Distant Progression-free Survival Research Articles

The role of combined ion-beam radiotherapy (CIBRT) with protons and carbon ions in a multimodal treatment strategy of inoperable osteosarcoma

BackgroundTo investigate the role of combined ion-beam radiotherapy (CIBRT) with protons and carbon ions in a multimodal treatment strategy of inoperable osteosarcoma; final analysis of a one-armed, single center phase I/II trial. MethodsBetween August 2011 until September 2018, 20 patients with primary (N = 18), metastatic (N = 3), or recurrent (N = 2) inoperable pelvic (70%) or craniofacial (30%) osteosarcoma were treated with protons up to 54 Gy (RBE) and a carbon ion boost of 18 Gy (RBE) and followed until May 2019. A Fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) was performed before CIBRT in search for a prognostic factor. The primary endpoint was toxicity. Secondary endpoints included treatment response, global, local and distant progression free survival (PFS, LPFS and DPFS) and overall (OS), among others. ResultsThe median age was 20; all patients finished treatment per protocol. LPFS, DPFS, PFS and OS were 73%, 74%, 60% and 75% after one year and 55%, 65% 65.3%, 45% and 68% after two years, respectively. The median clinical target volume (CTV) was 1042 cc and 415 cc for the primary and boost plan, respectively. Craniofacial localization, lower uptake of FDG in PET/CT and boost plan CTV ≤ median were associated with improved overall survival (p = 0.039, p = 0.016 and p = 0.0043, respectively). No acute toxicities > grade III were observed. We observed one case of secondary acute myeloid leukemia (AML) seven months after CIBRT for recurrent disease and one case of hearing loss. ConclusionCIBRT shows a favorable toxicity profile and promising results particularly for patients with inoperable craniofacial osteosarcoma.

Comparison of intrahepatic progression patterns of hepatocellular carcinoma and colorectal liver metastases following CT-guided high dose-rate brachytherapy

Introduction:Given the metachronous and multifocal occurrence of hepatocellular carcinoma (HCC) and colorectal cancer metastases in the liver (CRLM), this study aimed to compare intrahepatic progression patterns after computed tomography (CT)-guided high dose-rate brachytherapy.Patients and methods:This retrospective analysis included 164 patients (114 HCC, 50 CRLM) treated with brachytherapy between January 2016 and January 2018. Patients received multiparametric magnetic resonance imaging (MRI) before, and about 8 weeks after brachytherapy, then every 3 months for the first, and every 6 months for the following years, until progression or death. MRI scans were assessed for local or distant intrahepatic tumor progression according to RECIST 1.1 and electronic medical records were reviewed prior to therapy. The primary endpoint was progression-free survival (PFS). Specifically, local and distant intra-hepatic PFS were assessed to determine differences between the intrahepatic progression patterns of HCC and CRLM. Secondary endpoints included the identification of predictors of PFS, time to progression (TTP), and overall survival (OS). Statistics included Kaplan–Meier analysis and univariate and multivariate Cox regression modeling.Results:PFS was longer in HCC [11.30 (1.33–35.37) months] than in CRLM patients [8.03 (0.73–19.80) months, p = 0.048], respectively. Specifically, local recurrence occurred later in HCC [PFS: 36.83 (1.33–40.27) months] than CRLM patients [PFS: 12.43 (0.73–21.90) months, p = 0.001]. In contrast, distant intrahepatic progression occurred earlier in HCC [PFS: 13.50 (1.33–27.80) months] than in CRLM patients [PFS: 19.80 (1.43–19.80) months, p = 0.456] but without statistical significance. Multivariate Cox regression confirmed tumor type and patient age as independent predictors for PFS.Conclusion:Brachytherapy proved to achieve better local tumor control and overall PFS in patients with unresectable HCC as compared to those with CRLM. However, distant progression preceded local recurrence in HCC. As a result, these findings may help design disease-specific surveillance strategies and personalized treatment planning that highlights the strengths of brachytherapy. They may also help elucidate the potential benefits of combinations with other loco-regional or systemic therapies.

The role of postoperative radiotherapy after primary tumor resection in patients with de novo stage IV breast cancer.

This study was undertaken to investigate the role of postoperative radiotherapy (PORT) including post-breast conserving radiotherapy (PBCRT) and post-mastectomy radiotherapy (PMRT) in stage IV breast cancer patients who underwent planned primary tumor resection (PTR). This study enrolled 112 patients diagnosed with de novo stage IV breast cancer who were treated with potentially curative PTR with or without PORT. The primary outcome was overall survival (OS), and the secondary outcomes were locoregional recurrence-free survival (LRRFS) and distant progression-free survival (DPFS). At a median follow-up of 48.9 months (range, 3.5-183.4 months), the median OS was 54.9 months (range, 5.3-185.9 months) with a 5 year OS rate of 59.6%. Lower clinical T stage, Luminal A or B type tumors and PBCRT were significantly predictive of longer OS. The 5 year LRRFS and DMFS rates were 79.0% and 34.3%, respectively. In multivariate analysis for LRRFS, the PBCRT arm demonstrated significant superiority compared to the No PORT arm. A comparison of patients who did and did not receive PORT showed that patients with disseminated metastasis more likely did not receive PORT and were excluded from the analysis. PBCRT arm demonstrated significantly superior LRRFS of 100% while PMRT and No PORT arm demonstrated 81.5% and 84.0%, respectively CONCLUSIONS: De novo stage IV breast cancer patients who received planned PTR showed favorable survival outcomes compared with historical cohorts. PTR may be predictive of a good prognosis, especially in patients with luminal A or B type tumors. PORT, especially PBCRT was predictive of LRRFS, suggesting that patients may benefit from this treatment.

Stereotactic Ablative Radiotherapy (SABR) in Oligometastatic and Oligoprogressive Gynecologic Cancers: Clinical Outcomes of a Single Institution Analysis

The role of stereotactic ablative radiotherapy (SABR) for gynecologic malignancies has not been clearly defined despite recent clinical uptake. This study evaluates the outcomes of SABR in patients with metastatic gynecologic cancer at a single institution. Patients with gynecologic cancers treated from 2009-2019 were extracted from an institutional SABR database. Descriptive statistics were used to report patient and treatment characteristics, toxicity and chemotherapy-free interval. Local recurrence free survival (LRFS), distant progression-free survival (DPFS), and overall survival (OS) probabilities were calculated using Kaplan-Meier methods. The relationship of primary site, tumor grade, dose of radiotherapy, and disease-free interval (DFI) to LRFS and DPFS were assessed using Cox regression methods for multivariable analysis (MVA). One hundred nine lesions in 77 patients with gynecologic cancer were treated with SABR. Median age was 63 and follow up after SABR was 16.4 months (1-79.6). Patients were treated with SABR for oligoprogressive disease (n = 58), oligometastatic disease (n = 34), or for local progression in critical areas (n = 17). Primary site included cancers of the endometrium (n = 36), cervix (n = 19), ovary (n = 15), and vulva or vaginal (n = 7). Median DFI was 22.3 months (1.6-143.3) from diagnosis to metastasis. Treatment was delivered to lesions in the lung (n = 25), pelvis (n = 23) spine (n = 17), para-aortic (n = 16) and distant nodes (n = 7), abdominal organs (n = 13), and bone (n = 8). Radiotherapy doses ranged from 25-60Gy (median 35Gy) in 2-5 fractions. Patients had between 1 and 6 lesions treated. Thirteen lesions recurred locally (11.9%) at a median of 7.6 months (range 0.5-17.6), and 76% of patients eventually had a distant recurrence after SABR. Median DPFS was 7.8 months (95% CI 3.6-11.9), and OS 31.5 months (95% CI 12.2-45.7). At 2 years, LRFS was 77.6%, DPFS was 19.6%, and OS was 51.9%. Thirty-two patients eventually required chemotherapy at median 6 months (range 1-37). There were no grade 3-5 acute or late toxicities reported. On MVA, primary site, tumor grade, dose of radiotherapy and DFI were not significantly associated with LRFS or DRFS. This cohort of patients had excellent LRFS and DPFS when treated with SABR for oligoprogressive, oligometastatic and locally progressive disease. SABR also has the potential to delay time to chemotherapy in patients with gynecologic cancers. Prospective multi-center trials will be critical to establish which primary disease sites and characteristics procure the greatest benefit from SABR use, to delineate optimal dose regimens, and to define the ideal time to implement SABR with other oncologic treatments.

Outcomes Of Stereotactic Radiosurgery And Immunotherapy In Renal Cell Carcinoma With Brain Metastases

To investigate the impact of immunotherapy (IT) on outcomes of stereotactic radiosurgery (SRS) in treatment of brain metastases from renal cell carcinoma (RCC). We retrospectively reviewed 48 patients with RCC who were treated with SRS for brain metastases in our institution between 2006 and 2018. Chi-square and Mann-Whitney U tests were used to compare categorical and continuous variables, respectively. Kaplan-Meier curve was used to estimate survival and log-rank test was used to compare survival between groups. Median age and KPS at initial SRS for IT group (19 patients) vs non-IT group (29 patients) were 55 vs 61 years (p = 0.024) and 100 vs 90 (p = 0.11). Median DS-GPA for both groups was 3 (range 1-4). The number of patients with extracranial metastases at the time of SRS was not statistically different between the groups. Nine patients received IT concurrently with SRS. A total of 372 lesions were treated with Gamma Knife based SRS with a median radiation dose of 20 Gy (range 12-30 Gy) and 22 Gy (range 12-27 Gy) for IT group and non-IT group, respectively. Median tumor volume for IT group and non-IT group was 56.2 mm3 (range, 2.1-14610 mm3) and 88.6 mm3 (range, 2.6-23383 mm3) (p = 0.046). Median total number of lesions treated in IT group and non-IT group were 9 (range, 1-54) and 4 (range, 1-18) (p = 0.40). Median total number of treatment sessions was 2 (range, 1-6) in both groups. Median overall survival (OS) following first SRS was 23.1 months (range, 6.0-93.8 months) for entire cohort. Median OS for IT group and non-IT group were 32.2 months and 18.4 months (p = 0.02). No patient in the IT group had intracranial progression at 2 years. Two-year local progression free survival (PFS) for the non-IT group was 89%. One- and two-year distant intracranial PFS rate for IT group vs non-IT group were 57% vs 50% and 46% vs 34% (p = 0.59), respectively. Eleven patients (22.9%) developed radiation necrosis requiring treatment at a median period of 1 month (range, 0-7 months) following SRS. Cumulative incidence of radiation necrosis requiring intervention at 1 year, censoring for death, for IT group vs non-IT group were 32% vs 18% (p = 0.24). There were no incidences of radiation necrosis after 1 year that required intervention. RCC patients with brain metastases treated with SRS and IT had significantly longer OS than those without immunotherapy. Regardless of systemic therapy options, intracranial disease control offered by SRS remains excellent for RCC brain metastases. No significant difference was found between the two groups for distant PFS or rate of radiation necrosis requiring intervention despite a 2 Gy decrease in the median radiation dose delivered in the IT group. Larger studies are required to validate these findings.

Prognostic factors and clinical outcomes after stereotactic radiotherapy for primary lung tumors.

To characterize the population treated with SBRT for early-stage primary lung tumors in our institution, determine their outcomes, and identify potential prognosis factors. Stereotactic radiotherapy (SBRT) is an alternative treatment for inoperable patients with early-stage lung cancer. It confers a local control rate around 90% at 3 years, and 2-3 year overall survival rates of 43-60% in this population. We retrospectively analyzed all patients treated in our department between 2012 and 2017 and evaluated local progression-free survival (L-PFS), nodal or distant progression-free survival (ND-PFS), global progression-free survival (G-PFS), overall survival (OS), and disease specific survival (DSS). Univariate (UVA) and multivariate (MVA) models were built to assess the influence of each variable. We identified 218 patients with 233 tumors. Most were male (78.9%) with a median age of 73 years. Median follow-up was 22 months. At 18 months, L-PFS was 93.7%, ND-PFS was 82.2%, G-PFS was 76.0%, DSS was 90.5%, and OS was 78.0% in ≤ T2 tumors. On UVA, T2 tumors were associated with lower L-PFS, G-PFS and DSS than T1, with no significant impact on ND-PFS or OS, an effect that persisted on MVA. On UVA, L-PFS and G-PFS were negatively influenced by female gender and a 5-fraction schedule was associated with worse G-PFS, which was not confirmed on MVA. Our local and distant control rates and survival were similar to those previously reported. On MVA, T2 tumors displayed lower L-PFS, G-PFS and DSS, with no difference in OS.

Oncologic Outcomes After Isolated Limb Infusion for Advanced Melanoma: An International Comparison of the Procedure and Outcomes Between the United States and Australia

Isolated limb infusion (ILI) is a minimally invasive procedure for delivering high-dose chemotherapy to extremities affected by locally advanced or in-transit melanoma. This study compared the outcomes of melanoma patients treated with ILI in the United States of America (USA) and Australia (AUS). Patients with locally recurrent in-transit melanoma treated with ILI at USA or AUS centers between 1992 and 2018 were identified. Demographic and clinicopathologic characteristics were collected. Primary outcomes of treatment response, in-field progression-free survival (IPFS), distant progression-free survival (DPFS), and overall survival (OS) were evaluated by the Kaplan-Meier method. Multivariable analysis evaluated whether availability of new systemic therapies affected outcomes. More ILIs were performed in AUS (n = 411, 60 %) than in the USA (n = 276, 40 %). In AUS, more ILIs were performed for stage 3B disease than in the USA (62 % vs 46 %; p < 0.001). The reported complete response rates were similar (AUS 30 % vs USA 29 %). Among the stage 3B patients, AUS patients had better IPFS (p = 0.001), whereas DPFS and OS were similar between the two countries. Among the stage 3C patients, the USA patients had better OS (p < 0.001), whereas IPFS and DPFS were similar. Availability of new systemic therapies did not affect IPFS or DPFS in either country. However, the USA patients who received ILI after ipilimumab approval in 2011 had significantly improved OS (hazard ratio, 0.62; p = 0.013). AUS patients were treated at an earlier disease stage than the USA patients with better IPFS for stage 3B disease. The USA patients treated after the availability of new systemic therapies had a better OS.

Outcomes of adolescents and young adults treated for brain and skull base tumors with pencil beam scanning proton therapy.

The use of proton therapy (PT) in adolescents and young adults (AYAs) is becoming increasingly popular. This study aims to assess the outcomes and late toxicity consequences in AYAs (15-39years) with brain/skull base tumors treated with pencil beam scanning proton therapy. One hundred seventy six AYAs treated curatively at the Paul Scherrer Institute (PSI) were identified. Median age was 30years (range 15-39) and median prescribed dose was 70.0Gy (relative biological effectiveness [RBE]) (range 50.4-76.0). The most common tumors treated were chordomas/chondrosarcomas (61.4%), followed by gliomas (15.3%), and meningiomas (14.2%). After a median follow up of 66months (range 12-236), 24 (13.6%) local only failures and one (0.6%) central nervous system (CNS) distant only failure were observed. The 6-year local control, distant progression-free survival, and overall survival were 83.2%, 97.4%, and 90.2%, respectively. The 6-year high-grade (≥grade [G] 3) PT-related late toxicity-free survival was 88.5%. Crude late toxicity rates were 26.2% G1, 37.8% G2, 12.2% G3, 0.6% G4, and 0.6% G5. The one G4 toxicity was a retinopathy and one G5 toxicity was a brainstem hemorrhage. The 6-year cumulative incidences for any late PT-related pituitary, ototoxicity, and neurotoxicity were 36.3%, 18.3%, and 25.6%; whilst high-grade (≥G3) ototoxicity and neurotoxicity were 3.4% and 2.9%, respectively. No secondary malignancies were observed. The rate of unemployment was 9.5% pre-PT, increasing to 23.8% post-PT. Sixty-two percent of survivors were working whilst 12.7% were in education post-PT. PT is an effective treatment for brain/skull base tumors in the AYA population with a reasonable late toxicity profile. Despite good clinical outcomes, around one in four AYA survivors are unemployed after treatment.

Stereotactic body radiotherapy for adrenal oligometastasis in lung cancer patients.

To report our experience on stereotactic body radiotherapy (SBRT) in adrenal metastases from lung cancer. 37 oligometastatic lung cancer patients with 38 adrenal metastases submitted to SBRT were retrospectively analyzed. SBRT was delivered by volumetric modulated arc therapy (VMAT) or helical tomotherapy (HT). Primary study end point was local recurrence-free survival (LR-FS) and secondary end points were distant-progression free survival (d-PFS) and overall survival (OS). Median age was 67 years and primary tumor was non-small-cell lung cancer in 27 (73%) and small-cell lung cancer in 10 (27%) patients. Adrenal metastases were in the left side in 66% cases. Median prescribed dose was 30 Gy in 5 fractions for a median biologically equivalent dose (α/β ratio 10 Gy, BED10) of 48 Gy. Most patients (62%) were submitted to SBRT alone, while the others (38%) received chemo-, immune- or target- therapies. Median follow-up was 10.5 months, median OS 16 months and median d-PFS 3 months. 27 (70%) patients obtained a local control with a median LR-FS of 32 months. LR-FS was significantly related to BED10 with a better LC with BED10 ≥72 Gy, 1- and 2 year LR-FS rates were 54.1±11.6% and 45±12.7% vs 100 and 100% for BED ≤59.5 Gy and BED ≥72 Gy, respectively (p = 0.05). There was no severe toxicity. SBRT was effective and safe in lung cancer adrenal metastases. A dose-response relationship was found between BED10 >72 Gy and better local control. No significant toxicity was registered thanks to the respect of dose constraints and suspension of chemo- and target-therapies. SBRT with a BED10 >72 Gy is an effective treatment for adrenal oligometastatic lung cancer patients.

Value of CT-Guided Percutaneous Irreversible Electroporation Added to FOLFIRINOX Chemotherapy in Locally Advanced Pancreatic Cancer: A Post Hoc Comparison

PurposeTo compare survival after CT-guided percutaneous irreversible electroporation (IRE) and folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) chemotherapy versus FOLFIRINOX only in patients with locally advanced pancreatic cancer (LAPC). Materials and MethodsA post hoc comparison was performed of data derived from a prospective IRE-FOLFIRINOX cohort and a retrospective FOLFIRINOX-only cohort. All patients received a minimum of 3 cycles of FOLFIRINOX for LAPC and were considered eligible for CT-guided percutaneous IRE. Endpoints included overall survival (OS), local and distant progression-free survival, and time to progression (TTP) and were compared using stratified Kaplan-Meier analysis. Patients who received > 8 cycles of FOLFIRINOX before IRE and who had tumors > 6 cm in the FOLFIRINOX-only group were excluded. ResultsOf 103 patients with a diagnosis of LAPC, 52 were deemed eligible (n = 30 IRE-FOLFIRINOX and n = 22 FOLFIRINOX-only). Patients in the FOLFIRINOX-only arm had larger tumors (53 mm ± 19 vs 38 mm ± 7, P = .340), had more locoregional lymph node metastases (23% vs 7%, P = .622), and more often received radiotherapy (7 patients vs 2 patients, P = .027); all other baseline characteristics were comparable. Median OS was 17.0 months (range, 5–35 mo; SD = 6) for IRE-FOLFIRINOX versus 12.4 months (range, 3–22 mo; SD = 6) for FOLFIRINOX-only (P = .038). After sensitivity analyses, median OS was 17.2 months (range, 6–27 mo; SD = 6) versus 12.4 months (range, 7–32 mo; SD = 10) (P = .05). Median TTP was longer in the IRE-FOLFIRINOX group: 14.2 months (range, 5–25 mo; SD = 4) versus 5.2 months (range, 2–22; SD = 6) (P = .0001). ConclusionsIn patients with LAPC after FOLFIRINOX chemotherapy, CT-guided percutaneous IRE may improve OS and TTP. This study may facilitate the design of randomized controlled trials to compare survival after IRE-FOLRINOX versus FOLFIRINOX-only.

Metastasis-directed Therapy (SBRT) Guided by PET-CT 18F-CHOLINE Versus PET-CT 68Ga-PSMA in Castration-sensitive Oligorecurrent Prostate Cancer: A Comparative Analysis of Effectiveness.

The present analysis aims to compare the impact of 18F-fluorocholine (18F-choline) and gallium-68 prostate-specific membrane antigen (68Ga-PSMA) positron emission tomography (PET)-computed tomography (CT)-guided metastases-directed therapies (MDTs) in patients with castration-sensitive oligorecurrent prostate cancer (PC). Inclusion criteria were: (1) histologically proven prostate adenocarcinoma; (2) evidence of biochemical relapse after primary tumor treatment; (3)≤ 3 hypermetabolic oligorecurrent lesions detected by 18F-choline or 68Ga-PSMA PET-CT; (4) PET-CT imaging performed in a single nuclear medicine department; (5) patients treated with upfront stereotactic body radiotherapy (SBRT) without hormone therapy; and (6) SBRT delivered with a dose per fraction≥ 5 Gy. In the case of oligoprogression (≤ 3 lesions outside the previous RT field) after MTD, a further course of SBRT was proposed; otherwise, androgen deprivation therapy (ADT) was administered. A total of 118 lesions in 88 patients were analyzed. Forty-four (50%) patients underwent 68Ga-PSMA PET-guided SBRT, and the remaining underwent choline PET-based SBRT. The median follow-up was 25 months (range, 5-87 months) for the entire cohort. Overall survival and local control were both 100%. Distant progression occurred in 48 (54.5%) patients, for a median distant progression-free survival of 22.8 months (range, 14.4-28.8 months). The median pre-SBRT prostate-specific antigen was 2.04 ng/mL in the choline PET cohort and 0.58 ng/mL in the PSMA-PET arm. Disease-free survival rates were 63.6% and 34%, respectively, in the 68Ga-PSMA and choline PET group (P= .06). The ADT administration rate was higher after choline-PET-guided SBRT (P= .00) owing to the higher incidence of polymetastatic disease after first-course SBRT compared with 68Ga-PSMA-based SBRT. In the setting of oligorecurrent castration-sensitive PC, PSMA-PET-guided SBRT produced a higher rate of ADT-free patients when compared with the 18F-choline-PET cohort. Randomized trials are advocated.

Carbon ion reirradiation compared to intensity-modulated re-radiotherapy for recurrent head and neck cancer (CARE): a randomized controlled trial

BackgroundIntensity-modulated re-radiotherapy (reIMRT) has been established as a standard local treatment option in patients with non-resectable, recurrent head and neck cancer (rHNC). However, the clinical outcome is unfavorable and severe toxicities (≥grade III) occurred in 30–40% of patients. The primary aim of the current trial is to investigate carbon ion reirradiation (reCIRT) compared to reIMRT in patients with rHNC regarding safety/toxicity as well as local control, overall survival (OS), and quality of life (QoL).MethodsThe present trial will be performed as a single center, two-armed, prospective phase II study. A maximum of 72 patients will be treated with either reIMRT or reCIRT to evaluate severe (≥grade III) treatment-related toxicities (randomization ratio 1:1). The primary target value is to generate less than 35% acute/subacute severe toxicity (≥grade III), according to the Common Terminology Criteria for Adverse Events v5.0, within 6 months after study treatment. The total dose of reirradiation will range between 51 and 60 Gy or Gy (RBE), depending primarily on the radiotherapy interval and the cumulative dose to organs at risk. Individual dose prescription will be at the discretion of the treating radiation oncologist. The local and distant progression-free survival 12 months after reirradiation, the OS, and the QoL are the secondary endpoints of the trial. Explorative trial objectives are the longitudinal investigation of clinical patient-related parameters, tumor parameters on radiological imaging, and blood-based tumor analytics.DiscussionRecent retrospective studies suggested that reCIRT could represent a feasible and effective treatment modality for rHNC. This current randomized prospective trial is the first to investigate the toxicity and clinical outcome of reCIRT compared to reIMRT in patients with rHNC.Trial registrationClinicalTrials.gov; NCT04185974; December 4th 2019.

Stereotactic Body Radiation Therapy in the Management of Oligometastatic and Oligoprogressive Bladder Cancer and Other Urothelial Malignancies

AimsBladder cancer represents the most common type of urothelial carcinoma, with a median overall survival of 12.5–15 months in the case of metastatic disease. We evaluated the role of stereotactic body radiation therapy (SBRT) in the management oligometastatic urothelial cancer. Materials and methodsData on patients with a maximum of five metastases were collected from three institutions. Concomitant systemic therapy was allowed. End points were the local control of treated metastases, distant progression-free survival (PFS), overall PFS and overall survival. ResultsData for 82 lesions and 61 patients were included. The primary tumour was located in the bladder in 82% of patients, followed by kidney pelvis (11.5%). The most common treated site was lung (40.2%). Twenty-nine (47.5%) and 14 (23%) patients received systemic therapy before and during SBRT, respectively. The median BED10 value was 78.7 Gy. The median follow-up was 17.2 months. Rates of local control at 1 and 2 years were 92% and 88.9%, respectively, with correlation with systemic therapy before SBRT (hazard ratio 2.62, P = 0.034). Overall PFS at 1 and 2 years was 47.9% and 38.1%, respectively. The number of metastases was a predictive factor (hazard ratio 2.65, P = 0.008). The median overall survival was 25.6 months. Total dose (hazard ratio 0.93, P = 0.003) and BED10 (hazard ratio 0.97, P = 0.006) were correlated with overall survival. No grade ≥2 adverse events were reported. ConclusionsSBRT represents an effective and safe treatment in metastatic urothelial carcinoma. Prospective randomised trials are necessary to better evaluate the benefit on delaying the onset of new systemic therapies.

Abstract IA09: Beyond counting: Imaging flow cytometry-based detection of therapeutic molecular targets in circulating tumor cells

Abstract Detection of circulating tumor cells (CTCs) has been established as a blood-based biomarker of poor prognosis in most types of epithelial cancer. The observation of increased CTC detection rates in patients with metastatic disease supported the hypothesis that CTCs might represent the precursor cells of distant metastases. Experimental proof for this hypothesis was provided by studies in experimental mouse models in which single metastasis-initiating cells within the total pool of CTCs could be causally linked to the formation of distant metastases. In addition, a potential of CTCs of reseeding at the primary site has been reported, suggesting that CTCs could also play a role in local tumor recurrence. Enumeration and molecular characterization of CTCs might thus be clinically exploited for improving the clinical management of epithelial cancers both in the locally advanced and recurrent/metastatic disease setting. Numerous studies reported on the presence of CTCs in peripheral blood samples of head and neck squamous cell carcinoma (HNSCC) patients. Significant associations with clinical high-risk parameters such as advanced stage, high tumor burden, nodal disease, and distant metastasis were reported. Accordingly, CTC detection was correlated with increased risk of local and/or distant recurrence, progression-free and overall survival. Current data in HNSCC are not yet robust enough for the implementation of CTC detection in clinical routine. In addition, the mere enumeration of CTCs has proven insufficiently informative to prompt widespread clinical adoption. There is accumulating evidence that more extended phenotyping of CTCs might be necessary for improving their diagnostic value. Indeed, despite the estimated daily shedding of millions of tumor cells from the bulk tumor tissue, only a small subpopulation of CTCs is able to reach and survive in the blood circulation and to contribute to the formation of distant metastasis. Identification of the true metastasis-inducing subclones within the bulk CTC population remains a challenge but is imperative in order to improve the diagnostic potential of CTCs. In addition, improved knowledge of the relevant biologic mechanisms endowing CTCs with the potential to emigrate from the primary site to blood circulation, to survive their journey, and to reseed at distant organs will support the development of novel antimetastatic therapies. Several technologies are currently available that allow multiparametric CTC phenotyping at the single-cell level. These platforms include imaging flow cytometry (IFC), by which multispectral images from a large number of cells acquired in suspension can be analyzed. By combining the features of flow cytometry and fluorescent microscopy, information on the cell morphology together with the extent of target protein expression and its subcellular localization can be collected. This provides a unique opportunity for statistical analysis of large populations, but also helps in avoiding artifacts. In the talk, the evidence of a prognostic role of CTCs in HNSCc will be summarized. Results from recent studies reporting on multiparametric CTC phenotyping at the single-cell level will be presented. Examples of CTC-based biomarkers that could be exploited for the optimization of current molecular treatment strategies in HNSCC will be discussed. Citation Format: Ingeborg Tinhofer. Beyond counting: Imaging flow cytometry-based detection of therapeutic molecular targets in circulating tumor cells [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr IA09.

Stereotactic body radiotherapy in the management of oligometastatic and recurrent biliary tract cancer: single-institution analysis of outcome and toxicity

Biliary tract cancers (BTC) are rare malignancies arising from biliary system. Systemic therapy is the cornerstone for stage IV disease, with poor overall survival (OS). Evidence is lacking about safety and efficacy of local ablative treatments, such as surgery and stereotactic body radiotherapy (SBRT) in the context of metastatic BTC (mBTC). We retrospectively analyzed clinical outcomes for a cohort of mBTC patients treated with SBRT for oligometastatic disease. Inclusion criteria were 1-5 distant metastases; SBRT with a dose/fraction of a least 5Gy to a biological effective dose (BED) of at least 40Gy considering an α/β of 10Gy. Analyzed outcomes included local control (LC), distant progression-free survival (DPFS), PFS, and OS. 51 patients meeting the inclusion criteria. Primary tumor sites were intrahepatic cholangiocarcinoma (35%), extrahepatic cholangiocarcinoma (31%), ampullary adenocarcinoma (20%), gallbladder adenocarcinoma (14%). 21 patients were treated on liver lesions, 17 on nodal metastasis, 5 patients on lung lesions, 4 patients on recurrence along the extrahepatic bile duct. After a median follow-up of 14months median OS was 13.7months, 1- and 2-year OS were 58% and 41%, respectively. Node and lung as metastatic sites were associated with a longer OS (p < 0.001). Median LC was 26.8months, and intrahepatic cholangiocarcinoma was associated with longer LC (p = 0.036). Median DPFS was 11months, with 1- and 2-year DPFS of 48% and 27.8%, respectively. Ten patients reported grade 1-2 toxicity and 2 cases of acute G3 biliary obstruction. Stereotactic body radiotherapy (SBRT) is feasible in the context of mBTC. OS and PFS results are promising, considering that our patients were heavily pre-treated with systemic therapy. Patients with nodal or lung relapse have better prognosis. Distant relapses remain the main pattern of failure, but treatment of all metastatic sites seems to improve DMFS.

International Multicenter Experience of Isolated Limb Infusion for In-Transit Melanoma Metastases in Octogenarian and Nonagenarian Patients.

Isolated limb infusion (ILI) is used to treat in-transit melanoma metastases confined to an extremity. However, little is known about its safety and efficacy in octogenarians and nonagenarians (ON). ON patients (≥ 80years) who underwent a first ILI for American Joint Committee on Cancer seventh edition stage IIIB/IIIC melanoma between 1992 and 2018 at nine international centers were included and compared with younger patients (< 80years). A cytotoxic drug combination of melphalan and actinomycin-D was used. Of the 687 patients undergoing a first ILI, 160 were ON patients (median age 84years; range 80-100years). Compared with the younger cohort (n = 527; median age 67years; range 29-79years), ON patients were more frequently female (70.0% vs. 56.9%; p = 0.003), had more stage IIIB disease (63.8 vs. 53.3%; p = 0.02), and underwent more upper limb ILIs (16.9% vs. 9.5%; p = 0.009). ON patients experienced similar Wieberdink limb toxicity grades III/IV (25.0% vs. 29.2%; p = 0.45). No toxicity-related limb amputations were performed. Overall response for ON patients was 67.3%, versus 64.6% for younger patients (p = 0.53). Median in-field progression-free survival was 9months for both groups (p = 0.88). Median distant progression-free survival was 36 versus 23months (p = 0.16), overall survival was 29 versus 40months (p < 0.0001), and melanoma-specific survival was 46 versus 78months (p = 0.0007) for ON patients compared with younger patients, respectively. ILI in ON patients is safe and effective with similar response and regional control rates compared with younger patients. However, overall and melanoma-specific survival are shorter.

Pencil Beam Scanning Proton Therapy for Paediatric Neuroblastoma with Motion Mitigation Strategy for Moving Target Volumes

AimsMore efforts are required to minimise late radiation side-effects for paediatric patients. Pencil beam scanning proton beam therapy (PBS-PT) allows increased sparing of normal tissues while maintaining conformality, but is prone to dose degradation from interplay effects due to respiratory motion. We report our clinical experience of motion mitigation with volumetric rescanning (vRSC) and outcomes of children with neuroblastoma. Materials and methodsNineteen patients with high-risk (n = 16) and intermediate-risk (n = 3) neuroblastoma received PBS-PT. The median age at PBS-PT was 3.5 years (range 1.2–8.6) and the median PBS-PT dose was 21 Gy (relative biological effectiveness). Most children (89%) were treated under general anaesthesia. Seven patients (37%) underwent four-dimensional computed tomography for motion assessment and were treated with vRSC for motion mitigation. ResultsThe mean result of maximum organ motion was 2.7 mm (cranial–caudal), 1.2 mm (left–right), 1.0 mm (anterior–posterior). Four anaesthetised children (21%) showing <5 mm motion had four-dimensional dose calculations (4DDC) to guide the number of vRSC. The mean deterioration or improvement to the planning target volume covered by 95% of the prescribed dose compared with static three-dimensional plans were: 4DDC no vRSC, –0.6%; 2 vRSC, +0.3%; 4 vRSC, +0.3%; and 8 vRSC, +0.1%. With a median follow-up of 14.9 months (range 2.7–49.0) there were no local recurrences. The 2-year overall survival was 94% and distant progression-free survival was 76%. Acute grade 2–4 toxicity was 11%. During the limited follow-up time, no late toxicities were observed. ConclusionsThe early outcomes of mainly high-risk patients with neuroblastoma treated with PBS-PT were excellent. With a subset of our cohort undergoing PBS-PT with vRSC we have shown that it is logistically feasible and safe. The clinical relevance of vRSC is debatable in anaesthetised children with small pre-PBS-PT motion of <5 mm.

Influence of concurrent chemotherapy on locoregionally advanced nasopharyngeal carcinoma treated with neoadjuvant chemotherapy plus intensity-modulated radiotherapy: A retrospective matched analysis

Neoadjuvant chemotherapy (NAC) combined with intensity-modulated radiotherapy (IMRT) plus concurrent chemotherapy (CC) will be the new standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC) patients. However, many patients fail to receive CC for multiple reasons. We aimed to investigate long-term survival outcomes and toxicities in these patients with NPC treated with additional NAC plus concurrent chemoradiotherapy (CCRT) or IMRT alone. In total, 1,378 previously untreated, newly diagnosed locoregionally advanced NPC patients receiving NAC plus IMRT with or without CC were retrospectively reviewed. We used a propensity score-matched (PSM) method with 1:1 matching to identify paired patients according to various covariates. Survival outcomes and toxicities were compared between the two groups. In total, 288 pairs were identified. With a median follow-up of 86 (range: 8–110) months, the estimated 5-year locoregional relapse-free survival, distant metastasis-free survival, progression-free survival (PFS), and overall survival rates in patients treated with NAC plus CCRT vs. NAC plus IMRT alone were 96.1% vs. 94.7% (P = 0.201), 93.7% vs. 89.8% (P = 0.129), 91.3% vs. 85.1% (P = 0.024), and 93.0% vs. 90.6% (P = 0.362), respectively. Multivariate analysis showed that CC omission was a prognostic factor for worse PFS. In a subgroup analysis, PFS did not differ significantly between two groups of female patients or aged <60 years or stage T1–2 or stage N0-1 disease. However, fewer acute complications were observed in the NAC plus IMRT alone group. NAC with IMRT alone confers similar survival rates and less acute toxicities. Specifically, NAC plus IMRT alone may be enough for female patients <60 years with stage T1-2 or stage N0-1. However, a prospective randomised trial is needed to validate these results.

Stereotactic MR-guided on-table adaptive radiation therapy (SMART) for locally advanced pancreatic cancer.

TPS786 Background: Standard dose radiation therapy has been unsuccessful in inoperable pancreatic cancer; with a negative study (LAP07) for conventional chemoradiation and dropping of the stereotactic body radiation therapy arm in Alliance A021501. Recently, reports of using high dose ablative radiation therapy has been associated with increased survival in retrospective studies. Moreover, technological advances with MRI-guided radiation therapy offer improved targeting and the ability to change the radiation delivery on a daily fashion; allowing ablative radiation doses over one week. However, it is not clear whether this can be done safely on a multiinstitutional basis. Methods: We are conducting the largest prospective study of ablative radiation therapy in pancreatic cancer. The study is a single arm, multi-institutional phase II, industry sponsored study to investigate the safety and efficacy of Stereotactic, MR guided, on-table-Adaptive Radiation Therapy (SMART). Eligibility criteria include locally advanced and borderline resectable pancreatic cancer patients with ECOG PS of 0 or 1; who have non-metastatic disease after a minimum of 3 months of any systemic therapy; including investigational agents. Patients will receive MR-guided radiation therapy to a dose of 50 Gy / 5 fractions; with maximum tumor coverage delivered each fraction that allows keeping the gastrointestinal organs at risk to a dose of 33 Gy or less. Primary endpoint is grade 3 of higher gastrointestinal toxicity at 90 days. Secondary endpoints are overall survival at 2 years, distant progression free survival at 6 months, and changes in patient related quality of life at 3 and 12 months. Target sample size was calculated to show at a significance level 0.05, a reduction of the toxicity rate to 8% or lower by using SMART compared with 15.8%, the toxicity rate of conventionally delivered chemoradiation at a power level 0.8. Given an expected 15% drop-out, the enrollment goal is 133. Descriptive statistics will be used for secondary objectives. The study opened in January, 2019 and is currently opened at 4 centers; with other US and international sites pending. Sponsored by Viewray, Inc. Clinical trial information: NCT03621644.

Stereotactic ablative radiotherapy and systemic treatments for extracerebral oligometastases, oligorecurrence, oligopersistence and oligoprogression from lung cancer

BackgroundStereotactic irradiation (SBRT) is a standard of care for inoperable stage I lung cancer and brain oligometastases from lung cancer but is controversial for extracranial oligometastases. We assessed outcomes of lung cancer patients with extracranial metastases in oligometastatic, oligorecurrent, oligopersistent and oligoprogressive settings (“oligometastatic spectrum”) under strategies using SBRT +/− systemic treatments.MethodsA retrospective multicentric study of consecutive lung cancer adult patients with 1–5 extracranial metastases treated with SBRT was conducted.ResultsOf 91 patients (99 metastases, median age 63, 64.8% adenocarcinomas, 19.8% molecular alterations), 11% had oligometastases, 49.5% oligorecurrence, 19.8% oligopersistence and 19.8% oligoprogression. Of 36% of patients under systemic treatments at initiation of SBRT, systemic treatment interruption was performed in 58% of them. With median follow up of 15.3 months, crude local control at irradiated metastases was 91%, while median distant progression-free survival (dPFS) and overall survival were 6.3 and 28.4 months (2-year survival 54%). Initial nodal stage and oligometastatic spectrum were prognostic factors for dPFS; age, initial primary stage and oligometastatic spectrum were prognostic factors for survival on multivariate analysis. Patients with oncogene-addicted tumors more frequently had oligoprogressive disease. Repeat ablative irradiations were preformed in 80% of patients who had oligorelapses. Worst acute toxicities consisted of 5.5% and one late toxic death occurred.ConclusionThe oligometastatic spectrum is a strong prognosticator in patients undergoing SBRT for extracranial metastases. Median survival was over two years but dPFS was about 6 months. Continuation of systemic therapy in oligoprogressive patients should be investigated.