Practice-oriented solutions integrating intraoperative electron irradiation and personalized proton therapy for recurrent or unresectable cancers: Proof of concept and potential for dual FLASH effect

Abstract

Background: Oligo-recurrent disease has a consolidated evidence of long-term surviving patients due to the use of intense local cancer therapy. The latter combines real-time surgical exploration/resection with high-energy electron beam single dose of irradiation. This results in a very precise radiation dose deposit, which is an essential element of contemporary multidisciplinary individualized oncology.

Methods: Patient candidates to proton therapy were evaluated in Multidisciplinary Tumor Board to consider improved treatment options based on the institutional resources and expertise. Proton therapy was delivered by a synchrotron-based pencil beam scanning technology with energy levels from 70.2 to 228.7 MeV, whereas intraoperative electrons were generated in a miniaturized linear accelerator with dose rates ranging from 22 to 36 Gy/min (at Dmax) and energies from 6 to 12 MeV.

Results: In a period of 24 months, 327 patients were treated with proton therapy: 218 were adults, 97 had recurrent cancer, and 54 required re-irradiation. The specific radiation modalities selected in five cases included an integral strategy to optimize the local disease management by the combination of surgery, intraoperative electron boost, and external pencil beam proton therapy as components of the radiotherapy management. Recurrent cancer was present in four cases (cervix, sarcoma, melanoma, and rectum), and one patient had a primary unresectable locally advanced pancreatic adenocarcinoma. In re-irradiated patients (cervix and rectum), a tentative radical total dose was achieved by integrating beams of electrons (ranging from 10- to 20-Gy single dose) and protons (30 to 54-Gy Relative Biological Effectiveness (RBE), in 10-25 fractions).

Conclusions: Individual case solution strategies combining intraoperative electron radiation therapy and proton therapy for patients with oligo-recurrent or unresectable localized cancer are feasible. The potential of this combination can be clinically explored with electron and proton FLASH beams.

Keywords: cancer; electron FLASH; oligorrecurrent; proton therapy FLASH; reirradiation.

Figure 1

Recurrent plantar melanoma of the right foot treated with a combination of IOeRT and proton therapy. (A) Applicator positioning to encompass the post-resection bed including involved margins and the area at high risk for recurrence (skin is protected; key structure for the viability of the flap-repair maneuver). (B) Beam’s eye view of the target. (C) Linear accelerator and surgical room arrangement (notice the use of a beam-stopper). (D) Individualized bolus for proton therapy. (E, F) Dosimetric performance of the proton pencil beam. (G) Outcome of the myocutaneous flap employed for repair.

Figure 2

Recurrent synovial sarcoma of the lumbar fossae treated with proton therapy and IOeRT. (A) Restaging PET-CT after proton therapy. (B) Pre-proton therapy PET-CT showing metabolic active persistant disease before chemo-radiation in the retroperitoneal left lumbar fossae. (C) Single field proton beam arrangement and dose distribution. (D) Beam’s eye view of IOeRT: no mobile sensitive tissues in the target displaced mechanically.

Figure 3

Oligo-recurrent rectal cancer treated with proton therapy and IOeRT under re-irradiation conditions (previous treatment components included neoadjuvant chemoradiation, hypofractionated perioperative high-dose rate brachytherapy, and stereotactic body radiotherapy). (A) Oligo-recurrent pelvic disease for small bowel displacement progressing after previous tri-irradiation from the proton beam. (B) Beam’s eye view of the target and post-docking view of the surgical area. (C) Proton beam field arrangement and dosimetric distribution. (D) Spacer made of epiplon at the time of surgical resection and IOeRT procedure.

Figure 4

Recurrent cervix cancer patient treated with lymphadenectomy, IOeRT, and proton therapy after nodal oligo-progression outside the previous areas of external irradiation and brachytherapy. (A) Proton therapy field arrangements and dose-distributions. (B) Beam’s eye view of the IOeRT target (notice the absence of dose-sensitive tissues such as bowel and ureters).

Figure 5

Imaging studies evolution in a patient with unresectable pancreatic cancer treated with induction chemotherapy FOLFIRINOX, neoadjuvant chemo-radiation with proton therapy and IOeRT boost consolidation. (A) Initial diagnostic studies (angioCT, MRI, and PET-CT) showing the vascular involvement and unresectable nature of the disease. (B) Post-treatment imaging studies showing a complete metabolic remission and a 360° encasement of the superior mesenteric artery.

Figure 6

Treatment planning images from proton therapy. (A) Two-dimensional representation (red, 54 Gy; green line, 45 Gy). (B) Three-dimensioanl reconstruction dose distribution with special emphasis of the CTV and the duodenum (solid pink structure).

Figure 7

Combined surgical and IOeRT procedure in a patient with unresectable cancer of the body of the pancreas with 360° involvement of the superior mesenteric artery explored and treated after intense neoadjuvant therapy and complete metabolic remission (including tumor markers normalization). (A) Surgical maneuvers to guide the IOeRT procedure (ultrasound delimitation of residual abnormalities; target definition with surgical clips; measurements for applicator selection. (B) Ultrasound measures for electron energy, applicator size selection, and the effect of the displacement of the duodenum from the target by the use of a spacer. (C) External view of the surgical field and IOeRT applicator positioning. (D) Beam’s eye view of the target (notice the margin around the markers fixed at the time of intraoperative ultrasound assessment).