Freedom From Distant Metastasis Research Articles

High-Dose Rate Brachytherapy Alone for Treatment of Unfavorable Intermediate Risk Prostate Cancer: A Propensity-Score Matched Analysis.

To demonstrate the feasibility of high-dose rate brachytherapy (HDR BT) as monotherapy for unfavorable intermediate risk (UIR) prostate cancer by comparing survival outcomes of HDR BT alone against external beam radiation therapy (EBRT) + HDR BT boost, +/- androgen deprivation therapy (ADT) using propensity-score matched (PSM) data. This retrospective study queried two data registries collecting patient data from 1991 to present. 633 patients with UIR prostate cancer treated with HDR BT alone, HDR BT+EBRT or HDR+EBRT+ADT were included. HDR BT patients received 42-45Gy/6 fractions (fx) or 27 Gy/2 fx. For HDR BT+EBRT, the HDR dose was 20-24 Gy/2 fx, 24 Gy/4 fx, or 15 Gy/1 fx. EBRT patients received 45 Gy/25 fx to the prostate +/- pelvic nodes. GU/GI toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Time-to-event analyses were carried out to evaluate the relationship between treatments and five primary endpoints of interest: freedom from biochemical recurrence (FFBC), freedom from distant metastasis (FFDM), freedom from local failure (FFLF), cancer specific survival (CSS), and overall survival (OS) at 5 years. PSM was performed with one-to-n matching. Logistic regression was used to estimate the respective propensity scores. The five potential confounders identified were T-stage, Gleason score, pre-treatment PSA, age, and percent positive cores. Balance was checked using the standardized mean difference of covariates. Univariate and multivariate analyses were conducted on the matched data. Toxicity analysis was performed via association between a change in pre- and post-treatment GU/GI toxicity status and the treatment group, as well as incidence of post-treatment severe GI/GU toxicity (grade 3 or higher) and the treatment group. Univariate analysis with Kaplan-Meier method and log rank test comparison between the three cohorts demonstrated no significant difference in all survival outcomes FFBC, FFDM, FFLF, CSS, OS (p = 0.15, 0.19, 0.29, 0.57, 0.28, respectively). Multivariate analysis with Cox proportional hazard regression showed no differences in HR for FFBC and OS (p = 0.95, 0.11) with addition of EBRT, or with EBRT+ADT (p = 0.17, 0.24); no fit was obtainable for FFDM, CSS, FFLF. Toxicities between the three cohorts were not significantly different when comparing post-treatment and baseline GI/GU symptoms (p = 0.53/1). No Grade 2 or 3 GI toxicities were identified, while 8%/1% HDR patients, 10%/1% HDR+EBRT patients, and 12%/2% HDR+EBRT+ADT patients experienced Grade 2/3 GU toxicities. The incidence of grade 3 or higher GU toxicities between the three groups was not significantly different (p = 0.91). This propensity-score matched study demonstrates the feasibility of HDR BT alone for effective treatment of UIR prostate cancer when compared to HDR+EBRT or HDR+EBRT+ADT, while potentially minimizing the added toxicities of EBRT and the undesirable side effect profile of ADT.

Three Decade Single-Institution Experience of Safety and Efficacy of Radiotherapy and Adjuvant Chemotherapy for Young Adult Patients with Medulloblastoma

The rarity of medulloblastoma in the adult population limits information on optimal treatment and clinical outcomes. Adjuvant chemoradiation has been correlated to improved overall survival (OS) in a recent National Cancer Database (NCDB) analysis. We performed a retrospective safety and efficacy analysis of radiation (RT) +/- adjuvant chemotherapy (aCTH) in young adult patients with medulloblastoma to better understand outcomes, prognostic factors, and possibly optimal treatment strategies. We conducted an IRB-approved retrospective chart review on young adult (age ≥18 - 39 years old) patients with medulloblastoma treated at our institution (1992-2018) with a minimum follow-up of 6 months from completion of therapy. We gathered data on patient and disease characteristics, treatment, and clinical outcomes, including OS, progression-free survival (PFS), local control (LC), and freedom from distant metastasis (FDM). We employed Cox regression model for univariable and multivariable analyses and Kaplan-Meier (KM) test methods for survival analyses, using JMP version 15.0 software. Thirty-one patients were treated with postoperative RT including craniospinal irradiation (median dose: 2340 cGy/13 fractions) followed by tumor bed/posterior fossa (median total dose: 5580 cGy/31 fractions) either alone (n = 9; 29%) or with adjuvant chemotherapy (aCTH: n = 22; 71%); mostly as per COG A9961 Regimen A: oral lomustine, intravenous cisplatin, and intravenous vincristine (n = 12). 54.6% (n = 12) were known to complete the full aCTH course. Common RT acute toxicities included G1-2 nausea and/or vomiting (N/V; n = 8) and G1-2 fatigue (n = 6). Common aCTH acute toxicities included G1-2 N/V (n = 7) and peripheral neuropathy: G1-2 (n = 6) and G3 (n = 3). Late adverse events were primarily G1-2 peripheral neuropathy and gait imbalance (22.6%), G1-2 hormonal disturbances (19.4%) and G1-2 neurocognitive impairment (16.1%). Male patients had worse OS, PFS, FDM, and LC. Age at diagnosis, tumor location (lateral vs. central), and completion of aCTH course were shown on uni- and multi-variable analysis to be significantly associated with OS; p<0.05. KM survival analysis revealed superior 10-year PFS and OS in patients who completed aCTH compared to those who received RT alone or did not complete aCTH: 72.9% vs 59.3% vs 42%, p = 0.461, and 74.1% vs 63.5% vs 40%, p = 0.033, respectively. A similar trend was noted for LC and FDM. Our series provides a report of acute and late side effects of treatment of young adult patients with medulloblastoma. Significant OS and PFS advantage are seen of aCTH completion in this patient population. Since optimal treatment of these patients is still an unmet need, prospective studies for this rare disease entity are needed.

Outcomes Following Proton Therapy for Non-Metastatic Central Nervous System Germinoma in Children and Adolescents

Radiation is a key component in the treatment of central nervous system pure germinoma (PG) in children and adolescents. Compared to photons, proton therapy (PT) improves normal tissue sparing and potentially reduces adverse effects, but there are sparse data on long-term patient outcomes. Herein, we present the largest reported single institution experience utilizing PT for the management of PG. We performed an IRB-approved retrospective review of a prospective database containing 35 patients with non-metastatic PG treated with PT between July 2007 and September 2021. The median age at treatment was 13 years. All patients had > 6 months of follow up. Two patients were diagnosed based on cerebral spinal fluid B-HCG levels and the remaining 33 patients through histopathology. Eleven patients had bifocal or multifocal intracranial disease. Most patients (n = 31, 88.6%) received induction chemotherapy with carboplatin + etoposide (n = 25, 80.6%) with all demonstrating a radiographic response to neoadjuvant therapy. Twenty-nine were treated with whole ventricular irradiation (WVI) with an involved field (IF) boost, 2 with craniospinal irradiation + WVI + IF, 2 with IF, 1 with CSI + IF, and 1 with whole brain + IF. Among this subgroup, the most common total dose was 30 GyRBE (n = 18, 51.4%). Of the 4 patients that did not receive chemotherapy, 3 received WVI + IF and 1 was treated with CSI + WVI + IF. The total dose in the patients not receiving chemotherapy was 45 GyRBE. Twenty-nine patients were treated with double scattered PT (DS) and 6 patients with pencil beam scanning PT (PBS). We utilized the cumulative incidence method to estimate local control (LC), freedom from distant metastases (FFDM), freedom from progression (FFP), and overall survival (OS). Treatment related toxicity was assessed according to the CTCAEv5. Median follow up was 6.2 years (Range: 0.9-15.2 years). The 10-year KM estimates for LC, FFDM, FFP, and OS were 100%, 100%, 100%, and 97% respectively. One patient developed acute lymphocytic leukemia 8 months after treatment and died. The sole ³ grade 3 radiation-related toxicity was a cavernoma with hemorrhage 3.6 years post treatment requiring surgical resection. The most common adverse events were hearing impairment requiring hearing aids (n = 3), hypersomnia requiring medication (n = 3), and new onset endocrinopathy (n = 1). Of the 22 evaluable patients ³18 years old at last follow up, 7 were high school graduates/in college, 8 college graduates, and 5 others gainfully employed. The use of proton therapy in the multi-modality approach to non-metastatic PG does not compromise local control. Although serious side effects are rare and treatment has minimal impact on survivors' early educational/career trajectory, the 100% cure rate supports further investigation into selective radiation dose and volume de-escalation.

Long-Term Outcomes of De-Intensified Chemoradiotherapy for Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma

To report long-term oncologic outcomes among patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) treated with definitive de-intensified chemoradiotherapy. Major criteria for de-intensification were (1) AJCC 7th edition T0-T3, N0-N2c, M0 (AJCC 8th edition T0-T3, N0-N2, M0), (2) pathologically confirmed p16 positive, and (3) no or minimal/remote smoking history (non-mutated p53 if ≥30 pack-years). Treatment was 60 Gy intensity-modulated radiotherapy with first-choice concurrent cisplatin 30 mg/m2 once per week (alternative regimens permissible for cisplatin ineligible patients). Patients with T0-T2 N0-1 (AJCC 7th edition) were recommended 60 Gy radiation alone. Systemic therapy received included: cisplatin 30 mg/m2 (n = 122), cetuximab (n = 15), cisplatin 40 mg/m2 (n = 12), carboplatin/paclitaxel (n = 2), and radiation alone (n = 25). Kaplan Meier estimates for overall survival (OS), progression-free survival (PFS), locoregional control (LRC), and freedom from distant metastasis (FFDM) were calculated. Cox regression models were used for comparisons among subgroups. A total 176 patients received de-intensified treatment (n = 153 prospective protocol, n = 23 off-protocol). Median follow-up was 52.6 months (range 5.3 - 102.0, 90.8% with minimum 2-year follow-up); 56.8% (n = 100) were never smokers and 43.2% (n = 76) former smokers; former smokers had median 9 pack-years smoking history (range 0.25 - 50) with 46% ≥10 pack-years. Outcomes were as follows: 2-year OS 99.4% and 5-year OS 91.8%; 2-year PFS 94.1% and 5-year PFS 84.3%; 2-year LRC 98.3% and 5-year LRC 95.8%; 2-year FFDM 95.8% and 5-year FFDM 93.2%. Median time to progression events were 21.1 months (range, 7.2 - 54.1) with 37.5% (6 of 16) of recurrences occurring after 24 months. Six total locoregional events occurred (five recurrences and one site of persistent disease), within the 60 Gy planning target volume. Twenty-three patients with T0-T2 N0-1 disease received radiation alone with 2-year PFS 92.9% (5-year 83.8%) and 2-year LRC 100% (5-year 95.2%). Outcomes for former smokers with ≥10 pack-years were comparable to patients with less or no smoking history (2-year PFS 94.1% vs 94.1%; 5-year PFS 90.6% vs 82.7%; HR 0.58, p = 0.38). Early results suggest similar oncologic outcomes among those treated off-protocol (median follow-up 25.6 months) with 1 of 23 patients experiencing locoregional recurrence. Dose de-intensification of 60 Gy radiotherapy with weekly cisplatin results in favorable long-term tumor control in patients with HPV-associated OPSCC. De-intensified 60 Gy alone may be efficacious in carefully selected patients with T0-T2 N0-1 (AJCC 7th edition) disease. Inclusion of biologically favorable patients with more extensive former smoking history in de-intensification clinical trials may be warranted.

Asphericity derived from [18F]FDG PET as a new prognostic parameter in cervical cancer patients

The objective of this study was to assess the prognostic value of asphericity (ASP) and standardized uptake ratio (SUR) in cervical cancer patients. Retrospective analysis was performed on a group of 508 (aged 55 ± 12 years) previously untreated cervical cancer patients. All patients underwent a pretreatment [18F]FDG PET/CT study to assess the severity of the disease. The metabolic tumor volume (MTV) of the cervical cancer was delineated with an adaptive threshold method. For the resulting ROIs the maximum standardized uptake value (SUVmax) was measured. In addition, ASP and SUR were determined as previously described. Univariate Cox regression and Kaplan–Meier analysis with respect to event free survival (EFS), overall survival (OS), freedom from distant metastasis (FFDM) and locoregional control (LRC) was performed. Additionally, a multivariate Cox regression including clinically relevant parameters was performed. In the survival analysis, MTV and ASP were shown to be prognostic factors for all investigated endpoints. Tumor metabolism quantified with the SUVmax was not prognostic for any of the endpoints (p > 0.2). The SUR did not reach statistical significance either (p = 0.1, 0.25, 0.066, 0.053, respectively). In the multivariate analysis, the ASP remained a significant factor for EFS and LRC, while MTV was a significant factor for FFDM, indicating their independent prognostic value for the respective endpoints. The alternative parameter ASP has the potential to improve the prognostic value of [18F]FDG PET/CT for event-free survival and locoregional control in radically treated cervical cancer patients.

Brachytherapy boost improves survival and decreases risk of developing distant metastases compared to external beam radiotherapy alone in intermediate and high risk group prostate cancer patients

Background and purposeDespite several prospective trials showing a clinical benefit of combining external beam radiotherapy (EBRT) with brachytherapy boost (BTB) for the treatment of intermediate- and high-risk prostate cancer (PCa) patients, none of these trials was designed to test for a survival difference. In this study, we aimed to collect a large multi-institutional database to determine whether BT boost was associated with a statistically significant improvement in survival and a reduction of distant metastases based on real-world data. Material and methodsWe collected the data of patients treated for intermediate- or high-risk PCa with definitive EBRT or BTB, with or without androgen deprivation therapy (ADT), between January 2003 and December 2014 at two tertiary institutions. The statistical endpoints included overall survival (OS), freedom from distant metastases (FFDM), and metastases-free survival (MFS). The impact of treatment modality was assessed using Cox regression models and log-rank testing after one-to-one propensity score matching. ResultsA total of 1641 patients treated with EBRT (n = 1148) or high-dose-rate BTB (n = 493) were analyzed. The median survival and clinical follow-up were 117.8 (IQR 78–143.3) and 60.7 months, respectively. The radiotherapy modality (BTB) remained an independent prognostic factor for OS (HR 0.75; 95% CI 0.63–0.88; p < 0.001), FFDM (HR 0.54; 95% CI 0.4–0.73; p < 0.001), and MFS (HR 0.72; 95% CI 0.61–0.85; p < 0.001). After propensity score matching, the remaining 986 patients were well-balanced in terms of age, maximum PSA, ISUP grade group, and TNM T stage. OS (p < 0.001), FFDM (p = 0.001) and MFS (p < 0.001) were significantly higher in the BTB group. ConclusionsThere is a strong positive association between BTB and OS, FFDM, and MFS in PCa patients treated with definitive RT for intermediate- or high-risk PCa.

Long-Term Outcomes of Stereotactic Body Radiotherapy (SBRT) for Intraprostatic Relapse after Definitive Radiotherapy for Prostate Cancer: Patterns of Failure and Association between Volume of Irradiation and Late Toxicity.

The aim of this retrospective study was to assess the adverse effects and outcomes of salvage re-irradiation with stereotactic body radiotherapy (sSBRT) for local recurrence of prostate cancer (PCa) after definitive radiotherapy (RT). The study was focused on the adverse effects and prognostic factors for treatment toxicity, followed by an analysis of patterns of failure and survival. Patients treated with sSBRT between 2012 and 2020 at a tertiary institution were included. The exclusion criteria were a primary or salvage radical prostatectomy or a palliative sSBRT dose. Patients with oligorecurrence were eligible if all metastatic lesions were treated locally with curative intent. The Kaplan-Meier method was used to estimate time to grade ≥ 3 toxicity, local control (LC), freedom from distant metastases (FFDM), progression-free survival (PFS), biochemical control (BC) and overall survival (OS). The differences between groups (focal vs. whole-gland sSBRT) were compared using the log-rank test. The Cox proportional hazards model was used to assess prognostic factors for the listed endpoints. A total of 56 patients with a median age of 70.9 years and a median follow-up of 38.6 months were included in the analysis. The majority of them received local sSBRT only (45; 80.4%), while the rest were simultaneously treated for oligometastases (11; 19.6%). Overall, 18 (32.1%) patients experienced any grade ≥ 3 toxicity, including 1 (6.7%) patient who received focal sSBRT, and 17 (41.5%) patients treated with whole-gland sSBRT. The Planning Target Volume (per cc; HR 1.01; 95% CI 1-1.02; p = 0.025) and use of ADT (yes vs. no; HR 0.35; 95%CI 0.13-0.93; p = 0.035) were independent prognostic factors for the risk of grade ≥ 3 toxicity. The estimated rate of grade ≥ 3 adverse events was significantly higher (43.8% vs. 7.1% at 2 years; p = 0.006), and there was no improvement in the LC (92.9% vs. 85.3% at 2 years; p = 0.759) in patients treated with whole-gland sSBRT compared to focal sSBRT. The 2- and 5-year LC were 87.6% and 47.9%, respectively; the 2- and 5-year FFDM were 72.7% and 42.8%, respectively; and the 2- and 5-year PFS were 67.9% and 28.7%, respectively. The primary pattern of failure was distant metastasis. The sSBRT for local recurrence of PCa after definitive RT was associated with a high risk of severe grade ≥ 3 toxicity, which significantly increased with the volume and extent of re-irradiation.

Non-Operative Management is Feasible and Safe in Patients with Rectal Cancer Who Achieve Clinical Complete Response to Short-Course Radiation Therapy and Consolidation Chemotherapy

<h3>Purpose/Objective(s)</h3> The purpose of this study was to report on patients with localized rectal adenocarcinoma followed with non-operative management (NOM) with a watch-and-wait (W&W) strategy after achieving clinical complete response (cCR) to short-course radiation therapy (SCRT) and consolidation chemotherapy. <h3>Materials/Methods</h3> Patients with rectal adenocarcinoma who achieved cCR to SCRT and consolidation chemotherapy and were subsequently managed with NOM were included in this study. Endpoints included overall survival (OS), freedom from local failure (FFLF), freedom from distant metastasis (FFDM), and disease-free survival (DFS). cCR was defined by absence of residual tumor, nodularity, and ulceration on endoscopic evaluation. FFLF was defined as time from achieving cCR to development of intraluminal recurrence on endoscopic evaluation. DFS was defined as time from completion of SCRT to death, local-regional failure, or distant failure. Local failures that were successfully salvaged were not considered disease progression. Patients with sustained cCR were given surveys to assess general and bowel quality of life: 1. EORTC Quality of Life Questionnaire Core 30, 2. EORTC Quality of Life Questionnaire-Colorectal Cancer 29, and 3. Low anterior resection syndrome (LARS) score. <h3>Results</h3> A total of 87 patients were treated with SCRT and chemotherapy, of which 33 had cCR. Of the 33 with cCR, 26 patients were managed with NOM. Median age was 63 years (range, 44-79 years). Median follow-up was 20.4 months (range, 7.2-46.2 months). All patients were treated with SCRT to 25 Gy in 5 fractions. Chemotherapy regimens included mFOLFOX (n=20), CAPOX (n=3), mFOLFOX and CAPOX (n=1), mFOLFOX and FLOX (n=1), CAPOX and capecitabine (n=1), for a median of 4.5 months (range, 2.0-9.0 months). Median FFLF was not reached, with 6-month, 1-year, and 2-year FFLF rates of 85.7%, 68.0%, and 68.0%, respectively. Seven (26.9%) patients developed local failure at a median of 6.8 months (range, 3.4-30.2 months) after achieving cCR, of which 5 (71.4%) were successfully salvaged. Median OS was not reached with 6-month, 1-year, and 2-year OS rates of 100%. Median FFDM was not reached, with 6-month, 1-year, and 2-year FFDM rates of 100%, 94.7%, and 89.2%, respectively. Median DFS was not reached, with 6-month, 1-year, and 2-year DFS rates of 100%, 95.0%, and 89.4%, respectively. Survey response rate was 83.3%. Median LARS score was 27 (range, 0-37) and mean LARS score was 20.9. Major LARS, minor LARS, and no LARS occurred in 3 patients (20%), 6 patients (40%), and 6 patients (40%), respectively. There were no differences in EORTC and LARS survey scores between patients who had > 50% of their anal sphincter region included in the prescription-dose radiation volume and those who did not. <h3>Conclusion</h3> Non-operative management with W&W strategy may be an appropriate option for patients with rectal adenocarcinoma who achieve cCR to SCRT and consolidation chemotherapy. Furthermore, anorectal function appears to be adequate with this approach.

Anal squamous cell carcinoma: Impact of radiochemotherapy evolution over years and an explorative analysis of MRI prediction of tumor response in a mono-institutional series of 131 patients.

Radiochemotherapy (RCHT) for the treatment of anal squamous cell carcinoma (ASCC) has evolved dramatically, also thanks to intensity-modulated RT (IMRT) and 3D image guidance (3D IGRT). Despite most patients presenting fair outcomes, unmet needs still exist. Predictors of poor tumor response are lacking; acute toxicity remains challenging; and local relapse remains the main pattern of failure. Between 2010 and 2020, ASCC stages I-III treated with 3D conformal radiotherapy or IMRT and CDDP-5FU or Mytomicine-5FU CHT were identified. Image guidance accepted included 2D IGRT or 3D IGRT. The study endpoints included freedom from locoregional recurrence (FFLR), colostomy free survival (CFS), freedom from distant metastasis (FFDM), overall survival (OS), and acute and late toxicity as measured by common terminology criteria for adverse events (CTCAE) version 5.0. An exploratory analysis was performed to identify possible radiomic predictors of tumor response. Feature extraction and data analysis were performed in Python™, while other statistics were performed using SPSS® v.26.0 software (IBM®). A total of 131 patients were identified. After a median FU of 52 months, 83 patients (63.4%) were alive. A total of 35 patients (26.7%) experienced locoregional failure, while 31 patients (23.7%) relapsed with distant metastasis. Five year FFLR, CFS, DMFS and PS resulted 72.3%, 80.1%, 74.5% and 64.6%. In multivariate analysis, 2D IGRT was associated with poorer FFLR, OS, and CFS (HR 4.5, 4.1, and 5.6, respectively); 3DcRT was associated with poorer OS and CFS (HR 3.1 and 6.6, respectively). IMRT reduced severe acute gastro-intestinal (GI) and severe skin acute toxicity in comparison with 3DcRT. In the exploratory analysis, the risk of relapse depended on a combination of three parameters: Total Energy, Gray Level Size Zone Matrix's Large Area High Gray Level Emphasis (GLSZM's LAHGLE), and GTV volume. Advances in radiotherapy have independently improved the prognosis of ASCC patients over years while decreasing acute GI and skin toxicity. IMRT and daily 3D image guidance may be considered standard of care in the management of ASCC. A combination of three pre-treatment MRI parameters such as low signal intensity (SI), high GLSZM's LAHGLE, and GTV volume could be integrated in risk stratification to identify candidates for RT dose-escalation to be enrolled in clinical trials.

Cardiopulmonary Toxicity Following Intensity-Modulated Proton Therapy (IMPT) Versus Intensity-Modulated Radiation Therapy (IMRT) for Stage III Non-Small Cell Lung Cancer

IntroductionIntensity-modulated proton therapy (IMPT) has the potential to reduce radiation dose to normal organs when compared to intensity-modulated radiation therapy (IMRT). We hypothesized that IMPT is associated with a reduced rate of cardiopulmonary toxicities in patients with Stage III NSCLC when compared with IMRT. MethodsWe analyzed 163 consecutively treated patients with biopsy-proven, stage III NSCLC who received IMPT (n = 35, 21%) or IMRT (n = 128, 79%). Patient, tumor, and treatment characteristics were analyzed. Overall survival (OS), freedom-from distant metastasis (FFDM), freedom-from locoregional relapse (FFLR), and cardiopulmonary toxicities (CTCAE v5.0) were calculated using the Kaplan-Meier estimate. Univariate cox regressions were conducted for the final model. ResultsMedian follow-up of surviving patients was 25.5 (range, 4.6-58.1) months. Median RT dose was 60 (range, 45-72) Gy [RBE]. OS, FFDM, and FFLR were not different based on RT modality. IMPT provided significant dosimetric pulmonary and cardiac sparing when compared to IMRT. IMPT was associated with a reduced rate of grade more than or equal to 3 pneumonitis (HR 0.25, P = .04) and grade more than or equal to 3 cardiac events (HR 0.33, P = .08). Pre-treatment predicted diffusing capacity for carbon monoxide less than equal to 57% (HR 2.8, P = .04) and forced expiratory volume in the first second less than equal to 61% (HR 3.1, P = .03) were associated with an increased rate of grade more than or equal to 3 pneumonitis. ConclusionsIMPT is associated with a reduced risk of clinically significant pneumonitis and cardiac events when compared with IMRT without compromising tumor control in stage III NSCLC. IMPT may provide a safer treatment option, particularly for high-risk patients with poor pretreatment pulmonary function.

The role of neoadjuvant radiochemotherapy in the management of localized high-grade soft tissue sarcoma

BackgroundStandard treatment of soft tissue sarcoma (STS) of the extremities includes limb-sparing surgery combined with pre- or postoperative radiotherapy (RT). The role of perioperative chemotherapy (CTX) remains uncertain. STS patients with high-risk features for local recurrence, distant metastases, and increased mortality may require additional systemic therapy. The objective of this study was to evaluate predictors of outcome regarding local control (LC), overall survival (OS), and freedom from distant metastases (FFDM) in a large single-center cohort of patients suffering from localized high-grade STS (grade 2/3, G2/G3). Special emphasis was put on a subgroup of patients who received combined neoadjuvant radiochemotherapy (RCT).MethodsOverall, 115 adult STS patients were included in this retrospective study. The median follow-up was 34 months. Twenty-three patients (20.0%) were treated with neoadjuvant RCT, 92 (80.0%) received other therapies (adjuvant RT alone (n = 58); neoadjuvant CTX + adjuvant RT (n = 17); adjuvant RCT (n = 10), neoadjuvant RT alone (n = 7)). To assess potential prognostic factors on LC, OS, and FFDM, univariate (UVA) and multivariable (MVA) Cox proportional hazards models were applied.ResultsUVA showed significantly better LC rates in the neoadjuvant RCT group (p = 0.025), with trends in MVA (p = 0.057). The 3-year LC rate was 89.7% in the neoadjuvant RCT group vs. 75.6% in the "other therapies" group. UVA also showed significantly better OS rates in the neoadjuvant RCT group (p = 0.049), however, this was not confirmed in MVA (p = 0.205), the 3-year OS rate was 85.8% for patients treated with neoadjuvant RCT compared to 73.5% in the "other therapies" group. UVA showed significantly better FFDM rates in (p = 0.018) and a trend towards better FFDM rates in MVA (p = 0.059). The 3-year FFDM rate was 89.7% for patients treated with neoadjuvant RCT compared to 65.9% in the "other therapies" group. In the subgroup of patients with G3 STS, neoadjuvant RCT was a significant positive predictor of LC and FFDM in MVA (p = 0.047, p = 0.027) but not for OS. Overall grade 3 and 4 toxicities were significantly higher (p = 0.019) in the neoadjuvant RCT group and occurred in 73.9% vs. 38.0% in patients receiving other therapies.ConclusionsThe results suggest that neoadjuvant RCT might improve LC and FFDM in patients with localized G3 STS while also being associated with increased acute complication rates. Further prospective research is warranted to confirm these findings.

Analysis of MRI and CT-based radiomics features for personalized treatment in locally advanced rectal cancer and external validation of published radiomics models

Radiomics analyses commonly apply imaging features of different complexity for the prediction of the endpoint of interest. However, the prognostic value of each feature class is generally unclear. Furthermore, many radiomics models lack independent external validation that is decisive for their clinical application. Therefore, in this manuscript we present two complementary studies. In our modelling study, we developed and validated different radiomics signatures for outcome prediction after neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC) based on computed tomography (CT) and T2-weighted (T2w) magnetic resonance (MR) imaging datasets of 4 independent institutions (training: 122, validation 68 patients). We compared different feature classes extracted from the gross tumour volume for the prognosis of tumour response and freedom from distant metastases (FFDM): morphological and first order (MFO) features, second order texture (SOT) features, and Laplacian of Gaussian (LoG) transformed intensity features. Analyses were performed for CT and MRI separately and combined. Model performance was assessed by the area under the curve (AUC) and the concordance index (CI) for tumour response and FFDM, respectively. Overall, intensity features of LoG transformed CT and MR imaging combined with clinical T stage (cT) showed the best performance for tumour response prediction, while SOT features showed good performance for FFDM in independent validation (AUC = 0.70, CI = 0.69). In our external validation study, we aimed to validate previously published radiomics signatures on our multicentre cohort. We identified relevant publications on comparable patient datasets through a literature search and applied the reported radiomics models to our dataset. Only one of the identified studies could be validated, indicating an overall lack of reproducibility and the need of further standardization of radiomics before clinical application.

18F-Fluorodeoxyglucose Positron Emission Tomography of Head and Neck Cancer: Location and HPV Specific Parameters for Potential Treatment Individualization.

Purpose18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is utilized for staging and treatment planning of head and neck squamous cell carcinomas (HNSCC). Some older publications on the prognostic relevance showed inconclusive results, most probably due to small study sizes. This study evaluates the prognostic and potentially predictive value of FDG-PET in a large multi-center analysis.MethodsOriginal analysis of individual FDG-PET and patient data from 16 international centers (8 institutional datasets, 8 public repositories) with 1104 patients. All patients received curative intent radiotherapy/chemoradiation (CRT) and pre-treatment FDG-PET imaging. Primary tumors were semi-automatically delineated for calculation of SUVmax, SUVmean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Cox regression analyses were performed for event-free survival (EFS), overall survival (OS), loco-regional control (LRC) and freedom from distant metastases (FFDM).ResultsFDG-PET parameters were associated with patient outcome in the whole cohort regarding clinical endpoints (EFS, OS, LRC, FFDM), in uni- and multivariate Cox regression analyses. Several previously published cut-off values were successfully validated. Subgroup analyses identified tumor- and human papillomavirus (HPV) specific parameters. In HPV positive oropharynx cancer (OPC) SUVmax was well suited to identify patients with excellent LRC for organ preservation. Patients with SUVmax of 14 or less were unlikely to develop loco-regional recurrence after definitive CRT. In contrast FDG PET parameters deliver only limited prognostic information in laryngeal cancer.ConclusionFDG-PET parameters bear considerable prognostic value in HNSCC and potential predictive value in subgroups of patients, especially regarding treatment de-intensification and organ-preservation. The potential predictive value needs further validation in appropriate control groups. Further research on advanced imaging approaches including radiomics or artificial intelligence methods should implement the identified cut-off values as benchmark routine imaging parameters.

Impact of lymph node ratio on survival and recurrence outcomes in oral squamous cell carcinoma

Growing evidence supports the lymph node ratio (LNR) as a prognostic factor for survival in patients with oral squamous cell carcinoma (OSCC). However, there is a lack of data regarding its association with recurrence outcomes. Data on 163 patients with OSCC who underwent primary surgical treatment at a tertiary centre between January 2009 and December 2015 were collected retrospectively and analysed. Receiver operating characteristic curve analysis was performed to determine optimal cut-off values for the survival analyses. Survival endpoints were disease progression/relapse for disease-free time (DFT), freedom from loco-regional recurrence (FLR), and freedom from distant metastasis (FDM), and as death from any cause for overall survival (OS). Patients with a lower LNR were found to have significantly superior DFT (LNR < 14%, P < 0.001), FLR (LNR <14%, P < 0.001), FDM (LNR <16%, P = 0.004), and OS (LNR <7%, P = 0.004) in comparison to patients with a higher LNR. LNR is a good predictor of survival and recurrence outcomes in OSCC.

Prognostic Value of Pretherapeutic Primary Tumor MTV from [18F]FDG PET in Radically Treated Cervical Cancer Patients.

The aim of this study was to assess the usefulness of pretherapeutic primary tumor metabolic tumor volume (MTV) in the prognosis of radically treated cervical cancer patients. Retrospective, single-centre analysis was performed on a group of 508 cervical cancer patients. All patients underwent a pretreatment [18F]FDG PET/CT study for the assessment of the disease stage. Several PET-derived parameters—namely, maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), total lesion glycolysis (TLG) and MTV, as well as the clinical parameters, were analysed in terms of the overall survival (OS), event-free survival (EFS), locoregional control (LRC) and freedom from distant metastases (FFDM). Hyperthermia and brachytherapy were prognostic for EFS, OS, and LRC.FIGO stage > II showed a significant effect on EFS, OS, and FFDM. Moreover, hysterectomy was prognostic for OS and histology was prognostic for FFDM. From the PET-derived parameters only MTV of the primary tumor had a significant influence on OS (cutoff point: >12.7 mL, HR: 2.8, 1.75–4.48 95% CI, p < 0.001), LRC (cutoff point: >13.7 mL, HR 2.82, 1.42–5.61 95% CI, p = 0.003), EFS (cutoff point: >10.4 mL, HR: 2.57, 1.67–3.97 95% CI, p < 0.001) and FFDM (cutoff point: >10.4 mL, HR: 5.04, 1.82–13.99 95% CI, p = 0.002). Pretreatment MTV from the primary tumor is the only independent prognostic parameter in OS, LRC, EFS, and FFDM in radically treated cervical cancer patients and should be used in clinical practice in assessing prognosis in these patients.

Two-Weekly High-Dose-Rate Brachytherapy Boost After External Beam Radiotherapy for Localized Prostate Cancer: Long-Term Outcome and Toxicity Analysis.

PurposeEvaluation of clinical outcome of two-weekly high-dose-rate brachytherapy boost after external beam radiotherapy (EBRT) for localized prostate cancer.Methods338 patients with localized prostate cancer receiving definitive EBRT followed by a two-weekly high-dose-rate brachytherapy boost (HDR-BT boost) in the period of 2002 to 2019 were analyzed. EBRT, delivered in 46 Gy (DMean) in conventional fractionation, was followed by two fractions HDR-BT boost with 9 Gy (D90%) two and four weeks after EBRT. Androgen deprivation therapy (ADT) was added in 176 (52.1%) patients. Genitourinary (GU)/gastrointestinal (GI) toxicity was evaluated utilizing the Common Toxicity Criteria for Adverse Events (version 5.0) and biochemical failure was defined according to the Phoenix definition.ResultsMedian follow-up was 101.8 months. 15 (4.4%)/115 (34.0%)/208 (61.5%) patients had low-/intermediate-/high-risk cancer according to the D`Amico risk classification. Estimated 5-year and 10-year biochemical relapse-free survival (bRFS) was 84.7% and 75.9% for all patients. The estimated 5-year bRFS was 93.3%, 93.4% and 79.5% for low-, intermediate- and high-risk disease, respectively. The estimated 10-year freedom from distant metastasis (FFM) and overall survival (OS) rates were 86.5% and 70.0%. Cumulative 5-year late GU toxicity and late GI toxicity grade ≥ 2 was observed in 19.3% and 5.0% of the patients, respectively. Cumulative 5-year late grade 3 GU/GI toxicity occurred in 3.6%/0.3%.ConclusionsTwo-weekly HDR-BT boost after EBRT for localized prostate cancer showed an excellent toxicity profile with low GU/GI toxicity rates and effective long-term biochemical control.

Outcomes Using TORS or Definitive Chemoradiation for T3/T4 HPV+ Oropharynx Cancer

Patients with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) generally have a good prognosis, though those with locally advanced (LA) disease are at increased risk of locoregional failure (LRF) and distant metastases (DM). A recent SEER study suggested improvement in overall survival and cancer-specific mortality with trimodality therapy compared to definitive chemoradiation (dCRT) for LA HPV+ OPSCC, but is prone to confounding and lacks pattern of failure data. We therefore performed this retrospective analysis of oncologic outcomes for patients with T3/T4 HPV+ OPSCC treated at a high-volume TORS center with surgery +/- adjuvant therapy compared to dCRT alone.Included were patients with cT3/T4 HPV+ OPSCC treated with dCRT or upfront TORS +/- adjuvant therapy from 2010-2019 with ≥1 year of follow-up. Patients with DM at diagnosis were excluded. Primary outcomes were freedom from LRF (FF-LRF) and LRF leading to death, defined as LRF directly resulting in death or occurring at the same time or before DM resulting in death. Secondary outcomes were freedom from DM (FF-DM) and cancer-specific survival (CSS). Patients were risk stratified based on criteria in the secondary analysis of RTOG 0129 by Ang et al (NEJM 2010): Low-risk: ≤10 pack-year (py) smoking, or > 10 py and N0-N2a disease (AJCC 7th ed.); Intermediate-risk: > 10 py and N2b-N3 disease. Fisher's exact test was used to compare demographics and Kaplan-Meier estimates to compare endpoints.78 patients were treated with dCRT and 44 with upfront TORS. Significantly more dCRT patients were Intermediate-risk (per RTOG 0129 criteria) compared to TORS patients (35.9% vs 6.8%, P < 0.001). ECOG performance status was similar between groups with most 0-1. 87% of TORS patients received adjuvant therapy (32% CRT and 55% RT alone). The median follow-up was 43 months. There was no difference in 4-year FF-LRF for dCRT vs TORS (87% vs 93%, P = 0.33) and no difference in freedom from LRF leading to death (93% vs 98%, P = 0.30). There was also no difference in CSS (92% vs 95%, P = 0.14) or FF-DM (80% vs 86%, P = 0.45). On univariate analysis, RTOG 0129 risk group predicted for LRF (OR 3.4, P = 0.05) but not LRF leading to death (OR 3.14, P = 0.175). Multivariate analysis of LRF as a function of 0129 risk group and treatment modality showed neither were statistically significant (OR for risk group 3.22, P = 0.08; OR for surgery 0.85, P = 0.833), though risk group trended towards significance.This large, single-institution series of patients with T3/T4 HPV+ OPSCC treated with either dCRT or upfront TORS +/- adjuvant therapy shows high FF-LRF and low rates of LRF leading to death regardless of treatment. Even in patients with advanced T stage, dCRT was able to obtain excellent disease outcomes. Future prospective studies are warranted to determine which combinations of multimodality therapy are optimal for LA HPV+ OPSCC, incorporating both oncologic and functional outcome endpoints.

Prognostic Factors in Breast Cancer Patients With Clinical N3b (Ipsilateral Internal Mammary and Axillary) Disease

<h3>Purpose/Objective(s)</h3> Patients with clinical N3b (cN3b) breast cancer often do not undergo surgical resection of gross internal mammary (IM) nodes. Therefore, radiation is important for curative therapy. However, limited data exist to guide treatment recommendations. <h3>Materials/Methods</h3> We retrospectively reviewed 119 patients with non-metastatic cN3b breast cancer treated at our institution between 2014 and 2019 with curative intent. Staging included u/s evaluation of all regional nodal basins. All patients received neoadjuvant chemotherapy (NAC), surgical resection of the breast primary and nodal dissection, followed by adjuvant radiation to the chest wall/breast, infraclavicular (ICV), SCV and IM nodes. Institutional nodal boost guidelines recommend 10 Gy to radiographically resolved N3b nodal basins, and 16 Gy to unresolved N3b nodes, normal tissue constraints permitting. Patient, tumor, and treatment characteristics were collected and analyzed using a saturated multivariable analysis (MVA) model with backwards elimination to identify variables associated with improved overall survival (OS) at <i>P</i> < 0.10. Local (LC), regional control (RC), freedom from distant metastases (FFDM), and overall survival (OS) were evaluated with Kaplan Meier analysis. <h3>Results</h3> 119 patients were analyzed with a median follow-up of 2.78 years. Median age at diagnosis was 46 years, 56 (47%) were ER+/HER2-, 19 (16%) ER+/HER2+, 13 (11%) ER- /HER2+, and 31 (26%) ER-/HER2-, 86 (74%) had high grade histology, and 68 (57%) had cT3/T4 disease. Mastectomy was performed in 96 (81%) of patients, 36 (30%) had biopsy confirmed IMC involvement, and 8 (7%) had dissection of IM nodes. The median initial radiation dose was 50 Gy (range, 50-55), IMC boost 10 Gy (range, 8-16), and 41 (34%) received cumulative IMC dose > 60 Gy. The 3-year OS, FFDM, RC, and LC were 80%, 71%, 93%, and 94%, respectively. Patients with a nodal pCR of dissected nodes, had improved 3-year OS, 95% vs 71% (<i>P</i> = 0.008). Among patients who had a nodal pCR, nodal boost to > 60 Gy did not significantly improve 3-year OS, 100% vs. 93% (<i>P</i> = 0.40). In patients with less than a nodal pCR, who received IMC > 60 Gy, 3-year OS was numerically improved but was not statistically significant 81% vs. 64% (<i>P</i> = 0.33). In MVA, cumulative IMC dose > 60 Gy, nodal pCR, ER positivity, HER2 positivity, and lower clinical T-stage were independently associated with improved OS (Table 1). <h3>Conclusion</h3> Nodal pathologic response to NAC and cumulative IMC dose > 60 Gy were independently predictive for improved OS in patients with non-metastatic cN3b breast cancer treated with curative intent. Regional nodal control using a boost was excellent even among those with less than nodal pCR.

Outcomes of Phase I Trial of Patients With Recurrent Head and Neck Squamous Cell Carcinoma Treated With Re-Irradiation With Stereotactic Body Radiation Therapy and Concurrent Cisplatin

Stereotactic body radiation therapy (SBRT) offers a treatment option for patients with unresectable, previously radiated, locoregionally recurrent head and neck cancer. Given the resistant and advanced nature of many of these cancers, the addition of chemotherapy to radiotherapy is typically recommended as a radiosensitizer. We therefore performed a phase I clinical trial in order to establish a maximum tolerated dose of SBRT with concurrent chemotherapy in locoregionally recurrent head and neck cancer. We previously reported our safety data, and now present our secondary outcome endpoints.Major inclusion criteria were recurrence of previous squamous cell carcinoma of the head and neck in patients who had previously undergone radiotherapy to doses ≥ 45 Gy to the area of recurrence, ≥ 6 months prior to enrollment, and who were medically unfit for surgery, deemed unresectable, or refused surgery. Patients were treated with radiation therapy every other day for five fractions at three dose levels: 30 Gy, 35 Gy, and 40 Gy. Cisplatin was given prior to every SBRT fraction at a dose of 15 mg/m2. Secondary end points reported herein are locoregional control (LRC), freedom from distant metastasis (FFDM), and overall survival (OS).Twenty patients were enrolled and of those 18 patients were evaluable for secondary endpoints. Nine patients had a primary tumor in the oropharynx, four patients in the oral cavity, three in the neck, one in the larynx, and one simultaneously in the larynx and neck. Five patients received a radiation dose of 30 Gy, three patients received a dose of 35 Gy, and 9 patients received a dose of 40 Gy. With a median follow up of 9 months the 1-year OS was 38.9%. LRC at 1 year was 45.7% and FFDM at 1 year was 87.8%. Median time to locoregional progression was eight months. There was a trend to improved OS with increasing SBRT dose, 40 Gy vs < 40 Gy, (P = 0.08). Locoregional control at 1 year was also significantly improved with increased SBRT dose, 12.5% for patients that received < 40 Gy vs 85.7% for patients that received 40 Gy (P = 0.005). Median gross tumor volume (GTV) was 11.725 cm3. There was an improved 1-year locoregional control with a GTV ≤11.725 cm3 of 64.8% vs 0% for tumors > 11.725 cm3 (P = 0.01).Patients with recurrent head and neck cancer typically present with advanced, unresectable disease, and therefore have limited definitive treatment options. This phase I study demonstrates that SBRT with concurrent Cisplatin provides reasonable locoregional control and overall survival with radiation doses of 40 Gy.

Outcomes After Multimodality Therapy in Modern Breast Cancer Patients Presenting With Clinical N3c Supraclavicular Node Involvement

<h3>Purpose/Objective(s)</h3> Breast cancer patients with clinical N3c (cN3c) disease at diagnosis have poor outcomes relative to other breast cancer patients. Radiotherapy (RT) has an important role in the management of these patients as the supraclavicular (SCV) nodes are not routinely surgically dissected. However, outcomes and prognostic factors in the era of modern neoadjuvant chemotherapy (NAC) are not well-described. <h3>Materials/Methods</h3> We reviewed breast cancer patients with non-metastatic cN3c disease treated at our institution from 2014-2019 with curative intent NAC, surgery, and adjuvant RT. All patients received nodal RT including the SCV, infraclavicular, and internal mammary nodes. Institutional guidelines recommend a 10 Gy boost to clinically resolved N3 nodal basins and 16 Gy to unresolved N3 nodes. Variables including initial and boost dose, pathologic response, and type of nodal dissection were collected. Local (LC) and regional control (RC), freedom from distant metastases (FFDM), and overall survival (OS) were analyzed with the Kaplan Meier method. A saturated multivariable Cox proportional hazards model of OS with backward elimination identified clinical variables associated with OS at <b>P</b> < 0.10. <h3>Results</h3> A total of 176 consecutive patients were analyzed. The median follow-up time was 2.83 years. The median age was 54 years, 76 (43%) were ER+/HER2-, 20 (11%) ER+/HER2+, 26 (15%) ER-/HER2+, and 54 (31%) ER-/HER2-. 102 (57%) had T3/4 disease, 41 (23%) underwent lumpectomy, 142 (81%) had pathologic confirmation of N3c, and 10 (6%) had a neck dissection. The median initial radiation dose was 50 Gy (range, 44-56.25), SCV boost 10 Gy (range, 6-16), and 156 (89%) received cumulative SCV dose ≥60 Gy. The 3-year OS, FFDM, RC, and LC were 79%, 64%, 93%, and 96%, respectively. For cumulative SCV dose of ≥60 Gy vs. < 60 Gy, the 3-year OS was 81% vs. 61% (<i>P</i> = 0.03). Among patients with a nodal pCR after NAC, the 3-year OS for SCV dose ≥60 Gy vs. < 60 Gy was 93% vs. 53% (<i>P</i> = 0.03). In multivariable analysis, cumulative SCV dose ≥60 Gy, extranodal extension, ER status, HER2 status, number of dissected lymph nodes, and ECOG status were associated with OS (Table 1). <h3>Conclusion</h3> In a large, modern cohort of non-metastatic cN3c breast cancer patients treated with multimodality therapy, cumulative SCV dose ≥60 Gy was found to be associated with improved OS. Although optimal radiation dosing cannot be established from this data, a SCV radiation boost should be considered in cN3c patients treated with curative intent respecting normal tissue constraints.