Incidence Of Acute Grade Research Articles

Evaluating the reduction of elective radiotherapy fields for de novo metastatic nasopharyngeal carcinoma in the immunotherapy era.

This study evaluates the outcomes of omitting the high- and low-risk clinical tumor volume (CTV1 and CTV2) radiation in de novo metastatic nasopharyngeal carcinoma (dnm-NPC) patients in the immunotherapy era. We retrospectively analyzed 45 consecutive dnm-NPC patients receiving chemotherapy and immunotherapy combined with radiotherapy (CIR) from October 9, 2018 to June 1, 2022. Irradiation was only delivered to the primary tumor and retropharyngeal nodes (GTVnx+rn) and gross cervical lymph nodes (GTVnd). The median follow-up was 45 (range, 15-67) months. There was no recurrence in the omitted elective regions. The 36-month LRRFS, PFS, and OS were 95.4%, 44.6%, and 90.8%, respectively. The main grade 3/4 hematologic toxicities were neutropenia (42.2%), anemia (20.0%), and thrombocytopenia (13.3%). The incidence of acute grade 3/4 dermatitis, mucositis, and xerostomia were 4.4%, 8.9%, and 4.4%, respectively. Omitting CTV1 and CTV2 was well-tolerated and provided favorable clinical outcomes in the era of immunotherapy.

Postoperative Hypofractionated Intensity-Modulated Radiotherapy With Concurrent Chemotherapy in Cervical Cancer

Prospective data assessing the safety of hypofractionated (40 Gy in 16 fractions) radiotherapy (RT) among patients who receive postoperative concurrent chemoradiotherapy for cervical cancer are lacking. To evaluate the acute toxic effects of hypofractionated pelvic intensity-modulated radiotherapy (IMRT) with concurrent chemotherapy among women with cervical cancer who underwent radical hysterectomy. The POHIM-CCRT (Postoperative Hypofractionated Intensity-Modulated Radiation Therapy With Concurrent Chemotherapy in Cervical Cancer) study was designed as a multicenter, phase 2 nonrandomized controlled trial that accrued and followed up patients from June 1, 2017, to February 28, 2023. In total, 84 patients were enrolled from 5 institutions affiliated with the Korean Radiation Oncology Group. Eligible patients experienced lymph node metastasis, parametrial invasion, or positive resection margins after radical hysterectomy for treatment of confirmed cervical cancer. Postoperative pelvic radiation using hypofractionated IMRT with 40 Gy in 16 fractions to the whole pelvis combined with concurrent chemotherapy. The primary end point was incidence of acute grade 3 or higher gastrointestinal tract, genitourinary, and hematologic toxic effects (based on the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0) in the evaluable population during RT or within 3 months after RT completion. Of 84 patients enrolled, 5 dropped out prior to RT, and data from 79 patients were analyzed. The patients' median (IQR) age was 48 (42-58) years, and the median (IQR) tumor size was 3.7 (2.7-4.5) cm. Of these patients, 31 (39.7%) had lymph node metastasis, 4 (5.1%) had positive resection margins, and 43 (54.4%) had parametrial invasion. Grade 3 or higher acute toxic effects occurred in 2 patients (2.5% [90% CI, 0%-4.8%]). After a median (IQR) follow-up of 43.0 (21.1-59.0) months, the 3-year disease-free survival rate was 79.3%, and the overall survival rate was 98.0%. Findings from this nonrandomized control trial indicated that postoperative pelvic irradiation combined with concurrent chemotherapy using hypofractionated IMRT with 40 Gy in 16 fractions was safe and well-tolerated in women with cervical cancer. Studies assessing long-term toxic effects and oncological outcomes with longer follow-up periods are needed. ClinicalTrials.gov Identifier: NCT03239613.

Bone Marrow Versus Peripheral Blood in HLA-Matched Sibling Transplantation: Does the Stem Cell Source Matter in Severe Aplastic Anemia?

Background Selecting a graft source is critical in HLA-matched sibling donor hematopoietic stem cell transplantation (MSD-HCT) for severe aplastic anemia (SAA). Since graft-versus-host-disease (GVHD) is the major cause of mortality after MSD-HCT, and SAA patients do not need the graft-versus-leukemia effect, the selection of a suitable source of stem cells becomes critical. Although bone marrow (BM) is the preferable stem cell source based on the registry-based studies, mobilized peripheral blood stem cells (PBSC) may offer faster engraftment with rapid immune reconstitution. Moreover, the recent advances in conditioning regimens have significantly reduced transplantation-related complications. Here, we compared the long-term outcomes of BM vs PBSC as a graft source in adult patients with SAA who received MSD-HCT with the reduced intensity conditioning (RIC) regimen. Method We conducted a retrospective analysis of 171 consecutive SAA adult patients who received MSD-HCT with Flu6/Cy2/ATG4 RIC regimen (Flu, 30 mg/m 2 IV for 6 days: Cy, 50 mg/kg IV for 2 days; rabbit ATG, 2.5 mg/kg IV for 4 days) or total nodal irradiation (TNI) of 750 cGy combined with ATG as GVHD prophylaxis (TNI-750/ATG) from March 2002 to March 2021 at Seoul St. Mary's Hospital, Seoul, Korea. BM was the primary graft source, but PBSC was used in donors who refused BM harvest, were unsuitable for general anesthesia, or received TNI-750/ATG conditioning. The primary endpoint of this study was to compare the overall survival (OS), and the secondary endpoints included speed of hematologic recovery, primary or secondary graft failure (GF), and failure-free survival (FFS) between the BM and PBSC group. Results The median patient age in the BM group was 38 years (range, 15 - 59) and 44 years (range, 19 - 64) in the PBSC group (p=0.005). There were no differences of baseline characteristics between the two groups except for a donor-to-recipient sex discrepancy (female to male, BM vs. PBSC; 16.4% vs. 30.9%, p=0.029). The majority of BM group (114/116, 98.2%) received the Flu6/Cy2/ATG4 RIC regimen, while 38.2% (21/55) of PBSC group received TNI-750/ATG for the conditioning (p<0.001). The PBSC contained a median 4.71 (range, 1.22 - 17.03) x 10 6/kg CD34 + cells and 368.82 (range, 25.12 - 1234.70) x 10 6/kg CD3 + cells which were about 1.7-fold (BM 2.80 x 10 6/kg CD34 + cells; range, 0.25 - 10.05) and 10-fold (BM 39.61 x 10 6/kg CD3 + cells; range, 1.34 - 463.68) higher than the BM graft (p<0.001). Consequently, the PBSC group exhibited faster engraftment of neutrophils (median 13 vs. 11 days, p<0.001) and platelets (median 18 vs. 12 days, p=0.012). However, there were no differences in the incidence of secondary GF (19.0% vs. 12.7%, p=0.386) and donor-type aplasia (4.3% vs. 10.9%, p=0.178) between two groups. Furthermore, the incidence of acute grade I-II (8.6% vs. 10.9%, p=0.619) and moderate to severe chronic graft-versus-host disease (GVHD) (3.5% vs. 5.5%, p=0.542) were also not significantly different between two groups. However, the BM group has shown more CMV reactivation (44.0% vs. 24.9%, p=0.005), and higher incidence of respiratory infection (14.7% vs. 3.6%, p=0.037) than those of the PBSC group. The incidences of transplantation-related complications between the BM and PBSC group are summarized in Table. The 10-year OS (93.8% vs. 98.1%, p=0.246) and FFS (65.7% vs. 69.0%, p=0.455) were comparable (Figure). Moreover, there was no significant difference in FFS between BM and PBSC group by potential risk factors of patient and donor age at MSD-HCT, sex incompatibility, ABC mismatch, PNH clone presence, HCT-CI ≥3, infused CD34 + cell count, interval from diagnosis to transplant, prior IST history, heavy transfusion before allo-HCT, or severity of AA. Conclusions Our results suggest that survival outcomes of MSD-HCT showed no difference between BM and PBSC as graft sources, and using PBSC may be an efficient alternative offering faster engraftment without significant difference in graft failure or transplantation-related adverse events such as GVHD, and survival. Current analysis and results were drawn from the Asian population with a fludarabine-based conditioning regimen and therefore, need to validate in the Western population. In addition, well-designed prospective studies in a larger cohort are required to confirm our findings.

A pilot study of stereotactic body radiotherapy combined with pelvic radiotherapy and GTVp boost based on multiparameter magnetic resonance image in patients with high-risk prostate cancer.

This pilot study aimed to explore the preliminary effects and safety of stereotactic body radiotherapy (SBRT) combined with preventive pelvic radiotherapy and primary gross tumor volumes (GTVp) boost in patients with high-risk prostate cancer based on multiparameter magnetic resonance image (mpMRI). Tumors were contoured as GTVp based on mpMRI. The prostate and proximal seminal vesicles were considered as the clinical target volume1. The pelvic lymphatic drainage area constituted clinical target volume 2. Radiation doses were 40Gy or 45Gy/5fractions to planning target volume of primary tumor, 37.5Gy/5f to prostate, seminal vesicle, and positive pelvic lymph nodes, and 25Gy/5f to pelvic synchronously. The treatment was delivered 3 times per week. Volumetric modulated arc radiotherapy and intensity-modulated radiotherapy were used to complete SBRT. The genitourinary (GU) and gastrointestinal (GI) toxicities were evaluated. Quality of life data was also captured. A total of 15 patients were enrolled in this study with a median age of 78 (56-87) from 2017 to 2020. All patients received SBRT. At 3 months after radiotherapy, the proportion of PSA < 0.006 ng/mL was 66.7% (10/15). The 2-year biochemical relapse-free survival was 93.3%. The incidence of grade 1 acute GU side effects was 80% (12/15); the incidence of acute grade 1 GI toxicity was 66.7% (10/15); and no grade 2 or higher acute GU and GI side effects was observed. Two patients presented with temporary late grade 2 GI toxicity. International Prostatic System Score increased rapidly after a transient increase at 1 week (P = .001). There were no significant differences in EORTC quality of life scores in all domains except global health status. In this pilot study, it was revealed that SBRT combined with preventive pelvic radiotherapy and GTVp boost based on mpMRI image was effective and well tolerated for patients with high-risk prostate cancer.

Concurrent intensity-modulated radiation therapy and chemotherapy plus nimotuzumab for locally advanced cervical squamous cell cancer: A long-term follow-up result

The study aimed to evaluate the safety and efficacy of concurrent intensity-modulated radiation therapy (IMRT) and chemotherapy plus nimotuzumab for the treatment of locally advanced cervical squamous cell cancer (LACSCC). From December 2013 to March 2017, 34 patients with stages IB2&amp;ndash;IVA (FIGO 2009) cervical squamous cell cancer were enrolled and received concurrent chemoradiotherapy plus nimotuzumab. The prescription radiation dose was 50.4 Gy/28 F on the pelvic field with or without extended-field radiation. An additional 30&amp;ndash;36 Gy to Point A was delivered with high-dose-rate brachytherapy. Cisplatin 40 mg/m2 and nimotuzumab 200 mg were infused intravenously weekly. The main and secondary outcome measures were toxicity evaluated using common terminology criteria for adverse events 4.03. and the outcome evaluated using response evaluation criteria in solid tumors 1.1, respectively. The median follow-up duration was 66 months (13 &amp;ndash; 98 months). All patients received 6 times of IMRT, brachytherapy, and nimotuzumab. Among them, 24 received six cycles of chemotherapy, while 11 received 4&amp;ndash;5 cycles. No life-threatening toxicity was found. The incidence of acute Grade 3 bone marrow depression was 52.9% (18/34), and Grade 3 gastrointestinal tract reaction was 8.8% (3/34). The incidence of late toxicities was 58.8% (20/34), including vaginal-rectal fistula, intestinal obstruction, rectal hemorrhage, hematuria, vaginal stenosis, and paresthesia. About 90% of those were Grades 1&amp;ndash;2. Complete response was achieved in 33 cases (97.1%). The 3-year disease-free survival, local progression-free survival (LPFS), and overall survival rates were 79.4%, 91.2%, and 82.4%, respectively. The corresponding 5-year values were 79.4%, 91.2%, and 79.3%. In conclusion, concurrent IMRT and chemotherapy plus nimotuzumab may represent a well-tolerated and effective treatment regimen in patients with LACSCC.

A Multi-Institutional Phase 2 Trial of Ablative 5-Fraction Stereotactic Magnetic Resonance-Guided On-Table Adaptive Radiation Therapy for Borderline Resectable and Locally Advanced Pancreatic Cancer

Magnetic resonance (MR) image guidance may facilitate safe ultrahypofractionated radiation dose escalation for inoperable pancreatic ductal adenocarcinoma. We conducted a prospective study evaluating the safety of 5-fraction Stereotactic MR-guided on-table Adaptive Radiation Therapy (SMART) for locally advanced (LAPC) and borderline resectable pancreatic cancer (BRPC). Patients with LAPC or BRPC were eligible for this multi-institutional, single-arm, phase 2 trial after ≥3 months of systemic therapy without evidence of distant progression. Fifty gray in 5 fractions was prescribed on a 0.35T MR-guided radiation delivery system. The primary endpoint was acute grade ≥3 gastrointestinal (GI) toxicity definitely attributed to SMART. One hundred thirty-six patients (LAPC 56.6%, BRPC 43.4%) were enrolled between January 2019 and January 2022. Mean age was 65.7 (36-85) years. Head of pancreas lesions were most common (66.9%). Induction chemotherapy mostly consisted of (modified)FOLFIRINOX (65.4%) or gemcitabine/nab-paclitaxel (16.9%). Mean CA19-9 after induction chemotherapy and before SMART was 71.7 U/mL (0-468). On-table adaptive replanning was performed for 93.1% of all delivered fractions. Median follow-up from diagnosis and SMART was 16.4 and 8.8 months, respectively. The incidence of acute grade ≥3 GI toxicity possibly or probably attributed to SMART was 8.8%, including 2 postoperative deaths that were possibly related to SMART in patients who had surgery. There was no acute grade ≥3 GI toxicity definitely related to SMART. One-year overall survival from SMART was 65.0%. The primary endpoint of this study was met with no acute grade ≥3 GI toxicity definitely attributed to ablative 5-fraction SMART. Although it is unclear whether SMART contributed to postoperative toxicity, we recommend caution when pursuing surgery, especially with vascular resection after SMART. Additional follow-up is ongoing to evaluate late toxicity, quality of life, and long-term efficacy.

Magnetic Resonance Imaging–Guided vs Computed Tomography–Guided Stereotactic Body Radiotherapy for Prostate Cancer

Magnetic resonance imaging (MRI) guidance offers multiple theoretical advantages in the context of stereotactic body radiotherapy (SBRT) for prostate cancer. However, to our knowledge, these advantages have yet to be demonstrated in a randomized clinical trial. To determine whether aggressive margin reduction with MRI guidance significantly reduces acute grade 2 or greater genitourinary (GU) toxic effects after prostate SBRT compared with computed tomography (CT) guidance. This phase 3 randomized clinical trial (MRI-Guided Stereotactic Body Radiotherapy for Prostate Cancer [MIRAGE]) enrolled men aged 18 years or older who were receiving SBRT for clinically localized prostate adenocarcinoma at a single center between May 5, 2020, and October 1, 2021. Data were analyzed from January 15, 2021, through May 15, 2022. All patients had 3 months or more of follow-up. Patients were randomized 1:1 to SBRT with CT guidance (control arm) or MRI guidance. Planning margins of 4 mm (CT arm) and 2 mm (MRI arm) were used to deliver 40 Gy in 5 fractions. The primary end point was the incidence of acute (≤90 days after SBRT) grade 2 or greater GU toxic effects (using Common Terminology Criteria for Adverse Events, version 4.03 [CTCAE v4.03]). Secondary outcomes included CTCAE v4.03-based gastrointestinal toxic effects and International Prostate Symptom Score (IPSS)-based and Expanded Prostate Cancer Index Composite-26 (EPIC-26)-based outcomes. Between May 2020 and October 2021, 156 patients were randomized: 77 to CT (median age, 71 years [IQR, 67-77 years]) and 79 to MRI (median age, 71 years [IQR, 68-75 years]). A prespecified interim futility analysis conducted after 100 patients reached 90 or more days after SBRT was performed October 1, 2021, with the sample size reestimated to 154 patients. Thus, the trial was closed to accrual early. The incidence of acute grade 2 or greater GU toxic effects was significantly lower with MRI vs CT guidance (24.4% [95% CI, 15.4%-35.4%] vs 43.4% [95% CI, 32.1%-55.3%]; P = .01), as was the incidence of acute grade 2 or greater gastrointestinal toxic effects (0.0% [95% CI, 0.0%-4.6%] vs 10.5% [95% CI, 4.7%-19.7%]; P = .003). Magnetic resonance imaging guidance was associated with a significantly smaller percentage of patients with a 15-point or greater increase in IPSS at 1 month (6.8% [5 of 72] vs 19.4% [14 of 74]; P = .01) and a significantly reduced percentage of patients with a clinically significant (≥12-point) decrease in EPIC-26 bowel scores (25.0% [17 of 68] vs 50.0% [34 of 68]; P = .001) at 1 month. In this randomized clinical trial, compared with CT-guidance, MRI-guided SBRT significantly reduced both moderate acute physician-scored toxic effects and decrements in patient-reported quality of life. Longer-term follow-up will confirm whether these notable benefits persist. ClinicalTrials.gov Identifier: NCT04384770.

Acute skin toxicity of conventional fractionated versus hypofractionated radiotherapy in breast cancer patients receiving regional node irradiation: the real-life prospective multicenter HYPOBREAST cohort

BackgroundLarge-scale trials have shown that hypofractionated adjuvant breast radiotherapy was as effective in terms of survival and local control as conventional fractionated radiotherapy, and acute toxicity was reduced with hypofractionated radiotherapy. However, there is a lack of data about the toxicity of breast with regional nodal irradiation (RNI). The aim of this study was to assess the effect of fractionation on radiation-related acute skin toxicity in patients receiving RNI in addition to whole-breast or chest wall irradiation, using real-life data.MethodsWe conducted a prospective, multicenter cohort study with systematic computerized data collection integrated into Mosaiq®. Three comprehensive cancer centers used a standardized form to prospectively collect patient characteristics, treatment characteristics and toxicity.ResultsBetween November 2016 and January 2022, 1727 patients were assessed; 1419 (82.2%) and 308 (17.8%) patients respectively received conventional fractionated and hypofractionated radiation therapy. Overall, the incidence of acute grade 2 or higher dermatitis was 28.4% (490 patients). Incidence was lower with hypofractionated than with conventional fractioned radiation therapy (odds ratio (OR) 0.34 [0.29;0.41]). Two prognostic factors were found to increase the risk of acute dermatitis, namely 3D (vs IMRT) and breast irradiation (vs chest wall).ConclusionUsing real-life data from unselected patients with regional nodal irradiation, our findings confirm the decreased risk of dermatitis previously reported with hypofractionated radiation therapy in clinical trials. Expansion of systematic data collection systems to include additional centers as well as dosimetric data is warranted to further evaluate the short- and long-term effects of fractionation in real life.

Stereotactic MR-Guided On-Table Adaptive Radiation Therapy (SMART) for Patients with Borderline or Locally Advanced Pancreatic Cancer: Primary Endpoint Outcomes of a Prospective Phase II Multi-Center International Trial

<h3>Purpose/Objective(s)</h3> Retrospective studies demonstrate that ablative stereotactic MR-guided on-table adaptive radiation therapy (SMART) achieves favorable local control (LC) and overall survival (OS) with limited grade 3+ toxicity compared to historical non-ablative outcomes for locally advanced and borderline resectable pancreatic cancer (LAPC/BRPC). We conducted an international multi-center single-arm phase 2 trial of ablative 5-fraction SMART for LAPC/BRPC. <h3>Materials/Methods</h3> Subjectswere required to have biopsy-confirmed adenocarcinoma, receive ≥3 months of chemotherapy, have no distant metastasis and CA19-9 ≤500 U/mL. SMART was delivered on a 0.35T MR-⁶⁰Co or MR-linac system prescribed to 50 Gy in 5 fractions (biologically effective dose₁₀ [BED₁₀]=100 Gy) using continuous intrafraction cine-MRI, soft tissue tracking, and automatic beam gating. The original plan was recomputed onto the daily anatomy and if that plan would not have met constraints, on-table adaptive replanning using an isotoxicity approach was performed. The primary objective was to demonstrate <15.8% acute grade 3+ gastrointestinal (GI) toxicity definitely related to SMART measured through 90 days and evaluated according to Common Terminology Criteria for Adverse Events v5.0 (CTCAE). All patients have completed 90-day follow-up. Secondary objectives included OS, distant progression free survival (DPFS), and patient-reported quality of life. <h3>Results</h3> 136 patients across 13 sites were enrolled between 2019-2021. Mean age was 65.7 years. Head of pancreas lesions were most common (66.9%; n=91). 43.4% (n=59) had BRPC, 56.6% (n=77) LAPC. Mean induction chemotherapy duration was 155.7 days, typically with FOLFIRINOX 65.4% (n=89) or gemcitabine doublet 16.9% (n=23). Mean CA19-9 after induction chemotherapy was 71.7 U/mL. On-table adaptive replanning was used for 93.1% of fractions. SMART was delivered in consecutive days (56.6%) or every other day (43.4%). Median follow-up was 16.4 months and 8.8 months from diagnosis and SMART, respectively. 31.6% (n=43) had surgery after SMART. The incidence of acute grade 3+ GI toxicity definitely and probably related to SMART were 0% and 2.2% (n=3), respectively. 1-year LC and DPFS from SMART were 82.9% and 50.6%, respectively. 1-year OS was 93.9% from diagnosis and 65.0% from SMART. <h3>Conclusion</h3> This is the first prospective, multi-institutional study of ablative SMART with prescribed BED₁₀ of 100 Gy delivered in 5 fractions for BRPC/LAPC. The primary objective was met, signaling that further prospective evaluation of ablative SMART for BRPC/LAPC is warranted with a focus on long-term LC and OS compared to chemotherapy alone.

Comparison of the efficacy and toxicity of postoperative proton versus carbon ion radiotherapy for head and neck cancers

To compare the efficacy and toxicity of adjuvant proton beam vs. carbon-ion beam radiotherapy for head and neck cancers after radical resection and to explore the value of particle beam radiotherapy (PBRT) in postoperative radiotherapy for head and neck cancers. Data from 38 head and neck cancer patients who received adjuvant PBRT after complete surgical resection at the Shanghai Proton and Heavy Ion Center (SPHIC) between October 2015 and March 2019 were retrospectively analyzed. In total, 18 patients received adjuvant proton beam therapy (54-60 GyE/27-30 fractions) and 20 received adjuvant carbon-ion radiotherapy (CIRT) (54-60 GyE/18-20 fractions). Survival rates were calculated using Kaplan-Meier analysis. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Effects (version 4.03). With a median follow-up time of 21 (range, 3-45) months, the 2-year overall survival (OS), progression-free survival (PFS), local-regional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS) rates were 93.3%, 87.4%, 94.1%, and 90.7%, respectively, for the entire cohort. The rates after proton beam therapy vs. CIRT were 94.1% vs. 91.7% (P=0.96), 88.1% vs. 86.2% (P=0.96), 94.4% vs. 93.3% (P=0.97), and 88.1% vs. 92.9% (P=0.57), respectively. Furthermore, 16 of the 18 (88.9%) patients developed acute grade I/II dermatitis (13 grade I; 3 grade II) after proton beam therapy, and only 7 of the 20 (35%) patients developed acute grade I dermatitis after CIRT (P=0.001). The incidence of acute grade I/II mucositis and xerostomia in proton and carbon ion cases were 45% vs. 55% (P=0.75) and 56% vs. 50% (P=0.87) respectively. Adjuvant proton beam therapy and CIRT after radical surgical resection for head and neck cancers provided satisfactory therapeutic effectiveness, but no significant difference was observed between the two radiotherapy technologies. However, adjuvant CIRT was associated with a more favorable acute toxicity profile as compared to proton beam therapy with significantly lower frequency and severity of acute dermatitis observed.

A PROSPECTIVE STUDY ON DAILY LOW DOSE CISPLATIN CONCURRENT WITH INTENSITY MODULATED RADIOTHERAPY IN LOCALLY ADVANCED CARCINOMA CERVIX

Treatment of locally advanced cervical cancer evolved from EBRT alone to EBRT plus ICRT to EBRT with concurrent chemotherapy plus ICRT. Concurrent cisplatin therapy is usually administered on a weekly or three weekly basis. The doses of Cisplatin used in the weekly or three weekly regimen may not be tolerated well by all patients, resulting to fewer patients being able to receive the total planned effective dose of concurrent chemotherapy. Experimental data suggest that antitumor activity of cisplatin may be greater if administered by continuous infusion. Preliminary studies have also shown that low dose, daily Cisplatin with radiotherapy may be better tolerated along with similar response rates, especially in older age patients. Results: Overall 96.8 % (30 out of 31) of the patients had complete response and 3.2% (1 out of 31) patients had partial response. Almost all (except one) the patients in the study received a cumulative dose of 200 mg/m2 of concurrent Cisplatin. Acute grade 3 toxicities were observed mostly in the form of diarrhoea and skin toxicity. Grade 3 diarrhoea occurred in 14 patients (45.2%). Incidence of acute grade 3 skin reaction was seen in 2 patients (6.5%), whereas the incidence of acute grade 3 haematological toxicity , genitourinary toxicity and grade 3 nausea and vomiting was nil. Conclusions: Adaily low dose cisplatin prior to radiotherapy might lead to an increased radiosensitization as well as better tolerance than other regimens.

Long-Term Outcomes of Dose-Escalated Hypofractionated Radiotherapy in Localized Prostate Cancer.

Simple SummaryModerately hypofractionated radiotherapy (HFRT) has been shown to be isoeffective compared to conventional regimens in the treatment of prostate cancer (PCa). In addition, dose-escalation improves biochemical or metastasis control with minimal toxicity, although no overall survival benefit has been demonstrated. This work reports the results of HFRT on biochemical control, overall survival, toxicity and quality of life in patients with localized PCa treated with a dose-escalated schedule (66 Gy, 3 Gy/fraction) using volume modulated arc therapy (VMAT).This retrospective study aimed to provide some clinical outcomes regarding effectiveness, toxicity, and quality of life in PCa patients treated with dose-escalated moderately hypofractionated radiation therapy (HFRT). Patients received HFRT to a total dose of 66 Gy in 22 fractions (3 Gy/fraction) delivered via volume modulated arc therapy (VMAT) in 2011–2016. Treatment effectiveness was measured by the biochemical failure-free survival rate. Toxicity was assessed according to the criteria of the Radiation Therapy Oncology Group (RTOG) and quality of life according to the criteria of the European Organization for Research and Treatment of Cancer (EORTC). In this regard, quality of life (QoL) was measured longitudinally, at a median of 2 and 5 years after RT. Enrolled patients had low-risk (40.2%), intermediate-risk (47.5%), and high-risk (12.3%) PCa. Median follow-up was 75 months. The biochemical failure-free survival rate was 94.2%. The incidence of acute grade 2 or higher gastrointestinal (GI) and genitourinary (GU) toxicity was 9.84% and 28.69%, respectively. The incidence rate of late grade 2 or higher GI and GU toxicity was 1.64% and 4.10%, respectively. Expanded Prostate Cancer Index Composite (EPIC) scores showed that the majority of patients maintained their QoL. HFRT to 66 Gy with VMAT was associated with adequate biochemical control, low toxicity and good reported GU and GI quality of life.

Severe Toxicity and Provider-Reported Subjective Symptoms in Patients With Vulvar Cancer Receiving Curative-Intent Radiotherapy

Definitive or adjuvant radiotherapy (RT) for vulvar squamous cell carcinoma (VSCC) is associated with significant toxicity that can negatively impact a patient's health-related quality of life (HRQoL). Given the rarity of this disease, data on the incidence of acute and late severe toxicity as well as the real-world late-symptom burden from a modern cohort are lacking.Patients with VSCC treated with adjuvant or definitive radiotherapy with curative intent from 2009-2020 within our multi-center academic medical system were retrospectively analyzed. Treatment-related acute and late (≥3 months after RT) grade 3 or greater toxicities assessed by CTCAE version 5.0 were recorded. All provider-reported subjective symptoms (PRSS) documented from the date of RT completion to the date of last follow up were recorded. Kaplan-Meier model was used to estimate one-year overall survival (OS) and progression-free survival (PFS).Thirty-nine patients received either definitive (n = 22, 56.4%) or adjuvant (n = 17, 43.6%) RT to a median dose of 64.4 Gy and 59.4 Gy, respectively. Five patients (3 definitive, 2 adjuvant) received a brachytherapy boost with a median total EQD2 of 84.3 Gy. Intensity-modulated or volumetric-modulated arc RT was used in 34 (87.2%) of patients, and 22 patients (56.4%) received concurrent chemotherapy. Median follow up time was 12.5 months (Q1-Q3: 2.8-31.3 months) for all patients and 14.9 months (3.8-33.2) for alive patients. Seventy-four percent of patients (FIGO Stage I; n = 10, II; n = 5, III; n = 10, IVA; n = 4) had a complete response based on clinical (n = 26) or pathologic (n = 3) criteria, including 16 treated with adjuvant RT and 13 treated with definitive RT. The 1-year estimated OS and PFS were 90.4% and 90.5%, respectively. The incidence of acute grade ≥3 toxicity was 35.9% (n = 14). Acute grade ≥3 skin toxicity was most common (n = 10, 25.6%), followed by urinary (n = 1, 2.6%), gastrointestinal (n = 1, 2.6%), hematologic (n = 1, 2.6%), and fatigue (n = 1, 2.6%). Five (12.8%) patients experienced late grade ≥3 toxicity, including 2 patients (5.1%) with grade 3 dermatologic toxicity, 2 patients (5.1%) with grade 4 skin toxicity, and 1 patient (2.6%) with grade 3 gastrointestinal toxicity. Among the 32 patients with PRSS data available, 6 (15.3%) reported dyspareunia or inability to have sexual intercourse, 5 (12.8%) noted skin discoloration or fibrosis, 11 (28.2%) reported long-term vaginal pain or irritation, and 8 (20.5%) required long-term opiate pain medication.RT for VSCC is associated with considerable rates of severe acute and late toxicity as well as PRSS that affect both a patient's physical functioning and HRQoL. Taken together with the high rates of disease control and survival, these data argue for improved patient-reported outcome measures and investigation of therapeutic de-escalation strategies.N.S. McCall: Honoraria; PrecisCA.T.Y. Eng: Stock; Amgen. J.W. Shelton: None. S. Hanasoge: None. P.R. Patel: None. A.B. Patel: Honoraria; American College of Radiology. A. McCook: None. J. Switchenko: None. T. Cole: None. N. Khanna: None. C. Han: None. A.N. Gordon: None. K. Starbuck: None. J.S. Remick: None.

Positron Emission Tomography-Guided Bone Marrow-Sparing Radiation Therapy for Locoregionally Advanced Cervix Cancer: Final Results From the INTERTECC Phase II/III Trial

PurposeTo test effects of positron emission tomography (PET)–based bone marrow–sparing (BMS) image-guided intensity modulated radiation therapy (IG-IMRT) on efficacy and toxicity for patients with locoregionally advanced cervical cancer. Methods and MaterialsIn an international phase II/III trial, patients with stage IB-IVA cervical carcinoma were treated with either PET-based BMS-IG-IMRT (PET-BMS-IMRT group) or standard image-guided IMRT (IMRT group), with concurrent cisplatin (40 mg/m2 weekly), followed by brachytherapy. The phase II component nonrandomly assigned patients to PET-BMS-IMRT or standard IMRT. The phase III trial randomized patients to PET-BMS-IMRT versus IMRT, with a primary endpoint of progression-free survival (PFS) but was closed early for futility. Phase III patients were analyzed separately and in combination with phase II patients, comparing acute hematologic toxicity, cisplatin delivery, PFS, overall survival (OS), and patterns of failure. In a post-hoc exploratory analysis, we investigated the association between pretreatment absolute lymphocyte count (ALC) and OS. ResultsIn total, 101 patients were enrolled on the phase II/III trial, including 29 enrolled in phase III (PET-BMS-IMRT group: 16; IMRT group: 13) before early closure. Median follow-up was 33 months for phase III patients and 39 months for all patients. PFS and OS at 5 years for all patients were 73.6% (95% confidence interval [CI], 64.9%-84.3%) and 84% (95% CI, 76%-92.9%]), respectively. There were no differences in number of cisplatin cycles, OS, PFS, or patterns of failure between groups for the combined cohort. The incidence of acute grade ≥ 3 neutropenia was significantly lower in the PET-BMS-IMRT group compared with IMRT for randomized patients (19% vs 54%, χ2P = .048) and in the combined cohort (13% vs 35%, χ2P = .01). Patients with pretreatment ALC ≤ 1.5 k/µL had nonsignificantly worse OS on multivariable analysis (HR 2.85; 95% CI, 0.94-8.62; adjusted P = .216), compared with patients with ALC > 1.5 k/µL. There was no difference in posttreatment ALC by treatment group. ConclusionsPET-BMS-IMRT significantly reduced acute grade ≥3 neutropenia, but not treatment-related lymphopenia, compared with standard IMRT. We found no evidence that PET-BMS-IMRT affected chemotherapy delivery or long-term outcomes, and weak evidence of an association between pretreatment ALC and OS.

Impact of Omitting Post-Transplant Mini-Methotrexate Doses in Allogeneic Hematopoietic Cell Transplantation: A Single-Center Retrospective Study

Background: Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Despite its efficacy in combination with calcineurin inhibitors, methotrexate (MTX) may increase the risk of complications such as mucositis and delayed hematopoiesis and can contribute to hepatic and renal toxicities. As a result, doses are often omitted in the setting of treatment-related toxicities. Herein we report outcomes in the setting of omitting doses of mini-MTX (5 mg/m2 IV days 1, 3, 6, and 11) and describe management when these doses are omitted.Methods: This retrospective study identified patients aged 18 years or older who underwent HCT between 1/2008 and 12/2015 with planned GVHD prophylaxis of mini-MTX for four doses with a calcineurin inhibitor (cyclosporine or tacrolimus). Outcomes were compared between patients who had 1-3 doses omitted (group 1) and those who received all four planned doses of mini-MTX (group 2). Differences in baseline characteristics were determined using Chi-square, Fisher's exact, or Wilcoxon Rank-Sum tests as appropriate. Overall and relapse free survival (OS, RFS, respectively) were estimated using the Kaplan-Meier method with differences assessed with a log-rank test. The cumulative incidence method for competing risks was used in estimating non-relapse mortality (NRM), GVHD, as well as GVHD-related mortality, with differences assessed with Gray's test. Relapse was considered a competing risk for NRM while relapse or death were considered competing risks for GVHD. Non-GVHD related death was considered a competing risk for GVHD related mortality. For all analyses related to the number of MTX doses received, a landmark analysis was conducted at day 11 (scheduled date of 4th dose).Results: Of the 188 consecutive patients that were identified, 29 had 1-3 doses of MTX omitted. Baseline characteristics are summarized in Table 1. Notably, no patient in group 1 had ATG (0% vs 10.7%, p = 0.079). Omission of MTX was most commonly due to mucositis (14/29 patients), followed by hyperbilirubinemia, pleural effusions, acute kidney injury, and anasarca/ascites. When any mini-MTX was omitted, the most common strategies were to initiate mycophenolate mofetil (MMF) at 1g IV Q8H (17/29 patients) or corticosteroids (8/29 patients; both MMF and steroids were used in 4 patients). Overall, there was a non-significant increase in the incidence of acute grade 2-4 GVHD when comparing groups 1 and 2 (100-day incidence: 60.7% vs 50.9% respectively, p = 0.501) as well as more severe, grade 3-4 acute GVHD (100-day incidence 28.6% vs. 17%, p = 0.163). Similarly, there was an absolute, non-significant increase in the cumulative incidence of GVHD-related mortality (Table 2). Overall survival and NRM were negatively impacted when MTX was omitted (OS at 12 months: 55.2% vs 73%, respectively, p = 0.015; NRM at 12 months 32.1% vs. 10.1%, respectively, p = 0.003). The most common cause of NRM in both groups was GVHD (group 1: 6/11 patients vs. group 2: 20/29 patients), but organ toxicity was the second leading cause in group 1 (3/11 patients) compared to zero patients in group 2. Other results are summarized in Table 2.Conclusion: While limited by a small number of patients in group 1, it appears our management strategy of introducing an alternative agent (e.g. MMF ± corticosteroids) may ameliorate some of the increased risk of acute GVHD. The patients in group 1 did have worse OS and NRM compared to group 2. The presence of toxicities that caused the omission of MTX may have contributed to these findings. These results appear consistent with recent reports on outcomes, when the planned course of full-dose MTX as GVHD prophylaxis was not administered (Hamilton BK et al., Blood Cancer J 2015). The impact of omitting MTX doses on chronic GVHD incidence in this population will be reported in the future. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Magnetic resonance imaging-guided stereotactic body radiotherapy for prostate cancer (mirage): a phase iii randomized trial

BackgroundStereotactic body radiotherapy (SBRT) is becoming increasingly used in treating localized prostate cancer (PCa), with evidence showing similar toxicity and efficacy profiles when compared with longer courses of definitive radiation. Magnetic resonance imaging (MRI)-guided radiotherapy has multiple potential advantages over standard computed tomography (CT)-guided radiotherapy, including enhanced prostate visualization (abrogating the need for fiducials and MRI fusion), enhanced identification of the urethra, the ability to track the prostate in real-time, and the capacity to perform online adaptive planning. However, it is unknown whether these potential advantages translate into improved outcomes. This phase III randomized superiority trial is designed to prospectively evaluate whether toxicity is lower after MRI-guided versus CT-guided SBRT.MethodsThree hundred men with localized PCa will be randomized in a 1:1 ratio to SBRT using CT or MRI guidance. Randomization will be stratified by baseline International Prostate Symptom Score (IPSS) (≤15 or > 15) and prostate gland volume (≤50 cc or > 50 cc). Five fractions of 8 Gy will be delivered to the prostate over the course of fourteen days, with or without hormonal therapy and elective nodal radiotherapy (to a dose of 5 Gy per fraction) as per the investigator’s discretion. The primary endpoint is the incidence of physician-reported acute grade ≥ 2 genitourinary (GU) toxicity (during the first 90 days after SBRT), as assessed by the CTCAE version 4.03 scale. Secondary clinical endpoints include incidence of acute grade ≥ 2 gastrointestinal (GI) toxicity, 5-year cumulative incidences of physician-reported late grade ≥ 2 GU and GI toxicity, temporal changes in patient-reported quality of life (QOL) outcomes, 5-year biochemical recurrence-free survival and the proportion of fractions of MRI-guided SBRT in which online adaptive radiotherapy is used.DiscussionThe MIRAGE trial is the first randomized trial comparing MRI-guided with standard CT-guided SBRT for localized PCa. The primary hypothesis is that MRI-guided SBRT will lead to an improvement in the cumulative incidence of acute grade ≥ 2 GU toxicity when compared to CT-guided SBRT. The pragmatic superiority design focused on an acute toxicity endpoint will allow an early comparison of the two technologies.Trial registrationClinicaltrials.gov identifier: NCT04384770. Date of registration: May 12, 2020.https://clinicaltrials.gov/ct2/show/NCT04384770Protocol versionVersion 2.1, Aug 28, 2020.

Para-Aortic Nodal Radiation in the Definitive Management of Node-Positive Cervical Cancer.

ObjectivesTo investigate the safety and outcomes of elective para-aortic (PA) nodal irradiation utilizing modern treatment techniques for patients with node positive cervical cancer.MethodsPatients with pelvic lymph node positive cervical cancer who received radiation were included. All patients received radiation therapy (RT) to either a traditional pelvic field or an extended field to electively cover the PA nodes. Factors associated with survival were identified using a Cox proportional hazards model, and toxicities between groups were compared with a chi-square test.Results96 patients were identified with a mean follow up of 40 months. The incidence of acute grade ≥ 2 toxicity was 31% in the elective PA nodal RT group and 15% in the pelvic field group (Chi-square p = 0.067. There was no significant difference in rates of grade ≥ 3 acute or late toxicities between the two groups (p>0.05). The KM estimated 5-year OS was not statistically different for those receiving elective PA nodal irradiation compared to a pelvic only field, 54% vs. 73% respectively (log-rank p = 0.11).ConclusionsElective PA nodal RT can safely be delivered utilizing modern planning techniques without a significant increase in severe (grade ≥ 3) acute or late toxicities, at the cost of a possible small increase in non-severe (grade 2) acute toxicities. In this series there was no survival benefit observed with the receipt of elective PA nodal RT, however, this benefit may have been obscured by the higher risk features of this population. While prospective randomized trials utilizing a risk adapted approach to elective PA nodal coverage are the only way to fully evaluate the benefit of elective PA nodal coverage, these trials are unlikely to be performed and instead we must rely on interpretation of results of risk adapted approaches like those used in ongoing clinical trials and retrospective data.

Salvage radiotherapy for postoperative locoregional failure in esophageal cancer: a systematic review and meta-analysis.

Locoregional recurrences following surgery for esophageal cancers represent a significant clinical problem with no standard recommendations for management. We conducted this systematic review and meta-analysis with the objective of studying safety and efficacy of salvage radiotherapy in this setting. All prospective and retrospective cohort studies, which studied patients who developed locoregional recurrence following initial radical surgery for esophageal cancer and subsequently received salvage radiation therapy (RT)/chemoradiation with all relevant information regarding survival outcome and toxicity available, were included. The quality of eligible individual studies was assessed using the Newcastle-Ottawa Scale score for risk of bias. R package MetaSurv was used to obtain a summary survival curve from survival probabilities and numbers of at-risk patients collected at various time points and to test the overall heterogeneity using the I2 statistic. Thirty studies (27 retrospective, 3 prospective) published from 1995 to 2020 with 1553 patients were included. The median interval between surgery and disease recurrence was 12.5months. The median radiation dose used was 60Gy and 57% received concurrent chemotherapy. The overall incidence of acute grade 3/4 mucositis and dermatitis were 8 and 4%, respectively; grade 3/4 acute pneumonitis was reported in 5%. The overall median follow-up of all studies included was 27months. The 1-, 2- and 3-year overall survival (OS) probabilities were 67.9, 35.9 and 30.6%, respectively. Factors which predicted better survival on multivariate analysis were good PS, lower group stage, node negativity at index surgery, longer disease-free interval, nodal recurrence (as compared to anastomotic site recurrence), smaller disease volume, single site of recurrence, RT dose >50Gy, conformal RT, use of concomitant chemotherapy and good radiological response after radiotherapy. Salvage radiotherapy with or without concomitant chemotherapy for locoregional recurrences after surgery for esophageal cancer is safe and effective. Modern radiotherapy techniques may improve outcomes and reduce treatment-related morbidity.

High-dose-rate brachytherapy with external beam radiotherapy versus low-dose-rate brachytherapy with or without external beam radiotherapy for clinically localized prostate cancer

To compare the outcomes of localized prostate cancer treatment with high-dose-rate brachytherapy (HDR-BT) and low-dose-rate brachytherapy (LDR-BT), we examined 924 patients treated with HDR-BT + external beam radiotherapy (EBRT) and 500 patients treated with LDR-BT ± EBRT using multi-institutional retrospective data. The HDR-BT treated advanced disease with more hormonal therapy than LDR-BT. To reduce background selection bias, we performed inverse probability of treatment weighting (IPTW) analysis using propensity scores and excluded patients with T3b-4 disease/ initial prostate-specific antigen (PSA) levels > 50 ng/ml. The actuarial 5-year biochemical control rates (5y-bNED) were 96.3% and 95.7% in the HDR-BT and LDR-BT groups, respectively. The corresponding values were 100% and 96.5% in the low-risk group; 97.4% and 97.1% in the intermediate-risk group (97.2% and 97% in the higher titer group and 97.5% and 94.6% in the lower titer group, respectively); and 95.7% and 94.9% in the selected high-risk group, respectively. IPTW correction indicated no significant difference among the groups. The 5y-bNED in the HDR-BT + EBRT, LDR-BT + EBRT, and LDR-BT alone groups were 96.3%, 95.5%, and 97%, respectively (P = 0.3011). The corresponding values were 97.4%, 94.7%, and 96.6% (P = 0.1004) in the intermediate-risk group (97.5%, 100%, and 94.5% in the lower titer group [P = 0.122] and 97.2%, 96.2%, and 100% [P = 0.664] in the higher titer group, respectively) and 95.7%, 95.5%, and 100% (P = 0.859) in the high-risk group, respectively. The HDR-BT group showed a lower incidence of acute grade ≥ 2 genitourinary toxicities; the incidence of other early and late grade ≥ 2 toxicities were similar between the HDR-BT and LDR-BT groups. Acute genitourinary toxicity predicted the occurrence of late genitourinary toxicity. EBRT increased the risk of grade ≥ 2 gastrointestinal toxicity. HDR-BT + EBRT is a good alternative to LDR-BT ± EBRT for low-, intermediate-, and selected high-risk patients.

Efficacy and Safety of Large-field Postoperative Radiotherapy Using Three-dimensional Radiation Technique for Local Advanced Thoracic Esophageal Squamous Cell Carcinoma: A Phase II Clinical Trial

This trial aimed to explore the feasibility and safety of large-field postoperative radiotherapy for locally advanced (T3-4 or N+, M0) esophageal cancer using three-dimensional radiation technique. This trial is a single-center single-arm, phase II clinical trial initiated in 2014. Patients who underwent a radical transthoracic resection with negative margins within 3 months and histologically confirmed as esophageal squamous cell carcinoma (pT3-4 or N+, M0 according to AJCC 7th) were eligible for this study. Radiotherapy was delivered with total dose of 40Gy in 20 fractions using three-dimensional conformal radiation technique including conformal and intensity modulated radiotherapy. TV included tumor bed, anastomosis site, bilateral supraclavicular region, all mediastinal lymph node site, left gastric and celiac trunk lymph node site. The primary endpoint was 2-year local control rate. The secondary endpoint was overall survival (OS) and adverse events. 70 patients were enrolled in this phase II study from 2014 to 2016. The majority of patients were Ilia (40%), IIIA (27.1%) and IIIB (27.1%). 17 patients died. The 2 year-local control rate is 67.29%. Median OS was 57months. The 1, 2, 3 and 4-year OS rate were 92.75%, 69.57%, 60.87%, 53.47%. Locoregional recurrence was found in 28 patients (40%), most of which in mediastinal lymph node region (16 patients) and supraclavicular lymph node region (10 patients), followed by anastomosis (5 patients), celiac lymph node region (3 patients). 18 patients (25.7%) was found hematogenous recurrence. Nearly all patients complete the whole course postoperative radiotherapy with the completion rate of 97.1%, except for two patients. Although the tumor volume is relatively high with the median PTV volume of 1273.22cm3, despite the average dose of the heart is slightly higher, the dose volume histogram parameters of the other normal tissue and organ dose-volume are relatively ideal. Incidences of acute grade 3 hematological toxicity including 4(5.7%) leukopenia and 1(1.4%) neutropenia. In term of acute grade 3 nonhematological toxicity, nausea and vomiting (7.1%) were the most frequent AE followed by fatigue (2.8%) and radiation induced pneumonitis (1.4%). Nobody suffered grade 4 hematological or nonhematological AE. A No late AE occurred. This study is the first phase II study of postoperative radiotherapy in three-dimensional era, which proves that the dose distribution of large-field radiation is feasible and the toxicity is acceptable. It provides a basis for further exploration of higher dose large-field radiation and combined chemotherapy.