Simultaneous Integrated Boost Radiotherapy Research Articles

Efficacy and safety of MR-guided adaptive simultaneous integrated boost radiotherapy to primary lesions and positive lymph nodes in the neoadjuvant treatment of locally advanced rectal cancer: a randomized controlled phase III trial

BackgroundIn locally advanced rectal cancer (LARC), optimizing neoadjuvant strategies, including the addition of concurrent chemotherapy and dose escalation of radiotherapy, is essential to improve tumor regression and subsequent implementation of anal preservation strategies. Currently, dose escalation studies in rectal cancer have focused on the primary lesions. However, a common source of recurrence in LARC is the metastasis of cancer cells to the proximal lymph nodes. In our trial, we implement simultaneous integrated boost (SIB) to both primary lesions and positive lymph nodes in the experimental group based on magnetic resonance-guided adaptive radiotherapy (MRgART), which allows for more precise (and consequently intense) targeting while sparing neighboring healthy tissue. The objective of this study is to evaluate the efficacy and safety of MRgART dose escalation to both primary lesions and positive lymph nodes, in comparison with the conventional radiotherapy of long-course concurrent chemoradiotherapy (LCCRT) group, in the neoadjuvant treatment of LARC.MethodsThis is a multi-center, randomized, controlled phase III trial (NCT06246344). 128 patients with LARC (cT3-4/N+) will be enrolled. During LCCRT, patients will be randomized to receive either MRgART with SIB (60–65 Gy in 25–28 fractions to primary lesions and positive lymph nodes; 50–50.4 Gy in 25–28 fractions to the pelvis) or intensity-modulated radiotherapy (50–50.4 Gy in 25–28 fractions). Both groups will receive concurrent chemotherapy with capecitabine and consolidation chemotherapy of either two cycles of CAPEOX or three cycles of FOLFOX between radiotherapy and surgery. The primary endpoints are pathological complete response (pCR) rate and surgical difficulty, while the secondary endpoints are clinical complete response (cCR) rate, 3-year and 5-year disease-free survival (DFS) and overall survival (OS) rates, acute and late toxicity and quality of life.DiscussionSince dose escalation of both primary lesions and positive nodes in LARC is rare, we propose conducting a phase III trial to evaluate the efficacy and safety of SIB for both primary lesions and positive nodes in LARC based on MRgART.Trial registrationThe study was registered at ClinicalTrials.gov with the Identifier: NCT06246344 (Registered 7th Feb 2024).

Biological Dose Escalation—Do We Have a New Window of Opportunity in High-Grade Glioma?—A Feasibility Study

Despite multimodality treatment in high-grade glioma (HGG) involving maximal safe resection and adjuvant chemoradiotherapy, the prognosis remains dismal. In this study, we aimed to evaluate a method of biological enhancement by combining dose escalation with a condensed overall treatment time, aiming for maximal cytoreduction as a surrogate for improved outcomes. Hypofractionation has the dual advantage of enhanced cell kill with reduced overall treatment time. To this effect, we have employed a study involving hypofractionated simultaneous integrated boost (SIB) versus conventional treatment. As a secondary objective, we evaluated volumetric modulated arc therapy (VMAT) and intensity modulated radiotherapy (IMRT) in terms of optimal delivery technique for SIB boost. Forty patients were randomized into two arms, the study arm received 60 Gy in 25 fractions and the standard arm received 60 Gy in 30 fractions with concurrent and adjuvant temozolomide. The patients were assessed radiologically for tumor cytoreduction and acute toxicity parameters weekly during treatment, 6 weeks post-treatment, and 3 monthly follow-up. All patients were planned using VMAT and IMRT techniques in the study arm for the comparison of treatment time and dosimetric efficiency. However, the treatment was performed through VMAT technique. Data were analyzed using simple descriptive statistics including Student's t-tests, proportion tests, and Pearson correlation for association. The total sample size was estimated at 40, with 20 samples per group, providing a statistical power of 81% and a significance level (p-value) of 0.05. It was observed that tumor cytoreduction was significantly enhanced in a subgroup of patients in the study arm with smaller volume residual disease (p = 0.04) that was found at 6 weeks post-treatment evaluation. The tolerance, toxicity, and compliance were comparable in both arms. During the dosimetric evaluation, it was determined that VMAT had a significantly lower hot spot compared to the IMRT plan (64.22 Gy vs. 64.75 Gy, p = 0.02). It was also observed that the delivery with VMAT was faster and involved a lesser number of monitor units (555.7 MU vs. 679.6MU, p = 0.001). The hypofractionated SIB radiotherapy using the VMAT technique can provide a feasible method of biological dose enhancement without compromising toxicity and might have the future potential to improve local control in HGG.

Effectiveness of S-1–Based Chemoradiotherapy in Patients 70 Years and Older With Esophageal Squamous Cell Carcinoma

Double-agent intravenous chemotherapy concurrent with radiotherapy is the standard of care for patients with inoperable esophageal cancer. However, patients tend to tolerate intravenous chemotherapy less well with age and comorbidities. It is essential to find a better treatment modality that improves survival outcomes without reducing the quality of life. To evaluate the effectiveness of simultaneous integrated boost radiotherapy (SIB-RT) with concurrent and consolidated oral S-1 chemotherapy for patients aged 70 years and older with inoperable esophageal squamous cell carcinoma (ESCC). This multicenter, phase III randomized clinical trial was conducted between March 2017 and April 2020 in 10 centers in China. Patients with inoperable, locally advanced, clinical stage II to IV ESCC were enrolled and randomized to receive SIB-RT concurrent with and followed by oral S-1 chemotherapy (CRTCT group) or SIB-RT alone (RT group). Data analysis was completed on March 22, 2022. In both groups, the planning gross tumor volume was administered with radiation dose of 59.92 Gy and the planning target volume was administered with radiation dose of 50.4 Gy, in 28 fractions each. In the CRTCT group, concurrent S-1 was administered on radiotherapy days, and consolidated S-1 was administered at 4 to 8 weeks after SIB-RT. The primary end point was overall survival (OS) of the intent-to-treat population. Secondary end points were progression-free survival (PFS) and toxicity profile. A total of 330 patients (median [IQR] age, 75.5 [72-79] years; 220 [66.7%] male patients) were included, with 146 patients randomized to the RT group and 184 randomized to the CRTCT group. A total of 107 patients (73.3%) in the RT group and 121 patients (67.9%) in the CRTCT group were clinically diagnosed with stage III to IV disease. At the time of analysis of the 330 patients in the intent-to treat-population (March 22, 2022), OS was improved in the CRTCT group compared with the RT group at 1 year (72.2% vs 62.3%) and 3 years (46.2% vs 33.9%; log-rank P = .02). PFS was similarly improved in the CRTCT group compared with the RT group at 1 year (60.8% vs 49.3%) and 3 years (37.3% vs 27.9%; log-rank P = .04). There was no significant difference in the incidence of treatment-related toxic effects higher than grade 3 between the 2 groups. Grade 5 toxic effects occurred in each group, including 1 patient who experienced myelosuppression and 4 patients with pneumonitis in the RT group and 3 patients with pneumonitis and 2 patients with fever in the CRTCT group. These findings suggest that oral S-1 chemotherapy administered with SIB-RT should be considered as an alternative treatment option for patients aged 70 years and older with inoperable ESCC, since it improved survival outcomes without additional treatment-related toxic effects compared with SIB-RT alone. ClinicalTrials.gov Identifier: NCT02979691.

Isotoxic dose escalated radiotherapy for glioblastoma based on diffusion-weighted MRI and tumor control probability-an in-silico study.

Glioblastoma (GBM) is the most common malignant primary brain tumor with local recurrence after radiotherapy (RT), the most common mode of failure. Standard RT practice applies the prescription dose uniformly across tumor volume disregarding radiological tumor heterogeneity. We present a novel strategy using diffusion-weighted (DW-) MRI to calculate the cellular density within the gross tumor volume (GTV) in order to facilitate dose escalation to a biological target volume (BTV) to improve tumor control probability (TCP). The pre-treatment apparent diffusion coefficient (ADC) maps derived from DW-MRI of ten GBM patients treated with radical chemoradiotherapy were used to calculate the local cellular density based on published data. Then, a TCP model was used to calculate TCP maps from the derived cell density values. The dose was escalated using a simultaneous integrated boost (SIB) to the BTV, defined as the voxels for which the expected pre-boost TCP was in the lowest quartile of the TCP range for each patient. The SIB dose was chosen so that the TCP in the BTV increased to match the average TCP of the whole tumor. By applying a SIB of between 3.60 Gy and 16.80 Gy isotoxically to the BTV, the cohort's calculated TCP increased by a mean of 8.44% (ranging from 7.19 to 16.84%). The radiation dose to organ at risk is still under their tolerance. Our findings indicate that TCPs of GBM patients could be increased by escalating radiation doses to intratumoral locations guided by the patient's biology (i.e., cellularity), moreover offering the possibility for personalized RT GBM treatments. A personalized and voxel level SIB radiotherapy method for GBM is proposed using DW-MRI, which can increase the tumor control probability and maintain organ at risk dose constraints.

Effectiveness of S-1–Based Chemoradiotherapy and S-1 Consolidation in Elderly Patients with Esophageal Squamous Cell Carcinoma: A Multicenter Randomized Phase III Clinical Trial

<h3>Purpose/Objective(s)</h3> There has been a steady increase in the incidence of esophageal squamous cell carcinoma (ESCC) among elderly patients. The optimal treatment approach of elderly ESCC patients was still vague. <h3>Materials/Methods</h3> Between March 2017 and April 2020, 339 patients were screened in 10 centers in China; 184 and 146 patients were randomized into the S-1 based chemoradiotherapy followed by S-1 monotherapy (CRT-CT arm) or radiotherapy alone (RT arm). CRT-CT arm consisted simultaneous integrated boost radiotherapy (SIB-RT) (dose, 59.92 Gy/50.4 Gy) in 28 daily fractions administered using intensity-modulated radiotherapy or volumetric modulated arc therapy. S-1 was orally administered (40–60 mg/m2) concurrently with radiotherapy and 4–8 weeks later, for up to four 3-week cycles at the same dose. RT arm performed SIB-RT alone with the same radiotherapy dose. The primary endpoint was overall survival (OS) of the intention-to-treat (ITT) population. <h3>Results</h3> In the ITT population, 63.9% and 24.8% had T3 and T4 stage disease, and 68.8% had nodal metastases. The median OS was 27.8 months in the CRT-CT arm and 20.8 months in the RT arm and the OS rates were 72.5% vs 62.8% at 1 year; 55.2% vs 43.7% at 2 years; 45.5% vs 33.7% at 3 years ((hazard ratio, 0.75; 95% CI, 0.56–0.99; <i>P</i> = 0.041). The median PFS was 19.5 months in the CRT-CT arm and 11.5 months in the RT arm. Time dependent cox regression model revealed Charlson comorbidity index, BMI and cumulative chemotherapy cycles were independent prognostic factors associated with OS. OS and PFS of patients treated with 5–6 cycles of chemotherapy were superior to those of the patients treated with 0 (treated with radiotherapy alone), 1–2 and 3–4 cycles. There was no significant increase in the incidence of toxicities higher than grade 3 in the CRT-CT arm. Grades 4 and 5 toxicities were reported in 2.8% and 2.8%, respectively, of the CRT-CT arm compared with 0% and 4.2%, respectively, of the RT arm <h3>Conclusion</h3> Oral S-1 chemotherapy administered with SIB-RT is highly recommended for elderly patients with inoperable ESCC as an alternative treatment modality that improves survival outcomes with a more favorable side-effects profile.

Novel Hypofractionated Accelerated Radiotherapy Dose (HARD) Utilizing Simultaneous Integrated for Unresectable Soft Tissue Sarcomas

<h3>Purpose/Objective(s)</h3> Hypofractionated accelerated radiotherapy dose (HARD) in soft tissue sarcoma (STS) can exploit their lower α/β (∼3), while condensing treatment time and improving cost. Due to the large sarcoma treatment volumes, this novel simultaneous integrated boost (SIB) isotoxic technique was created to dose escalate gross disease, with lower dosing to intermediate and low risk volumes, mitigating the long-term toxicity of definitively treated STS. The present study evaluated the acute toxicity of unresectable hypofractionated SIB radiotherapy (RT) of 3 Gy/fraction for STS patients (HARD_3Gy). <h3>Materials/Methods</h3> A prospectively maintained database was retrospectively reviewed for STS patients treated with the HARD_3Gy regimen, defined as hypofractionated RT SIB at 3 Gy per fraction to gross disease for 20-22 fractions (60-66 Gy), with 2.5 Gy and 2-2.3 Gy per fraction for intermediate and low risk volumes, respectively. Acute toxicity during and after radiation treatment was reported as per CTCAE (v5). Time-to-event outcomes were estimated with Kaplan-Meier analysis from the current diagnosis and included local control (LC), distant control (DC), and overall survival (OS). Equivalent dose at 2 Gy (EQD₂) was calculated assuming an α/β ratio of 3. <h3>Results</h3> A total of 22 patients were identified, and most cases consisted of grade 3 (63%) recurrent sarcoma (59%) located in the lower extremity (36%). There were 8 patients (36%) who had received overlapping prior RT. At the time of RT, 8 had localized disease and 14 had evidence of distant metastatic disease, with a median size of 6cm (1-21cm) and age of 70 years (20-94 years). Patients were either treated to 60 Gy (n=16) or 66 Gy (n=6) in 20 or 22 fractions, with an EQD₂ of 72-79.2 Gy. With a median follow up of 14 months (3-25 months), there was a 12-month LC, DC, and OS of 100%, 68%, and 85%, respectively. There was a 91% limb preservation rate, with 2 amputations after re-irradiation with 66 Gy, due to infection with intractable pain. Acute toxicity included 14 cases (64%) of grade 2 and 5 cases (23%) of grade 3 skin toxicity only, which completely resolved/healed by 3 month follow up. <h3>Conclusion</h3> This novel definitive hypofractionation regimen of 3 Gy per fraction (HARD_3Gy) is well-tolerated and effective in STS patients, with caution dosing >60Gy in the re-irradiation setting. Long-term follow up is required to assess durable local control and chronic sequela.

Dosimetric and radiobiological comparison of simultaneous integrated boost radiotherapy for early stage right side breast cancer between three techniques: IMRT, hybrid IMRT and hybrid VMAT

PurposeThis study aimed at evaluating the clinical impact of full intensity-modulated radiotherapy (IMRT), hybrid IMRT (H-IMRT) and hybrid volumetric-modulated arc therapy (H-VMAT) for early-stage breast cancer with simultaneous integrated boost (SIB), in terms of plan quality and second cancer risk (SCR).MethodsThree different plans were designed in full IMRT, hybrid IMRT, and hybrid VMAT for each of twenty patients with early-stage breast cancer. Target quality, organs at risk (OARs) sparing, and SCR were compared among the three plans for each case.ResultsIn compared with H-IMRT, IMRT plans showed deterioration in terms of D2% of SIB, V10 of ipsilateral lung, and excess absolute risk (EAR) to contralateral lung (C-Lung) and esophagus. D2% and the homogeneity index (HI) of SIB, V5 of ipsilateral lung (I-Lung), the Dmean of the esophagus, the EAR to C-Lung and the esophagus with hybrid VMAT dramatically increased by 0.63%, 10%, 17.99%, 149.27%, 230.41%, and 135.29%, respectively (p = 0.024; 0.025; 0.046; 0.011; 0.000; 0.014). Dmean of the heart, the EAR to contralateral breast (C-Breast) and C-Lung by full IMRT was significantly decreased in comparison to the H-VMAT (4.67%, p = 0.033, 26.76%, p = 0.018; 48.05%, p = 0.036).ConclusionThe results confirmed that H-IMRT could achieve better target quality and OARs sparing than IMRT and H-VMAT for SIB radiotherapy of early-stage right breast cancer. H-IMRT was the best treatment option, while H-VMAT performed the worst among the three plans in terms of SCR to peripheral OARs.

A Prospective Phase II Clinical Study of Simultaneous Integrated Boost Radiotherapy on Stage III Local-advanced Non-Small Cell Lung Cancer Patients

In consideration of the results of the RTOG0617 study, researchers began to adopt a prudent policy to high-dose radiotherapy. Based on the assume that radiation dose escalation to the primary tumor can improve local control and therefore producing survival benefits under the condition of limiting the dose to the organ at risk (OAR), we launched the study to evaluate the effect of simultaneous Integrated boost (SIB) radiotherapy implemented on the stage III local-advanced non-small cell lung cancer (LA-NSCLC) patients.42 Patients with stage III LA-NSCLC who were eligible for definite concurrent chemoradiotherapy were prospectively given the radiation regimen of single dose of 2.0Gy for PTV, 2.2Gy for CTV, and 2.4 -2.8Gy for GTV with 25 fractions. Other stage III LA-NSCLC patients retrospectively collected with routinely radiotherapy were matched through PSM. 2 Cycles of platinum based concurrent chemotherapy were carried on patients in both groups. The primary endpoints were progression-free survival (PFS), toxic effects and dose for normal tissues, with the secondary end point of overall survival (OS). The Kaplan-Meier method was used to evaluate PFS and OS, and the Mann-Whitney U test for toxic effects and the dose for normal tissues.The median PFS time was 20.6 vs 9.0 months (P = 0.01), and the median OS was 40.0 vs 24.5 months (P = 0.02) in the SIB group and the control group respectively, all were obviously longer in the SIB group. No significant differences of radiation-related pneumonitis (P = 0.95) and myelosuppression (P = 0.40) have been observed between the two groups, as well as nausea, vomiting, esophagitis and dyspnea. The dose and the radiation-effected volume to the surrounding normal tissues also did not show the tendency of increasement in the SIB group.The results of our research has revealed that the dose escalation did improve the PFS and OS while not increased the dose to the surrounding normal tissues and the occurrence of toxic effects. Simultaneous integrated boost radiotherapy to the primary tumor might be a safe and feasible regimen to improve survival benefit for the stage III LA-NSCLC patients eligible for definite concurrent chemoradiotherapy in the future.

A Pilot Study of Hypofractionated Simultaneous Integrated Boost Radiotherapy in Stage 0-IIIB Breast Cancer Patients

In the UK START and Canadian hypofractionated whole breast radiotherapy (RT) trials, few patients were Black, received prior chemotherapy, or had large breast size, all factors associated with RT-induced breast toxicity. The purpose of this prospective trial was to assess the safety and efficacy of delivering 15 fractions of hypofractionated simultaneous integrated boost (SIB) RT to patients under-represented on trials of hypofractionated breast RT and who have characteristics which increase their risk for local recurrence and cutaneous toxicity from breast RT.We conducted a prospective, single-arm pilot study to evaluate a once daily 15 fraction SIB RT regimen of 39.9 Gy in 2.66 Gy fractions to the breast/chest wall with or without regional nodal irradiation (RNI) and SIB of 8.1 Gy in 0.54 Gy fractions. Women with Stage 0-IIIB breast cancer who had one or more of the following characteristics were approached for enrollment: 1) prior chemotherapy for breast cancer; 2) > 25 cm breast/chest wall separation; 3) non-White race; 4) ≤ 50 years old; or 5) requiring RNI. Primary endpoint was Grade 3 cutaneous toxicity rate by CTCAE v.5. Among patients who received RNI (n = 30), rates of Grade 3 brachial plexopathy by RTOG criteria and 20% or greater increase in arm lymphedema, were additional primary endpoints. Patients were assessed prior to RT, last day of RT, and 3 weeks, 9 weeks and 1 year post RT. Local regional recurrence free survival (LRFS) was a secondary endpoint.Among 74 participants, 57% received prior chemotherapy, 19% had breast/chest wall separation > 25cm, 39% were Black, 36% were ≤ 50 years old, and 41% were prescribed RNI. Median body mass index was 30.0 (range 17.3 - 54.9). Ten patients received post mastectomy RT. One patient developed Grade 3 radiation dermatitis 3 weeks post RT. No other Grade 3 or higher cutaneous toxicities were observed up to 1 year post RT. One patient developed a grade 3 axillary infection 3 weeks post RT, which resolved after intravenous antibiotics. No patients who received RNI developed grade 3 brachial plexopathy or a 20% increase in the ipsilateral arm volume during the study period. With a median follow up of 60 months (range 12-113 months), one in-breast recurrence with simultaneous distant metastases occurred. Two additional patients developed distant metastases alone. The 5-year LRFS and overall survival rates were 98.6% and 98.5%, respectively.Our results indicate that SIB radiation therapy is well-tolerated with acceptable cutaneous toxicity rates up to 1 year post RT even among patients who are at high risk for RT-induced breast side effects. The high rates of local control and overall survival following SIB treatment are promising and support condensed courses of RT in patients who would typically receive a sequential boost due to higher risk for local recurrence.

Dose escalated simultaneous integrated boost of gross nodal disease in gynecologic cancers: a multi-institutional retrospective analysis and review of the literature.

PurposeTypical doses of 45–50.4 Gy used to treat regional nodes have demonstrated inadequate control of gross nodal disease (GND) in gynecologic cancer, and accelerated repopulation may limit the efficacy of a sequential boost. We reviewed outcomes of patients treated with a simultaneous integrated boost (SIB) at 2.25 Gy per fraction to positron emission tomography (PET) avid GND to evaluate toxicity and tumor control using this dose-escalated regimen.Materials and MethodsA total of 83 patients with gynecologic cancer and PET avid inguinal, pelvic, or para-aortic lymphadenopathy were treated using intensity-modulated radiation therapy (IMRT) with SIB. Primary cancers were mostly cervical (51%) and endometrial (34%), and included patients who received concurrent chemotherapy (59%) and/or brachytherapy boost (78%).ResultsMedian follow-up from radiation completion was 12.6 months (range, 2.7 to 92.9 months). Median dose to elective lymphatics was 50.4 Gy (range, 45 to 50.4 Gy) at 1.8 Gy/fraction. Median SIB dose and volume were 63 Gy (range, 56.3 to 63 Gy) and 72.8 mL (range, 6.8 to 1,134 mL) at 2–2.25 Gy/fraction. Nodal control was 97.6% in the SIB area while 90.4% in the low dose area (p = 0.013). SIB radiotherapy (RT) field failure-free, non-SIB RT field failure-free, and out of RT field failure-free survival at 4 years were 98%, 86%, and 51%, respectively. Acute and late grade ≥3 genitourinary toxicity rates were 0%. Acute and late grade ≥3 gastrointestinal toxicity rates were 7.2% and 12.0%, respectively.ConclusionDose escalated SIB to PET avid adenopathy results in excellent local control with acceptable toxicity.

Dosimetric feasibility on hypofractionated intensity-modulated radiotherapy and simultaneous integrated boost for locally advanced unresectable pancreatic cancer with helical tomotherapy.

This dosimetric study on locally advanced pancreatic cancer (LAPC) and the surrounding gastrointestinal organs at risk (OARs) aimed at exploring the potential of further improving the internal dose and reducing the fractionation number by concurrent hypofractionated simultaneous integrated boost (SIB) radiotherapy using helical tomotherapy (HT). We collected computed tomography positioning images from a LAPC study of 17 consecutive patients. Gross tumor volume (GTV)1, GTV2, and GTV3 were defined as the GTV minus a margin of 3, 6, and 9 mm from the external part in all directions, respectively. Under the same physical parameters and limited dose on normal organs, each case had 4 sets of SIB radiotherapy plans. Upon dose escalation, we statistically analyzed the difference of dosimetric parameters received by the OARs between group A [planning target volume (PTV)/GTV=50 Gy/70 Gy] and the other groups. According to the equivalent bioradiotherapy formula, we calculated the hypofractionated standard dose by converting the average tolerated dose of each OAR with the corresponding number of fractions. Then, we compared the dose and volume parameters of the gastrointestinal tract from the less-than-20-fraction modes with the corresponding gastrointestinal hypofractionated standard dose. For dose escalation, although there were a few differences in the parameters of the OAR between group A and group D, all OAR doses of group D (PTV/GTV/GTV1/GTV2/GTV3=50 Gy/70 Gy/80 Gy/90 Gy/100 Gy) were within the limited dose range. In the hypofractionated mode, there was a statistically significant difference between the gastrointestinal dose-volume parameters and the dose-limiting reference standard when the fraction number was less than 14 or 15 for group A or D, respectively. The dose of the internal target can be increased to 100 Gy with 15 fractions in the hypofractionated SIB radiotherapy for LAPC with HT. The corresponding tolerance dose of OARs may also be acceptable.

Hypofractionated Simultaneous Integrated Boost Radiotherapy Versus Conventional Fractionation Radiotherapy of Early Breast Cancer After Breast-Conserving Surgery: Clinical Observation and Analysis.

Purpose: The objective of this retrospective study is to evaluate the efficacy and safety of hypofractionated simultaneous integrated boost radiotherapy for early breast cancer patients undergoing breast-conserving surgery. Methods: A total of 185 women with early breast cancer undergoing breast-conserving surgery were retrospectively divided into hypofractionated simultaneous integrated boost group and conventional fractionation group. Hypofractionated simultaneous integrated boost included 104 patients and the dose of whole-breast radiation reached 42.56 Gy in 16 fractions and simultaneously tumor bed boost to 48 Gy in 16 fractions, which course of radiotherapy was 22 days. The 81 patients of the conventional fractionation group received whole breast radiation to 50 Gy in 25 fractions and followed by tumor bed boost to 10 Gy in 5 fractions, which course of radiotherapy was 40 days. Clinical information including patients’ characteristics, skin toxicity, myelosuppression, radiation pneumonia, and cosmetic effects was recorded to analyze the influence of age, chemotherapy, position, and breast volume on the results of radiotherapy. Results: Hypofractionated simultaneous integrated boost group had no case of recurrence after a median follow-up of 25.6 months (9-47 months)) as compared with 2 after a median follow-up of 33.4 months (25-45 months) in the conventional fractionation group. The 2 groups had similar results in skin toxicity, cosmetic outcomes, and radiation pneumonia. In terms of myelosuppression, grade 1, grade 2, and grade 3 of myelosuppression in the hypofractionated simultaneous integrated boost group accounted for 16.7%, 12.3%, and 3.5% as compared with 30.0%, 21.1%, and 12.3% of the conventional fractionation group, respectively (P = .000). Conclusions: HF-SIB RT is a considerable option in patients after breast-conserving surgery with a lower degree of myelosuppression and shorter treatment time.

Clinical Observation of Hypofractionated Simultaneous Integrated Boost Radiotherapy in Breast-Conserving Surgery

Comparing the skin toxicity, cosmetic effect, myelosuppression and other adverse reactions between hypofractionated simultaneous integrated boost (HF-SIB) and conventional fractionated (CF) radiotherapy for breast cancer patients after breast-conserving surgery, to evaluate the short-term efficacy and safety of HF-SIB. A total of 236 early breast cancer patients received radiotherapy after breast-conserving surgery were prospectively enrolled in this study. All patients divided into two groups according to the dose of radiotherapy. HF-SIB included 126 patients and the dose of whole-breast radiation reach to 42.56Gy in 16 fractions and simultaneously tumor bed boost to 48Gy in 16 fractions, which course of radiotherapy was 22 days. The 110 patients of CF group received whole breast radiation to 50Gy in 25 fractions and followed by tumor bed boost to 10Gy in 5 fractions, which course of radiotherapy was 40 days. The indexes such as acute skin reaction, late skin toxicity, myelosuppression, cosmetic effect and radiation pneumonia were recorded and analyzed by Rank sum test and chi-square test. After a median follow-up of 14.6 months (7-18 months), HF-SIB group have no cases of recurrence (0/126) and the survival rate was 100% (126/126). After a median follow-up of 33.4 month (25-45 months) in CF group, the recurrence rate was 3.6% (4/110) and the 2-year survival rate was 100% (110/ 110). The incidence of acute skin reaction of grade 1, grade 2 and grade 3 in HF-SIB group was 52.7%, 15.8% and 2.6%, respectively and that in CF group is 50%, 25% and 5%. The incidence of late skin reaction in grade 1 and grade 2 was 25% and 5.2% in HF-SIB group and 20% and 3.3% in CF group respectively. The excellent and good rate of cosmetic effect of HF-SIB group and CF group at an interval of six months after radiotherapy was 97.4% vs 90%, and that of one year after radiotherapy was 93.1% vs 86.7%. The incidence of grade 1 and 2 radiation pneumonia in the HF-SIB group was 6.6% and 3.9%, while that in the CF group was 5.0% and 1.7%, respectively. There was no statistical difference in skin toxicity, cosmetic effect and radiation pneumonia between the two groups. In terms of myelosuppression, the HF-SIB group was better than the CF group. There was no significant difference in age, chemotherapy, fractionated dose and posture on skin reaction and cosmetic effect, but there was a correlation between the volume of breast and the incidence of skin reaction. The evaluation of clinic effect in HF-SIB group was not inferior to that in CF group, and there was no significant difference between HF-SIB group and CF group in terms of skin reaction and cosmetic effect. The degree of myelosuppression in HF-SIB group was lower than that in CF group. HF-SIB group can shorten the treatment time and reduce medical expenses. Moreover, the short-term effect was similar to that of CF group, so it can be used as one of the radiotherapy modes for early breast cancer patients after breast-conserving surgery.

A multicenter prospective phase III clinical randomized study of simultaneous integrated boost intensity-modulated radiotherapy with or without concurrent chemotherapy in patients with esophageal cancer: 3JECROG P-02 study protocol

BackgroundSince the development of three-dimensional conformal radiotherapy and intensity-modulated radiotherapy (IMRT), no prospective study has investigated whether concurrent chemoradiotherapy (SIB-IMRT with 60 Gy) remains superior to radiotherapy (SIB-IMRT) alone for unresectable esophageal cancer (EC). Furthermore, the optimal therapeutic regimen for patients who cannot tolerate concurrent chemoradiotherapy is unclear. We recently completed a phase I/II radiation dose-escalation trial using simultaneous integrated boost (SIB), elective nodal irradiation, and concurrent chemotherapy for unresectable EC. We now intend to conduct a prospective, phase III, randomized study of SIB-IMRT with or without concurrent chemotherapy. We aim to find a safe, practical, and effective therapeutic regimen to replace the conventional segmentation (1.8–2.0 Gy) treatment mode (radiotherapy ± chemotherapy) for unresectable EC.MethodsThis two-arm, open, randomized, multicenter, phase III trial will recruit esophageal squamous cell carcinoma patients (stage IIA–IVB [UICC 2002]; IVB only with metastasis to the supraclavicular or celiac lymph nodes). In all, 164 patients will be randomized using a 1:1 allocation ratio, and stratified by study site and disease stage, especially the extent of lymph node metastasis. Patients in the SIB arm will receive definitive SIB radiotherapy (95% planning target volume/planning gross tumor volume, 50.4 Gy/59.92 Gy/28 f, equivalent dose in 2-Gy fractions = 60.62 Gy). Patients in the SIB + concurrent chemotherapy arm will receive definitive SIB radiotherapy with weekly paclitaxel and a platinum-based drug (5–6 weeks). Four cycles of consolidated chemoradiotherapy will also be recommended. The primary objective is to compare the 1-year, 2-year, and 3-year overall survival of the SIB + chemotherapy group and SIB groups. Secondary objectives include progression-free survival, local recurrence-free rate, completion rate, and adverse events. Detailed radiotherapy protocol and quality-assurance procedures have been incorporated into this trial.DiscussionIn unresectable, locally advanced EC, a safe and effective total radiotherapy dose and reasonable segmentation doses are required for the clinical application of SIB-IMRT + two-drug chemotherapy. Whether this protocol will replace the standard treatment regimen will be prospectively investigated. The effects of SIB-IMRT in patients with poor physical condition who cannot tolerate definitive chemoradiotherapy will also be investigated.Trial registrationclinicaltrials.gov (NCT03308552, November 1, 2017).

Simultaneous Integrated Boost Radiotherapy in Unresectable Stage IV (M0) Head and Neck Squamous Cell Cancer Patients: Daily Clinical Practice.

To evaluate clinical outcome in locally-advanced stage IV (M0) head and neck cancer patients treated using intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) in daily clinical practice. Despite SIB-IMRT has been reported as a feasible and effective advanced head and neck cancer treatment, there are few data about its concurrent use with systemic therapies. We reviewed 41 staged IV (M0) head and neck cancer patients treated in two radiotherapy units in the city of Messina (Italy) during the last six years, using intensity modulated techniques-SIB. 22/41 patients had concomitant chemotherapy or cetuximab. Acute and late toxicities, objective response (OR) rate, local control (LC) and overall survival (OS) have been evaluated. 37/41 patients received the planned doses of radiotherapy, 2 patients died during the therapy. The major acute regional toxicities were skin reaction and mucositis. A case of mandibular osteoradionecrosis was recorded. At completion of treatment, OR was evaluated in 38 patients: 32/38 patients (84.2%) had complete (55.3%) and partial (28.9%) response. The 1- and 5-year LC rates were 73.4% and 69.73%, respectively. The 1-, 3-, and 5-year OS rates were 85.93%, 51.49% and 44.14%, respectively. No statistically significant differences in outcomes have been observed in patients treated with radiotherapy alone vs. irradiation concomitant to chemo/biotherapy. The median OS was 45 months. SIB-IMRT is safeand can be used with concomitant chemotherapy/biotherapy in real-life daily clinical practice. SIB-IMRT alone is a valid alternative in patients unfit for systemic therapies.

S-1 Based Simultaneous Integrated Boost Radiotherapy Followed by Consolidation Chemotherapy with S-1 for Esophageal Squamous Cell Carcinoma in the Elderly – A Multicenter Phase II Study (3JECROG P-01)

S-1 Based Simultaneous Integrated Boost Radiotherapy Followed by Consolidation Chemotherapy with S-1 for Esophageal Squamous Cell Carcinoma in the Elderly – A Multicenter Phase II Study (3JECROG P-01)

A multicenter phase III study comparing Simultaneous Integrated Boost (SIB) radiotherapy concurrent and consolidated with S-1 versus SIB alone in elderly patients with esophageal and esophagogastric cancer \u2013 the 3JECROG P-01 study protocol

BackgroundThe importance of definitive radiotherapy for elderly patients with esophageal and esophagogastric-junction cancer is pronounced. However, little is known in terms of the best way to combine radiotherapy with other treatment options. This study aims to compare the efficiency of SIB radiotherapy alone with SIB radiotherapy concurrent and consolidated with S-1 for elderly patients. Comprehensive geriatric assessment is also incorporated in the procedure of treatment.Methods/designThe study is a two arm, open, randomized multicenter Phase III trial with patients over 70 years old with stage IIA-IVB (UICC 2002, IVB only with metastasis to supraclavicular or celiac lymph nodes) squamous cell carcinoma or adenocarcinoma of esophagus or gastroesophageal junction. A total of 300 patients will be randomized using a 1:1 allocation ratio stratified by disease stage and study site. Patients allocated to the SIB arm will receive definitive SIB radiotherapy (95%PTV/PGTV 50.4Gy/59.92Gy/28f) while those randomized to SIB + S-1 arm will receive definitive SIB radiotherapy concurrent and consolidated with S-1. The primary endpoint of the trial is 1-year overall survival. Secondary objectives include progression-free survival, recurrence-free survival (local-regional and distant), disease failure pattern, toxicity profile as well as quality of life. Besides, detailed radiotherapy protocol and quality assurance procedure have been incorporated into this trial.DiscussionThe proportion of elderly patients in esophageal cancer is now growing, but there is a lack of evidence in term of treatment standard for this group of patients, which is what we aim to obtain through this prospective phase III study.Trial registrationclinicaltrials.govNCT02979691. Registered November 22, 2016.

A novel 3D-printed phantom insert for 4D PET/CT imaging and simultaneous integrated boost radiotherapy.

To construct a 3D-printed phantom insert designed to mimic the variable PET tracer uptake seen in lung tumor volumes and a matching dosimetric insert to be used in simultaneous integrated boost (SIB) phantom studies, and to evaluate the design through end-to-end tests. A set of phantom inserts was designed and manufactured for a realistic representation of gated radiotherapy steps from 4D PET/CT scanning to dose delivery. A cylindrical phantom (φ80 × 120 mm) holds inserts for PET/CT scanning. The novel 3D printed insert dedicated to 4D PET/CT mimics high PET tracer uptake in the core and low uptake in the periphery. This insert is a variable density porous cylinder (φ44.5 × 70.0 mm), ABS-P430 thermoplastic, 3D printed by fused deposition modeling an inner (φ11 × 42 mm) cylindrical void. The square pores (1.8 × 1.8 mm2 each) fill 50% of outer volume, resulting in a 2:1 PET tracer concentration ratio in the void volume with respect to porous volume. A matching cylindrical phantom insert is dedicated to validate gated radiotherapy. It contains eight peripheral holes and one central hole, matching the location of the porous part and the void part of the 3D printed insert, respectively. These holes accommodate adaptors for Farmer-type ion chamber and cells vials. End-to-end tests were designed for imaging, planning, and dose measurements. End-to-end test were performed from 4D PET/CT scanning to transferring data to the planning system, target volume delineation, and dose measurements. 4D PET/CT scans were acquired of the phantom at different respiratory motion patterns and gating windows. A measured 2:1 18F-FDG concentration ratio between inner void and outer porous volume matched the 3D printed design. Measured dose in the dosimetric insert agreed well with planned dose on the imaging insert, within 3% for the static phantom and within 5% for most breathing patterns. The novel 3D printed phantom insert mimics variable PET tracer uptake typical of tumors. Obtained 4D PET/CT scans are suitable for segmentation and treatment planning and delivery in SIB gated treatments. Our experiments demonstrate the feasibility of this set of phantom inserts serving as end-to-end quality-assurance phantoms of SIB radiotherapy.

MO-FG-BRA-05: Dosimetric and Radiobiological Validation of Respiratory Gating in Conventional and Hypofractionated Radiotherapy of the Lung: Effect of Dose, Dose Rate, Gating Window and Breathing Pattern

Purpose: to evaluate the dosimetric and radiobiological consequences from having different gating windows, dose rates, and breathing patterns in gated VMAT lung radiotherapy. Methods: A novel 3D-printed moving phantom with central high and peripheral low tracer uptake regions was 4D FDG-PET/CT-scanned using ideal, patient-specific regular, and irregular breathing patterns. A scan of the stationary phantom was obtained as a reference. Target volumes corresponding to different uptake regions were delineated. Simultaneous integrated boost (SIB) 6 MV VMAT plans were produced for conventional and hypofractionated radiotherapy, using 30–70 and 100% cycle gating scenarios. Prescribed doses were 200 cGy with SIB to 240 cGy to high uptake volume for conventional, and 800 with SIB to 900 cGy for hypofractionated plans. Dose rates of 600 MU/min (conventional and hypofractionated) and flattening filter free 1400 MU/min (hypofractionated) were used. Ion chamber measurements were performed to verify delivered doses. Vials with A549 cells placed in locations matching ion chamber measurements were irradiated using the same plans to measure clonogenic survival. Differences in survival for the different doses, dose rates, gating windows, and breathing patterns were analyzed. Results: Ion chamber measurements agreed within 3% of the planned dose, for all locations, breathing patterns and gating windows. Cell survival depended on dose alone, and not on gating window, breathing pattern, MU rate, or delivery time. The surviving fraction varied from approximately 40% at 2Gy to 1% for 9 Gy and was within statistical uncertainty relative to that observed for the stationary phantom. Conclusions: Use of gated VMAT in PET-driven SIB radiotherapy was validated using ion chamber measurements and cell survival assays for conventional and hypofractionated radiotherapy.

WE-AB-204-03: A Novel 3D Printed Phantom for 4D PET/CT Imaging and SIB Radiotherapy Verification

Purpose: To construct and test a 3D printed phantom designed to mimic variable PET tracer uptake seen in lung tumor volumes. To assess segmentation accuracy of sub-volumes of the phantom following 4D PET/CT scanning with ideal and patient-specific respiratory motion. To plan, deliver and verify delivery of PET-driven, gated, simultaneous integrated boost (SIB) radiotherapy plans. Methods: A set of phantoms and inserts were designed and manufactured for a realistic representation of lung cancer gated radiotherapy steps from 4D PET/CT scanning to dose delivery. A cylindrical phantom (40x 120 mm) holds inserts for PET/CT scanning. The novel 3D printed insert dedicated to 4D PET/CT mimics high PET tracer uptake in the core and lower uptake in the periphery. This insert is a variable density porous cylinder (22.12×70 mm), ABS-P430 thermoplastic, 3D printed by uPrint SE Plus with inner void volume (5.5×42 mm). The square pores (1.8×1.8 mm2 each) fill 50% of outer volume, resulting in a 2:1 SUV ratio of PET-tracer in the void volume with respect to porous volume. A matching in size cylindrical phantom is dedicated to validate gated radiotherapy. It contains eight peripheral holes matching the location of the porous part of the 3D printed insert, and one central hole. These holes accommodate adaptors for Farmer-type ion chamber and cells vials. Results: End-to-end test were performed from 4D PET/CT scanning to transferring data to the planning system and target volume delineation. 4D PET/CT scans were acquired of the phantom with different respiratory motion patterns and gating windows. A measured 2:1 18F-FDG SUV ratio between inner void and outer volume matched the 3D printed design. Conclusion: The novel 3D printed phantom mimics variable PET tracer uptake typical of tumors. Obtained 4D PET/CT scans are suitable for segmentation, treatment planning and delivery in SIB gated treatments of NSCLC.