Safety and feasibility of prostate stereotactic ablative radiotherapy using multi-modality imaging and flattening filter free

OBJECTIVE: To investigate feasibility and safety of stereotactic ablative radiotherapy in the management of prostate cancer while employing MR/CT fusion for delineation, fiducial marker seeds for positioning and Varian RapidArc with flattening filter free (FFF) delivery. METHODS: 41 patients were treated for low-intermediate risk prostate cancer with initial prostate-specific antigen of ≤20 ng ml−1, Gleason score 6–7. Patients had MR/CT fusion for delineation of prostate ±seminal vesicles. CT/MR fusion images were used for delineation and planned using flattening filter free modality. Verification on treatment was cone beam CT imaging with fiducial markers for matching. Patients had Radiation Therapy Oncology Group scoring for genitourinary and gastointestinal symptoms at baseline, week 4, 10 and 18. RESULTS: Clinically acceptable plans were achieved for all patients, all plans achieved the objective clinical target volume D99% ≥ 95%, and for planning target volume D95% ≥ 95%. Rectum dose constraints were met for 95.1% for V18 Gy ≤ 35%, 80% V28 Gy ≤ 10%. A total of 32 (78.0%) plans achieved all rectum dose constraints. Grade 1 acute genitourinary symptoms were 53.7% of patients at baseline, 90.2% [95% CI (76.8–97.3%)] (p = 0.0005) at treatment 5, falling to 78.0% (62.4–89.4%) at week 4, and 75.0% (58.8–87.3%) by week 10 and 52.5% (36.1–68.5%) (p = 1.00) at week 18. Acute gastrointestinal symptoms were 5% at baseline, 46.3% [95% CI (30.7–62.6%)] at treatment 5, week 4 43.9% [95% CI (28.5–60.3%)], week 10 25.0% (11.1–42.3%), and declined slightly by week 18 [–20.095% CI (12.7–41.2)] p = 0.039. Overall 75.6% (31/41) of patients experienced Grade 1–2 toxicity during or after treatment. CONCLUSION: This planning and delivery technique is feasible, safe and efficient. A homogeneous dose can be delivered to prostate with confidence, whilst limiting high dose to nearby structures. The use of this technology can be applied safely within further randomized study protocols

Tisotumab Vedotin in Combination With Carboplatin, Pembrolizumab, or Bevacizumab in Recurrent or Metastatic Cervical Cancer: Results From the innovaTV 205/GOG-3024/ENGOT-cx8 Study.

PURPOSE: Tissue factor is highly expressed in cervical carcinoma and can be targeted by tisotumab vedotin (TV), an antibody-drug conjugate. This phase Ib/II study evaluated TV in combination with bevacizumab, pembrolizumab, or carboplatin for recurrent or metastatic cervical cancer (r/mCC). METHODS: This open-label, multicenter study (ClinicalTrials.gov identifier: NCT03786081) included dose-escalation arms that assessed dose-limiting toxicities (DLTs) and identified the recommended phase II dose (RP2D) of TV in combination with bevacizumab (arm A), pembrolizumab (arm B), or carboplatin (arm C). The dose-expansion arms evaluated TV antitumor activity and safety at RP2D in combination with carboplatin as first-line (1L) treatment (arm D) or with pembrolizumab as 1L (arm E) or second-/third-line (2L/3L) treatment (arm F). The primary end point of dose expansion was objective response rate (ORR). RESULTS: A total of 142 patients were enrolled. In dose escalation (n = 41), no DLTs were observed; the RP2D was TV 2 mg/kg plus bevacizumab 15 mg/kg on day 1 once every 3 weeks, pembrolizumab 200 mg on day 1 once every 3 weeks, or carboplatin AUC 5 on day 1 once every 3 weeks. In dose expansion (n = 101), the ORR was 54.5% (n/N, 18/33; 95% CI, 36.4 to 71.9) with 1L TV + carboplatin (arm D), 40.6% (n/N, 13/32; 95% CI, 23.7 to 59.4) with 1L TV + pembrolizumab (arm E), and 35.3% (12/34; 19.7 to 53.5) with 2L/3L TV + pembrolizumab (arm F). The median duration of response was 8.6 months, not reached, and 14.1 months, in arms D, E, and F, respectively. Grade ≥3 adverse events (≥15%) were anemia, diarrhea, nausea, and thrombocytopenia in arm D and anemia in arm F (none ≥15%, arm E). CONCLUSION: TV in combination with bevacizumab, carboplatin, or pembrolizumab demonstrated manageable safety and encouraging antitumor activity in treatment-naive and previously treated r/mCC

Tisotumab Vedotin in Combination with Carboplatin, Pembrolizumab, or Bevacizumab in Recurrent or Metastatic Cervical Cancer:Results from the innovaTV 205/GOG-3024/ENGOT-cx8 Study

PURPOSE Tissue factor is highly expressed in cervical carcinoma and can be targeted by tisotumab vedotin (TV), an antibody-drug conjugate. This phase Ib/II study evaluated TV in combination with bevacizumab, pembrolizumab, or carboplatin for recurrent or metastatic cervical cancer (r/mCC). METHODS This open-label, multicenter study (ClinicalTrials.gov identifier: NCT03786081) included dose-escalation arms that assessed dose-limiting toxicities (DLTs) and identified the recommended phase II dose (RP2D) of TV in combination with bevacizumab (arm A), pembrolizumab (arm B), or carboplatin (arm C). The dose-expansion arms evaluated TV antitumor activity and safety at RP2D in combination with carboplatin as first-line (1L) treatment (arm D) or with pembrolizumab as 1L (arm E) or second-/third-line (2L/3L) treatment (arm F). The primary end point of dose expansion was objective response rate (ORR). RESULTS A total of 142 patients were enrolled. In dose escalation (n = 41), no DLTs were observed; the RP2D was TV 2 mg/kg plus bevacizumab 15 mg/kg on day 1 once every 3 weeks, pembrolizumab 200 mg on day 1 once every 3 weeks, or carboplatin AUC 5 on day 1 once every 3 weeks. In dose expansion (n = 101), the ORR was 54.5% (n/N, 18/33; 95% CI, 36.4 to 71.9) with 1L TV + carboplatin (arm D), 40.6% (n/N, 13/32; 95% CI, 23.7 to 59.4) with 1L TV + pembrolizumab (arm E), and 35.3% (12/34; 19.7 to 53.5) with 2L/3L TV + pembrolizumab (arm F). The median duration of response was 8.6 months, not reached, and 14.1 months, in arms D, E, and F, respectively. Grade ≥3 adverse events (≥15%) were anemia, diarrhea, nausea, and thrombocytopenia in arm D and anemia in arm F (none ≥15%, arm E).CONCLUSION TV in combination with bevacizumab, carboplatin, or pembrolizumab demonstrated manageable safety and encouraging antitumor activity in treatment-naive and previously treated r/mCC.</p

Dosimetric impact of organ at risk daily variation during prostate stereotactic ablative radiotherapy

Objective: Prostate stereotactic ablative radiotherapy (SABR) delivers large doses using a fast dose rate. This amplifies the effect geometric uncertainties have on normal tissue dose. The aim of this study was to determine whether the treatment dose–volume histogram (DVH) agrees with the planned dose to organs at risk (OAR). Methods: 41 low–intermediate risk prostate cancer patients were treated with SABR using a linac based technique. Dose prescribed was 35 Gy in five fractions delivered on alternate days, planned using volumetric modulated arc therapy (VMAT) with 10X flattening filter free (FFF). On treatment, prostate was matched to fiducial markers on cone beam CT (CBCT). OAR were retrospectively delineated on 205 pre-treatment CBCT images. Daily CBCT contours were overlaid on the planning CT for dosimetric analysis. Verification plan used to evaluate the daily DVH for each structure. The daily doses received by OAR were recorded using the D%. Results: The median rectum and bladder volumes at planning were 67.1 cm3 (interquartile range 56.4–78.2) and 164.4 cm3 (interquartile range 120.3–213.4) respectively. There was no statistically significant difference in median rectal volume at each of the five treatment scans compared to the planning scan (p = 0.99). This was also the case for median bladder volume (p = 0.79). The median dose received by rectum and bladder at each fraction was higher than planned, at the majority of dose levels. For rectum the increase ranged from 0.78–1.64Gy and for bladder 0.14–1.07Gy. The percentage of patients failing for rectum D35% &lt; 18 Gy (p = 0.016), D10% &lt; 28 Gy (p = 0.004), D5% &lt; 32 Gy (p = 0.0001), D1% &lt; 35 Gy (p = 0.0001) and bladder D1% &lt; 35 Gy (p = 0.001) at treatment were all statistically significant. Conclusion: In this cohort of prostate SABR patients, we estimate the OAR treatment DVH was higher than planned. This was due to rectal and bladder organ variation. Advances in knowledge: OAR variation in prostate SABR using a FFF technique, may cause the treatment DVH to be higher than planned