Pancreatic cancer represents a modern oncological urgency. Its management is aimed to both distal and local disease control. Resectability is the cornerstone of treatment aim. It influences the clinical presentation’s definitions as up-front resectable, borderline resectable and locally advanced (unresectable). The main treatment categories are neoadjuvant (preoperative), definitive and adjuvant (postoperative). This review will focus on (i) the current indications by the available national and international guidelines; (ii) the current standard indications for target volume delineation in radiotherapy (RT); (iii) the emerging modern technologies (including particle therapy and Magnetic Resonance [MR]-guided-RT); (iv) stereotactic body radiotherapy (SBRT), as the most promising technical delivery application of RT in this framework; (v) a particularly promising dose delivery technique called simultaneous integrated boost (SIB); and (vi) a multimodal integration opportunity: the combination of RT with immunotherapy.

Background and Objective: The aim of this study was to assess the ability of Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (¹⁸F-FDG PET/CT) to provide functional information useful in predicting pathological response to an intensive neoadjuvant chemo-radiotherapy (nCRT) protocol for both esophageal squamous cell carcinoma (SCC) and adenocarcinoma (ADC) patients.Material and Methods: Esophageal carcinoma (EC) patients, treated in our Center between 2014 and 2018, were retrospectively reviewed. The nCRT protocol schedule consisted of an induction phase of weekly administered docetaxel, cisplatin, and 5-fluorouracil (TCF) for 3 weeks, followed by a concomitant phase of weekly TCF for 5 weeks with concurrent radiotherapy (50–50.4 Gy in 25–28 fractions). Three ¹⁸F-FDG PET/CT scans were performed: before (PET₁) and after (PET₂) induction chemotherapy (IC), and prior to surgery (PET₃). Correlation between PET parameters [maximum and mean standardized uptake value (SUV_max and SUV_mean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG)], radiomic features and tumor regression grade (TGR) was investigated.Results: Fifty-four patients (35 ADC, 19 SCC; 48 cT3/4; 52 cN+) were eligible for the analysis. Pathological response to nCRT was classified as major (TRG1-2, 41/54, 75.9%) or non-response (TRG3-4, 13/54, 24.1%). A major response was statistically correlated with SCC subtype (p = 0.02) and smaller tumor length (p = 0.03). MTV and TLG measured prior to IC (PET₁) were correlated to TRG1-2 response (p = 0.02 and p = 0.02, respectively). After IC (PET₂), SUV_mean and TLG correlated with major response (p = 0.03 and p = 0.04, respectively). No significance was detected when relative changes of metabolic parameters between PET₁ and PET₂ were evaluated. At textural quantitative analysis, three independent radiomic features extracted from PET₁ images ([JointEnergy and InverseDifferenceNormalized of GLCM and LowGrayLevelZoneEmphasis of GLSZM) were statistically correlated with major response (p < 0.0002).Conclusions: ¹⁸F-FDG PET/CT traditional metrics and textural features seem to predict pathologic response (TRG) in EC patients treated with induction chemotherapy followed by neoadjuvant chemo-radiotherapy. Further investigations are necessary in order to obtain a reliable predictive model to be used in the clinical practice.

Background and Objective: To assess the dosimetric feasibility of a stereotactic body radiotherapy (SBRT) dose escalated protocol, with a simultaneous integrated boost (SIB) and a simultaneous integrated protection (SIP) approach, in patients with locally advanced pancreatic cancer (LAPC).Material and Methods: Twenty LAPC lesions, previously treated with SBRT at our Institution, were re-planned. The original prescribed and administered dose was 50/30/25 Gy in five fractions to PTV_sib (tumor-vessel interface [TVI])/PTV_t (tumor volume)/PTV_sip (overlap area between PTV_t and planning organs at risk volume [PRV_oars]), respectively. At re-planning, the prescribed dose was escalated up to 60/40/33 Gy in five fractions to PTV_sib/PTV_t/PTV_sip, respectively. All plans were performed using an inspiration breath hold (IBH) technique and generated with volumetric modulated arc therapy (VMAT). Well-established and accepted OAR dose constraints were used (D_0.5cc < 33 Gy for luminal OARs and D_0.5cc < 38 Gy for corresponding PRV_oars). The primary end-point was to achieve a median dose equal to the prescription dose for the PTV_sib with D₉₈≥ 95% (95% of prescription dose is the minimum dose), and a coverage for PTV_t and PTV_sip of D₉₅≥95%, with minor deviations in OAR dose constraints in < 10% of the plans.Results: PTV_sib median (± SD) dose/D₉₅/conformity index (CI) were 60.54 (± 0.85) Gy/58.96 (± 0.86) Gy/0.99 (± 0.01), respectively; whilst PTV_t median (± SD) dose/D₉₅ were 44.51 (± 2.69) Gy/38.44 (± 0.82) Gy, and PTV_sip median (± SD) dose/D₉₅ were 35.18 (± 1.42) Gy/33.01 (± 0.84) Gy, respectively. With regard to OARs, median (± SD) maximum dose (D_0.5cc) to duodenum/stomach/bowel was 29.31 (± 5.72) Gy/25.29 (± 6.90) Gy/27.03 (± 5.67) Gy, respectively. A minor acceptable deviation was found for a single plan (bowel and duodenum D_0.5cc=34.8 Gy). V38 < 0.5 cc was achieved for all PRV luminal OARs.Conclusions: In LAPC patients SBRT, with a SIB/SIP dose escalation approach up to 60/40/33 Gy in five fractions to PTV_sib/PTV_t/PTV_sip, respectively, is dosimetrically feasible with adequate PTVs coverage and respect for OAR dose constraints.

Different options for locally advanced pancreatic cancer (LAPC) are available based on international guidelines: chemotherapy (CHT), chemoradiation (CRT), and stereotactic body radiotherapy (SBRT). However, the role of radiotherapy is debated in LAPC. We retrospectively compared CHT, CRT, and SBRT ± CHT in a real-world setting in terms of overall survival (OS), local control (LC), and distant metastasis-free survival (DMFS). LAPC patients from a multicentric retrospective database were included (2005–2018). Survival curves were calculated using the Kaplan–Meier method. Multivariable Cox analysis was performed to identify predictors of LC, OS, and DMFS. Of the 419 patients included, 71.1% were treated with CRT, 15.5% with CHT, and 13.4% with SBRT. Multivariable analysis showed higher LC rates for CRT (HR: 0.56, _95%CI 0.34–0.92, p = 0.022) or SBRT (HR: 0.27, _95%CI 0.13–0.54, p < 0.001), compared to CHT. CRT (HR: 0.44, _95%CI 0.28–0.70, p < 0.001) and SBRT (HR: 0.40, _95%CI 0.22–0.74, p = 0.003) were predictors of prolonged OS with respect to CHT. No significant differences were recorded in terms of DMFS. In selected patients, the addition of radiotherapy to CHT is still an option to be considered. In patients referred for radiotherapy, CRT can be replaced by SBRT considering its duration, higher LC rate, and OS rate, which are at least comparable to that of CRT.

Background and Objective: To assess the efficacy of a Risk-Adapted Ablative Radiotherapy (RAdAR) approach, after intensive induction chemotherapy, in patients with locally advanced pancreatic cancer (LAPC).Material and Methods: Patients with LAPC who received RAdAR following induction chemotherapy from January 2017 to December 2019 were included in this observational study. The RAdAR approach consisted of an anatomy- and simultaneous integrated boost (SIB)-based dose prescription strategy. RAdAR was delivered with stereotactic ablative radiation therapy (SAbR), administering 30 Gy in 5 fractions to the tumor volume (PTV_t) and 50 Gy SIB (BED₁₀ 100 Gy) to the vascular involvement, or with (hypo-)fractionated ablative radiotherapy (HART) prescribing 50.4 Gy in 28 fractions to the PTV_t, with a vascular SIB of 78.4 Gy (BED₁₀ 100 Gy). Primary end points were freedom from local progression (FFLP), overall survival (OS), and progression-free survival (PFS).Results: Sixty-four LAPC patients were included. Induction chemotherapy consisted of gemcitabine/nab-paclitaxel in 60.9% and FOLFIRINOX in 39.1% of cases. SAbR was used in 52 (81.2%) patients, and HART in 12 (18.8%). After RAdAR, surgery was performed in 17 (26.6%) patients. Median follow-up was 16.1 months. Overall local control (LC) rate was 78.1%, with no difference between resected and non-resected patients (2-year FFLP 75.3% vs 56.4%; p = 0.112). Median OS and PFS were 29.7 months and 8.7 months, respectively, for the entire cohort. Resected patients had a better median OS (not reached versus 26.1 months; p = 0.0001) and PFS (19 versus 5.6 months; p < 0.0001) compared to non-resected patients. In non-resected patients, no significant difference was found between SAbR and HART for median FFLP (28.1 versus 18.5 months; p = 0.614), OS (27.4 versus 25.3 months; p = 0.624), and PFS (5.7 versus 4.3 months; p = 0.486). One patient (1.6%) experienced acute grade 4 gastro-intestinal bleeding. No other acute or late grade ≥ 3 toxicities were observed.Conclusions: The RAdAR approach, following intensive induction chemotherapy, is an effective radiation treatment strategy for selected LAPC patients, representing a promising therapeutic option in a multimodality treatment regimen.