Caution against simultaneous integrated boost radiotherapy for upper thoracic esophageal squamous cell carcinoma: results from a single-arm phase II trial.

PURPOSE: To explore the feasibility and safety of simultaneous integrated boost technology (SIB) with elective nodal irradiation (ENI) to the cervical and upper mediastinal lymph node (LN) regions in upper thoracic esophageal squamous cell carcinoma (ESCC). MATERIAL AND METHODS: Patients with pathologically proven unresectable upper thoracic ESCC were assigned 50.4 Gy/28 fractions (F) to the clinical target volume (encompassing the ENI area of cervical and upper mediastinal LN regions) and a boost of 63 Gy/28 F to the gross tumor volume. Chemotherapy consisted of courses of concurrent cisplatin (20 mg/m2) and docetaxel (20 mg/m2) weekly for 6 weeks. The primary endpoint was toxicity. RESULTS: Between Jan 2017 and Dec 2019, 28 patients were included. The median follow-up time for all patients was 24.6 months (range 1.9-53.5). Radiation-related acute toxicity included esophagitis, pneumonia and radiodermatitis, all of which were well managed and reversed. Late morbidity included esophageal ulcer, stenosis, fistula and pulmonary fibrosis. Grade III esophageal stenosis and fistula was seen in 11% (3/28) and 14% (4/28) patients, respectively. The cumulative incidence rate of late esophageal toxicity was 7.7%, 19.2% and 24.6% at 6, 12 and 18 months, respectively. There was significant difference of the occurrence of severe late esophageal toxicity among the different volume levels of the esophagus, and cervical and upper mediastinal LNs which received ≥ 63 Gy stratified by the tertiles (p = 0.014). CONCLUSIONS: Despite the acceptably tolerated acute toxicity of SIB in concurrent CRT with ENI to the cervical and upper mediastinal LN regions for upper thoracic ESCC, the incidence of severe late esophageal toxicity was relatively high. Cautions are provided against easy clinical application of SIB (50.4 Gy/28F to the CTV, 63 Gy/28F to the GTV) in upper thoracic ESCC. Further exploration on dose optimization is warranted.

Long-Term Results of a Phase 2 Study of Definitive Chemoradiation Therapy Using S-1 for Esophageal Squamous Cell Carcinoma Patients Who Were Elderly or With Serious Comorbidities.

Background: The optimal evidence-based management for the subsets of locally advanced esophageal squamous cell carcinoma (ESCC) patients who rejected or were intolerant to intravenous chemotherapy due to old age or serious comorbidities is currently lacking. This study aimed to assess the safety and local control rate (LCR) of S-1 (tegafur-gimeracil-oteracil potassium) combined with radiotherapy in these subsets of ESCC patients. Methods: Locally advanced ESCC patients who rejected or were intolerant to intravenous chemotherapy due to age >75 years or serious comorbidities were enrolled in a prospective, single-arm, phase 2 trial. The patients were treated with definitive concurrent chemoradiotherapy with S-1, which was administered orally twice daily for 28 days. The radiotherapy dose was 61.2 Gy delivered in 34 fractions. The primary end-point was the 3-year LCR. Results: One hundred five ESCC patients were recruited between March 2013 and October 2015. At the median follow-up of 73.1 months (IQR 65.5-81.4 months), 3-year LCR was 61.1%, and 1, 3, and 5-year overall survival was 77.9, 42.3, and 24.8% respectively. For safety analysis, ≥grade 3 acute adverse events included thrombocytopenia (6.7%), leukopenia (2.9%), anemia (1.0%), anorexia (1.0%), fatigue (10.5%), hiccup (1.0%), pneumonitis (4.8%), and esophagitis (3.8%). Two patients (1.9%) died of late esophageal hemorrhage, and one patient (1.0%) died of late radiation-induced pneumonitis. Conclusion: S-1 is a promising regimen in concurrent chemoradiotherapy with low toxicity and a favorable LCR in ESCC patients who rejected or were intolerant to intravenous chemotherapy due to old age or serious comorbidities. Clinical Trial Registration: ClinicalTrials.gov, NCT01831531.

Involved-Field Irradiation in Definitive Chemoradiotherapy for Locoregional Esophageal Squamous Cell Carcinoma: Results From the ESO-Shanghai 1 Trial.

PURPOSE: To evaluate the feasibility and efficacy of involved-field irradiation in definitive chemoradiation therapy for locoregional esophageal squamous cell carcinoma. METHODS AND MATERIALS: Patterns in recurrence and elective nodal failure were analyzed in patients from the previously published ESO-Shanghai 1 trial, who received definitive chemoradiation therapy with involved-field irradiation to 61.2 Gy in 34 fractions using intensity modulated radiation therapy planning. Nodal regions were delineated using the lymph node map from the sixth edition of the American Joint Committee on Cancer staging system. Elective nodal failure was defined as recurrence in the regional nodal area outside the planning target volume. Extensive elective nodal failure, defined as an extensive nodal area regardless of tumor location, was calculated for additional analysis. The incidental (ie, mean) irradiation dose of each node and each region was evaluated. RESULTS: With a median follow-up of 48.7 months among survivors, the 3-year actuarial rate for overall survival was 53.6%, and the median overall survival was 44.8 months (95% confidence interval, 34.6-55.0). Of the 436 patients included in this study, 258 patients (59.2%) experienced treatment failure. Elective nodal failure was experienced by 37 patients (8.5%), 7 (1.6%) of whom encountered nodal-only failure. The 3-year actuarial rates of elective nodal control and elective nodal-only control were 89.7% and 97.9%, respectively. The median incidental dose of these nodes was 33.2 Gy (interquartile range [IQR], 1.3-50.7 Gy). The median distance of each node to the planning target volume was 1.4 cm (IQR, 0.6-4.9 cm). Extensive elective nodal failure was experienced by 51 patients (11.6%), and 20 (4.6%) patients had nodal-only failure. The 3-year extensive elective nodal control and extensive elective nodal control-only rates were 86.0% and 94.3%, respectively. The median incidental dose of these nodes was 23.2 Gy (IQR, 1.1-53.5 Gy). The median distance of each node to the planning target volume was 2.0 cm (IQR, 0.6-5.5 cm). CONCLUSION: Involved-field irradiation can achieve a low rate of isolated nodal failure and a satisfactory survival outcome. The use of elective nodal irradiation may be unnecessary in definitive chemoradiation therapy for the treatment of locoregional esophageal squamous cell carcinoma.

Ovarian transposition before radiotherapy in cervical cancer patients: functional outcome and the adequate dose constraint.

BACKGROUND: The data regarding a transposed ovary in intensity-modulated radiotherapy (IMRT) are not sufficient. Here we aim to investigate the adequate dose constraint of ovarian transposition before radiotherapy in cervical cancer patients. METHODS: This was a retrospective analysis of 118 patients with cervical cancer who received a radical hysterectomy and ovarian transposition before pelvic irradiation from April 2012 to July 2017. A total of 105 patients underwent IMRT with a limited radiation dose to the ovaries; 48 of these patients received unilateral ovary limitation, while 57 received bilateral ovary limitations. Patient follow up regarding sex hormone levels (estrogen [E2], follicle stimulating hormone [FSH]) and menopausal symptoms was completed one year after their radiation therapy. RESULTS: A total of 41 out of 105 patients (39.0%) who underwent IMRT with a limited radiation dose to the ovaries preserved their normal ovarian function. The cutoff dose of comparatively lower side ovarian maximum dose was 9.985Gy and the cutoff of mean dose was 5.32Gy. The optimal dose-volume constrains to ovaries was V5.5 < 29.65%. Age ≤ 38 (P = 0.001) was an independent predictors of ovarian function, while limited ovarian side numbers were excluded. CONCLUSION: Using IMRT, preservation of ovarian function was possible when the limited dose was as low as possible to the ovaries regardless of bilateral or unilateral limitation to the ovaries. The ovarian maximum dose of less than 9.985Gy, the mean dose less than 5.32Gy and V5.5 < 29.65% could be better at preventing ovarian dysfunction. Patients younger than 38 years old were more likely to keep normal ovarian function while limited ovarian side numbers did not appear to exert an obvious effect.

Comparing Paclitaxel Plus Fluorouracil Versus Cisplatin Plus Fluorouracil in Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Cancer: A Randomized, Multicenter, Phase III Clinical Trial.

PURPOSE: This trial aimed to assess the efficacy and safety of the paclitaxel plus fluorouracil regimen versus the cisplatin plus fluorouracil regimen in definitive concurrent chemoradiotherapy (dCRT) in patients with locally advanced esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: Patients with locally advanced ESCC were enrolled and randomly assigned to either the paclitaxel plus fluorouracil group or the cisplatin plus fluorouracil group. The patients in the paclitaxel plus fluorouracil group were treated with paclitaxel and fluorouracil one cycle per week in dCRT for five cycles followed by paclitaxel and fluorouracil one cycle per month in consolidation chemotherapy for two cycles. The patients in the cisplatin/5-fluorouracil group were treated with cisplatin and fluorouracil one cycle per month in dCRT for two cycles followed by two cycles in consolidation chemotherapy. The radiotherapy dose was 61.2 Gy delivered in 34 fractions. The primary end point was 3-year overall survival (OS). RESULTS: Four hundred thirty-six patients with ESCC in six centers were recruited at a 1:1 ratio between April 2012 and July 2015. The median follow-up of the surviving patients was 48.7 months (interquartile range, 42.6-60.9). The 3-year OS was 55.4% in the paclitaxel plus fluorouracil group and 51.8% in the cisplatin plus fluorouracil group (hazard ratio, 0.905 [95% CI, 0.698 to 1.172]; P = .448). The 3-year progression-free survival was also not significantly different between the paclitaxel plus fluorouracil group and the cisplatin plus fluorouracil group (43.7% v 45.5%, respectively; hazard ratio, 0.973 [95% CI, 0.762 to 1.243]; P = .828). Compared with the cisplatin plus fluorouracil group, the paclitaxel plus fluorouracil group had significantly lower incidences of acute grade 3 or higher anemia, thrombocytopenia, anorexia, nausea, vomiting, and fatigue (P < .05), but higher incidences of acute grade 3 or higher leukopenia, radiation dermatitis, and radiation pneumonitis (P < .05). CONCLUSION: The paclitaxel plus fluorouracil regimen did not significantly prolong the OS compared with the standard cisplatin plus fluorouracil regimen in dCRT in patients with locally advanced ESCC.

Is it possible for knowledge-based planning to improve intensity modulated radiation therapy plan quality for planners with different planning experiences in left-sided breast cancer patients?

BACKGROUND: Knowledge-based planning (KBP) is a promising technique that can improve plan quality and increase planning efficiency. However, no attempts have been made to extend the domain of KBP for planners with different planning experiences so far. The purpose of this study was to quantify the potential gains for planners with different planning experiences after implementing KBP in intensity modulated radiation therapy (IMRT) plans for left-sided breast cancer patients. METHODS: The model libraries were populated with 80 expert clinical plans from treated patients who previously received left-sided breast-conserving surgery and IMRT with simultaneously integrated boost. The libraries were created on the RapidPlanTM. 6 planners with different planning experiences (2 beginner planners, 2 junior planners and 2 senior planners) generated manual and KBP optimized plans for additional 10 patients, similar to those included in the model libraries. The plan qualities were compared between manual and KBP plans. RESULTS: All plans were capable of achieving the prescription requirement. There were almost no statistically significant differences in terms of the planning target volume (PTV) coverage and dose conformality. It was demonstrated that the doses for most of organs-at-risk (OARs) were on average lower or equal in KBP plans compared to manual plans except for the senior planners, where the very small differences were not statistically significant. KBP data showed a systematic trend to have superior dose sparing at most parameters for the heart and ipsilateral lung. The observed decrease in the doses to these OARs could be achieved, particularly for the beginner and junior planners. Many differences were statistically significant. CONCLUSIONS: It is feasible to generate acceptable IMRT plans after implementing KBP for left-sided breast cancer. KBP helps to effectively improve the quality of IMRT plans against the benchmark of manual plans for less experienced planners without any manual intervention. KBP showed promise for homogenizing the plan quality by transferring planning expertise from more experienced to less experienced planners.

Identical Quality Assurance for Volumetric Modulated Arc Therapy in Elekta and Varian Machines.

Volumetric modulated arc therapy (VMAT) has been adopted by many clinics for its higher delivery efficiency compared to conventional intensity modulated radiotherapy techniques. Currently, the quality assurance (QA) has remained a challenge in that no identical tests are available for accelerators from different vendors. This study is the first attempt to design identical QA tests for the VMAT technique for Varian and Elekta machines. Identical procedures testing MLC positions and movements, dose rate variations, and gantry positions and movement were created for both machines. These included picket fence (PF), dose rate vs. gantry speed (DRGS) and MLC speed vs. dose rate (MLCDR) tests. Deliverable plans for these tests were made with in-house software that was deliverable for linacs from two vendors (Elekta Synergy and Varian Trilogy). The electronic portal imaging device (EPID) was used for these tests. An automated analysis method was established and software was created to quantitatively evaluate the result. The systematic gap position and width errors from PF tests were within 0.5 mm. We evaluated the detectability of this program for introduced errors down to 0.2 mm. Linear relationships existed between the introduced errors and measured errors. In the DRGS test, 99.8% and 100.0% of the intensity deviations from expected profiles were less than 3% for the Synergy and Trilogy, respectively. For the MLCDR, the intensity deviations from expected profiles less than 3% were 100.0% for Synergy and 98.1% for Trilogy. Identical test series were created and implemented for VMAT accelerators from two vendors. Test results were reported from both accelerators. Comparable results were obtained from both vendors, enabling uniform criteria to be established for VMAT quality assurance.

Investigation of plan quality between RapidArc and IMRT for gastric cancer based on a novel beam angle and multicriteria optimization technique.

A novel beam angle and multicriteria optimization (BAMCO) for intensity modulated radiotherapy (IMRT) was tested in ten gastric cancer patients. BAMCO IMRT has similar target coverage and organs at risk sparing to RapidArc. A reasonable delivery time (189.3±26.0s) was found for the BAMCO IMRT technique although longer than VMAT's (65.0±9.7s).