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A phase I/II radiation dose escalation trial using simultaneous integrated boost technique with elective nodal irradiation and concurrent chemotherapy for unresectable esophageal Cancer.

ABSTRACT: BACKGROUND:To investigate the safety and tolerability of simultaneous integrated boost (SIB) technique concurrent with elective nodal irradiation (ENI) and dual-drug chemotherapy for patients with unresectable esophageal cancer. METHODS:In phase I, the prophylactic PTV received a stable dose of 50.40Gy/1.80Gy/28f while the boost area was planned with 3 consecutive dose levels: the first dose level was 60.76Gy/2.17Gy/28f, and then escalated approximately every 2?Gy. ENI was incorporated in Clinical Target Volume (CTV), and paclitaxel and nedaplatin were given concurrently for at least 5?weeks. In phase II, enrolled patients were treated with Maximum Tolerated Dose (MTD) obtained in phase I and the compliance rate, survival results and toxicities were evaluated. RESULTS:From December 2014 to April 2017, 53 patients were enrolled. In phase I, 2 out of 6 patients developed Dose-Limiting Toxicity (DLT) at dose level 1. Due to excessive treatment-related toxicities, the escalation process was suspended and de-escalated to 59.92Gy /2.14Gy /28?f. Three patients were treated at this dose level, all of whom completed at least 5?weeks of chemotherapy and none of whom reached a DLT, determining the newly added dose level to be the MTD. In phase II, 44 patients were treated with MTD, 31 of them (70.0%) completed at least 5?weeks of chemotherapy. The most common Grade 3 or 4 toxicities in phase II included leukopenia (21%) and esophagitis (15%). With a median follow-up time of 16.9?months, 1-y OS, DFS and local failure-free survival were 76.9, 63.6 and 78.8% respectively. CONCLUSION:The SIB technique was feasible and safe at the MTD (95% PGTV/PTV 59.92/50.40Gy/28f) concurrent with ENI and dual-drug chemotherapy for patients with unresectable esophageal cancer. TRIAL REGISTRATION:clinicaltrials.gov NCT02429622 . Retrospectively registered on April 24, 2015.

SUBMITTER: Li C

PROVIDER: S-EPMC6420772 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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A phase I/II radiation dose escalation trial using simultaneous integrated boost technique with elective nodal irradiation and concurrent chemotherapy for unresectable esophageal Cancer.

Li Chen C Ni Wenjie W Wang Xin X Zhou Zongmei Z Deng Wei W Chang Xiao X Chen Dongfu D Feng Qinfu Q Liang Jun J Wang Xiaozhen X Deng Lei L Wang Wenqing W Bi Nan N Zhang Tao T Xiao Zefen Z

Radiation oncology (London, England) 20190315 1

<h4>Background</h4>To investigate the safety and tolerability of simultaneous integrated boost (SIB) technique concurrent with elective nodal irradiation (ENI) and dual-drug chemotherapy for patients with unresectable esophageal cancer.<h4>Methods</h4>In phase I, the prophylactic PTV received a stable dose of 50.40Gy/1.80Gy/28f while the boost area was planned with 3 consecutive dose levels: the first dose level was 60.76Gy/2.17Gy/28f, and then escalated approximately every 2 Gy. ENI was incorpo ...[more]

PMID: 30876442

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Project description:PurposeWe evaluate the feasibility of the elective nodal irradiation strategy in stereotactic body radiotherapy (SBRT) for pancreatic cancer.MethodsThree simultaneous integrated boost (SIB)-SBRT plans (Boost1, Boost2, and Boost3) were retrospectively generated for each of 20 different patients. Boost1 delivered 33 and 25 Gy to PTV1 and PTV2, respectively. Boost2 delivered 40, 33, and 25 Gy to boostCTV, PTV1, and PTV2, respectively. Boost3 delivered 33 and 25 Gy to PTV1 and PTV3, respectively. PTV1 covered the initial standard SBRT plan (InitPlan) gross tumor volume (GTV). PTV2 covered CTVgeom which was created by a 10-mm expansion (15 mm posterior) of GTV. PTV3 covered CTVprop which included elective nodal regions. The boostCTV included GTV as well as involved vasculature. The planning feasibility in each scenario and dose-volume histograms (DVHs) were analyzed and compared with the InitPlan (delivered 33 Gy only to PTV1) by paired t-test. Next, a novel DVH prediction model was developed and its performance was evaluated according to the prediction accuracy (AC) of planning violations. Then, the model was used to simulate the impacts of GTV-to-organs at risk (OAR) distance and gastrointestinal (GI) OAR volume variations on planning feasibility.ResultsSignificant dose increases were observed in GI-OARs in SIB-SBRT plans when compared with InitPlan. All dose constraints were met in 63% of cases in InitPlan, Boost1, and Boost2, whereas Boost3 developed DVH violations in all cases. Utilizing previous patient anatomy, the novel DVH prediction model achieved a high AC in the prediction of violations for GI-OARs; the positive predictive value, negative predictive value, and AC were 66%, 90%, and 84%, respectively. Experiments with the model demonstrated that the larger proximity volume of GI-OAR at the shorter distance substantially impacted on planning violations.ConclusionsSIB-SBRT plan with geometrically defined prophylactic areas can be dosimetrically feasible, but including all nodal areas with 25 Gy in five fractions appears to be unrealistic.

Project description:BACKGROUND:To assess the comparative efficacy and safety of elective nodal irradiation (ENI) and involved-field irradiation (IFI) in patients with esophageal cancer (EC) receiving neoadjuvant chemoradiotherapy plus surgery (nCRTS). MATERIAL AND METHODS:PubMed, Embase, Cochrane Library, Web of Science and major meetings were searched for randomized controlled trials (RCTs) that compared at least two of the following treatment regimens: nCRTS, neoadjuvant chemotherapy plus surgery (nCTS), and surgery (S) alone. Overall survival (OS) was the primary outcomes of interest, reported as hazard ratio (HR) and 95% confidence intervals (CIs). A Bayesian network meta-analysis was performed to compare all regimens simultaneously. RESULTS:Twenty-nine RCTs with a total of 5212 patients were included in the meta-analysis. Both nCRTS adopting ENI (nCRTS-ENI) (HR?=?0.63, 95% CI: 0.48-0.83) and nCRTS adopting IFI (nCRTS-IFI) (HR?=?0.75, 95% CI: 0.66-0.86) significantly improved OS compared to S alone. No significant differences in OS, locoregional recurrence, distant metastases, R0 resection and postoperative mortality were observed between nCRTS-ENI and nCRTS-IFI. In subgroup analyses, nCRTS-IFI showed a significant OS advantage over nCTS (HR?=?0.78, 95% CI: 0.63-0.96) and S alone (HR?=?0.50, 95% CI: 0.38-0.68) for esophagus squamous cell carcinoma (ESCC), but nCRTS-ENI did not; nCRTS-ENI using three-dimensional radiotherapy (3D-RT) resulted in an improved OS compared to that with 2D-RT (HR?=?0.58, 95% CI: 0.34-0.99). Based on treatment ranking in term of OS, nCRTS-IFI (0.90) and nCRTS-ENI (0.96) was ranked the most effective treatment for ESCC and esophagus adenocarcinoma (EAC), respectively. CONCLUSION:Either adopting ENI or IFI, nCRTS is likely to be the optimal treatment for resectable EC, and nCRTS-IFI and nCRTS-ENI seem to be more effective for patients with ESCC and EAC, respectively. Future head to head comparison trials are needed to confirm these findings.

Project description:Objectives: To compare treatment plans of intensity modulated radiotherapy (IMRT), volumetric modulated arc radiotherapy (VMAT), and helical tomotherapy (HT) with simultaneous integrated boost (SIB) technique for esophageal cancer (EC) of different locations using dosimetry and radiobiology. Methods: Forty EC patients were planned for IMRT, VMAT, and HT plans, including 10 cases located in the cervix, upper, middle, and lower thorax, respectively. Dose-volume metrics, conformity index (CI), homogeneity index (HI), tumor control probability (TCP), and normal tissue complication probability (NTCP) were analyzed to evaluate treatment plans. Results: HT showed significant improvement over IMRT and VMAT in terms of CI (p = 0.007), HI (p < 0.001), and TCP (p < 0.001) in cervical EC. IMRT yielded more superior CI, HI and TCP compared with VMAT and HT in upper and middle thoracic EC (all p < 0.05). Additionally, V30 (27.72 ± 8.67%), mean dose (1801.47 ± 989.58cGy), and NTCP (Niemierko model: 0.44 ± 0.55%; Lyman-Kutcher-Burman model: 0.61 ± 0.59%) of heart in IMRT were sharply reduced than VMAT and HT in middle thoracic EC. For lower thoracic EC, the three techniques offered similar CI and HI (all p > 0.05). But VMAT dramatically lowered liver V30 (9.97 ± 2.84%), and reduced NTCP of lungs (Niemierko model: 0.47 ± 0.48%; Lyman-Kutcher-Burman model: 1.41 ± 1.07%) and liver (Niemierko model: 0.10 ± 0.08%; Lyman-Kutcher-Burman model: 0.17 ± 0.17%). Conclusions: HT was a good option for cervical EC with complex target coverage but little lungs and heart involvement as it achieved superior dose conformity and uniformity. Due to potentially improving tumor control and reducing heart dose with acceptable lungs sparing, IMRT was a preferred choice for upper and middle thoracic EC with large lungs involvement. VMAT could ameliorate therapeutic ratio and lower lungs and liver toxicity, which was beneficial for lower thoracic EC with little thoracic involvement but being closer to heart and liver. Individually choosing optimal technique for EC in different location will be warranted.

Project description:ImportanceEffective treatment options for locally advanced esophageal cancer are limited, and rates of local recurrence after standard chemoradiotherapy remain high.ObjectiveTo evaluate toxic effects, local control, and overall survival rates after chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose to the gross tumor and nodal disease for patients with unresectable locally advanced esophageal cancer.Design, setting, and participantsA phase 1/2, single-arm trial was conducted in 46 patients from April 28, 2010, to April 9, 2015 (median follow-up, 52 months [range, 2-86 months]), at a tertiary academic cancer center. Outcomes of the study patients were compared with those of 97 similar patients treated at the same institution from January 10, 2010, to December 5, 2014, as part of the interim analysis. Statistical analysis was performed from December 15, 2018, to February 12, 2019.InterventionsChemoradiotherapy with a simultaneous integrated boost of radiotherapy dose (50.4 Gy to subclinical areas at risk and 63.0 Gy to the gross tumor and involved nodes, all given in 28 fractions) with concurrent docetaxel and capecitabine or fluorouracil.Main outcomes and measuresToxic effects, local (in-field) control, and overall survival rates.ResultsAll 46 patients (11 women and 35 men; median age, 65.5 years [range, 37.3-84.4 years]) received per-protocol therapy, as intensity-modulated photon therapy (39 [85%]) or intensity-modulated proton therapy (7 [15%]); 11 patients (24%) ultimately underwent resection. No patients experienced grade 4 or 5 toxic effects; the 10 acute grade 3 toxic events were esophagitis (4), dysphagia (3), and anorexia (3) and the 3 late grade 3 toxic events were all esophageal strictures. The actuarial local recurrence rates were 22% (95% CI, 11%-35%) at 6 months, 30% (95% CI, 18%-44%) at 1 year, and 33% (95% CI, 20%-46%) at 2 years. Overall, 15 patients (33%) experienced local failure, at a median interval of 5 months (range, 1-24 months). The median overall survival time was 21.5 months (range, 2.3-86.4 months). Exploratory comparison with a 97-patient contemporaneous institutional cohort receiving standard-dose (non-simultaneous integrated boost) chemoradiotherapy showed superior local control (hazard ratio, 0.49; 95% CI, 0.26-0.92; P = .03) and overall survival (hazard ratio, 0.66; 95% CI, 0.47-0.94; P = .02) in the group that received chemoradiotherapy with a simultaneous integrated boost.Conclusions and relevanceThese findings suggest that chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose for locally advanced esophageal cancer is well tolerated, with encouraging local control, and thus warrants further study.Trial registrationClinicalTrials.gov identifier: NCT01102088.

Project description:BackgroundThe patterns of nodal relapse in submandibular gland carcinoma (SMGC) patients treated with postoperative radiotherapy (PORT) remain unclear. This study aims to investigate the nodal failure patterns and the utility of elective nodal irradiation (ENI) in SMGC patients undergoing PORT.MethodsWe retrospectively enrolled 65 SMGC patients who underwent PORT between 2000 and 2014. The nodal failure sites in relation to irradiation fields and pathological parameters were analyzed. ENI regions were categorized into three bilateral echelons (first, levels I-II; second, level III; and third, levels IV-V). Extended ENI was defined as coverage of at least the immediately adjacent uninvolved echelons bilaterally; otherwise, limited ENI was administered.ResultsThirty patients (46%) were stage III-IV, and 18 (28%) were pN+. Neck irradiation included limited (72%) and extended ENI (28%). With a median follow-up of 79 months, 11 patients (17%) developed nodal failures (ipsilateral, N?=?6; contralateral, N?=?7), 7 (64%) of whom relapsed in the adjacent uninvolved echelons. We identified pN+ (P?=?0.030), extranodal extension (ENE, P?=?0.002), pT3-4 (P?=?0.021), and lymphovascular invasion (LVI, P?=?0.004) as significant predictors of contralateral neck recurrence. Extended ENI significantly improved regional control (RC) in patients with pN+ (P?=?0.003), ENE (P?=?0.022), pT3-4 (P?=?0.044), and LVI (P?=?0.014), and improved disease-free survival (DFS) in patients with pN+ (P?=?0.034). For patients with ?2 coincident adverse factors, extended ENI significantly increased RC (P?<?0.001), distant metastasis-free survival (P?=?0.019), and DFS (P?=?0.007); conversely, no nodal recurrence was observed in patients without these adverse factors, even when only the involved echelon was irradiated.ConclusionsNodal failure is not uncommon in SMGC patients treated with PORT if pN+, ENE, pT3-4, and LVI are present. Extended ENI should be considered, particularly in patients with multiple pathological adverse factors.

Project description:BackgroundThis study's initial results revealed significant decreases in treatment-related esophagitis and pneumonitis cases in patients with thoracic esophageal squamous cell carcinoma (ESCC) treated with involved-field irradiation (IFI), compared to elective nodal irradiation (ENI). This report outlines the long-term trial results, specifically; overall survival (OS), progression-free survival (PFS), metastasis-free survival (MFS), and locoregional progression-free survival (LRFS).Materials and methodsStage II-III thoracic ESCC patients were assigned randomly, in a 1:1 ratio, into either the ENI or IFI arm. Radiation therapy was delivered once a day in 1.8-2.0 Gy fractions to a total dose of 60.0-66.0 Gy to the gross tumor volume and 50.0-54.0 Gy to the clinical target volume. The primary endpoints were acute treatment-related esophagitis and pneumonitis. The results for the primary endpoints were previously published in 2018. In this article, we analyzed the secondary endpoints including PFS, LRFS, MFS, and OS.ResultsBetween April 2012 and October 2016, 228 patients from nine participating centers in China were enrolled into this study and randomly assigned to two treatment groups. For ENI and IFI groups, respectively, the results showed similarity and were as follows: median PFS (20.3 months vs 21.4 months), OS (32.5 months vs 34.9 months), MFS (28.2 months vs 26.0 months), and LRFS (25.0 months vs 26.6 months). In particular, respective OS rates in the ENI and IFI groups were 84.6% and 82.5% after 1 year, 45.1% and 48.7% after 3 years, and 29.8% and 30.7% at 5 years. PFS rates after 1, 3, and 5 years were 58.9%, 34.2%, and 26.9%, respectively, in the ENI arm compared to 64.4%, 30.8%, and 27.7%, respectively, in the IFI arm. Multivariate analysis identified clinical stage and tumor responses as independent predictors of OS. Meanwhile, tumor location, cStage, and tumor response were identified as independent factors influencing PFS.ConclusionIFI was associated with similar survival as ENI in patients with thoracic ESCC, suggesting that IFI is an acceptable treatment method for thoracic ESCC.

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A phase I/II radiation dose escalation trial using simultaneous integrated boost technique with elective nodal irradiation and concurrent chemotherapy for unresectable esophageal Cancer.

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A phase I/II radiation dose escalation trial using simultaneous integrated boost technique with elective nodal irradiation and concurrent chemotherapy for unresectable esophageal Cancer.

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