Neoadjuvant Stereotactic Body Radiation Therapy Research Articles

Patterns of Failure Following Preoperative Chemotherapy and Stereotactic Body Radiation Therapy and Resection for Patients with Borderline Resectable or Locally Advanced Pancreatic Cancer.

The role of neoadjuvant stereotactic body radiation therapy (SBRT) in the treatment of pancreatic adenocarcinoma (PDAC) is controversial and the optimal target volumes and dose-fractionation are unclear. The aim of this study is to report on treatment outcomes and patterns of failure of patients with borderline resectable (BL) or locally advanced (LA) pancreatic cancer following preoperative chemotherapy and SBRT. We conducted a single-institution, retrospective study of patients with BL or LA PDAC. Patients received neoadjuvant chemotherapy and SBRT was prescribed to 30 Gy over 5 fractions to the pancreas planning tumor volume (PTV). A subset of patients received a simultaneous integrated boost to the high risk vascular PTV and/or elective nodal irradiation (ENI). Following neoadjuvant chemoradiation, all patients underwent subsequent resection. Overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMPFS), and locoregional control (LRC) estimates were obtained using Kaplan-Meier analysis. Twenty-two patients with BL (18) or LA (4) PDAC were treated with neoadjuvant chemotherapy and SBRT followed by resection from 2011-2022. Following neoadjuvant treatment, 5 patients (23%) achieved a pathologic complete response (pCR) and 16 patients (73%) had R0 resection. At 24 months, there were no isolated locoregional recurrences (LRRs), 9 isolated distant recurrences (DRs), and 5 combined LRRs and DRs. Two LRRs were in-field, 2 LRRs were marginal, and 1 LRR was both in-field and marginal. 2-year median LRC, LRRFS, DMPFS, PFS, and OS were 77.3%, 45.5%, 31.8%, 31.8%, and 59.1%, respectively. For BL and LA cancers, 2-year LRC, DMPFS, and OS were 83% vs. 75%, (p = 0.423), 39% vs. 0% (p = 0.006), and 61% vs. 50% (p = 0.202), respectively. ENI was associated with improved LRC (p = 0.032) and LRRFS (p = 0.033). Borderline resectability (p = 0.018) and lower tumor grade (p = 0.027) were associated with improved DMPFS. Following preoperative chemotherapy and SBRT, locoregional failure outside of the target volume occurred in 3 of 5 recurrences; ENI was associated with improved LRC and LRRFS. Further studies are necessary to define the optimal techniques for preoperative radiation therapy.

Neoadjuvant SBRT plus regional nodal irradiation with concurrent capecitabine for patients with resectable pancreatic cancer: Survival analysis of prospective phase 1 trial.

652 Background: Radiation may have a role in management of patients with early-stage pancreatic cancer. However, the role of regional nodal irradiation (RNI) is not well defined despite the high frequency of occult nodal disease. The goal of this trial was to evaluate the safety and feasibility of stereotactic body radiation therapy (SBRT) to primary disease with RNI, combined with capecitabine as a neoadjuvant approach for patients with resectable pancreatic cancer. Updated survival analysis will be presented here. Methods: This is a prospective, single institution, phase IA/B dose-escalation trial that enrolled patients with biopsy-proven, resectable, pancreatic adenocarcinoma between 2014 – 2019 (NCT1918644). Patients were enrolled into one of the 3 cohorts with escalating dose levels. Neoadjuvant SBRT to the primary tumor was delivered in 5 fractions of 5, 6, or 7 Gy with concomitant capecitabine. All patients received RNI 5 Gy x 5 fractions. Our initial report found no dose-limiting toxicities (Witt et al IJROBP 2020). Clinicopathologic features were summarized using descriptive statistics. Kaplan-Meier curves were employed for survival analysis. Results: Seventeen patients were enrolled on the protocol with sixteen evaluable (94.1%). Thirteen (76.5%) patients proceeded to surgery. Median follow up was 31.1 months (2.0 – 73.2). Among the evaluable patients, 63% were male, median age at diagnosis was 73 years (63 – 84), pre-treatment CA 19-9 149.5 U/mL (2.0 – 19358.0). The majority of patients had cT2-3 (94%) and cN0 (87.5%) disease. In patients who underwent resection, median time from radiation to surgery was 19.7 days (14.8 – 42.4), with median of 18 lymph nodes removed (11 – 27). Pathologically involved nodes were present in 69.2% of patients with a median of 2 nodes (1 – 10). Five patients (31.3%) received neoadjuvant chemotherapy, and ten (62.5%) received adjuvant chemotherapy. At the time of data cutoff, median overall survival was 31.1 months (2.3 – 73.6), and median locoregional control and distant metastasis free survivals were 32.8 months (4.0 – 59.5) and 15.3 months (0.4 – 73.6), respectively. No further radiation related toxicities were noted since the prior report. Conclusions: Neoadjuvant chemoradiation with SBRT and capecitabine to primary disease with RNI is feasible and provided a promising signal of durable local control in our study, despite high rates of pathological nodal involvement. Further investigation of this strategy is warranted in a larger cohort of patients. Clinical trial information: NCT1918644 .

Longitudinal Profiling of Tumor RNA Expression Signatures Reveal Key Biological Features Associated with Response to Neoadjuvant Stereotactic Body Radiation Therapy in High-Risk Prostate Cancer

Stereotactic body radiation therapy (SBRT) is a safe and effective treatment for localized prostate cancer (PCa). PREPARE-SBRT is a clinical trial testing the safety of neoadjuvant MRI-guided SBRT for men with high-risk localized PCa. We leveraged paired samples from pre-treatment biopsy and irradiated prostatectomy (RP) specimens to evaluate transcriptomic changes in irradiated tumors at acute time points following neoadjuvant SBRT. Tumor RNA expression profiles were generated using Decipher GRID by Veracyte on 12 subjects with paired pre- and post-SBRT tissues (n = 24). Descriptive statistics using gene expression profiles describing key biological features [DNA damage & repair (DDR), tumor proliferation, suppressed immune, activated immune, tumor microenvironment (TME)] and an exploratory analysis of RT sensitivity score with binary classification as sensitive or resistant were reported. A control cohort of transcriptomic profiles of 803 matched untreated biopsy and matching RP samples from the same subjects were used to control for signature differences attributable to sample type. Key tumor biology signatures most frequently observed were DDR (15/24), TME (11/24) and tumor proliferation (11/24). Signatures associated with tumor proliferation were disproportionately represented in pre-treatment samples (10/11) whereas TME-associated signatures were enriched predominantly in irradiated RP samples (8/11). Collectively, immune-related immune signatures skewed towards immune activation. All 3 samples annotated with suppressed immune signatures were from pre-treatment specimens whereas 75% (6/8) of samples annotated with activated immune status were from irradiated specimens. Additionally, conversion from suppressed to activated immune status was observed in 2 of 3 subjects (66%). In total, 42% of specimens (10/24) were designated as radio-resistant by RT sensitivity score. Among 8 baseline specimens annotated with RT resistant status, 75% of subjects (6/8) converted to RT sensitive status after neoadjuvant SBRT. Interestingly, in the two subjects with persistent radio-resistant status in pre- and post-samples there was associated with upregulation of TGF-β or PI3K-AKT pathway activation signatures. Pre- and post-SBRT transcriptomic signatures were heterogeneous and dynamic in a cohort of 12 patients with high-risk localized PCa highlighting the importance of studying longitudinal changes in individual patients. These data highlight an opportunity to leverage tumor RNA expression profiles to personalize patient and treatment selection and augment radiation response assessment. gov ID (NCT03663218).

Neoadjuvant SBRT combined with immunotherapy in NSCLC: from mechanisms to therapy.

The utilisation of neoadjuvant immunotherapy has demonstrated promising preliminary clinical outcomes for early-stage resectable non-small-cell lung cancer (NSCLC). Nevertheless, it is imperative to develop novel neoadjuvant combination therapy regimens incorporating immunotherapy to further enhance the proportion of patients who derive benefit. Recent studies have revealed that stereotactic body radiotherapy (SBRT) not only induces direct tumour cell death but also stimulates local and systemic antitumour immune responses. Numerous clinical trials have incorporated SBRT into immunotherapy for advanced NSCLC, revealing that this combination therapy effectively inhibits local tumour growth while simultaneously activating systemic antitumour immune responses. Consequently, the integration of SBRT with neoadjuvant immunotherapy has emerged as a promising strategy for treating resectable NSCLC, as it can enhance the systemic immune response to eradicate micrometastases and recurrent foci post-resection. This review aims to elucidate the potential mechanism of combination of SBRT and immunotherapy followed by surgery and identify optimal clinical treatment strategies. Initially, we delineate the interplay between SBRT and the local tumour immune microenvironment, as well as the systemic antitumour immune response. We subsequently introduce the preclinical foundation and preliminary clinical trials of neoadjuvant SBRT combined with immunotherapy for treating resectable NSCLC. Finally, we discussed the optimal dosage, schedule, and biomarkers for neoadjuvant combination therapy in its clinical application. In conclusion, the elucidation of potential mechanism of neoadjuvant SBRT combined immunotherapy not only offers a theoretical basis for ongoing clinical trials but also contributes to determining the most efficacious therapy scheme for future clinical application.

Stereotactic body radiation therapy with sequential immunochemotherapy as neoadjuvant therapy in resectable non-small cell lung cancer (SACTION-01 study).

8540 Background: Neoadjuvant PD-1 inhibitor plus chemotherapy increases pathological response for resectable non-small cell lung cancer (NSCLC) compared with chemotherapy alone. Previous phase II trial indicated that stereotactic body radiation therapy (SBRT) served as an immunomodulator and enhanced the effect of preoperative immuno-monotherapy. However, whether SBRT would further increase the efficacy of immunochemotherapy for NSCLC remains unknown. Methods: In this phase II trial, patients with resectable EGFR wild-type stage IIA to IIIB NSCLC were recruited to receive SBRT (24 Gy in 3 daily fractions) to the primary tumor followed by two cycles of PD-1 inhibitor tislelizumab (200 mg) plus platinum-based doublet chemotherapy (Q3W) before surgical resection. The primary endpoint was major pathological response (MPR) defined as no more than 10% of viable tumor cells in the specimen. Simon’s optimal two-stage design was used for conducting the trial. The null hypothesis was that the MPR rate is 0.30, and the alternative hypothesis was that the true MPR rate was 0.50. More than 4 MPRs were needed in stage 1 (n=15) to continue, and if there were 19 or more MPRs in 46 patients by the end of stage 2, the null hypothesis can be rejected. The design controls the type I error rate at 0.05 and yields the power of 0.80. (NCT05319574). Results: Between May 2022 and Jan 2023, 32 patients were enrolled with 31 (96.9%) male and 19 (59.4%) having squamous cell lung cancer. Twenty-six (81.3%) patients had stage IIIA/B disease. All patients received at least one cycle of immunochemotherapy; 23 of the 25 patients (92.0%) who completed treatment had undergone R0 resections, except for one patient who had disease progression and the other one that unable to tolerate surgery because of grade 4 neutropenia. Twenty-two patients underwent minimally invasive approaches and 3 of them (13.6%) converted to thoracotomy. The median percentage of the viable tumor was 0 (interquartile range: 0-4.0%). Twenty patients achieved MPR, which surpassed the prespecified required number to reject the null hypothesis, resulting in the MPR rate of 80.0% (20/25) in the intention-to-treat population, and 87.0% (20/23) in the per-protocol population. Pathological complete response (pCR) was found in 14 patients (56.0% in the intention-to-treat population and 60.9% in the per-protocol population). Nodal clearance status (pN0) was found in 20 of 23 cN1/2 cases (87.0%). Grade 3-4 adverse events related to neoadjuvant treatment included neutropenia (13.0%), anemia (4.3%), and pneumonia (4.3%). No 30-day or 90-day mortality was observed. Conclusions: Neoadjuvant SBRT followed by immunochemotherapy yields unprecedently high MPR and pCR rates in NSCLC without EGFR mutation. The trial will continue to recruit 14 more patients to reach a final sample size of 46 participants. Clinical trial information: NCT05319574 .

Neoadjuvant stereotactic body radiotherapy plus dalpiciclib and exemestane for hormone receptor-positive, HER2-negative breast cancer.

e12604 Background: Despite cyclin dependent kinase 4/6 (CDK4/6) inhibitors having revolutionized treatment for advanced hormone receptor (HR)-positive, HER2-negative (HR+/HER2-) breast cancer, it still has limited efficacy in the neoadjuvant setting. Preclinical studies have indicated radiotherapy followed by CDK4/6 inhibitors can enhance antineoplastic effects. Stereotactic body radiotherapy (SBRT) is more effective than conventional fractionation. This MUKDEN 03 pilot study aimed to explore the efficacy and safety of a chemotherapy-free neoadjuvant regimen with SBRT followed by CDK4/6 inhibitors and endocrine therapy in patients with HR+/HER2- breast cancer. Methods: In this single-center, single-arm prospective study, treatment-naïve patients with unilateral invasive, pathologically confirmed HR+/HER2- breast cancer at stage II-III would be enrolled. Eligible patients received neoadjuvant SBRT (24Gy/3f) to breast target lesion followed by dalpiciclib (150mg daily for 3 weeks on and 1 week off) and exemestane (25mg daily) every 4 weeks for 6 cycles. Patients without menopause also received goserelin 3.6 mg every 4 weeks. The primary endpoint was the proportion of patients with residual cancer burden (RCB) score of 0-I. Key secondary endpoints included objective response rate (ORR), pathologic complete response (pCR), and safety. Results: Between November 2021 and August 2022, 12 enrolled patients completed the study treatment and surgery. The median age was 48.5 years (95% confidence interval [CI], 36-56) and half of them were premenopausal women. 5 (41.7%) patients had stage III disease. The results met the primary endpoint as the therapy resulted in RCB 0-I of 16.7% (2/12, 95% CI 3.5%-46.0%) with the ORR of 91.7% (11/12, 95% CI 62.5%-100%). 2 (16.7%, 95% CI 3.5%-46.0%) patients achieved pCR in the breast and axilla (ypT0/is ypN0). 3 (25.0%, 95% CI 8.3%-53.9%) patients reached pCR in the breast (ypT0/is). The most common grade 3 adverse events (AEs) were neutropenia (8 [66.7%]) and leukopenia (3 [25%]). No patient experienced grade 4-5 AE or death. There was no patient with radiation-related dermatitis and skin hyperpigmentation. Conclusions: Neoadjuvant SBRT followed by dalpiciclib and exemestane seems effective and tolerable, which may offer an alternative for patients with HR+/HER2- breast cancer. The results warranted further validation. Clinical trial information: NCT05132790 .

High Recurrence for HPV-Positive Oropharyngeal Cancer With Neoadjuvant Radiation Therapy to Gross Disease Plus Immunotherapy: Analysis From a Prospective Phase Ib/II Clinical Trial

Moderate reduction of radiation to elective volumes has demonstrated encouraging results for human papillomavirus (HPV)-associated oropharyngeal carcinoma (OPSCC). However, it remains unknown whether omitting elective volume radiation completely can maintain adequate locoregional control. This trial (NCTXXX) assessed outcomes of Stereotactic Body Radiation Therapy (SBRT) to the gross disease without elective volume irradiation combined with durvalumab and tremelimumab before surgery in patients with HPV+ OPSCC. This phase Ib/II trial included patients with previously untreated locally advanced HPV+ OPSCC from September 2019 to March 2021. Patients received neoadjuvant durvalumab±tremelimumab for 2 doses, with the first dose concurrent with SBRT of 25 Gy in 5 fractions to gross disease only, prior to TransOral Robotic Surgery, followed by adjuvant durvalumab for up to 4 cycles. The primary endpoint was safety/efficacy for the phase Ib portion; and two-year progression-free survival for the phase II portion. This report describes patterns of failure after early closure of the trial following a separate study demonstrating a lack of efficacy of durvalumab±tremelimumab in the metastatic/recurrent setting. Nineteen patients were enrolled (phase Ib: 6; phase II: 13). Three were treated with durvalumab only while 16 with durvalumab+tremelimumab. Median follow-up was 12.7 months. No safety signals were seen. Overall, 18 out of 19 (95%) achieved a clinical to pathological downstaging, and 9 (47%) had a pathological complete response (pCR). Five patients (26%) developed locoregional recurrence, with a median time to recurrence was 3 months. Failing to achieve pCR was significantly associated with locoregional recurrence (p=0.033). None developed distant metastasis. Neoadjuvant SBRT delivered only to the gross tumor before surgery is associated with a high early risk of lymph node recurrence in HPV+ OPSCC despite concurrent/adjuvant immunotherapy. The results caution against omitting elective volume irradiation even in this group of patients with relatively favorable prognosis.

Effect of neoadjuvant stereotactic body radiation therapy (SBRT) on the immune microenvironment of high-risk localized prostate cancer in paired transcriptomic analysis of pretreatment biopsy and irradiated prostatectomy specimens.

371 Background: SBRT is a treatment option for men with prostate cancer. PREPARE-SBRT (NCT03663218) is a clinical trial testing the safety of neoadjuvant MRI-guided SBRT for men with high-risk localized prostate cancer. We leveraged paired samples from pre-treatment biopsy (Bx) and irradiated prostatectomy (RP) specimens to evaluate immune-related transcriptomic changes in irradiated tumors at acute timepoints following neoadjuvant SBRT. Methods: Transcriptomic profiles were generated using Decipher GRID (Veracyte, Inc). Differences in transcriptional signatures were assessed between Bx samples taken before treatment and RP samples post-treatment using a paired T-Test. A control cohort of transcriptomic profiles of 803 untreated Bx samples and matching RP samples from the same patients were used to account for differential effects in tissue preservation between Bx and RP. Linear regression model with the interaction effect of cohort (SBRT vs control) and by treatment status (Bx vs RP) to select signatures significantly impacted by neoadjuvant SBRT. Signatures with interaction p-value <0.01 and paired T-test value <0.05 were considered statistically significant. Results: 10 patients with paired pre-treatment Bx and post-SBRT RP specimens (n=20 samples) were analyzed with a median interval from completion of SBRT to RP of 5 days. Neoadjuvant SBRT was associated with upregulation of the T-cell inflamed signature (p=0.028) and immune190 signature (p=0.0031) supported by enrichment of transcriptomic features associated with IFN-gamma response (p=0.022), TCR signaling (p=0.0052) and antigen presentation (p=0.0048). Increased gene expression associated with effector memory/activated CD4 T-cells (p=0.0005 and p=0.0013, respectively) and effector memory/activated CD8 T-cells (p=0.0015 and p=0.013, respectively) were paralleled by a significant reduction in immunosuppressive regulatory T-cell (Treg; p=0.0015) and myeloid derived suppressor cell (MDSC; p=0.005) signatures. Additionally, macrophage-specific signatures were significantly enriched among SBRT-irradiated samples including CD68 and CSF1 gene clusters (both p=0.0041) as well as a decreased expression of the M2-to-M1 ratio signature (p=0.0052). Interestingly, WNT/β-catenin signaling, a putative oncogenic mediator of immune exclusion, was significantly downregulated in irradiated RP samples relative to pre-treatment Bx (p=2.6x10-5). Conclusions: Neoadjuvant SBRT was associated with significant immune remodeling of the irradiated prostate microenvironment. Collectively, immune-related transcriptional signatures skewed towards immune activation, increased effector T-cell and macrophage signatures and a reduction in immunosuppressive transcriptomic features.

Short- and Long-Term Outcomes of Neoadjuvant Stereotactic Body Radiation Therapy vs. Neoadjuvant Conventional Radiation Therapy in Patients with Pancreatic Cancer

<h3>Purpose/Objective(s)</h3> While neoadjuvant chemotherapy is widely accepted in treatment of pancreatic cancer, there is no consensus on the modality of neoadjuvant radiotherapy (NRT) with neoadjuvant Stereotactic Body Radiation Therapy (SBRT) gaining more interest. Our goal was to compare SBRT versus conventional radiation therapy (CRT). <h3>Materials/Methods</h3> A retrospective analysis of NCDB data from 2004 – 2018 was conducted. Patients who underwent NRT followed by surgical resection with known radiation and survival data were included. The primary outcome was overall survival (OS) and secondary outcomes include 30- and 90-day postoperative mortality, pathologic complete response (pCR) and R0 resection. <h3>Results</h3> The SBRT group (average 33Gy/5fx) comprised 392 patients, and 467 patients received CRT (average 45Gy/25fx). Median OS for patients undergoing CRT compared to SBRT group was 22 vs 34 months (p<0.001). The SBRT group had better median OS among AJCC clinical stage 1, 2 and 3 compared to CRT (32 vs 26 months, p = 0.078), (34 vs 21 months, p< 0.001) and (37 vs 23 months, p < 0.001), respectively. The 30- and 90-day postoperative mortality for CRT compared to SBRT group was 5% vs 2% (p = 0.02) and 12% vs 6% (p = 0.002), respectively. R0 resection and pCR rate for CRT compared to SBRT was 85% vs 87% (p = 0.96), and 3.7% vs 3.8% (p=0.77), respectively. <h3>Conclusion</h3> Patients who underwent neoadjuvant SBRT compared with CRT had superior OS, particularly in AJCC stage 2 and 3, along with decreased post operative mortality. Further randomized controlled trials are warranted.

Stereotactic Body Radiation Therapy (SBRT) in a Standardized Neoadjuvant Therapy Pathway for Pancreatic Cancer across a Geographically Large and Diverse Healthcare System

<h3>Purpose/Objective(s)</h3> The role of SBRT as part of a neoadjuvant therapy pathway (NATP) is actively being defined in the setting of growing multidisciplinary approach to pancreatic cancer (PC). A standardized approach to neoadjuvant therapy (NAT) has been shown to improve outcomes. We evaluated whether patients who received SBRT as part of our standardized NATP had better outcomes than patients in our institution who were not enrolled in our NATP. <h3>Materials/Methods</h3> The NATP was established at Northwell Health in June 2019, consisting of a single-day pancreas multi-disciplinary clinic (PMDC) visit, followed by neoadjuvant chemotherapy with interval scans and PMDC re-reviews prior to consideration of radiation and/ or surgical resection. Prior to consideration for resection, SBRT was standardized for borderline resectable PC (BRPC) and locally advanced PC (LAPC) patients after completion of chemotherapy. We retrospectively analyzed patients undergoing neoadjuvant SBRT in the last 5 years prior and after the establishment of NATP. Primary endpoints included resection rates, quality assurance (QA) measures and overall survival (OS). Kaplan-Meier analysis was used to estimate OS. <h3>Results</h3> A total of 38 non-metastatic patients were identified between January 2017 and December 2021 undergoing neoadjuvant SBRT after completion of at least 1 cycle of chemotherapy with 19 (50%) enrolled in the newly established NATP. Between NATP and non-NATP SBRT, mean age was 66.3 vs 63.3 years (p=.519) and additional baseline characteristics listed in Table 1 were comparable. SBRT BED (10) was 87.4Gy in NATP vs 68.8Gy in non-NATP (p<0.001). NATP patients underwent surgery at 47% vs. 26% in non-NATP (p=.179). Median OS was 19.7 months for all patients undergoing SBRT, with median follow-up (FU) of 13.0 mo (IQR: 9.2-18.8 mo). With Median FU of 10.0 mo vs 18.5 mo (p<0.001), NATP Median OS was 16.0 mo vs. non-NATP 22.8 mo (p=0.157). Surgery was the only significant predictor of OS, Median OS 28.3 mo vs. 18.5 mo (p=0.047). Implementation of NATP showed QA improvements in time of biopsy to start of chemotherapy (NATP 21 days (d) vs. 28 d) and time of radiation to surgery (NATP 35 d vs. 68d). <h3>Conclusion</h3> Implementation of a NATP with standardized incorporation of SBRT increased the percentage of PC patients who underwent timely radiation therapy and surgical resection. Further follow-up is required for assessing OS benefit. A standardized NATP increases access for patients to radiation therapy and sets the groundwork for multi-disciplinary care in PDAC.

Short- and Long-Term Outcomes of Neoadjuvant Stereotactic Body Radiation Therapy vs Neoadjuvant Conventional Radiation Therapy in Patients with Pancreatic Cancer

INTRODUCTION: Although neoadjuvant chemotherapy is widely accepted in treatment of pancreatic cancer, there is no consensus on the modality of neoadjuvant radiotherapy (NRT) with neoadjuvant Stereotactic Body Radiation Therapy (SBRT) gaining more interest. Our goal was to compare SBRT vs conventional radiation therapy (CRT). METHODS: A retrospective analysis of National Cancer Database data from 2004 to 2018 was conducted. Patients who underwent NRT followed by surgical resection with known radiation and survival data were included. The primary outcome was overall survival (OS) and secondary outcomes include 30- and 90-day postoperative mortality, pathologic complete response (pCR), and R0 resection. RESULTS: The SBRT group (average 33 Gy/5 fx) comprised 392 patients, and 467 patients received CRT (average 45 Gy/25 fx). Median OS for patients undergoing CRT compared with the SBRT group was 22 vs 34 months (p < 0.001). The SBRT group had better median OS among AJCC clinical stage 1, 2 and 3 compared with CRT (32 vs 26 months, p = 0.078; 34 vs 21 months, p < 0.001; and 37 vs 23 months, p < 0.001, respectively). The 30- and 90-day postoperative mortality for CRT compared with SBRT group was 5% vs 2% (p = 0.02) and 12% vs 6% (p = 0.002), respectively. R0 resection and pCR rate for CRT compared with SBRT was 85% vs 87% (p = 0.96) and 3.7% vs 3.8% (p = 0.77), respectively (Figure).FigureCONCLUSION: Patients who underwent neoadjuvant SBRT compared with CRT had superior OS, particularly in AJCC stage 2 and 3, along with decreased postoperative mortality. Further randomized controlled trials are warranted.

Protocol of notable-HCC: a phase Ib study of neoadjuvant tislelizumab with stereotactic body radiotherapy in patients with resectable hepatocellular carcinoma

IntroductionLiver resection is the mainstay of curative-intent treatment for hepatocellular carcinoma (HCC), but the postoperative 5-year recurrence rate reaches 70%, and there are no adjuvant or neoadjuvant therapies recommended by...

A Phase I Trial of Neoadjuvant Stereotactic Body Radiotherapy Prior to Radical Prostatectomy for Locally Advanced Prostate Cancer

Men with locally advanced prostate cancer who undergo radical prostatectomy (RP) often develop recurrence and require postoperative radiotherapy. We aimed to determine the safety of neoadjuvant stereotactic body radiotherapy (SBRT) before RP in this population. A single-institution phase 1 trial (NCT02946008) of men with high-risk or node-positive prostate cancer were enrolled between March and October 2017. The primary endpoint was to determine the maximum tolerated dose of SBRT based on a composite 30-day post-RP toxicity goal of ≤28% of patients experiencing a dose-limiting toxicity (DLT). Secondary outcomes included toxicity, efficacy, and multiple quality of life (QoL) inventories. SBRT (30-35 Gy/5 fractions) was delivered to the prostate and seminal vesicles, and 25 Gy/5 fractions to the pelvic lymph nodes. RP was performed for a median of 6 weeks post-SBRT. Hormone therapy was not allowed. Median follow-up was 40 months (range, 33-44). Twenty-five percent of the patients (n=4) experienced a DLT within 30 days post-RP; however, the trial was stopped early (n=16 of planned 38 patients) owing to the proportion and severity of the late adverse events. Post-RP grade 3 genitourinary and gastrointestinal toxicities occurred in 75% (n=12) and 25% (n=4) of patients, respectively. Two patients required cystectomy and urinary diversion ≥2 years post-RP. At 24 months post-RP, 75% (n=12) of men used ≥1 pad/d and 0% had erections suitable for intercourse. Surgical margins were negative in all patients and 31% (n=5) had complete or partial (pre-RP) MRI-response to SBRT. Three-year biochemical recurrence and distant metastasis were 45% (95% CI, 5%-68%) and 28% (95% CI, 0%-49%), respectively. Neoadjuvant SBRT followed by RP resulted in unacceptably high toxicity and severe QoL declines.

A phase II clinical trial of neoadjuvant sasanlimab and stereotactic body radiation therapy as an in situ vaccine for cisplatin-ineligible muscle invasive bladder cancer (RAD VACCINE MIBC).

TPS4611 Background: The utilization of neoadjuvant immune checkpoint inhibitor (ICI) therapy, including anti-PD1/L1 agents, prior to radical cystectomy (RC), is an emerging paradigm in muscle invasive bladder cancer (MIBC). Pathologic complete responses (pCR) have been observed in 25-40% of patients with neoadjuvant PD1/L1 inhibitor monotherapy for cisplatin-ineligible MIBC. In situ vaccination using stereotactic body radiation therapy (SBRT) may augment T-cell responses to tumor-specific antigens through immunogenic cell death. Sasanlimab (PF-06801591) is a humanized IgG monoclonal antibody that targets PD-1 selectively, for which there are both Phase 1 data and ongoing Phase 3 trials in early-stage urothelial carcinoma. There exists a strong rationale to evaluate a novel strategy of combination neoadjuvant ICI therapy with SBRT as an in situ vaccine to improve loco-regional control and decrease the risk of distant recurrence in cisplatin-ineligible patients with MIBC. Methods: This is a prospective, investigator-initiated, single-arm, single-institution, phase II trial that evaluates neoadjuvant sasanlimab in combination with SBRT as neoadjuvant therapy for patients with MIBC before RC. Eligibility requires patients to be cisplatin-ineligible (one of the following: ECOG-PS=2, creatinine clearance &lt;60 ml/min, or comorbidities such as hearing loss or neuropathy) or those who refuse cisplatin-based chemotherapy. Sasanlimab (300 mg) will be administered subcutaneously on Day 1 of each 28-day cycle for a total of 2 cycles, in combination with SBRT to the primary tumor at a dose of 24Gy given in 3 fractions, starting on Day 1 of Cycle 2 with a 48-hour interval between fractions. The combination treatment will be assessed by using a Simon’s 2-Stage design, which the first 10 patients are enrolled as a safety lead-in to evaluate the safety and feasibility. Futility analysis will be performed after a total of 18 patients. The primary endpoint is pCR rate after neoadjuvant sasanlimab/SBRT, followed by RC. If pCR is observed in 4 or fewer patients, further enrollment of patients may be stopped with the conclusion that pT0 cannot be 40% or greater. Otherwise, an additional 15 patients will be accrued in stage II, resulting in a total of 33 patients. Secondary endpoints include adverse events, surgical complication rates, health related quality-of-life, overall survival, and recurrence free survival. Exploratory endpoints include analysis of and association with pCR of the tumor/germline genetic signatures, circulating tumor DNA, tumor PD-L1 expression, blood cytometry time-of-flight analysis to identify immune response. Enrollment opened on February 15, 2022. Clinical trial information: NCT05241340.

The histologic effects of neoadjuvant stereotactic body radiation therapy (SBRT) followed by pulmonary metastasectomy-rationale and protocol design for the Post SBRT Pulmonary Metastasectomy (PSPM) trial.

BackgroundFor the local management of pulmonary malignancies, surgical resection and stereotactic body radiation therapy (SBRT) are mutually exclusive treatments. This study aims to assess the effectiveness of SBRT on reducing tumor viability at a histologic level in the context of pulmonary metastases.MethodsThis protocol describes an open-label unblinded single-arm prospective Phase 2 trial to determine the effects of dual treatment of pulmonary metastasis amenable to curative resection using neoadjuvant SBRT followed by surgical resection, the Post SBRT Pulmonary Metastasectomy (PSPM) trial. Sample size require 39 patients, with an anticipated study duration of 30–36 months. Following completion of SBRT, eligible patients will be assessed at the 4–6-week mark by the treating radiation oncologist and thoracic surgeon with a post-treatment computed tomography (CT) of the chest. Patients with no disease progression will undergo scheduled surgical resection of all metastatic tumors at 8–12 weeks post SBRT. Patients will then be evaluated postoperatively at 30 days, and every 6 months for a total of 36 months with surveillance CT scans. Patients will also undergo sequential serologic evaluation of circulating tumor DNA (ctDNA) levels throughout their respective treatment pathway. The primary outcome of this study is the rate of complete pathologic response (pCR) following SBRT, assess using the International Association for the Study of Lung Cancer (IASLC) multidisciplinary recommendations for pathologic assessment of lung cancer resection specimens after neoadjuvant therapy. Secondary outcomes include overall survival (OS), disease free survival (DFS), local recurrence rates, cancer histology effects on pCR and treatment related complications, and treatment effect on ctDNA levels. Primary and secondary outcomes will be analyzed using Fisher’s Exact test and Student’s t-test based on data type. Cox-proportional hazard ratios will be used to evaluate OS and DFS, using the log rank test.DiscussionIn evaluating the effect of SBRT on pulmonary metastasis at a histologic level, this trial may increase the use of this modality in selected patients who would otherwise only undergo surgery for disease that has already metastasized. Also, the trial provides secondary benefits of evaluating the abscopal effects of radiation on pulmonary metastatic disease, and serves as a platform for more comprehensive large-scale research in this field.Trial RegistrationClinicalTrials.gov identifier: NCT04160143 (HiREB: 7925).

Neoadjuvant Programmed Cell Death Protein 1 Blockade Combined With Stereotactic Body Radiation Therapy for Stage III(N2) Non-Small Cell Lung Cancer: A Case Series

The addition of radiotherapy in neoadjuvant chemotherapy did not improve event-free or overall survival in resectable non-small cell lung carcinoma (NSCLC). Neoadjuvant immunotherapy produced major pathologic response(MPR) rate of up to 45%. The potential synergy between radiotherapy and immunotherapy has been described in several studies. We reported outcomes of three cases of stage III/N2 NSCLC treated with neoadjuvant immunotherapy and stereotactic body radiation therapy (SBRT) in a single center. This explanatory trial included treatment-naive patients with stage III resectable NSCLC who received two doses of the programmed cell death protein 1 (PD-1) inhibitor toripalimab after 1 week of receiving SBRT for lung lesions. Thereafter, surgery was planned 4–6 weeks after the second dose. The primary endpoints were safety and feasibility, while the secondary endpoint was the pathologic response rate. Toripalimab combined with SBRT as a neoadjuvant treatment had well-tolerable side effects and did not lead to a delay in surgery. Among the included patients, one achieved pathologic complete response (PCR), one achieved MPR, and one with 20% residual tumor did not achieve MPR. There were few side effects of toripalimab combined with SBRT as a neoadjuvant treatment, and the treatment did not cause a delay in surgery. This study preliminarily explored the outcomes of a new neoadjuvant treatment.

Neoadjuvant Stereotactic Body Radiotherapy After Upfront Chemotherapy Improves Pathologic Outcomes Compared With Chemotherapy Alone for Patients With Borderline Resectable or Locally Advanced Pancreatic Adenocarcinoma Without Increasing Perioperative Toxicity

BackgroundPatients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) are at high risk of margin-positive resection. Neoadjuvant stereotactic body radiation therapy (SBRT) may help sterilize margins, but its additive benefit beyond neoadjuvant chemotherapy (nCT) is unclear. The authors report long-term outcomes for BRPC/LAPC patients explored after treatment with either nCT alone or nCT followed by five-fraction SBRT (nCT-SBRT).MethodsPatients with BRPC or LAPC from 2011 to 2016 who underwent resection after nCT alone or nCT-SBRT were retrospectively reviewed. Baseline characteristics were compared, and the propensity score with inverse probability weighting (IPW) was used to compare pathologic/survival outcomes.ResultsOf 198 patients, 76 received nCT, and 122 received nCT-SBRT. The nCT-SBRT cohort had a higher proportion of LAPC (53% vs 22%; p < 0.001). The duration of nCT was longer for nCT-SBRT (4.6 vs 2.9 months; p = 0.03), but adjuvant chemotherapy was less frequently administered (53% vs 67.1%; p < 0.001). Adjuvant radiation was administered to 30% of the nCT patients. The nCT-SBRT regimen more frequently achieved negative margins (92% vs 70%; p < 0.001), negative nodes (59% vs 42%; p < 0.001), and pathologic complete response (7% vs 0%; p = 0.02). In the multivariate analysis, nCT-SBRT remained associated with R0 resection (p < 0.001). The nCT-SBRT cohort experienced no significant difference in median overall survival (OS) (22.1 vs 24.5 months), local progression-free survival (LPFS) (13.5 vs. 15.4 months), or distant metastasis-free survival (DMFS) (11.7 vs 16.3 months) after surgery. After SBRT, 1-year OS was 77.0% and 2-year OS was 50.4%. Perioperative Claven-Dindo grade 3 or greater morbidity did not differ significantly between the nCT and nCT-SBRT cohorts (p = 0.81).ConclusionsDespite having more advanced disease, the nCT-SBRT cohort was still more likely to undergo an R0 resection and experienced similar survival outcomes compared with the nCT alone cohort.

High-dose hypofractionated stereotactic body radiotherapy for spinal chordoma.

Spinal chordoma is locally aggressive and has a high rate of recurrence, even after en bloc resection. Conventionally fractionated adjuvant radiation leads to suboptimal tumor control, and data regarding hypofractionated regimens are limited. The authors hypothesized that neoadjuvant stereotactic body radiotherapy (SBRT) may overcome its intrinsic radioresistance, improve surgical margins, and allow preservation of critical structures during surgery. The purpose of this study is to review the feasibility and early outcomes of high-dose hypofractionated SBRT, with a focus on neoadjuvant SBRT. Electronic medical records of patients with spinal chordoma treated using image-guided SBRT between 2009 and 2019 at a single institution were retrospectively reviewed. Twenty-eight patients with 30 discrete lesions (24 in the mobile spine) were included. The median follow-up duration was 20.8 months (range 2.3-126.3 months). The median SBRT dose was 40 Gy (range 15-50 Gy) in 5 fractions (range 1-5 fractions). Seventeen patients (74% of those with newly diagnosed lesions) received neoadjuvant SBRT, of whom 15 (88%) underwent planned en bloc resection, all with negative margins. Two patients (12%) developed surgical wound-related complications after neoadjuvant SBRT and surgery, and 4 (two grade 3 and two grade 2) experienced postoperative complications unrelated to the surgical site. Of the remaining patients with newly diagnosed lesions, 5 received adjuvant SBRT for positive or close surgical margins, and 1 received SBRT alone. Seven recurrent lesions were treated with SBRT alone, including 2 after failure of prior conventional radiation. The 2-year overall survival rate was 92% (95% confidence interval [CI] 71%-98%). Patients with newly diagnosed chordoma had longer median survival (not reached) than those with recurrent lesions (27.7 months, p = 0.006). The 2-year local control rate was 96% (95% CI 74%-99%). Among patients with radiotherapy-naïve lesions, no local recurrence was observed with a biologically effective dose ≥ 140 Gy, maximum dose of the planning target volume (PTV) ≥ 47 Gy, mean dose of the PTV ≥ 39 Gy, or minimum dose to 80% of the PTV ≥ 36 Gy (5-fraction equivalent doses). All acute toxicities from SBRT were grade 1-2, and no myelopathy was observed. Neoadjuvant high-dose, hypofractionated SBRT for spinal chordoma is safe and does not increase surgical morbidities. Early outcomes at 2 years are promising, although long-term follow-up is pending.

A Phase I Trial of Neoadjuvant Stereotactic Body Radiotherapy (SBRT) Prior to Radical Prostatectomy (RP) in Locally Advanced Prostate Cancer

A Phase I Trial of Neoadjuvant Stereotactic Body Radiotherapy (SBRT) Prior to Radical Prostatectomy (RP) in Locally Advanced Prostate Cancer

PD08-02 NEOADJUVANT STEREOTACTIC BODY RADIOTHERAPY (SBRT) PRIOR TO RADICAL PROSTATECTOMY (RP) IN LOCALLY ADVANCED PROSTATE CANCER: A PHASE I TRIAL

PD08-02 NEOADJUVANT STEREOTACTIC BODY RADIOTHERAPY (SBRT) PRIOR TO RADICAL PROSTATECTOMY (RP) IN LOCALLY ADVANCED PROSTATE CANCER: A PHASE I TRIAL