Preoperative chemoradiation-induced hematological toxicity and related vertebral dosimetry evaluations in patients with locally advanced gastric cancer: data from a phase III clinical trial

Preoperative chemoradiation-induced hematological toxicity and related vertebral dosimetry evaluations in patients with locally advanced gastric cancer: data from a phase III clinical trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Preoperative chemoradiation-induced hematological toxicity and related vertebral dosimetry evaluations in patients with locally advanced gastric cancer: data from a phase III clinical trial Ji-jin Wang, Han Shao, Li Zhang, Ming Jing, Wen-jing Xu, Heng-wen Sun, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2202715/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background To explore the hematological toxicity (HT) induced by neoadjuvant chemoradiotherapy (nCRT) compared with neoadjuvant chemotherapy (nCT) and to identify the appropriate vertebral body (VB) dosimetric parameters for predicting HT in patients with locally advanced gastric cancer (GC). Methods In the phase III study, 302 patients with GC from an ongoing multi-center randomized clinical trial (NCT 01815853) were included. Patients from two major centers were grouped into training and external validation cohorts. The nCT group received three cycles of XELOX chemotherapy, while the nCRT received the same dose-reduced chemotherapy plus 45 Gy radiotherapy. The complete blood counts at baseline, during neoadjuvant treatment, and in the preoperative period were compared between the nCT and nCRT groups. The VB was retrospectively contoured and the dose-volume parameters were extracted in the nCRT group. Patients’ clinical characteristics, VB dosimetric parameters, and HTs were statistically analyzed. Instances of HT were graded according to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE v5.0). The receiver operating characteristic (ROC) curves were generated to identify the optimal cut-off points for dosimetric variables and verify the prediction efficiency of the dosimetric index in both training and external validation cohorts. Results In the training cohort, 27.4% Grade 3 + HTs were noted in the nCRT group and 16.2% in the nCT group ( P = 0.042). A similar result was exhibited in the validation cohort, with 35.0% Grade 3 + HTs in the nCRT group and 13.2% in the nCT group ( P = 0.025). The multivariate analysis of the training cohort revealed that V 5 was associated with Grade 3 + leukopenia ( P = 0.000), Grade 3 + thrombocytopenia ( P = 0.001), and Grade 3 + total HTs ( P = 0.042). The Spearman correlation analysis identified a significant correlation of V 5 with the white blood cell nadir ( P = 0.0001) and platelet nadir ( P = 0.0002). The ROC curve identified the optimal cut-off points for V 5 and showed that V 5 < 88.75% could indicate a decreased risk of Grade 3 + leukopenia, thrombocytopenia, and total HTs in the training as well as the external validation cohorts. Conclusions Compared with nCT, nCRT could increase the risk of Grade 3 + HT in patients with locally advanced GC. Dose constraints of V 5 < 88.75% in irradiated VB could reduce the incidence of Grade 3 + HT. Vertebral body Dosimetric parameter Hematologic toxicity Gastric Chemoradiotherapy Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide, with > 40% of new cases being detected in China ( 1 ). Surgical resection with perioperative chemotherapy is a standard treatment for most cases of locally advanced GC ( 2 ). In the absence of positive results from adjuvant chemoradiotherapy studies ( 3 , 4 ), there is increasing expectation of neoadjuvant chemoradiotherapy (nCRT) for improving survival. Several prospective randomized clinical trials have compared nCRT with neoadjuvant chemotherapy (nCT) for GC and esophagogastric junction (EGJ) adenocarcinoma, including the published POET ( 5 ) and Neo-AEGIS trials ( 6 ), and the ongoing TOPGEAR ( 7 ), CRITICS-II ( 8 ), PREACT ( 9 ), and the Neo-CRAG trials ( 10 ). Most published results have not shown a particularly increase in hematological toxicity (HT) in the nCRT arm than in the nCT arm; for example, the TOPGEAR interim results showed that 52% of Grade 3 + HTs occurred in the nCRT group and 50% occurred in the nCT group ( 7 ). However, tumor location and pattern of lymphatic extension can influence the characteristics of the radiation field and theoretically, the addition of a major treatment modality can potentially increase the risk of adverse effects. Previous studies have reported the relationship between HT and bone marrow radiotherapy dosimetry, though the majority of them were about pelvic bone irradiation in cervical cancer and colorectal cancer ( 11 , 12 ). Similar studies have also been performed on radiotherapy for esophageal and pancreatic cancers ( 13 , 14 ). In radiotherapy for GC and EGJ cancer, vertebral bone marrow can be considerably affected given its anatomical adjacency to the clinical target volume (CTV) and the necessity for sparing the lateral organs at risk (OARs), such as the kidneys, liver, lungs, and heart. Studies have shown that up to 50% of the spinal bone marrow is hematopoietically active ( 15 ). Since bone marrow stem cells are highly radiosensitive, the hematopoietic function of vertebral bone marrow can directly be impaired by radiotherapy for GC ( 16 , 17 ). Therefore, it is necessary to explore the influence of dosimetric factors on HT due to nCRT for GC. The Neo-CRAG trial (NCT 01815853) ( 10 ) is a large multi-center phase III clinical trial that has just completed patient recruitment. The inclusion criteria was the most advanced non-metastatic GC (e.g., T3N2-3, T4aN+, T4bNany, and M0), with the lower border of station 16a2 lymph nodes always being included in the CTV of radiotherapy. In the preliminary data analysis, we noted a trend of increased HT in the nCRT group than in the nCT group, as well as an association between vertebral body (VB) dosimetry and HT grade. Thus, identifying the dosimetric parameters associated with HT could be critical for bone marrow-sparing in radiotherapy planning. Therefore, this study aimed to explore the difference in the risk of HT between nCRT and nCT groups and to identify the best predictive dosimetric factors of HT for locally advanced GC. Methods Patients This study was based on an ongoing multi-center randomized controlled phase III clinical study (Neo-CRAG trial, NCT 01815853) that compared nCRT with nCT for patients with locally advanced gastric adenocarcinoma. The inclusion criteria were patients with histologically confirmed gastric adenocarcinoma, at cT3N2-3M0, cT4aN + M0, or cT4bNanyM0 clinical stage, aged 18–75 years, with adequate organ function, and with an Eastern Cooperative Oncology Group performance status score ≤ 2. The clinical stage was based on gastroscopy or endoscopic ultrasound (EUS), computed tomography (CT), and exploratory laparoscopy findings. The primary endpoint was disease-free survival (DFS) and the secondary endpoint was overall survival (OS), pathological complete remission (pCR) rate, and treatment safety. The clinical trial has completed the recruitment of 620 patients as of July 2022. Among the patients enrolled in the Neo-CRAG trial, we included 302 patients from two major participating centers who completed preoperative therapy between June 2013 and November 2021. The clinical characteristics of these patients are shown in Table 1 . Of them, 113 treated with nCRT and 111 treated with nCT at Sun Yat-sen University Cancer Center were grouped under the training cohort, while 40 treated with nCRT and 38 treated with nCT at the Guangdong Provincial People's Hospital were grouped under the external validation cohort. Treatment As per the trial protocol ( 10 ), patients in the nCT group received three 21-day cycles of XELOX chemotherapy (capecitabine 1000 mg/m², bid, d1-14 + oxaliplatin 130 mg/m², d1). Patients in the nCRT group received one cycle of XELOX induction chemotherapy, followed by radiotherapy of 45 Gy in 25 daily fractions, concurrently with two 21-day cycles of dose-reduced XELOX chemotherapy (capecitabine 825 mg/m², bid, d1-14 + oxaliplatin 100 mg/m², d1). Subsequently, radical gastrectomy was performed 3–4 weeks and 6–8 weeks after the conclusion of nCT and nCRT, respectively. The patients then continued to receive three 21-day cycles of adjuvant XELOX chemotherapy (standard dose intensity as in nCT group) 3–4 weeks after surgery. Radiation Therapy And Target Volume Delineation Patients in the nCRT group were treated as follows: three-dimensional conformal radiation therapy (3D-CRT) for seven patients (one in the training cohort, six in the validation cohort) and intensity-modulated radiation therapy (IMRT) for the other patients. During the scan, the patients were immobilized in the supine position with a vacuum cushion and scanned with simulation computed tomography (CT-sim), including plain and venous-enhanced scans from T4 to L5 vertebral levels. The inter-slice thickness of the CT scan was 5 mm. About 50–100 mL of prepared iopamidol solution was orally administered as the contrast agent 20 minutes before and at the time of CT-sim. Patients were required to fast for at least 3 hours before the CT-sim and before each radiation treatment to account for inter-fractional variability in gastric distention due to gastric filling. Before the scan, gastroscopy was performed to place titanium clips at the cephalic and caudal edges of the tumor as a fiducial marker for target volume delineation. The principle of target volume delineation was designed at beginning of the Neo-CRAG trial and was based on preoperative radiation recommendations of the European Organization for Research and Treatment of Cancer (EORTC-ROC) ( 18 , 19 ), the National Comprehensive Cancer Network (NCCN) guidelines for GC ( 20 ), and preoperative chemoradiation studies published the M.D. Anderson Cancer Center ( 21 ). To elaborate, the gross tumor volume of the primary tumor (GTVt) and involved lymph nodes (GTVnd) were delineated based on baseline CT scan, gastroscopy or EUS, and exploratory laparoscopic findings. The CTV included GTVt with a 3 cm mucosal expansion and a 1.0–1.5 cm extragastric expansion, GTVnd with a 5 mm expansion, and elective regional lymphatic drainage regions. The mucosal expansion included the distal esophagus or proximal duodenum when appropriate. The inclusion of adjacent high-risk structures, including the inner half of the left diaphragm, parts of the pancreas, and neighboring parietal peritoneum were also considered. The CTV delineation had to avoid the vertebral body and include no more than 5 mm of liver tissues. The CTV was expanded by 5 mm in three dimensions to decide the planning target volume (PTV). The location of the primary tumor determined which elective lymph node groups would be included as per the JGCA classification, considering a 5 mm margin around the corresponding vessels: (a) Proximal 1/3 stomach and distal EGJ primaries: a. Essential: groups 1, 2, 3, 4sa, 7, 9, 10 (for neighboring greater curvature tumor), 11p, 12 (for lesser curvature tumor), 16a, 19, 20, 110, and 111. b. Optional: groups 4sb (for greater curvature tumor), 5, 8, 11d, and 13. (b) Middle 1/3 stomach primaries: a. Essential: groups 1, 2, 3, 4sa, 4sb, 4d, 5, 6, 7, 8, 9, 10, 11p, 11d, 12, 13, and 16a. b. Optional: groups 14, 17, 18, and 19. (c) Distal 1/3 stomach primaries: a. Essential: groups 1, 3, 4d, 5, 6, 7, 8, 9, 11p, 12, 13, 16a, 17, and 18. b. Optional: groups 4sb, 10, and 11d. For dose limitations of the OAR, the liver volume percentage that received ≥ 30 Gy (V 30 ) had to be less than 30% (V 30 < 30%) and the mean dose (D mean ) had to be < 22–25 Gy. For the duodenum and small intestine, D mean was ≤ 50 Gy and V 45 < 33%. For the kidneys, V 18 was < 33% and D mean was ≤ 17 Gy. For the heart, V 40 was < 30% and V 25 < 50%. For the spinal cord, the maximum dose (D max ) was ≤ 40 Gy. Forward or inverse treatment planning was used for 3D-CRT or IMRT, respectively, based on modern Monaco (Elekta, Crawley, UK), Eclipse (Varian Medical Systems, Palo Alto, CA, USA), or Pinnacle (Philips Medical Systems, Madison, WI, USA) treatment planning systems, using the direct machine parameter optimization algorithm. Vertebral Body Target Delineation As illustrated in Fig. 1 , the VB was retrospectively delineated manually based on CT simulation. The unified protocol of VB delineation was designed as follows: (a) VB and anterior pedicle were delineated, not including the vertebral appendages. The boundary of pedicle delineation was at the horizontal line across the center of the vertebral foramen. (b) The window width/level was set at W1600 Hu/L400 Hu to share the advantages of both the bone and mediastinal windows. (c) Only the cancellous bone was delineated and the cortical bone was avoided. (d) The upper boundary of the delineated VB was 2 cm above the CTV and the lower boundary was 3 cm below the CTV, not counting the intervertebral discs (IVD). The thoracic IVD thickness was set as 0.5 cm (one slice) and the lumbar IVD thickness as 1 cm (two slices). All the VB contours were delineated under the guidance of one single chief physician. After delineation, a dose-volume histogram (DVH) was obtained from the original treatment plan. The dosimetric parameters of VB including the total vertebral body volume (VBV), D max , D mean , minimum dose (D min ), and the volume percentage of dose receiving ≥ x Gy (V 5 , V 10 , V 20 , V 30 , V 40 , and V 45 ) were recorded. Hematological Toxicity Evaluation Routine blood investigations were regularly performed for all patients. Complete blood counts were determined at the time of diagnosis and weekly during neoadjuvant therapy and pre-operative evaluation. Instances of HT were graded according to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE v5.0). Statistical analysis The clinicopathological characteristics, hematological indicators, and dosimetric parameters were evaluated by t-test or Chi-squared test or Fisher’s exact test, when appropriate. Univariate (UVA) and multivariate (MVA) logistic regression was performed to identify dosimetric variables associated with the development of Grade3 + HT. Spearman correlation analysis was used to test correlations between dosimetric variables and absolute blood cell nadirs. Receiver Operating Characteristic (ROC) curves with the Youden method were used to identify the optimal dose-volume thresholds of predictive dosimetric parameters and to evaluate the predictive efficiency of the cutoff value both in the training cohort and the external validation cohort. All statistical analyses were performed with SPSS software 23.0, and P < 0.05 was considered to be significant. GraphPad Prism 8.0 and RStudio version 4.1.2 were used for plotting. Results Comparison of clinicopathological characteristics between the nCRT and nCT groups The clinicopathological characteristics including sex ( P = 0.612), age ( P = 0.143), Lauren type ( P = 0.826), primary tumor site ( P = 0.146), histological grade ( P = 0.158), and cTNM stage ( P = 0.70) were not significantly different between the nCRT and nCT groups in the training cohort (Table 1 ). Similarly, there were no significant differences between the two groups in the validation cohort. Differences In Ht Between The Ncrt And Nct Groups Patients in the nCRT group experienced more Grade 3 + leukopenia (11.5% vs. 0.9%, P = 0.001), Grade 3 + thrombocytopenia (11.5% vs. 0%, P = 0.000), and Grade 3 + total HTs (27.4% vs. 16.2%, P = 0.042) compared with patients in the nCT group (Table 1 ). The incidences of Grade 3 + neutropenia ( P = 0.084) and Grade 3 + anemia ( P = 0.956) were not significantly different between the two groups. Grade 4 HT was rare and Grade 5 HT did not occur during the entire neoadjuvant treatment period. In the validation cohort, patients who received nCRT also suffered more Grade 3 + HTs ( P = 0.025) than those in the nCT group. The different grades of HT in the training and external validation cohorts are shown in detail in Fig. 2 . Further, the influence of the addition of radiotherapy on blood cell nadirs was explored (Table 1 ). The mean ± standard deviation (SD) nadir counts of white blood cell (WBC) count, absolute neutrophil count (ANC), hemoglobin (HGB), and platelet (PLT) in the nCRT group were 3.05 ± 0.91*10 9 /L, 1.82 ± 0.68*10 9 /L, 98.69 ± 16.94g/L, and 97.08 ± 43.22*10 9 /L, respectively. The corresponding blood cell nadirs in the nCT group were 4.83 ± 1.67*10 9 /L, 2.60 ± 1.43*10 9 /L, 105.96 ± 22.83 g/L, and 156.94 ± 51.88*10 9 /L, respectively. Patients in the nCRT group had significantly lower WBC nadir ( P = 0.000), ANC nadir ( P = 0.000), HGB nadir ( P = 0.008), and PLT nadir ( P = 0.000) compared with those in the nCT group. In the validation cohort, the difference in the blood cell nadirs between the two groups showed the same trend as that in the training cohort. Modeling Dosimetric Predictors Of Hematological Toxicity In The Training Cohort The VB radiation dosimetric parameters of all patients treated with nCRT from two centers are summarized in Table 2 . Only V 30 ( P = 0.049) was significantly different between the training and validation cohorts, while the other dose-volume parameters were not. The dose-volume metrics of the VB were entered into UVA in the training cohort. The results showed that increased D min , D mean , V 5 , V 10 , V 20 , V 30 , and V 40 were risk factors for Grade 3 + leukopenia; increased V 5 and V 10 were risk factors for Grade 3 + thrombocytopenia; and D max and V 5 were risk factors for Grade 3 + total HTs. Subsequently, variables with P ≤ 0.15 in the UVA were included in the MVA. The results showed that V 5 was a risk factor for Grade 3 + leukopenia (odds ratio [OR]: 1.353, 95% confidence interval [CI]: 1.179–1.553, P = 0.000), Grade 3 + thrombocytopenia (OR: 1.192, 95% CI: 1.074–1.324, P = 0.001), and Grade 3 + total HTs (OR: 1.086, 95% CI: 0.987–1.195, P = 0.042). Table 3 detailed the results of UVA and MVA. Spearman correlation analysis revealed that increased V 5 was correlated with a lower WBC nadir (r = -0.508, P < 0.0001) and lower PLT nadir (r = -0.345, P = 0.0002) (Fig. 3 ). Based on the results of MVA, the ROC curve was generated to identify the optimal cut-off values of V 5 for predicting different HTs. V 5 < 91.7% (area under the curve [AUC] = 0.86, P < 0.0001), V 5 < 89.2% (AUC = 0.76, P = 0.0018), and V 5 < 88.75% (AUC = 0.70, P = 0.0014) were the optimal cut-off values for predicting Grade 3 + leukopenia, Grade 3 + thrombocytopenia, and Grade 3 + total HTs, respectively (Fig. 4 A). Validation Of The Predictive Efficiency Of The Best Cut-off Value Considering the safety and convenience of clinical application, a lower dose-volume metric of V 5 < 88.75% was chosen as the best cut-off value for decreasing Grade 3 + HT. As shown in Fig. 4B, V 5 < 88.75% showed a satisfactory predictive ability for a lower incidence of Grade 3 + leukopenia (AUC = 0.83), Grade 3 + thrombocytopenia (AUC = 0.76), and Grade 3 + total HTs (AUC = 0.71) in the training cohort. Limiting VB V 5 < 88.75% could reduce the rate of Grade 3 + leukopenia, Grade 3 + thrombocytopenia, and Grade 3 + total HTs by 44.3%, 37.5%, and 54%, respectively. Furthermore, as is shown in Fig. 4 C, we tested the predictive power of V 5 < 88.75% in the external validation cohort of 40 patients who received nCRT. The AUCs for Grade 3 + leukopenia, Grade 3 + thrombocytopenia, and Grade 3 + total HTs were 0.76, 0.83, and 0.74, respectively, which indicates good predictive ability. The rates of Grade 3 + leukopenia, Grade 3 + thrombocytopenia, and Grade 3 + total HTs decreased by 6.3%, 14.6%, and 14.6%, respectively. Discussion The present study explored the difference in the incidence of HT between nCRT and nCT. Additionally, it investigated the vertebral radiation dosimetric parameters associated with HT in patients with locally advanced GC. To our knowledge, this is the first detailed report characterizing VB dose-volume parameters and their association with HT in GC treated with nCRT. The results demonstrated that the HT of preoperative chemoradiotherapy could be higher than that of preoperative chemotherapy and limiting VB (V 5 < 88.75%) could decrease the risk of Grade 3 + HT in GC. The ARTIST trial—the representative study of adjuvant chemoradiotherapy versus adjuvant chemotherapy—showed that Grade 3 + neutropenia occurred in 48.4% of the patients in the postoperative chemoradiotherapy arm and 40.7% of those in the postoperative chemotherapy arm. Further, the rate of Grade 3 + thrombocytopenia was 0.9% in the postoperative chemoradiotherapy arm while none occurred in the postoperative chemotherapy arm ( 22 ). Until now, the TOPGEAR trial is the only large phase III study that has reported a difference in HT in neoadjuvant treatment for GC. The interim results showed that Grade 3 + neutropenia, anemia, thrombocytopenia, and total HTs in the nCRT group reached 45%, 5%, 2%, and 52%, respectively, while the corresponding results in the nCT group were 40%, 7%, 3%, and 50%, respectively ( 7 ). Despite the different rates of HT between these two trials, the frequency of Grade 3 + total HTs was not higher in the nCRT group than in the nCT group. A similar trend of different rates of HT between the two groups was also observed in the ARTIST-2 trial ( 4 ). The CRITICS trial even reported that patients experienced less Grade 3 + neutropenia in the nCRT group (4.4%) than in the nCT group (27%) ( 23 ). Further details of HT differences between chemoradiotherapy and chemotherapy in the above four clinical trials are summarized in Table 4 . However, there was no report of HT in the POET trial ( 5 ). Compared with the above studies, this study reported more Grade 3 + leukopenia, thrombocytopenia, and total HTs in the nCRT group than in the nCT group. The ARTIST and ARTIST-2 studies enrolled GC patients with clinical or pathological stage II and the CRITICS and TOPGEAR studies enrolled patients even with stage IB ( 7 , 23 ), Meanwhile, we only enrolled patients with more advanced clinical stages of GC (III–IVA). In our study, the lymphatic group 16a 2 , the lower border of which is located at the lower margin of the left renal vein, was included in the CTV of all patients; thus, the delineated target volume was longer and wider. The larger the target volume, the more radiation enters or passes through the unprotected organs, which also aggravates radiation exposure to the VB. More advanced clinical stages and larger target volumes may contribute to the higher HT in the nCRT group in our study. Though it is well known that radiation to the bone marrow can cause myelosuppression, VB is not yet considered an OAR in major radiotherapy guidelines including those for GC ( 19 , 24 – 26 ). Prior studies reported that VB dosimetric parameters can predict radiation-induced HT in pancreatic and lung cancers ( 14 , 27 ). In radiotherapy for GC, to protect the important OARs including the kidneys and liver, the radiation beam has to be arranged along the opposed anteroposterior direction, resulting in high irradiation of the VB. The stomach and its lymphatic drainage region are adjacent to the VB, therefore, delineation of the target volume may have a greater impact on the VB in GC than that in the lung or pancreatic cancers. Totally, it is important to protect the VB and set the best VB dose parameters during radiotherapy for GC. The VB dosimetric studies by Fabian et al. ( 28 ), Lee et al. ( 29 ), and Zhang et al. ( 13 ) focused on esophageal cancer treated with nCRT. The radiotherapy doses were 50.4–59.4 Gy, 41.4–48 Gy, and 41.4–70 Gy, respectively. The first study reported that V 30 < 14% could reduce the risk of Grade 3 + HT. The second concluded that V 10 < 77%, V 20 < 70%, and D mean < 25.9 Gy could decrease the occurrence of Grade 3 + leukopenia. Zhang’s study also demonstrated the correlation of Grade 3 + leukopenia with V 10 , V 20 , and D mean . In the above three studies, the differences in their predictive index may be due to differences in their prescribed dose and target volume delineation. Wang et al. ( 30 ) found that 20% of patients experienced Grade 3 + HT during capecitabine-based CRT in locally advanced GC and recommended dose constraints of VB V 5 ≤ 90% to avoid Grade 3 + leukopenia, V 20 ≤ 78% to avoid Grade 3 + neutropenia, and V 30 ≤ 60% to avoid Grade 3 + thrombocytopenia during adjuvant CRT. However, the limited sample size of 25 patients in their study makes it challenging to draw conclusive findings. Thus, it is recommended that the dosimetric predictors of Grade 3 + HT be re-evaluated in a larger patient cohort. In the present study, 113 patients with GC who received nCRT in the training cohort were recruited, and the results showed that higher Dmin, Dmean, V 5 , V 10 , V 20 , and V 30 significantly increased HT of different types. However, V 5 was the only independent dosimetric factor predictive of Grade 3 + leukopenia, thrombocytopenia, and total HTs in subsequent multivariate analyses. Limmiting VB V 5 < 88.75% may serve as a proper dosimetric recommendation to reduce the risk of Grade 3 + HT in patients with GC. The predictive value of V 5 was emphasized in our study, which may due to: (a) patients in our study were from a prospective clinical trial, all received 45 Gy of radiotherapy and the same chemotherapy regimen and cycles; (b) the principle of target volume delineation was highly consistent and possessed a narrow fluctuation range and a relatively small heterogeneity of VB dosimetric parameters. In daily practice of GC radiotherapy, however, the predictive value of other dosimetric parameters, such as V 10 , V 20 , V 30 , may also be considered, based on the studies referred above. We delineated VB based on the CT simulation in this study, and designed the delineation protocol which was proved convenient and practical. Mahantshetty et al. ( 31 ) proposed to contour the inner cavity of the bone as it could be a better surrogate of the active bone marrow. Some studies used positron emission tomography-computed tomography (PET-CT) or magnetic resonance imaging (MRI) to identify and delineate active bone marrow ( 30 , 32 ), which caused difficulty to some extent in radiation planning. In the clinical practice, the delineation method based on CT scanning is more commonly used and economical for GC radiotherapy, and the VB dosimetric parameters that we concluded are more clinically instructive than those based on PET-CT or MRI. To our knowledge, this is the first study to predict acute HT using VB dosimetric parameters in patients with GC receiving nCRT, which excluded the impact of surgery. Studies on lung and esophageal cancers have considered the effect of radiation doses to the ribs, clavicle, sternum, and scapula on bone marrow suppression outside the VB ( 27 , 28 ), but the effect of these bones on HT was not considered in our patients. Given the lower location of the GC treatment fields, it’s not likely that these bones receiving meaningful low-dose radiation exposure. Meanwhile, we were not able to correlate bone dose-volume metrics with the long-term changes in blood cell counts that may affect the patients’ quality of life, which required a longer follow-up. Conclusions In conclusion, nCRT could increase the risk of Grade 3 + HT compared with nCT. Dose constraints of V 5 < 88.75% should be considered to reduce the incidence of Grade 3 + HT in patients with GC treated with IMRT, especially when oxaliplatin and capecitabine are used as chemotherapeutic agents. Abbreviations HT hematological toxicity GC gastric cancer nCRT neoadjuvant chemoradiotherapy nCT neoadjuvant chemotherapy VB vertebral body CTCAE Common Terminology Criteria for Adverse Events ROC receiver operating characteristic EGJ esophagogastric junction CTV clinical target volume OAR organ at risk EUS endoscopic ultrasound CT computed tomography DFS disease-free survival OS overall survival XELOX capecitabine + oxaliplatin 3D-CRT three-dimensional conformal radiation therapy IMRT intensity-modulated radiation therapy CT-sim simulation computed tomography EORTC-ROC European Organization for Research and Treatment of Cancer NCCN National Comprehensive Cancer Network GTV gross tumor volume PTV planning target volume IVD intervertebral discs DVH dose-volume histogram VBV vertebral body volume D max maximum dose D mean mean dose D min minimum dose V x the volume percentage of dose receiving ≥ x Gy WBC white blood cell ANC absolute neutrophil count HGB hemoglobin PLT platelet SD standard deviation UVA univariate logistic regression analysis MVA multivariate logistic regression analysis OR odds ratio CI confidence interval AUC area under the curve PET-CT positron emission tomography-computed tomography MRI magnetic resonance imaging. Declarations Ethics approval and consent to participate Our study was approved by the Medical Ethics Committee of Affiliated Hospital of Sun Yat-sen University Cancer Center (the number of ethic approval: 5010-2012-05-03). Consent for publication Not applicable. Availability of data and materials All data generated or analyzed during this study are included in this published article. Competing interests The authors declare that they have no competing interests. Funding This work was funded by grant 2012013 from the Sun Yat-sen University Clinical Research 5010 Program. Authors’ contributions JJW was responsible for data analysis and manuscript writing. HS was responsible for data analysis and study designing. LZ and MJ were responsible for project administration and data collection. WJX contributed to data collection. ZWZ provided clinical and pathological data. HWS and YJZ contributed to study designing and project administration. 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Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT01815853?term=01815853&draw=2&rank=1 . Accessed 20 May 2022. Mell LK, Kochanski JD, Roeske JC, Haslam JJ, Mehta N, Yamada SD, et al. Dosimetric predictors of acute hematologic toxicity in cervical cancer patients treated with concurrent cisplatin and intensity-modulated pelvic radiotherapy. Int J Radiat Oncol Biol Phys. 2006;66(5):1356–65. Yang TJ, Oh JH, Apte A, Son CH, Deasy JO, Goodman KA. Clinical and dosimetric predictors of acute hematologic toxicity in rectal cancer patients undergoing chemoradiotherapy. Radiother Oncol. 2014;113(1):29–34. Zhang A, Deek MP, Kim S, Sayan M, Grann A, Wagman RT, et al. Vertebral body irradiation during chemoradiation therapy for esophageal cancer contributes to acute bone marrow toxicity. J Gastrointest Oncol. 2019;10(3):513–22. Shaikh T, Wang LS, Egleston B, Burki M, Hoffman JP, Cohen SJ, et al. Dosimetric predictors of hematologic toxicity in patients undergoing concurrent gemcitabine-based chemoradiation for localized pancreatic cancer. Practical Radiation Oncology. 2016;6(4):e107-e15. Hayman JA, Callahan JW, Herschtal A, Everitt S, Binns DS, Hicks RJ, et al. Distribution of proliferating bone marrow in adult cancer patients determined using FLT-PET imaging. Int J Radiat Oncol Biol Phys. 2011;79(3):847–52. Blomlie V, Rofstad EK, Skjonsberg A. Female Pelvic Bone Marrow: Serial MR Imaging before, during, and after Radiation Therapy. Radiology. 1995(194):537–43. Sacks EL, Goris ML, Glatstein E. ea. Bone marrow regeneration following large field radiation: Influence of volume, age, dose, and time. Cancer 1978(42):1057–65. Matzinger O, Gerber E, Bernstein Z, Maingon P, Haustermans K, Bosset JF, et al. EORTC-ROG expert opinion: radiotherapy volume and treatment guidelines for neoadjuvant radiation of adenocarcinomas of the gastroesophageal junction and the stomach. Radiother Oncol. 2009;92(2):164–75. Ajani JA, D'Amico TA, Bentrem DJ, Chao J, Cooke D, Corvera C, et al. Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022;20(2):167–92. Ajani JA, Bentrem DJ, Besh S, D’Amico TA, Das P, Denlinger C, et al. Gastric cancer, version 2.2013. 2013;11(5):531–46. Ajani JA, Winter K, Okawara GS, Donohue JH, Pisters PW, Crane CH, et al. Phase II trial of preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response. J Clin Oncol. 2006;24(24):3953–8. Lee J, Lim DH, Kim S, Park SH, Park JO, Park YS, et al. Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial. J Clin Oncol. 2012;30(3):268–73. Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, et al. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19(5):616–28. Hawrylewicz L, Leszczynski W, Namysl-Kaletka A, Bronclik I, Wydmanski J. Protection of organs at risk during neoadjuvant chemoradiotherapy for gastric cancer based on a comparison between conformal and intensity-modulated radiation therapy. Oncol Lett. 2016;12(1):692–8. Yu C, Yu R, Zhu W, Song Y, Li T. Intensity-modulated radiotherapy combined with chemotherapy for the treatment of gastric cancer patients after standard D1/D2 surgery. J Cancer Res Clin Oncol. 2012;138(2):255–9. Schernberg A, Hennequin C. Normal tissue tolerance to external beam radiation therapy: Bone marrow and cortical bone structures. Cancer Radiother. 2017;21(6–7):619–25. Barney CL, Scoville N, Allan E, Ayan A, DiCostanzo D, Haglund KE, et al. Radiation Dose to the Thoracic Vertebral Bodies Is Associated With Acute Hematologic Toxicities in Patients Receiving Concurrent Chemoradiation for Lung Cancer: Results of a Single-Center Retrospective Analysis. Int J Radiat Oncol Biol Phys. 2018;100(3):748–55. Fabian D, Ayan A, DiCostanzo D, Barney CL, Aljabban J, Diaz DA, et al. Increasing Radiation Dose to the Thoracic Marrow Is Associated With Acute Hematologic Toxicities in Patients Receiving Chemoradiation for Esophageal Cancer. Front Oncol. 2019;9:147. Jie Lee MD, Jhen-Bin Lin MF-JS. MS et. Dosimetric predictors of acute haematological toxicity in oesophageal cancer patients treated with neoadjuvant chemoradiotherapy. The British journal of radiology. 2016. Wang J, Tian Y, Tang Y, Wang X, Li N, Ren H, et al. A Phase II prospective nonrandomized trial of magnetic resonance imaging-guided hematopoietic bone marrow-sparing radiotherapy for gastric cancer patients with concurrent chemotherapy. Onco Targets Ther. 2016;9:2701–7. Mahantshetty U, Krishnatry R, Chaudhari S, Kanaujia A, Engineer R, Chopra S, et al. Comparison of 2 contouring methods of bone marrow on CT and correlation with hematological toxicities in non-bone marrow-sparing pelvic intensity-modulated radiotherapy with concurrent cisplatin for cervical cancer. Int J Gynecol Cancer. 2012;22(8):1427–34. Rose BS, Liang Y, Lau SK, Jensen LG, Yashar CM, Hoh CK, et al. Correlation between radiation dose to 18 F-FDG-PET defined active bone marrow subregions and acute hematologic toxicity in cervical cancer patients treated with chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2012;83(4):1185–91. Tables Table 1 to 5 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Tables.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 02 Apr, 2023 Reviews received at journal 31 Mar, 2023 Reviewers agreed at journal 22 Mar, 2023 Reviewers invited by journal 28 Dec, 2022 Editor assigned by journal 30 Oct, 2022 Submission checks completed at journal 27 Oct, 2022 First submitted to journal 25 Oct, 2022 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2202715","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":155267759,"identity":"2e0c6b50-d737-4ce7-8c83-b1e4bb05d416","order_by":0,"name":"Ji-jin Wang","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ji-jin","middleName":"","lastName":"Wang","suffix":""},{"id":155267760,"identity":"e437781b-9e01-46e4-afbf-4789638294eb","order_by":1,"name":"Han Shao","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Han","middleName":"","lastName":"Shao","suffix":""},{"id":155267761,"identity":"5fd238e9-7f5d-4bf5-a4d6-11ad1ff678dc","order_by":2,"name":"Li Zhang","email":"","orcid":"","institution":"Renmin Hospital, Hubei University of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Zhang","suffix":""},{"id":155267762,"identity":"ab8f7da7-db26-455a-9db9-2019ee0fd462","order_by":3,"name":"Ming Jing","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ming","middleName":"","lastName":"Jing","suffix":""},{"id":155267763,"identity":"a0c06266-52a1-4999-a376-9efdb8333abf","order_by":4,"name":"Wen-jing Xu","email":"","orcid":"","institution":"Guangdong Provincial People's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wen-jing","middleName":"","lastName":"Xu","suffix":""},{"id":155267764,"identity":"88502eb9-b612-4dba-8929-e7a679e18169","order_by":5,"name":"Heng-wen Sun","email":"","orcid":"","institution":"Guangdong Provincial People's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Heng-wen","middleName":"","lastName":"Sun","suffix":""},{"id":155267765,"identity":"add9dd2f-00f6-41e4-8cee-ad6f37145f52","order_by":6,"name":"Zhi-wei Zhou","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhi-wei","middleName":"","lastName":"Zhou","suffix":""},{"id":155267766,"identity":"cba639db-5004-44be-979e-e8ab396b25fb","order_by":7,"name":"Yu-jing Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA50lEQVRIiWNgGAWjYDACCTDJJke6FmOStTAkNhCtQ35287OHX9v40ufPSH8m8aOGQc68fwHj5wI8WhjnHDM3lm1jy91wI8dMsucYg7HMjQfM0jPwaGGWSDCTlgRpkchhk2ZsYEicIXGAjZkHjxY2ifRvIC3p8kCHEaeFRwLono9tbAkMN4DWgbXwN+DXIiGRUybNcI7NcMOZN8aWPcckjCUkGJul8WkBumeb5I+yY/Ly7ekPb/yosZGT4D988DM+LSDAzMt2jIFBIAFsKxAREUeMP/7UMDDwH4By4YxRMApGwSgYBRAAAPdyQzXT42IqAAAAAElFTkSuQmCC","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Yu-jing","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2022-10-25 13:59:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2202715/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2202715/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":30227977,"identity":"7a045555-0f7a-4503-8ed5-bc83214295c2","added_by":"auto","created_at":"2022-12-12 21:10:27","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":70001,"visible":true,"origin":"","legend":"\u003cp\u003eDelineation of the vertebral body and dose-volume histogram for a radiation treatment plan.\u003c/p\u003e\n\u003cp\u003e(A) Transverse section; (B) Sagittal section; (C) Transverse section with dose coverage; (D) The Dose-Volume Histogram (DVH).\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2202715/v1/4d55c9f182d7337660384b5e.jpg"},{"id":30227979,"identity":"6006bb1d-51e9-4ae3-9c54-5db301e0b8b6","added_by":"auto","created_at":"2022-12-12 21:10:27","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":82076,"visible":true,"origin":"","legend":"\u003cp\u003eDifferent grades of hematological toxicity in the training and validation cohorts.\u003c/p\u003e\n\u003cp\u003e(A) Training cohort: Grade 3+ Leukopenia (\u003cem\u003eP \u003c/em\u003e= 0.001), thrombocytopenia (\u003cem\u003eP \u003c/em\u003e= 0.000), and total HTs (\u003cem\u003eP \u003c/em\u003e= 0.042) showed great significance between nCRT and nCT group; (B) External validation cohort: Grade 3+ Leukopenia (\u003cem\u003eP \u003c/em\u003e= 0.026), thrombocytopenia (\u003cem\u003eP \u003c/em\u003e= 0.045), and total HTs (\u003cem\u003eP \u003c/em\u003e= 0.025) showed great significance between nCRT and nCT group.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2202715/v1/1970beedf9e04e074cc8d856.jpg"},{"id":30228556,"identity":"c7b322fb-17cd-4d8d-bede-d1794eb5f881","added_by":"auto","created_at":"2022-12-12 21:18:28","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":48638,"visible":true,"origin":"","legend":"\u003cp\u003eSpearman correlation analysis between V\u003csub\u003e5\u003c/sub\u003e and blood cell nadirs in the training cohort.\u003c/p\u003e\n\u003cp\u003e(A) Increased V\u003csub\u003e5\u003c/sub\u003e was correlated with lower WBC nadir (r = -0.508, \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.0001); (B) Increased V\u003csub\u003e5\u003c/sub\u003e was correlated with lower PLT nadir (r = -0.345, \u003cem\u003eP \u003c/em\u003e= 0.0002).\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2202715/v1/c5298ae5bfffe95963b9ba23.jpg"},{"id":30227980,"identity":"523f1d73-dc69-4891-a959-83b2dcce94ca","added_by":"auto","created_at":"2022-12-12 21:10:27","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":72754,"visible":true,"origin":"","legend":"\u003cp\u003e(A) ROC curves showing optimal thresholds of vertebral body V\u003csub\u003e5 \u003c/sub\u003efor Grade 3+ leukopenia, Grade 3+ thrombocytopenia, and Grade 3+ total HTs. The optimal cutoff value were V\u003csub\u003e5 \u003c/sub\u003e\u0026lt; 91.7% (AUC = 0.86, \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.0001), V\u003csub\u003e5 \u003c/sub\u003e\u0026lt; 89.2% (AUC = 0.76, \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.0001), V\u003csub\u003e5 \u003c/sub\u003e\u0026lt; 88.75% (AUC = 0.70, \u003cem\u003eP \u003c/em\u003e= 0.0014), respectively; (B) The predictive efficiency of V\u003csub\u003e5 \u003c/sub\u003e\u0026lt; 88.75% for Grade 3+ leukopenia (AUC = 0.83), Grade 3+ thrombocytopenia (AUC = 0.76), and Grade 3+ total HTs (AUC = 0.71) in the training cohort; (C) The predictive power of V\u003csub\u003e5 \u003c/sub\u003e\u0026lt; 88.75% for Grade 3+ leukopenia (AUC = 0.76), Grade 3+ thrombocytopenia (AUC = 0.83), and Grade 3+ total HTs (AUC = 0.74) in the external validation cohort.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2202715/v1/cb00e745dcc9d98e2d209d7b.jpg"},{"id":30228557,"identity":"9f481135-b4f0-4359-b738-943c41f4e54e","added_by":"auto","created_at":"2022-12-12 21:18:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":568687,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2202715/v1/0b4a54fe-3c31-4993-90e8-99acc04677b1.pdf"},{"id":30227978,"identity":"d9950912-96a1-46dd-a50d-9efaeeb301f8","added_by":"auto","created_at":"2022-12-12 21:10:27","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":28443,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-2202715/v1/8c1ab8bcb66744600b8fca01.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Preoperative chemoradiation-induced hematological toxicity and related vertebral dosimetry evaluations in patients with locally advanced gastric cancer: data from a phase III clinical trial","fulltext":[{"header":"Background","content":"\u003cp\u003eGastric cancer (GC) is the third leading cause of cancer-related deaths worldwide, with \u0026gt;\u0026thinsp;40% of new cases being detected in China (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Surgical resection with perioperative chemotherapy is a standard treatment for most cases of locally advanced GC (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). In the absence of positive results from adjuvant chemoradiotherapy studies (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e), there is increasing expectation of neoadjuvant chemoradiotherapy (nCRT) for improving survival. Several prospective randomized clinical trials have compared nCRT with neoadjuvant chemotherapy (nCT) for GC and esophagogastric junction (EGJ) adenocarcinoma, including the published POET (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) and Neo-AEGIS trials (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), and the ongoing TOPGEAR (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), CRITICS-II (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), PREACT (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), and the Neo-CRAG trials (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Most published results have not shown a particularly increase in hematological toxicity (HT) in the nCRT arm than in the nCT arm; for example, the TOPGEAR interim results showed that 52% of Grade 3\u0026thinsp;+\u0026thinsp;HTs occurred in the nCRT group and 50% occurred in the nCT group (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). However, tumor location and pattern of lymphatic extension can influence the characteristics of the radiation field and theoretically, the addition of a major treatment modality can potentially increase the risk of adverse effects.\u003c/p\u003e \u003cp\u003ePrevious studies have reported the relationship between HT and bone marrow radiotherapy dosimetry, though the majority of them were about pelvic bone irradiation in cervical cancer and colorectal cancer (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Similar studies have also been performed on radiotherapy for esophageal and pancreatic cancers (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). In radiotherapy for GC and EGJ cancer, vertebral bone marrow can be considerably affected given its anatomical adjacency to the clinical target volume (CTV) and the necessity for sparing the lateral organs at risk (OARs), such as the kidneys, liver, lungs, and heart. Studies have shown that up to 50% of the spinal bone marrow is hematopoietically active (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Since bone marrow stem cells are highly radiosensitive, the hematopoietic function of vertebral bone marrow can directly be impaired by radiotherapy for GC (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Therefore, it is necessary to explore the influence of dosimetric factors on HT due to nCRT for GC.\u003c/p\u003e \u003cp\u003eThe Neo-CRAG trial (NCT 01815853) (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) is a large multi-center phase III clinical trial that has just completed patient recruitment. The inclusion criteria was the most advanced non-metastatic GC (e.g., T3N2-3, T4aN+, T4bNany, and M0), with the lower border of station 16a2 lymph nodes always being included in the CTV of radiotherapy.\u003c/p\u003e \u003cp\u003eIn the preliminary data analysis, we noted a trend of increased HT in the nCRT group than in the nCT group, as well as an association between vertebral body (VB) dosimetry and HT grade. Thus, identifying the dosimetric parameters associated with HT could be critical for bone marrow-sparing in radiotherapy planning. Therefore, this study aimed to explore the difference in the risk of HT between nCRT and nCT groups and to identify the best predictive dosimetric factors of HT for locally advanced GC.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv class=\"Section2\" id=\"Sec3\"\u003e\n \u003ch2\u003ePatients\u003c/h2\u003e\n \u003cp\u003eThis study was based on an ongoing multi-center randomized controlled phase III clinical study (Neo-CRAG trial, NCT 01815853) that compared nCRT with nCT for patients with locally advanced gastric adenocarcinoma. The inclusion criteria were patients with histologically confirmed gastric adenocarcinoma, at cT3N2-3M0, cT4aN\u0026thinsp;+\u0026thinsp;M0, or cT4bNanyM0 clinical stage, aged 18\u0026ndash;75 years, with adequate organ function, and with an Eastern Cooperative Oncology Group performance status score\u0026thinsp;\u0026le;\u0026thinsp;2. The clinical stage was based on gastroscopy or endoscopic ultrasound (EUS), computed tomography (CT), and exploratory laparoscopy findings. The primary endpoint was disease-free survival (DFS) and the secondary endpoint was overall survival (OS), pathological complete remission (pCR) rate, and treatment safety. The clinical trial has completed the recruitment of 620 patients as of July 2022.\u003c/p\u003e\n \u003cp\u003eAmong the patients enrolled in the Neo-CRAG trial, we included 302 patients from two major participating centers who completed preoperative therapy between June 2013 and November 2021. The clinical characteristics of these patients are shown in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Of them, 113 treated with nCRT and 111 treated with nCT at Sun Yat-sen University Cancer Center were grouped under the training cohort, while 40 treated with nCRT and 38 treated with nCT at the Guangdong Provincial People\u0026apos;s Hospital were grouped under the external validation cohort.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eTreatment\u003c/h3\u003e\n\u003cp\u003eAs per the trial protocol (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e), patients in the nCT group received three 21-day cycles of XELOX chemotherapy (capecitabine 1000 mg/m\u0026sup2;, bid, d1-14\u0026thinsp;+\u0026thinsp;oxaliplatin 130 mg/m\u0026sup2;, d1). Patients in the nCRT group received one cycle of XELOX induction chemotherapy, followed by radiotherapy of 45 Gy in 25 daily fractions, concurrently with two 21-day cycles of dose-reduced XELOX chemotherapy (capecitabine 825 mg/m\u0026sup2;, bid, d1-14\u0026thinsp;+\u0026thinsp;oxaliplatin 100 mg/m\u0026sup2;, d1). Subsequently, radical gastrectomy was performed 3\u0026ndash;4 weeks and 6\u0026ndash;8 weeks after the conclusion of nCT and nCRT, respectively. The patients then continued to receive three 21-day cycles of adjuvant XELOX chemotherapy (standard dose intensity as in nCT group) 3\u0026ndash;4 weeks after surgery.\u003c/p\u003e\n\u003ch3\u003eRadiation Therapy And Target Volume Delineation\u003c/h3\u003e\n\u003cp\u003ePatients in the nCRT group were treated as follows: three-dimensional conformal radiation therapy (3D-CRT) for seven patients (one in the training cohort, six in the validation cohort) and intensity-modulated radiation therapy (IMRT) for the other patients. During the scan, the patients were immobilized in the supine position with a vacuum cushion and scanned with simulation computed tomography (CT-sim), including plain and venous-enhanced scans from T4 to L5 vertebral levels. The inter-slice thickness of the CT scan was 5 mm. About 50\u0026ndash;100 mL of prepared iopamidol solution was orally administered as the contrast agent 20 minutes before and at the time of CT-sim. Patients were required to fast for at least 3 hours before the CT-sim and before each radiation treatment to account for inter-fractional variability in gastric distention due to gastric filling. Before the scan, gastroscopy was performed to place titanium clips at the cephalic and caudal edges of the tumor as a fiducial marker for target volume delineation.\u003c/p\u003e\n\u003cp\u003eThe principle of target volume delineation was designed at beginning of the Neo-CRAG trial and was based on preoperative radiation recommendations of the European Organization for Research and Treatment of Cancer (EORTC-ROC) (\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e), the National Comprehensive Cancer Network (NCCN) guidelines for GC (\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e), and preoperative chemoradiation studies published the M.D. Anderson Cancer Center (\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eTo elaborate, the gross tumor volume of the primary tumor (GTVt) and involved lymph nodes (GTVnd) were delineated based on baseline CT scan, gastroscopy or EUS, and exploratory laparoscopic findings. The CTV included GTVt with a 3 cm mucosal expansion and a 1.0\u0026ndash;1.5 cm extragastric expansion, GTVnd with a 5 mm expansion, and elective regional lymphatic drainage regions. The mucosal expansion included the distal esophagus or proximal duodenum when appropriate. The inclusion of adjacent high-risk structures, including the inner half of the left diaphragm, parts of the pancreas, and neighboring parietal peritoneum were also considered. The CTV delineation had to avoid the vertebral body and include no more than 5 mm of liver tissues. The CTV was expanded by 5 mm in three dimensions to decide the planning target volume (PTV).\u003c/p\u003e\n\u003cp\u003eThe location of the primary tumor determined which elective lymph node groups would be included as per the JGCA classification, considering a 5 mm margin around the corresponding vessels:\u003c/p\u003e\n\u003cp\u003e(a) Proximal 1/3 stomach and distal EGJ primaries:\u003c/p\u003e\n\u003cp\u003ea. Essential: groups 1, 2, 3, 4sa, 7, 9, 10 (for neighboring greater curvature tumor), 11p, 12 (for lesser curvature tumor), 16a, 19, 20, 110, and 111.\u003c/p\u003e\n\u003cp\u003eb. Optional: groups 4sb (for greater curvature tumor), 5, 8, 11d, and 13.\u003c/p\u003e\n\u003cp\u003e(b) Middle 1/3 stomach primaries:\u003c/p\u003e\n\u003cp\u003ea. Essential: groups 1, 2, 3, 4sa, 4sb, 4d, 5, 6, 7, 8, 9, 10, 11p, 11d, 12, 13, and 16a.\u003c/p\u003e\n\u003cp\u003eb. Optional: groups 14, 17, 18, and 19.\u003c/p\u003e\n\u003cp\u003e(c) Distal 1/3 stomach primaries:\u003c/p\u003e\n\u003cp\u003ea. Essential: groups 1, 3, 4d, 5, 6, 7, 8, 9, 11p, 12, 13, 16a, 17, and 18.\u003c/p\u003e\n\u003cp\u003eb. Optional: groups 4sb, 10, and 11d.\u003c/p\u003e\n\u003cp\u003eFor dose limitations of the OAR, the liver volume percentage that received\u0026thinsp;\u0026ge;\u0026thinsp;30 Gy (V\u003csub\u003e30\u003c/sub\u003e) had to be less than 30% (V\u003csub\u003e30\u003c/sub\u003e \u0026lt; 30%) and the mean dose (D\u003csub\u003emean\u003c/sub\u003e) had to be \u0026lt; 22\u0026ndash;25 Gy. For the duodenum and small intestine, D\u003csub\u003emean\u003c/sub\u003e was \u0026le; 50 Gy and V\u003csub\u003e45\u003c/sub\u003e \u0026lt; 33%. For the kidneys, V\u003csub\u003e18\u003c/sub\u003e was \u0026lt; 33% and D\u003csub\u003emean\u003c/sub\u003e was \u0026le; 17 Gy. For the heart, V\u003csub\u003e40\u003c/sub\u003e was \u0026lt; 30% and V\u003csub\u003e25\u003c/sub\u003e \u0026lt; 50%. For the spinal cord, the maximum dose (D\u003csub\u003emax\u003c/sub\u003e) was \u0026le; 40 Gy.\u003c/p\u003e\n\u003cp\u003eForward or inverse treatment planning was used for 3D-CRT or IMRT, respectively, based on modern Monaco (Elekta, Crawley, UK), Eclipse (Varian Medical Systems, Palo Alto, CA, USA), or Pinnacle (Philips Medical Systems, Madison, WI, USA) treatment planning systems, using the direct machine parameter optimization algorithm.\u003c/p\u003e\n\u003ch3\u003eVertebral Body Target Delineation\u003c/h3\u003e\n\u003cp\u003eAs illustrated in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, the VB was retrospectively delineated manually based on CT simulation. The unified protocol of VB delineation was designed as follows: (a) VB and anterior pedicle were delineated, not including the vertebral appendages. The boundary of pedicle delineation was at the horizontal line across the center of the vertebral foramen. (b) The window width/level was set at W1600 Hu/L400 Hu to share the advantages of both the bone and mediastinal windows. (c) Only the cancellous bone was delineated and the cortical bone was avoided. (d) The upper boundary of the delineated VB was 2 cm above the CTV and the lower boundary was 3 cm below the CTV, not counting the intervertebral discs (IVD). The thoracic IVD thickness was set as 0.5 cm (one slice) and the lumbar IVD thickness as 1 cm (two slices). All the VB contours were delineated under the guidance of one single chief physician.\u003c/p\u003e\n\u003cp\u003eAfter delineation, a dose-volume histogram (DVH) was obtained from the original treatment plan. The dosimetric parameters of VB including the total vertebral body volume (VBV), D\u003csub\u003emax\u003c/sub\u003e, D\u003csub\u003emean\u003c/sub\u003e, minimum dose (D\u003csub\u003emin\u003c/sub\u003e), and the volume percentage of dose receiving\u0026thinsp;\u0026ge;\u0026thinsp;x Gy (V\u003csub\u003e5\u003c/sub\u003e, V\u003csub\u003e10\u003c/sub\u003e, V\u003csub\u003e20\u003c/sub\u003e, V\u003csub\u003e30\u003c/sub\u003e, V\u003csub\u003e40\u003c/sub\u003e, and V\u003csub\u003e45\u003c/sub\u003e) were recorded.\u003c/p\u003e\n\u003ch3\u003eHematological Toxicity Evaluation\u003c/h3\u003e\n\u003cp\u003eRoutine blood investigations were regularly performed for all patients. Complete blood counts were determined at the time of diagnosis and weekly during neoadjuvant therapy and pre-operative evaluation. Instances of HT were graded according to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE v5.0).\u003c/p\u003e\n\u003cdiv class=\"Section2\" id=\"Sec8\"\u003e\n \u003ch2\u003eStatistical analysis\u003c/h2\u003e\n \u003cp\u003eThe clinicopathological characteristics, hematological indicators, and dosimetric parameters were evaluated by t-test or Chi-squared test or Fisher\u0026rsquo;s exact test, when appropriate. Univariate (UVA) and multivariate (MVA) logistic regression was performed to identify dosimetric variables associated with the development of Grade3\u0026thinsp;+\u0026thinsp;HT. Spearman correlation analysis was used to test correlations between dosimetric variables and absolute blood cell nadirs. Receiver Operating Characteristic (ROC) curves with the Youden method were used to identify the optimal dose-volume thresholds of predictive dosimetric parameters and to evaluate the predictive efficiency of the cutoff value both in the training cohort and the external validation cohort.\u003c/p\u003e\n \u003cp\u003eAll statistical analyses were performed with SPSS software 23.0, and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered to be significant. GraphPad Prism 8.0 and RStudio version 4.1.2 were used for plotting.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv class=\"Section2\" id=\"Sec10\"\u003e\n \u003ch2\u003eComparison of clinicopathological characteristics between the nCRT and nCT groups\u003c/h2\u003e\n \u003cp\u003eThe clinicopathological characteristics including sex (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.612), age (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.143), Lauren type (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.826), primary tumor site (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.146), histological grade (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.158), and cTNM stage (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.70) were not significantly different between the nCRT and nCT groups in the training cohort (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Similarly, there were no significant differences between the two groups in the validation cohort.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eDifferences In Ht Between The Ncrt And Nct Groups\u003c/h3\u003e\n\u003cp\u003ePatients in the nCRT group experienced more Grade 3\u0026thinsp;+\u0026thinsp;leukopenia (11.5% vs. 0.9%, \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.001), Grade 3\u0026thinsp;+\u0026thinsp;thrombocytopenia (11.5% vs. 0%, \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.000), and Grade 3\u0026thinsp;+\u0026thinsp;total HTs (27.4% vs. 16.2%, \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.042) compared with patients in the nCT group (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). The incidences of Grade 3\u0026thinsp;+\u0026thinsp;neutropenia (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.084) and Grade 3\u0026thinsp;+\u0026thinsp;anemia (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.956) were not significantly different between the two groups. Grade 4 HT was rare and Grade 5 HT did not occur during the entire neoadjuvant treatment period. In the validation cohort, patients who received nCRT also suffered more Grade 3\u0026thinsp;+\u0026thinsp;HTs (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.025) than those in the nCT group. The different grades of HT in the training and external validation cohorts are shown in detail in Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eFurther, the influence of the addition of radiotherapy on blood cell nadirs was explored (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). The mean \u0026plusmn; standard deviation (SD) nadir counts of white blood cell (WBC) count, absolute neutrophil count (ANC), hemoglobin (HGB), and platelet (PLT) in the nCRT group were 3.05 \u0026plusmn; 0.91*10\u003csup\u003e9\u003c/sup\u003e/L, 1.82 \u0026plusmn; 0.68*10\u003csup\u003e9\u003c/sup\u003e/L, 98.69 \u0026plusmn; 16.94g/L, and 97.08 \u0026plusmn; 43.22*10\u003csup\u003e9\u003c/sup\u003e/L, respectively. The corresponding blood cell nadirs in the nCT group were 4.83 \u0026plusmn; 1.67*10\u003csup\u003e9\u003c/sup\u003e/L, 2.60 \u0026plusmn; 1.43*10\u003csup\u003e9\u003c/sup\u003e/L, 105.96 \u0026plusmn; 22.83 g/L, and 156.94 \u0026plusmn; 51.88*10\u003csup\u003e9\u003c/sup\u003e/L, respectively. Patients in the nCRT group had significantly lower WBC nadir (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.000), ANC nadir (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000), HGB nadir (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008), and PLT nadir (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000) compared with those in the nCT group. In the validation cohort, the difference in the blood cell nadirs between the two groups showed the same trend as that in the training cohort.\u003c/p\u003e\n\u003ch3\u003eModeling Dosimetric Predictors Of Hematological Toxicity In The Training Cohort\u003c/h3\u003e\n\u003cp\u003eThe VB radiation dosimetric parameters of all patients treated with nCRT from two centers are summarized in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. Only V\u003csub\u003e30\u003c/sub\u003e (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.049) was significantly different between the training and validation cohorts, while the other dose-volume parameters were not.\u003c/p\u003e\n\u003cp\u003eThe dose-volume metrics of the VB were entered into UVA in the training cohort. The results showed that increased D\u003csub\u003emin\u003c/sub\u003e, D\u003csub\u003emean\u003c/sub\u003e, V\u003csub\u003e5\u003c/sub\u003e, V\u003csub\u003e10\u003c/sub\u003e, V\u003csub\u003e20\u003c/sub\u003e, V\u003csub\u003e30\u003c/sub\u003e, and V\u003csub\u003e40\u003c/sub\u003e were risk factors for Grade 3\u0026thinsp;+\u0026thinsp;leukopenia; increased V\u003csub\u003e5\u003c/sub\u003e and V\u003csub\u003e10\u003c/sub\u003e were risk factors for Grade 3\u0026thinsp;+\u0026thinsp;thrombocytopenia; and D\u003csub\u003emax\u003c/sub\u003e and V\u003csub\u003e5\u003c/sub\u003e were risk factors for Grade 3\u0026thinsp;+\u0026thinsp;total HTs. Subsequently, variables with \u003cem\u003eP\u003c/em\u003e \u0026le; 0.15 in the UVA were included in the MVA. The results showed that V\u003csub\u003e5\u003c/sub\u003e was a risk factor for Grade 3\u0026thinsp;+\u0026thinsp;leukopenia (odds ratio [OR]: 1.353, 95% confidence interval [CI]: 1.179\u0026ndash;1.553, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000), Grade 3\u0026thinsp;+\u0026thinsp;thrombocytopenia (OR: 1.192, 95% CI: 1.074\u0026ndash;1.324, \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.001), and Grade 3\u0026thinsp;+\u0026thinsp;total HTs (OR: 1.086, 95% CI: 0.987\u0026ndash;1.195, \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.042). Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e detailed the results of UVA and MVA. Spearman correlation analysis revealed that increased V\u003csub\u003e5\u003c/sub\u003e was correlated with a lower WBC nadir (r = -0.508, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.0001) and lower PLT nadir (r = -0.345, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0002) (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eBased on the results of MVA, the ROC curve was generated to identify the optimal cut-off values of V\u003csub\u003e5\u003c/sub\u003e for predicting different HTs. V\u003csub\u003e5\u003c/sub\u003e \u0026lt; 91.7% (area under the curve [AUC]\u0026thinsp;=\u0026thinsp;0.86, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.0001), V\u003csub\u003e5\u003c/sub\u003e \u0026lt; 89.2% (AUC\u0026thinsp;=\u0026thinsp;0.76, \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.0018), and V\u003csub\u003e5\u003c/sub\u003e \u0026lt; 88.75% (AUC\u0026thinsp;=\u0026thinsp;0.70, \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.0014) were the optimal cut-off values for predicting Grade 3\u0026thinsp;+\u0026thinsp;leukopenia, Grade 3\u0026thinsp;+\u0026thinsp;thrombocytopenia, and Grade 3\u0026thinsp;+\u0026thinsp;total HTs, respectively (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eA).\u003c/p\u003e\n\u003ch3\u003eValidation Of The Predictive Efficiency Of The Best Cut-off Value\u003c/h3\u003e\n\u003cp\u003eConsidering the safety and convenience of clinical application, a lower dose-volume metric of V\u003csub\u003e5\u003c/sub\u003e \u0026lt; 88.75% was chosen as the best cut-off value for decreasing Grade 3\u0026thinsp;+\u0026thinsp;HT. As shown in Fig. 4B, V\u003csub\u003e5\u003c/sub\u003e \u0026lt; 88.75% showed a satisfactory predictive ability for a lower incidence of Grade 3\u0026thinsp;+\u0026thinsp;leukopenia (AUC\u0026thinsp;=\u0026thinsp;0.83), Grade 3\u0026thinsp;+\u0026thinsp;thrombocytopenia (AUC\u0026thinsp;=\u0026thinsp;0.76), and Grade 3\u0026thinsp;+\u0026thinsp;total HTs (AUC\u0026thinsp;=\u0026thinsp;0.71) in the training cohort. Limiting VB V\u003csub\u003e5\u003c/sub\u003e \u0026lt; 88.75% could reduce the rate of Grade 3\u0026thinsp;+\u0026thinsp;leukopenia, Grade 3\u0026thinsp;+\u0026thinsp;thrombocytopenia, and Grade 3\u0026thinsp;+\u0026thinsp;total HTs by 44.3%, 37.5%, and 54%, respectively.\u003c/p\u003e\n\u003cp\u003eFurthermore, as is shown in Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eC, we tested the predictive power of V\u003csub\u003e5\u003c/sub\u003e \u0026lt; 88.75% in the external validation cohort of 40 patients who received nCRT. The AUCs for Grade 3\u0026thinsp;+\u0026thinsp;leukopenia, Grade 3\u0026thinsp;+\u0026thinsp;thrombocytopenia, and Grade 3\u0026thinsp;+\u0026thinsp;total HTs were 0.76, 0.83, and 0.74, respectively, which indicates good predictive ability. The rates of Grade 3\u0026thinsp;+\u0026thinsp;leukopenia, Grade 3\u0026thinsp;+\u0026thinsp;thrombocytopenia, and Grade 3\u0026thinsp;+\u0026thinsp;total HTs decreased by 6.3%, 14.6%, and 14.6%, respectively.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present study explored the difference in the incidence of HT between nCRT and nCT. Additionally, it investigated the vertebral radiation dosimetric parameters associated with HT in patients with locally advanced GC. To our knowledge, this is the first detailed report characterizing VB dose-volume parameters and their association with HT in GC treated with nCRT. The results demonstrated that the HT of preoperative chemoradiotherapy could be higher than that of preoperative chemotherapy and limiting VB (V\u003csub\u003e5\u003c/sub\u003e \u0026lt; 88.75%) could decrease the risk of Grade 3\u0026thinsp;+\u0026thinsp;HT in GC.\u003c/p\u003e\n\u003cp\u003eThe ARTIST trial\u0026mdash;the representative study of adjuvant chemoradiotherapy versus adjuvant chemotherapy\u0026mdash;showed that Grade 3\u0026thinsp;+\u0026thinsp;neutropenia occurred in 48.4% of the patients in the postoperative chemoradiotherapy arm and 40.7% of those in the postoperative chemotherapy arm. Further, the rate of Grade 3\u0026thinsp;+\u0026thinsp;thrombocytopenia was 0.9% in the postoperative chemoradiotherapy arm while none occurred in the postoperative chemotherapy arm (\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e). Until now, the TOPGEAR trial is the only large phase III study that has reported a difference in HT in neoadjuvant treatment for GC. The interim results showed that Grade 3\u0026thinsp;+\u0026thinsp;neutropenia, anemia, thrombocytopenia, and total HTs in the nCRT group reached 45%, 5%, 2%, and 52%, respectively, while the corresponding results in the nCT group were 40%, 7%, 3%, and 50%, respectively (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e). Despite the different rates of HT between these two trials, the frequency of Grade 3\u0026thinsp;+\u0026thinsp;total HTs was not higher in the nCRT group than in the nCT group. A similar trend of different rates of HT between the two groups was also observed in the ARTIST-2 trial (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e). The CRITICS trial even reported that patients experienced less Grade 3\u0026thinsp;+\u0026thinsp;neutropenia in the nCRT group (4.4%) than in the nCT group (27%) (\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e). Further details of HT differences between chemoradiotherapy and chemotherapy in the above four clinical trials are summarized in Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e. However, there was no report of HT in the POET trial (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e). Compared with the above studies, this study reported more Grade 3\u0026thinsp;+\u0026thinsp;leukopenia, thrombocytopenia, and total HTs in the nCRT group than in the nCT group.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eThe ARTIST and ARTIST-2 studies enrolled GC patients with clinical or pathological stage II and the CRITICS and TOPGEAR studies enrolled patients even with stage IB (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e), Meanwhile, we only enrolled patients with more advanced clinical stages of GC (III\u0026ndash;IVA). In our study, the lymphatic group 16a\u003csub\u003e2\u003c/sub\u003e, the lower border of which is located at the lower margin of the left renal vein, was included in the CTV of all patients; thus, the delineated target volume was longer and wider. The larger the target volume, the more radiation enters or passes through the unprotected organs, which also aggravates radiation exposure to the VB. More advanced clinical stages and larger target volumes may contribute to the higher HT in the nCRT group in our study.\u003c/p\u003e\n\u003cp\u003eThough it is well known that radiation to the bone marrow can cause myelosuppression, VB is not yet considered an OAR in major radiotherapy guidelines including those for GC (\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e). Prior studies reported that VB dosimetric parameters can predict radiation-induced HT in pancreatic and lung cancers (\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e). In radiotherapy for GC, to protect the important OARs including the kidneys and liver, the radiation beam has to be arranged along the opposed anteroposterior direction, resulting in high irradiation of the VB. The stomach and its lymphatic drainage region are adjacent to the VB, therefore, delineation of the target volume may have a greater impact on the VB in GC than that in the lung or pancreatic cancers. Totally, it is important to protect the VB and set the best VB dose parameters during radiotherapy for GC.\u003c/p\u003e\n\u003cp\u003eThe VB dosimetric studies by Fabian et al. (\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e), Lee et al. (\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e), and Zhang et al. (\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e) focused on esophageal cancer treated with nCRT. The radiotherapy doses were 50.4\u0026ndash;59.4 Gy, 41.4\u0026ndash;48 Gy, and 41.4\u0026ndash;70 Gy, respectively. The first study reported that V\u003csub\u003e30\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;14% could reduce the risk of Grade 3\u0026thinsp;+\u0026thinsp;HT. The second concluded that V\u003csub\u003e10\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;77%, V\u003csub\u003e20\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;70%, and D\u003csub\u003emean\u003c/sub\u003e \u0026lt; 25.9 Gy could decrease the occurrence of Grade 3\u0026thinsp;+\u0026thinsp;leukopenia. Zhang\u0026rsquo;s study also demonstrated the correlation of Grade 3\u0026thinsp;+\u0026thinsp;leukopenia with V\u003csub\u003e10\u003c/sub\u003e, V\u003csub\u003e20\u003c/sub\u003e, and D\u003csub\u003emean\u003c/sub\u003e. In the above three studies, the differences in their predictive index may be due to differences in their prescribed dose and target volume delineation. Wang et al. (\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e) found that 20% of patients experienced Grade 3\u0026thinsp;+\u0026thinsp;HT during capecitabine-based CRT in locally advanced GC and recommended dose constraints of VB V\u003csub\u003e5\u003c/sub\u003e \u0026le; 90% to avoid Grade 3\u0026thinsp;+\u0026thinsp;leukopenia, V\u003csub\u003e20\u003c/sub\u003e \u0026le; 78% to avoid Grade 3\u0026thinsp;+\u0026thinsp;neutropenia, and V\u003csub\u003e30\u003c/sub\u003e \u0026le; 60% to avoid Grade 3\u0026thinsp;+\u0026thinsp;thrombocytopenia during adjuvant CRT. However, the limited sample size of 25 patients in their study makes it challenging to draw conclusive findings. Thus, it is recommended that the dosimetric predictors of Grade 3\u0026thinsp;+\u0026thinsp;HT be re-evaluated in a larger patient cohort. In the present study, 113 patients with GC who received nCRT in the training cohort were recruited, and the results showed that higher Dmin, Dmean, V\u003csub\u003e5\u003c/sub\u003e, V\u003csub\u003e10\u003c/sub\u003e, V\u003csub\u003e20\u003c/sub\u003e, and V\u003csub\u003e30\u003c/sub\u003e significantly increased HT of different types. However, V\u003csub\u003e5\u003c/sub\u003e was the only independent dosimetric factor predictive of Grade 3\u0026thinsp;+\u0026thinsp;leukopenia, thrombocytopenia, and total HTs in subsequent multivariate analyses. Limmiting VB V\u003csub\u003e5\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;88.75% may serve as a proper dosimetric recommendation to reduce the risk of Grade 3\u0026thinsp;+\u0026thinsp;HT in patients with GC. The predictive value of V\u003csub\u003e5\u003c/sub\u003e was emphasized in our study, which may due to: (a) patients in our study were from a prospective clinical trial, all received 45 Gy of radiotherapy and the same chemotherapy regimen and cycles; (b) the principle of target volume delineation was highly consistent and possessed a narrow fluctuation range and a relatively small heterogeneity of VB dosimetric parameters. In daily practice of GC radiotherapy, however, the predictive value of other dosimetric parameters, such as V\u003csub\u003e10\u003c/sub\u003e, V\u003csub\u003e20\u003c/sub\u003e, V\u003csub\u003e30\u003c/sub\u003e, may also be considered, based on the studies referred above.\u003c/p\u003e\n\u003cp\u003eWe delineated VB based on the CT simulation in this study, and designed the delineation protocol which was proved convenient and practical. Mahantshetty et al. (\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e) proposed to contour the inner cavity of the bone as it could be a better surrogate of the active bone marrow. Some studies used positron emission tomography-computed tomography (PET-CT) or magnetic resonance imaging (MRI) to identify and delineate active bone marrow (\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e), which caused difficulty to some extent in radiation planning. In the clinical practice, the delineation method based on CT scanning is more commonly used and economical for GC radiotherapy, and the VB dosimetric parameters that we concluded are more clinically instructive than those based on PET-CT or MRI.\u003c/p\u003e\n\u003cp\u003eTo our knowledge, this is the first study to predict acute HT using VB dosimetric parameters in patients with GC receiving nCRT, which excluded the impact of surgery. Studies on lung and esophageal cancers have considered the effect of radiation doses to the ribs, clavicle, sternum, and scapula on bone marrow suppression outside the VB (\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e), but the effect of these bones on HT was not considered in our patients. Given the lower location of the GC treatment fields, it\u0026rsquo;s not likely that these bones receiving meaningful low-dose radiation exposure. Meanwhile, we were not able to correlate bone dose-volume metrics with the long-term changes in blood cell counts that may affect the patients\u0026rsquo; quality of life, which required a longer follow-up.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, nCRT could increase the risk of Grade 3\u0026thinsp;+\u0026thinsp;HT compared with nCT. Dose constraints of V\u003csub\u003e5\u003c/sub\u003e \u0026lt; 88.75% should be considered to reduce the incidence of Grade 3\u0026thinsp;+\u0026thinsp;HT in patients with GC treated with IMRT, especially when oxaliplatin and capecitabine are used as chemotherapeutic agents.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehematological toxicity\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003egastric cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003enCRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eneoadjuvant chemoradiotherapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003enCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eneoadjuvant chemotherapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003evertebral body\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCTCAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCommon Terminology Criteria for Adverse Events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eROC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ereceiver operating characteristic\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEGJ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eesophagogastric junction\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCTV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eclinical target volume\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOAR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eorgan at risk\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEUS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eendoscopic ultrasound\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecomputed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDFS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edisease-free survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eoverall survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eXELOX\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecapecitabine\u0026thinsp;+\u0026thinsp;oxaliplatin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e3D-CRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ethree-dimensional conformal radiation therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIMRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eintensity-modulated radiation therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCT-sim\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esimulation computed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEORTC-ROC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEuropean Organization for Research and Treatment of Cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNCCN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNational Comprehensive Cancer Network\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGTV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003egross tumor volume\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePTV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eplanning target volume\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIVD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eintervertebral discs\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDVH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edose-volume histogram\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVBV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003evertebral body volume\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eD\u003csub\u003emax\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emaximum dose\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eD\u003csub\u003emean\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emean dose\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eD\u003csub\u003emin\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eminimum dose\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eV\u003csub\u003ex\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ethe volume percentage of dose receiving\u0026thinsp;\u0026ge;\u0026thinsp;x Gy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWBC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ewhite blood cell\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eANC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eabsolute neutrophil count\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHGB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehemoglobin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePLT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eplatelet\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estandard deviation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUVA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eunivariate logistic regression analysis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMVA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emultivariate logistic regression analysis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eodds ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAUC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003earea under the curve\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePET-CT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epositron emission tomography-computed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emagnetic resonance imaging.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur study was approved by the Medical Ethics Committee of Affiliated Hospital of Sun Yat-sen University Cancer Center (the number of ethic approval: 5010-2012-05-03).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was funded by grant 2012013 from the Sun Yat-sen University Clinical Research 5010 Program.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJJW was responsible for data analysis and manuscript writing. HS was responsible for data analysis and study designing. LZ and MJ were responsible for project administration and data collection. WJX contributed to data collection. ZWZ provided clinical and pathological data. HWS and YJZ contributed to study designing and project administration. All authors contributed to the revision of the manuscript and approval of the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTorre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87\u0026ndash;108.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmalley SR, Benedetti JK, Haller DG, Hundahl SA, Estes NC, Ajani JA, et al. 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Dosimetric predictors of acute haematological toxicity in oesophageal cancer patients treated with neoadjuvant chemoradiotherapy. The British journal of radiology. 2016.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang J, Tian Y, Tang Y, Wang X, Li N, Ren H, et al. A Phase II prospective nonrandomized trial of magnetic resonance imaging-guided hematopoietic bone marrow-sparing radiotherapy for gastric cancer patients with concurrent chemotherapy. Onco Targets Ther. 2016;9:2701\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahantshetty U, Krishnatry R, Chaudhari S, Kanaujia A, Engineer R, Chopra S, et al. Comparison of 2 contouring methods of bone marrow on CT and correlation with hematological toxicities in non-bone marrow-sparing pelvic intensity-modulated radiotherapy with concurrent cisplatin for cervical cancer. 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Int J Radiat Oncol Biol Phys. 2012;83(4):1185\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 5 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"radiation-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"raon","sideBox":"Learn more about [Radiation Oncology](http://ro-journal.biomedcentral.com/)","snPcode":"13014","submissionUrl":"https://submission.nature.com/new-submission/13014/3","title":"Radiation Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Vertebral body, Dosimetric parameter, Hematologic toxicity, Gastric, Chemoradiotherapy","lastPublishedDoi":"10.21203/rs.3.rs-2202715/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2202715/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eTo explore the hematological toxicity (HT) induced by neoadjuvant chemoradiotherapy (nCRT) compared with neoadjuvant chemotherapy (nCT) and to identify the appropriate vertebral body (VB) dosimetric parameters for predicting HT in patients with locally advanced gastric cancer (GC).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn the phase III study, 302 patients with GC from an ongoing multi-center randomized clinical trial (NCT 01815853) were included. Patients from two major centers were grouped into training and external validation cohorts. The nCT group received three cycles of XELOX chemotherapy, while the nCRT received the same dose-reduced chemotherapy plus 45 Gy radiotherapy. The complete blood counts at baseline, during neoadjuvant treatment, and in the preoperative period were compared between the nCT and nCRT groups. The VB was retrospectively contoured and the dose-volume parameters were extracted in the nCRT group. Patients\u0026rsquo; clinical characteristics, VB dosimetric parameters, and HTs were statistically analyzed. Instances of HT were graded according to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE v5.0). The receiver operating characteristic (ROC) curves were generated to identify the optimal cut-off points for dosimetric variables and verify the prediction efficiency of the dosimetric index in both training and external validation cohorts.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn the training cohort, 27.4% Grade 3\u0026thinsp;+\u0026thinsp;HTs were noted in the nCRT group and 16.2% in the nCT group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.042). A similar result was exhibited in the validation cohort, with 35.0% Grade 3\u0026thinsp;+\u0026thinsp;HTs in the nCRT group and 13.2% in the nCT group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.025). The multivariate analysis of the training cohort revealed that V\u003csub\u003e5\u003c/sub\u003e was associated with Grade 3\u0026thinsp;+\u0026thinsp;leukopenia (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000), Grade 3\u0026thinsp;+\u0026thinsp;thrombocytopenia (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), and Grade 3\u0026thinsp;+\u0026thinsp;total HTs (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.042). The Spearman correlation analysis identified a significant correlation of V\u003csub\u003e5\u003c/sub\u003e with the white blood cell nadir (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0001) and platelet nadir (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0002). The ROC curve identified the optimal cut-off points for V\u003csub\u003e5\u003c/sub\u003e and showed that V\u003csub\u003e5\u003c/sub\u003e \u0026lt; 88.75% could indicate a decreased risk of Grade 3\u0026thinsp;+\u0026thinsp;leukopenia, thrombocytopenia, and total HTs in the training as well as the external validation cohorts.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eCompared with nCT, nCRT could increase the risk of Grade 3\u0026thinsp;+\u0026thinsp;HT in patients with locally advanced GC. Dose constraints of V\u003csub\u003e5\u003c/sub\u003e \u0026lt; 88.75% in irradiated VB could reduce the incidence of Grade 3\u0026thinsp;+\u0026thinsp;HT.\u003c/p\u003e","manuscriptTitle":"Preoperative chemoradiation-induced hematological toxicity and related vertebral dosimetry evaluations in patients with locally advanced gastric cancer: data from a phase III clinical trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-12-12 21:10:22","doi":"10.21203/rs.3.rs-2202715/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2023-04-02T12:55:56+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-03-31T09:57:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"7f210d29-946d-4fd1-a863-1b31c69f8926","date":"2023-03-22T06:26:39+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-12-28T18:19:07+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-10-30T07:54:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2022-10-27T06:53:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"Radiation Oncology","date":"2022-10-25T13:55:21+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"radiation-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"raon","sideBox":"Learn more about [Radiation Oncology](http://ro-journal.biomedcentral.com/)","snPcode":"13014","submissionUrl":"https://submission.nature.com/new-submission/13014/3","title":"Radiation Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cdb1210c-8a19-4f4f-97d9-0f182ae3e278","owner":[],"postedDate":"December 12th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2023-04-21T14:59:28+00:00","versionOfRecord":[],"versionCreatedAt":"2022-12-12 21:10:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2202715","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2202715","identity":"rs-2202715","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}