment if locoregional recurrence occurs. However, radiation injury before surgery may delay wound healing. We performed cervical anastomosis directly inside the left supraclavicular fossa (SCF), the irradiation target for esophageal cancer. The significance of radiation injury in patients with cervical anastomotic leak (AL) remains unclear. Thus, we assessed the influence of radiation on cervical AL in patients undergoing preoperative CCRT followed by esophagectomy.Patients and MethodsWe defined the SYC zone, a portion of the region overlapping the left SCF. The radiation dose to the SYC zone was analyzed and correlated with AL in patients with locally advanced esophageal squamous cell carcinoma (ESCC) who were administered preoperative CCRT (radiation dose with 50–50.4 Gy/25-28 Fx to the primary esophageal tumor) followed by esophagectomy between October 2009 and January 2018. Receiver operating characteristic curve analysis and logistic regression were used to identify the optimal radiation factor to predict AL and the cutoff value.ResultsThe optimal radiation factor to predict AL was the mean dose to the SYC zone (area under the curve (AUC)=0.642), and the cutoff point of the mean dose was 48.55 Gray (Gy). For a mean SYC zone dose ≥48.55 Gy, the AL risk was sevenfold greater than that for <48.55 Gy (OR = 7.805; 95% CI: 1.184 to 51.446; P value = 0.033).ConclusionRecognizing the SYC zone as an organ at risk and performing radiation evaluation are meaningful. A reduced mean dose of the SYC zone below 48.55 Gy results in a lower cervical AL rate following esophagectomy.

Simultaneous Integrated Boost Volumetric Modulated Arc Therapy for Rectal Cancer: Long-Term Results after Protocol-Based Treatment.

Background Volumetric modulated arc therapy (VMAT) with simultaneous integrated boost (SIB) is an advanced form of radiotherapy (RT) technology. The purpose of this study was to report long-term treatment outcomes in patients with locally advanced rectal cancer undergoing VMAT-SIB based concurrent chemoradiotherapy (CRT). Methods Between January 2016 and January 2018, a total of 22 patients with operable stage II-III rectal adenocarcinoma were recruited for the pre-designed VMAT-SIB RT protocol. All patients underwent standard diagnostic and staging work-up. The RT target volumes included the following areas: PTV1 = mesorectum that contained gross tumors and enlarged lymph node regions and PTV2 = mesorectum and regional lymphatics from L4-5/S1 to 3-4 cm below the tumor or levator ani muscle, excluding PTV1. The VMAT-SIB dose prescription was as follows: PTV1 = 52.5 Gy/daily 2.1 Gy/25 fractions, PTV2 = 45 Gy/daily 1.8 Gy/25 fractions. Results The mean age of the study population was 64 (range, 18-84) years, and 15 (68.2%) patients were male. Radical operation (total mesorectal excision) was performed by either low anterior resection, ultralow anterior resection, or abdominal perineal resection. All five (22.7%) of the patients with confirmed increasing serum carcinoembryonic antigen (CEA) level at diagnosis showed normalization of serum CEA level after the planned treatment. Among 20 patients who underwent preoperative CRT and surgery, tumor down staging in T- and N-stages was achieved in 10 patients (50%) and 13 patients (65%), respectively, with 20% of ypT0/Tis. With a median follow-up of 54.2 (range, 22.6-61.1) months, the 5-year disease-free survival, overall survival, and local control rates were 64.6%, 81.8%, and 84.4%, respectively. Five patients developed distant metastasis and one developed local recurrence as a first event. Two cases with anastomosis site leakage, three with adhesive ileus, and two with abscess formation were observed during postoperative periods. Conclusions The current VMAT-SIB-based CRT protocol provided acceptable treatment and toxicity outcomes.

Neoadjuvant therapy of metformin is associated with good tumor response after preoperative concurrent chemoradiotherapy for rectal cancer

Metformin is associated with good tumor response in preoperative concurrent chemoradiotherapy (CCRT) for rectal cancer. This study aims to demonstrate that the timing of metformin is related to the tumor response on preoperative CCRT for rectal cancer. From January 2010 to December 2017, 232 patients who underwent curative resection after preoperative CCRT were reviewed. Patients were divided into groups with or without diabetes or metformin. The timing of metformin administration was divided based on before and from initiation of CCRT. Multivariate logistic regression analysis was used to identify predictors for tumor response. Tumor downstaging (p = 0.02) and good response rates of tumor regression grade (TRG) (p = 0.008) were significantly higher in the group administered metformin before CCRT than other groups. In the multivariate analysis, metformin administration before CCRT was a significant factor in predicting tumor downstaging [odds ratio (OR) 10.31, 95% confidence interval (CI) 1.76–102.08, p = 0.02] and good TRG (OR 12.55, 95% CI 2.38–80.24, p = 0.004). In patients with rectal cancer who underwent preoperative CCRT, neoadjuvant therapy of metformin before CCRT was significantly associated with good tumor response.

Can pretreatment platelet-to-lymphocyte and neutrophil-to-lymphocyte ratios predict long-term oncologic outcomes after preoperative chemoradiation followed by surgery for locally advanced rectal cancer?

PurposeSystemic inflammation is associated with various malignancies, including colorectal cancer, as possible prognostic predictors. We aimed to evaluate the correlation of pretreatment the platelet-to-lymphocyte (PLR) and the neutrophil-to-lymphocyte (NLR) ratio with long-term oncologic outcomes and pathologic complete response (pCR) in locally ad vanced rectal cancer patients who received neoadjuvant concurrent chemoradiotherapy (CRT) followed by curative resection.MethodsBetween October 1996 and December 2015, 168 rectal cancer patients treated with preoperative CRT followed by surgery were enrolled. The set cut-off/mean PLR and NLR were 170 and 2.8. We analyzed the relationship between PLR, NLR, and the 5-year overall survival (OS), disease-free survival (DFS), and pCR rate.ResultsThe 5-year OS rates were 75.9% and 59.8% in the highand low-PLR groups. The 5-year DFS rates were 62.9% and 50.8% in the high- and low-PLR groups, with no significant difference. In addition, the 5-year OS rates were 75.7% and 58.4%, and the 5-year DFS rates were 62.5% and 50.0% in the high- and low-NLR groups, respectively, both without any significant difference. Multivariate analysis showed only pretreatment PLR as an independent prognostic factor for OS (hazard ratio, 1.850; 95% confidence interval, 1.041–3.287; P=0.036), and both serologic markers were not independent prognostic factors for 5-year DFS.ConclusionNeither PLR nor NLR was associated with 5-year DFS nor pCR to neoadjuvant CRT. Only pretreatment PLR can be used in predicting OS in locally advanced rectal cancer patients who received neoadjuvant CRT followed by curative resection.

Deep regional hyperthermia combined with modern concurrent chemoradiotherapy increases T-downstaging rate in locally advanced rectal cancer

Background Deep regional hyperthermia might have an additional effect on radiotherapy in treating locally advanced rectal cancer (LARC). This study aimed to investigate the role of hyperthermia combined with modern preoperative concurrent chemoradiotherapy (CRT) for LARC. Methods and materials From 2012 to 2018, 152 consecutive patients with LARC treated with neoadjuvant chemoradiation were enrolled and analyzed retrospectively. Pelvic radiotherapy (45–50 Gy) was delivered as volumetric modulated arc therapy (VMAT), concurrently with capecitabine chemotherapy. Fifty patients received hyperthermia combined with CRT (HCRT group) twice a week. Treatment response and outcomes were compared between the two groups. Furthermore, the relationships between peripheral blood neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) in response to hyperthermia were analyzed. Results Patients treated with hyperthermia had a significantly higher T-downstaging rate than those without hyperthermia (82.0 vs. 62.7%; p = .016). Hyperthermia was an independent favorable predictor of T-downstaging (odds ratio [OR] = 2.473; 95% confidence interval [CI] 1.050–5.826; p = .038). In the HCRT group, a pre-therapeutic elevated NLR (≥3) was associated with a higher T-downstaging rate (100.0 vs. 73.5%, p = .043). However, NLR was not associated with the T-downstaging rate in the CRT group. Five-year rates of locoregional recurrence-free survival (96.8 vs. 94.7%, p = .959), disease-free survival (DFS; 61.4 vs. 79.3%, p = .242), and overall survival (OS; 92.7 vs. 89.8%, p = .831) were not statistically different between the CRT and HCRT groups. Conclusions Hyperthermia can improve preoperative treatment response in LARC. Pretreatment NLR may be a predictive factor for hyperthermia.