Chemoradiation Therapy For Esophageal Cancer Research Articles

Severe Lymphopenia During Chemoradiation Therapy for Esophageal Cancer: Comprehensive Analysis of Randomized Phase 2B Trial of Proton Beam Therapy Versus Intensity Modulated Radiation Therapy

Lymphocytes play an important role in antitumor immunity; however, they are also especially vulnerable to depletion during chemoradiation therapy (CRT). The purpose of this study was to compare the incidence of grade 4 lymphopenia (G4L) between proton beam therapy (PBT) and intensity modulated photon radiation therapy (IMRT) in patients with esophageal cancer treated with CRT in a completed randomized trial and to ascertain patient heterogeneity to G4L risk based on treatment and established prognostic factors. Between April 2012 and March 2019, a single-institution, open-label, nonblinded, phase 2 randomized trial (NCT01512589) was conducted at the University of Texas MD Anderson Cancer Center. Patients were randomly assigned to IMRT or PBT, either definitively or preoperatively. This secondary analysis of the randomized trial was G4L during concurrent CRT according to Common Terminology Criteria for Adverse Events version 5.0. Among 105 patients evaluable for analysis, 44 patients (42%) experienced G4L at a median of 28 days after the start date of concurrent CRT. Induction chemotherapy (P=.003), baseline absolute lymphocyte count (P < .001), radiation therapy modality (P=.002), and planning treatment volume (P=.033) were found to be significantly associated with G4L. Multivariate classification analysis partitioned patients into 5 subgroups for whom the incidence of G4L was observed in 0%, 14%, 35%, 70%, and 100% of patients. The benefit of PBT over IMRT was most pronounced in patients with an intermediate baseline absolute lymphocyte count and large planning treatment volume (P=.011). This is the first prospective evidence that limiting dose scatter by PBT significantly reduced the incidence of G4L, especially in the intermediate-risk patients. The implication of this immune-sparing effect of PBT, especially in the context of standard adjuvant immunotherapy, needs further examination in the current phase 3 randomized trials.

The Impact of Radiation Dose to Heart Substructures on Major Coronary Events and Patient Survival after Chemoradiation Therapy for Esophageal Cancer.

Simple SummaryWhether it is necessary to evaluate the radiation exposure of cardiac substructures when making radiotherapy plans is one of the current research hotspots. In this cohort study of 355 patients with esophageal cancer, the radiation dose to key coronary substructures such as the left anterior descending artery V30Gy and mean left main coronary artery was closely associated with major coronary events and overall patient survival, and showed better predictive value than the mean heart dose or heart V30Gy recommended by current guidelines. Our findings suggest that, in addition to the whole heart, key coronary substructures should be contoured as organs at risk during radiotherapy plan optimization.Background: There is a paucity of data regarding the association between radiation exposure of heart substructures and the incidence of major coronary events (MCEs) in patients with esophageal cancer (ESOC) undergoing chemoradiation therapy. We studied radiation dosimetric determinants of MCE risk and measured their impact on patient prognosis using a cohort of ESOC patients treated at a single institution. Methods: Between March 2005 and October 2015, 355 ESOC patients treated with concurrent chemoradiotherapy were identified from a prospectively maintained and institutional-regulatory-board-approved clinical database. Dose-distribution parameters of the whole heart, the atria, the ventricles, the left main coronary artery, and three main coronary arteries were extracted for analysis. Results: Within a median follow-up time of 67 months, 14 patients experienced MCEs at a median of 16 months. The incidence of MCEs was significantly associated with the left anterior descending coronary artery (LAD) receiving ≥30 Gy (V30Gy) (p = 0.048). Patients receiving LAD V30Gy ≥ 10% of volume experienced a higher incidence of MCEs versus the LAD V30Gy < 10% group (p = 0.044). The relative rate of death increased with the left main coronary artery (LMA) mean dose (Gy) (p = 0.002). Furthermore, a mutual promotion effect of hyperlipidemia and RT on MCEs was observed. Conclusion: Radiation dose to coronary substructures is associated with MCEs and overall survival in patients with ESOC. In this study, the doses to these substructures appeared to be better predictors of toxicity outcomes than mean heart dose (MHD) or whole-heart V30Gy. These findings have implications for reducing coronary events through radiation therapy planning.

Influence of Caregiver Presence During Physician Office Visits on Patients Undergoing Chemoradiation Therapy for Esophageal Cancer

PurposeAlthough the association of marital status with outcomes for patients with cancer has been widely studied, the mechanisms underpinning the protective effect of marriage are still not fully understood. The social support that marriage imparts is often discussed as an explanation for why patients with cancer who are married have better outcomes. Social support has been difficult to objectively quantify. Accompaniment of the patient at physician visits may be more meaningful than marital status itself. This study investigated the effect of caregiver presence at physician visits on treatment tolerance and outcome in patients undergoing chemoradiation therapy (CRT) for esophageal cancer.Methods and MaterialsPatients who received a diagnosis of esophageal cancer who underwent CRT from January 1, 2005, to January 1, 2016, as part of their curative-intent management were retrospectively reviewed. Data collected included the patients’ marital status, caregiver presence at each physician visit, baseline performance status, serum albumin values and leukocyte values throughout treatment, patient weight values throughout treatment, tumor response to therapy, and overall survival. Patients were divided into 2 groups based on frequency of caregiver presence at physician visits (<50% or ≥50% of visits). Using χ2 tests, Wilcoxon rank sum tests, and log-rank tests, the patients’ characteristics, treatment tolerance and treatment outcome, and overall survival, respectively, were compared.ResultsIn total, 35 of 59 patients were defined as having frequent caregiver presence at physician visits (≥50% of all documented visits), whereas 24 patients were categorized as having infrequent caregiver accompaniment. No significant difference in performance status or weight loss before the diagnosis of esophageal cancer was found. Patients who had frequent caregiver presence at physician visits maintained body weight better than those who had infrequent caregiver presence (median weight loss of 2.7 kg compared with 4.9 kg; P = .04). There was no difference in overall survival between the 2 groups.ConclusionsAlthough patients with esophageal cancer undergoing CRT who had frequent caregiver presence at physician visits were not found to have an overall survival benefit, they had less weight loss, which may confer favorable treatment tolerance and maintenance of nutritional status during cancer treatment.

Lymph Node Status after Neoadjuvant Chemoradiation Therapy for Esophageal Cancer according to Radiation Field Coverage.

BackgroundTo explore the effect of radiation on metastatic lymph nodes (LNs) after neoadjuvant chemoradiation therapy (nCRT), we examined the metastatic features of LNs according to their inclusion in the radiation field.MethodsThe patient group included 88 men and 2 women, with a mean age of 61.1±8.1 years, who underwent esophagectomy and lymphadenectomy after nCRT. Dissected LNs were compared in terms of clinical suspicion of metastasis, nodal station, and inclusion in the radiation field.ResultsLN positivity did not differ between LNs that were inside (in-field [IF]) and outside (out-field [OF]) of the radiation field (IF: 40 of 465 [9%], OF: 40 of 420 [10%]; p=0.313). In clinical N+ nodal stations, IF stations had a lower incidence of metastasis than OF stations (IF/cN+: 16 of 142 [11%], OF/cN+: 9/30 [30%]; p=0.010). However, in clinical N- nodal stations, pathological positivity was not affected by whether the nodal stations were included in the radiation field (IF/cN-: 24 of 323 [7%], OF/cN-: 31 of 390 [8%]; p=0.447).ConclusionRadiation therapy for nCRT could downstage clinically suspected nodal metastasis. However, such therapy was ineffective when used to treat nodes that were not suspicious for metastasis. Because significant numbers of residual metastases were identified irrespective of coverage by the radiation field, lymphadenectomy should be performed to ensure complete removal of residual nodal metastases after nCRT.

Final Trial Results of Repeated Diffusion-Weighted MRI and FDG-PET Imaging for the Prediction of Response to Chemoradiation Therapy in Esophageal Cancer

To present the final results of a prospective study to evaluate imaging predictors for pathologic complete response (pathCR) to chemoradiation therapy (CRT) in esophageal cancer using repeated diffusion-weighted magnetic resonance imaging (DW-MRI) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging before, during, and after CRT. Between January 2014 and July 2017, 60 patients with stage II-III esophageal cancer were prospectively enrolled. DW-MRI and FDG-PET imaging were acquired before treatment (baseline), 12-14 days after initiation of CRT (interim, IM), and at first follow-up 4-6 weeks after completing CRT. The primary outcome was pathCR as assessed after subsequent surgery, with secondary outcomes evaluating locoregional and distant progression-free survival (LPFS and DPFS), and overall survival (OS) according to the imaging parameters. Logistic regression analysis was used to evaluate the association of primary tumor apparent diffusion coefficient (ADC) values, maximum and mean standardized uptake value (SUV), metabolic tumor volume (MTV), and tumor lesion glycolysis (TLG) at baseline and their relative changes (Δ) at interim and follow-up scans with pathCR. Survival analyses applied to evaluate the association of the imaging parameters with LPFS, DPFS, and OS. Surgery after CRT was performed in 29 (48%) of 60 included patients. Imaging data was eligible for analysis in 28 patients in whom pathCR was observed in 7 (25%). The change in tumor mean ADC from the baseline to the interim DW-MRI scan, at a threshold of +27.7%, was best predictive for pathCR (c-statistic=0.98). The change in TLG from the baseline to interim FDG-PET scan, at a threshold of 58% decrease, was the best FDG-PET-based predictor of pathCR (c-statistic=0.77). Multivariable logistic regression suggested no significant added value of ΔTLGIM to ΔADCIM for the prediction of pathCR. Median follow-up was 29 months (range: 5-59) overall and 36 months (range: 24-59) for survivors. In surgical patients no locoregional progression was seen, and studied DW-MRI and FDG-PET parameters were not significantly associated with DPFS or OS. For non-surgical patients with ΔADCIM above vs below +27.7%, observed locoregional recurrence rates were 1/5 (20%) vs 7/25 (28%) (NS), and distant recurrence rates were 1/5 (20%) vs 15/25 (60%) (NS). For non-surgical patients with ΔTLGIM below vs above -58%, observed locoregional recurrence rates were 2/11 (18%) vs 5/17 (29%) (NS), and distant recurrence rates were 3/11 (27%) vs 12/17 (71%) (log-rank test, p=0.04). No association between imaging parameters and OS was observed. ΔADC on DW-MRI after 2 weeks of CRT strongly predicts pathologic complete response in esophageal cancer, with superior performance to repeated FDG-PET imaging. Early response assessment using DW-MRI is potentially useful for stratification of esophageal cancer patients to treatment intensification or organ-preserving strategies.

Prediction of Severe Lymphopenia During Chemoradiation Therapy for Esophageal Cancer: Development and Validation of a Pretreatment Nomogram

IntroductionIn patients with esophageal cancer, occurrence of severe radiation-induced lymphopenia during chemoradiation therapy has been associated with worse progression-free and overall survival. The aim of this study was to develop and validate a pretreatment clinical nomogram for the prediction of grade 4 lymphopenia. Methods and MaterialsA development set of consecutive patients who underwent chemoradiation therapy for esophageal cancer and an independent validation set of patients from another institution were identified. Grade 4 lymphopenia was defined as an absolute lymphocyte count nadir during chemoradiation therapy of <0.2 × 103/μL. Multivariable logistic regression analysis was used to create a prediction model for grade 4 lymphopenia in the development set, which was internally validated using bootstrapping and externally validated by applying the model to the validation set. The model was presented as a nomogram yielding 4 risk groups. ResultsAmong 860 included patients, 322 (37%) experienced grade 4 lymphopenia. Higher age, larger planning target volume in interaction with lower body mass index, photon- rather than proton-based therapy, and lower baseline absolute lymphocyte count were predictive in the final model (corrected c-statistic, 0.76). External validation in 144 patients, among whom 58 (40%) had grade 4 lymphopenia, yielded a c-statistic of 0.71. Four nomogram-based risk groups yielded predicted risk rates of 10%, 24%, 43%, and 70%, respectively. ConclusionsA pretreatment clinical nomogram was developed and validated for the prediction of grade 4 radiation-induced lymphopenia during chemoradiation therapy for esophageal cancer. The nomogram can risk stratify individual patients suitable for lymphopenia-mitigating strategies or potential future therapeutic approaches to ultimately improve survival.

A Comparison of Patient-Reported Health-Related Quality of Life During Proton Versus Photon Chemoradiation Therapy for Esophageal Cancer

PurposeThe purpose of this study was to compare Functional Assessment of Cancer Therapy-Esophagus (FACT-E) questionnaire changes during proton (PRT) or photon (XRT) chemoradiation therapy (CRT) for esophageal cancer (EC). Methods and MaterialsWe reviewed patients enrolled in a prospective registry who received preoperative or definitive CRT for EC. Patients completed the FACT-E before CRT and during the last week of CRT. Analysis of variance testing was used to assess associations between patient and treatment characteristics and FACT-E score changes. ResultsOne hundred twenty-five patients completed a baseline and posttreatment FACT-E; 63 received XRT and 62 received PRT. The mean age was 65 years; the PRT group was older (68 vs 64 years, P = .0063). The following characteristics were similar between cohorts: 83% male, 78% adenocarcinoma, and 89% stage II-III. The radiation therapy prescription dose was higher in the PRT group (≥50 Gy in 94% vs 67%, P < .0001), whereas the median clinical target volume was smaller in the PRT group (553 vs 668 cm3, P = .013). Most (96%) received concurrent weekly carboplatin-paclitaxel. The mean FACT-E score was 136.3 (standard deviation [SD] 21.0) at baseline and 119.6 (SD 24.8) post-CRT, with mean change of –16.7 (SD 19.8). Baseline scores were comparable between XRT and PRT groups (135.9 vs 136.7, P = .82). On univariate and multivariate analyses, less mean decline in FACT-E score was observed for PRT versus XRT (–12.7 vs –20.6, P = .026) and for trimodality versus definitive therapy (–13.0 vs –22.5, P = .008). ConclusionsFor patients receiving CRT for EC, PRT was associated with less decline in FACT-E scores compared with XRT.

Vertebral body irradiation during chemoradiation therapy for esophageal cancer contributes to acute bone marrow toxicity.

Hematologic toxicity (HT) commonly occurs during chemoradiation therapy (CRT) for esophageal cancer. We sought to determine radiation doses that correlate with declines in blood counts due to vertebral body (VB) irradiation during CRT. We analyzed 53 esophageal cancer patients who were treated with weekly neoadjuvant carboplatin, paclitaxel and RT with weekly complete blood counts (CBC) available during treatment. HTs were graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). Dose volume histogram (DVH) parameters of Vx, defined as percentage of entire bony vertebra (body, pedicles, laminae, processes) receiving at least x Gy of radiation, were collected for VB V5 (VBV5), VBV10-VBV60 in increments of 10, and mean vertebral dose (MVD). Linear and logistic regressions were performed to identify associations between leukopenia nadirs and DVH parameters. Receiver operator curves identified thresholds to avoid grade ≥3 leukopenia. A proportion of 32.1% of patients (n=17) developed grade 3 leukopenia and 5.7% (n=3) developed grade 4 leukopenia. VBV5, VBV10, VBV20, VBV30, and MVD were significantly associated with worsening leukopenia on univariate and multivariate analysis. Associations with leukopenia were not seen with VBV40 and VBV50 DVH values. Thresholds to avoid grade ≥3 leukopenia were VBV10 <49.1%, VBV20 <45.6%, and MVD <17.2 Gy. VBV5, VBV10, VBV20, VBV30 associate with leukopenia during CRT for esophageal cancer patients. Improved radiation sparing of the VB may decrease HT and may improve tolerability of concurrent chemotherapy and allow for intensification of systemic therapy during RT.

Relationship Between Sarcopenia and Prognosis in Patient With Concurrent Chemo-Radiation Therapy for Esophageal Cancer.

Background: Sarcopenia, defined as skeletal muscle loss, has been known as a poor prognosis factor in various malignant diseases The aim of this study is to investigate the effect of sarcopenia on prognosis in patients with esophageal cancer who received concurrent chemo- and radiotherapy (CCRT).Methods: We retrospectively collected clinical data of 287 patients with esophageal cancer who were treated by definite CCRT at Gangnam Severance and Severance hospital from August 2005 to December 2014. The cross-sectional area of muscle at the level of the third lumbar vertebra was measured using pre- and post-CCRT computed tomography images. Sarcopenia was defined as skeletal muscle index <49 cm2/m2 for men and of <31 cm2/m2 for women by Korean-specific cutoffs. Overall survival (OS) and progression free survival (PFS) were analyzed according to sarcopenia.Results: Sarcopenia identified before CCRT did not affect OS and PFS. However, patients with post-CCRT sarcopenia showed shorter OS and PFS than patients without it (median OS: 73 months vs. 28 months; median PFS: 34 months vs. 25 months, respectively). Post-CCRT sarcopenia was an independent prognostic factor of poor OS (hazards ratio: 1.697; 95% confidence interval: 1.036–2.780; P = 0.036). In multivariate analysis, male sex (P = 0.004) and presence of CCRT-related complications, such as esophagitis or general weakness were significantly associated with post-CCRT sarcopenia (P = 0.016).Conclusions: Sarcopenia after CCRT can be a useful predictor for long-term prognosis in patients with esophageal cancer. To control CCRT-related complications may be important to prevent skeletal muscle loss during CCRT.

The role of bone marrow and spleen irradiation in the development of acute hematologic toxicity during chemoradiation for esophageal cancer

PurposeThe purpose of this study was to determine the impact of splenic and thoracic bone marrow irradiation on hematologic toxicity in the setting of chemoradiation therapy for esophageal cancer. Methods and materialsWe analyzed 60 patients with carcinoma of the distal esophagus or gastroesophageal junction who received concurrent chemoradiation in the preoperative or definitive setting. Dosimetric and volumetric parameters were calculated for the spleen, thoracic spine, and posterior ribs. The primary endpoint was grade ≥3 hematologic toxicity (HT3+). Associations were assessed using logistic and linear regression models. ResultsTwenty-one patients (35%) experienced HT3+, including 18 patients with leukopenia and 5 with thrombocytopenia. Higher spleen V5-V20 was correlated with a lower risk of HT3+ on multivariable analysis (odds ratio: 0.83 per 10 cm3 increase in V10; P = .013). A dose-dependent decrease in spleen volume was observed after radiation therapy, and a greater decrease was independently associated with a lower risk of HT3+ (odds ratio: 0.93 per 1% volume decrease; P = .014). Dosimetric parameters of the thoracic spine were not significantly associated with HT3+. ConclusionsA greater decrease in spleen size after radiation therapy and a higher spleen V5-V20 were independently associated with a lower risk of severe hematologic toxicity. Splenic irradiation may mitigate leukopenia associated with chemoradiation therapy.

Radiation dose in neoadjuvant chemoradiation therapy for esophageal cancer: patterns of care and outcomes from the National Cancer Data Base.

Neoadjuvant chemoradiotherapy (CRT) for locally advanced esophageal cancer (EC) may utilize a wide variety of RT doses, without clear consensus to date. This study evaluated national practice patterns between lower dose (LD) (40-41.4 Gy) or higher dose (HD) (50-50.4 Gy) therapy, in addition to differences in survival and postoperative events. The National Cancer Data Base (NCDB) was queried [2004-2013] for patients with newly-diagnosed cT1a-T4aN0/N+M0 EC that received neoadjuvant CRT followed by esophagectomy. Multivariable logistic regression determined factors predictive of receiving LD RT. Kaplan-Meier analysis evaluated overall survival (OS), and Cox proportional hazards modeling determined variables associated with OS. Propensity score matching assessed groups in a balanced manner while reducing indication biases. Altogether, 5,025 patients met inclusion criteria; 257 (5%) received LD RT, while 4,768 (95%) received HD RT. LD RT was more likely delivered at academic centers (P=0.038), in more recent years (2009-2013, P=0.011), and to squamous cell carcinomas (P=0.001). HD RT tended to be administered with higher T stage as well as node-positive disease (P<0.05). The median OS in the LD and HD cohorts was 39.0 vs. 35.6 months (P=0.072), and 39.0 vs. 42.7 months after propensity matching (P=0.812). Dose did not independently correlate with OS on multivariate analysis (P=0.069), but treatment at academic centers correlated with improved OS (P=0.028). There were no differences between groups in the rates of 30-day readmission (P=0.182), 30-day mortality (P=0.314), or length of postoperative hospital stay (P=0.665), but the LD group experienced lower 90-day mortality (P=0.007). Although neoadjuvant LD CRT has been underutilized for EC in the United States, it is rising in more recent years. Dose did not significantly impact survival before or after propensity matching, nor did it independently predict for survival. Treatment at academic facilities independently correlated with higher survival, which has implications for patient counseling.

Vertebral Bone Marrow Irradiation Contributes to Hematologic Toxicity During Chemoradiation Therapy for Esophageal Cancer

Hematological toxicity (HT) commonly occurs during chemoradiation therapy (CRT) for esophageal cancer, with both modalities contributing to the decline in blood counts. Since leukopenia commonly precludes chemotherapy delivery, we sought to determine the dose volume histogram (DVH) constraints that correlate with decline in leukocyte counts due to comprehensive vertebra (CV) irradiation during CRT. 32 esophageal cancer patients treated with weekly neoadjuvant CRT were selected to be in the study. The typical chemotherapy regimen consisted of weekly intravenous carboplatin (area under the curve = 2) and paclitaxel (50 mg/m2). Radiation therapy (RT) was delivered using 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT). Patients who missed CRT for reasons other than neutropenia or received colony-stimulating factors were excluded. HT was scored using the Common Terminology Criteria for Adverse Events version 4.0. CV were contoured from C2 to L2 vertebra on 4DCT simulation scans. DVH data in both percentages and cubic centimeters was collected for CV V10-V60 (CVV) in increments of 10s. CVV5 and mean vertebral dose (MVD) were included as well. A DVH parameter of Vx was defined as either the percentage or volume in cubic centimeters of organ receiving at least x Gy of radiation. Univariate linear regression was performed to identify associations between leukopenia nadirs and DVH parameters. β represents the change in blood counts in k/μL for every 1 unit increase in DVH parameter. Receiver operator curves demonstrate cutoffs to avoid grade ≥ 3 leukopenia. Of the 32 esophageal patients, 6 patients developed grade 1 leukopenia, 12 developed grade 2 leukopenia, 8 developed grade 3 leukopenia, and 3 developed grade 4 leukopenia. CVV30, CVV20, CVV10, and MVD were significantly associated with decreasing WBC when calculated either as a percentage or by volume of the organ on univariate analysis. CVV5 was significantly associated with decreasing WBC counts only when calculated as a percentage of the volume and not as volume by cubic centimers. Associations with leukopenia were not seen with higher DVH values. CVV60, CVV50, and CVV40 did not significantly influence WBC levels during CRT. Cutoffs to avoid grade ≥ 3 leukopenia were CVV20 < 44.3%, CVV10 < 54.2%, CVV20 < 225 cc, CVV10 < 260 cc, and MVD < 18.8 Gy.< table class=”abstracttable>< tbody>< tr> CVV30 CVV20 CVV10 CVV5 MVD WBC (DVH by %) β p-value . -0.00528 0.0154 . -0.00767 0.0016 . -0.00826 0.0005 . -0.00828 0.0005 . -0.00014 0.0125 WBC (DVH by cc) . . . . . β p-value -0.00111 0.022 -0.00109 0.0269 -0.00107 0.0268 -0.000804 0.0577 -0.00014 0.0125 Leukopenia is associated with higher RT doses to the CVV30, CVV20, CVV10, CVV5, and MVD during CRT for esophageal cancer patients. Improved low dose radiation sparing of the CV may decrease HT.

Intratreatment FDG-PET Imaging to Predict Radiation Induced Esophagitis During Chemoradiation Therapy for Esophageal Cancer

Intratreatment FDG-PET Imaging to Predict Radiation Induced Esophagitis During Chemoradiation Therapy for Esophageal Cancer

Potential of Proton Therapy to Reduce Acute Hematologic Toxicity in Concurrent Chemoradiation Therapy for Esophageal Cancer

PurposeRadiation therapy dose escalation using a simultaneous integrated boost (SIB) is predicted to improve local tumor control in esophageal cancer; however, any increase in acute hematologic toxicity (HT) could limit the predicted improvement in patient outcomes. Proton therapy has been shown to significantly reduce HT in lung cancer patients receiving concurrent chemotherapy. Therefore, we investigated the potential of bone marrow sparing with protons for esophageal tumors.Methods and MaterialsTwenty-one patients with mid-esophageal cancer who had undergone conformal radiation therapy (3D50) were selected. Two surrogates for bone marrow were created by outlining the thoracic bones (bone) and only the body of the thoracic vertebrae (TV) in Eclipse. The percentage of overlap of the TV with the planning treatment volume was recorded for each patient. Additional plans were created retrospectively, including a volumetric modulated arc therapy (VMAT) plan with the same dose as for 3D50; a VMAT SIB plan with a dose prescription of 62.5 Gy to the high-risk subregion within the planning treatment volume; a reoptimized TV-sparing VMAT plan; and a proton therapy plan with the same SIB dose prescription. The bone and TV dose metrics were recorded and compared across all plans and variations with respect to PTV and percentage of overlap for each patient.ResultsThe 3D50 plans showed the highest bone mean dose and TV percentage of volume receiving ≥30 Gy (V30Gy) for each patient. The VMAT plans irradiated a larger bone V10Gy than did the 3D50 plans. The reoptimized VMAT62.5 VT plans showed improved sparing of the TV volume, but only the proton plans showed significant sparing for bone V10Gy and bone mean dose, especially for patients with a larger PTV.ConclusionsThe results of the present study have shown that proton therapy can reduced bone marrow toxicity.

Recursive Partitioning Analysis Identifies Pretreatment Risk Groups for the Utility of Induction Chemotherapy Before Definitive Chemoradiation Therapy in Esophageal Cancer

To assess the contribution of induction chemotherapy (IC) before definitive chemoradiation therapy (dCRT) in patients with esophageal cancer (EC) based on recursive partitioning analysis (RPA). A total of 496 eligible patients with EC staged by positron emission tomography (PET) who received dCRT from 1998 to 2015 were included, 162 (32.7%) of whom underwent IC before dCRT. RPA was used to risk-stratify patients on the basis of independent prognostic factors to predict progression-free survival (PFS). Outcomes were compared between treatment groups. The median follow-up time was 49.1months (range, 7.0-155.9months) for survivors. Compared with the non-IC group, the IC group had a comparable 5-year PFS rate (21.0% vs 23.4%; P=.726) in the whole cohort. Multivariate analysis identified age, performance status, primary tumor length, baseline PET maximum standard uptake value (SUVmax), and maximum lymph node diameter as independent prognostic factors for PFS. RPA segregated patients into 3 prognostic groups: low-risk group (PET SUVmax <9.7 and tumor length ≤5cm), intermediate-risk group (PETSUVmax ≥9.7 and age ≥67), and high-risk group (PET SUVmax <9.7 and tumor length >5cm, or PET SUVmax ≥9.7 and age <67). Significant improvements in PFS (P=.006) and locoregional failure-free survival (P=.028) in the IC group in comparison with the non-IC group were observed in high-risk patients, whereas no differences in survival were found between the 2 treatment groups in low-risk or intermediate-risk patients. After propensity score matching, the high-risk group still demonstrated a significantly improved PFS with IC (P=.009). The RPA prognostic grouping provides a useful method of selecting high-risk EC patients who may benefit from IC before receiving dCRT. Prospective validation is warranted.

Lymphocyte Nadir and Esophageal Cancer Survival Outcomes After Chemoradiation Therapy

Host immunity may affect the outcome in patients with esophageal cancer. We sought to identify factors that influenced absolute lymphocyte count (ALC) nadir during chemoradiation therapy (CRT) for esophageal cancer (EC) and looked for clinically relevant associations with survival. 504 patients with stage I-III EC (2007-2013) treated with neoadjuvant or definitive CRT with weekly ALC determinations made during treatment were analyzed. Grade of lymphopenia from ALC nadir during CRT was based on Common Terminology Criteria for Adverse Events version 4.0. Associations of ALC nadir with survival were examined using multivariate Cox proportional hazards analysis (MVA) and competing risks regression analysis. The median follow-up time was 36months. The incidences of grade 1, 2, 3, and 4 ALC nadir during CRT were 2%, 12%, 59%, and 27%, respectively. The impact was lymphocyte-specific because this was not seen for monocyte or neutrophil count. On MVA, grade 4 ALC nadir (G4 nadir) was significantly associated with worse overall and disease-specific survival outcomes. Predictors of G4 nadir included distal tumor location, definitive CRT, taxane/5-fluorouracil chemotherapy, and photon-based radiation type (vs proton-based). Radiation type strongly influenced the mean body dose exposure, which was a strong predictor for G4 nadir (odds ratio 1.22 per Gray, P<.001). G4 nadir during CRT for EC was associated with poor outcomes, suggesting a role of host immunity in disease control. This observation provides a rationale to prospectively test chemotherapeutic and radiation treatment strategies that may have a lower impact on host immunity.

Definitive Chemoradiation Therapy for Esophageal Cancer in the Elderly: Clinical Outcomes for Patients Exceeding 80 Years Old

The optimal treatment approach for patients ≥80years ("elderly") with esophageal cancer is not well established. We assessed the clinical outcomes in elderly patients treated with definitive chemoradiation therapy (CCRT) at our institution. 56 consecutive patients ≥80years with esophageal cancer treated with conventional CCRT between 2001 and 2016 were propensity score matched 1:2 to generate 2 younger patient cohorts treated with CCRT without surgery: "intermediate" (65-79years, n=112) and "younger" (<65years, n=112). Treatment related toxicity was assessed using the Common Terminology Criteria for Adverse Events version 4.0. The rates of overall survival (OS) and recurrence-free survival (RFS) were calculated with the Kaplan-Meier method. The median ages of the 3 cohorts were 81years (elderly, 80-92years), 71years (intermediate, 65-79years), and 58years (younger, 20-64years). The elderly cohort was more likely to have cardiac comorbidities. Although the clinical complete response (cCR) rate deviated significantly among the 3 cohorts, (78%, 72%, and 56%; P=.004), the data failed to identify statistically significant differences among RFS, 2-year, and 5-year OS, or in median survival, which was 15.5months, 23.6months, and 20.2months (P=.468), respectively. The overall severe toxicity rates were 38%, 32%, and 30%, respectively (P=.644), including comparable rate of radiation pneumonitis (P>.05). The elderly cohort, however, did show statistically significant evidence of an increased rate of severe radiation pneumonitis (grade ≥3) which was observed to be 11% versus 4% and 0%, respectively (P=.003). The studied elderly population showed evidence of similar long-term clinical efficacy after definitive CCRT when compared with cohorts of younger patients with similar prognostic status. An increased rate of pulmonary toxicity was identified, without evidence of differences for nonpulmonary severe adverse events. Understanding the prognostic risk factors of pulmonary toxicity after CCRT may effectuate improved long-term outcomes for elderly population.

The impact of proton beam therapy on blood cell count nadir during neoadjuvant chemoradiation therapy for esophageal cancer.

137 Background: To analyze the blood cell count nadir, particularly grade 4 hematologic toxicities, in patients with esophageal cancer who were treated with neoadjuvant chemoradiation (nCRT) with either Proton Beam Therapy (PBT) or Intensity Modulated Radiation Therapy (IMRT) in a propensity-matched pair analysis. Methods: Esophageal cancer patients (n = 480) treated from 2005-2016 with nCRT with (n = 167) or without (n = 313) induction chemotherapy (ICT) were analyzed. White blood cell, neutrophil, lymphocyte and platelet counts nadir during ICT and CRT were obtained, and graded according to the CTCAE v.4.0. Univariate and multivariable logistic regression models to identify factors associated with increased risk of grade 4 lymphopenia were fitted. By propensity score matching, 136 PBT cases and 136 propensity score matched IMRT controls were selected for comparison. Results: In the entire study cohort during CRT (n = 480), 2 (0.4%), 1 (0.2%), 159 (33%), and 2 (0.4%) patients experienced grade 4 leukopenia, neutropenia, lymphopenia and thrombocytopenia, respectively. This is not seen in patients who received ICT (n = 167), as only 0 (0%), 2 (1.2%), 1 (0.6%) and 0 (0%) patients experienced grade 4 leukopenia, neutropenia, lymphopenia and thrombocytopenia during the ICT phase. Multivariable analyses identified older age (p = 0.0139), larger planning tumor volume (PTV) (p = 0.0213), distal vs upper/mid tumor location (borderline significance, p = 0.0779) and IMRT vs PBT (p &lt; 0.0001) as factors associated with increased risk of grade 4 lymphopenia during CRT. Among the 272 propensity-matched patients treated with either PBT or IMRT, 24 (17.6 %) and 55 (40.4 %) patients experienced grade 4 lymphopenia, respectively (p &lt; 0.001). Grade 4 lymphopenia correlates with poorer survival (p = 0.0587), lower progression free survival (p = 0.0384) and distant metastatic recurrence (p = 0.0185). Conclusions: The use of PBT may be an important modifying factor in altering the incidence of grade 4 lymphopenia during CRT in esophageal cancer. The dosimetric factors that can modulate this risk is a subject of continued investigation.

Long-term complications of definitive chemoradiotherapy for esophageal cancer using the classical method.

Chemoradiation therapy is widely used to treat both inoperable and operable patients, and is less invasive than surgery. Although the number of long-term survivors who have received chemoradiation therapy is increasing, the long-term toxicity pattern and cumulative incidence of toxicity regarding this modality are poorly understood. Classically, chemoradiation therapy for esophageal cancer consists of an anterior–posterior field and a subsequent oblique boost field. We retrospectively analyzed patients who were treated with definitive chemoradiation therapy for esophageal cancer using this classical method from 1999 to 2008. For the assessment of toxicity, the National Cancer Institute Common Toxicity Criteria Version 3.0 was adopted. A total of 101 patients were analyzed. The median follow-up time was 16 months for all patients and 62 months for the surviving patients. Eleven patients experienced late toxicities of ≥Grade 3. Two patients died of late toxicities. The 3- and 5-year cumulative incidences for the first late cardiopulmonary toxicities of ≥Grade 3 were 17.4% and 20.8%, respectively. Cardiopulmonary effusions were observed within the first 3 years of completion of the initial treatment in seven out of eight patients. Sudden death and cardiac ischemia were observed over a 10-year period. Older age was found to be a risk factor for late toxicity after definitive chemoradiation therapy for esophageal cancer. Substantial toxicities were observed in patients who had received chemoradiation therapy for esophageal cancer using the classical method. To minimize the incidence of late toxicity, more sophisticated radiation techniques may be useful.

Circulating Lymphocyte Count During Neoadjuvant Chemoradiation Therapy for Esophageal Cancer as a Predictive Biomarker of Pathologic Complete Response

Circulating Lymphocyte Count During Neoadjuvant Chemoradiation Therapy for Esophageal Cancer as a Predictive Biomarker of Pathologic Complete Response