Phase 1 trial of preoperative image guided intensity modulated proton radiation therapy with simultaneously integrated boost to the high risk margin for retroperitoneal sarcomas

Abstract

PurposeTo conduct phase 1 and 2 trials with photon intensity modulated radiation therapy and intensity modulated proton therapy (IMPT) arms to selectively escalate the retroperitoneal sarcoma preoperative radiation dose to tumor volume (clinical target volume [CTV] 2) that is judged to be at a high risk for positive margins and aim to reduce local recurrence. We report on the IMPT study arm in phase 1.Methods and materialsPatients aged ≥18 years with primary or locally recurrent retroperitoneal sarcoma were treated with preoperative IMPT, 50.4 GyRBE in 28 fractions, to CTV1 (gross tumor volume and adjacent tissues at risk of subclinical disease) with a simultaneous integrated boost to CTV2 to doses of 60.2, 61.6, and 63.0 GyRBE in 28 fractions of 2.15, 2.20, and 2.25 GyRBE, respectively. The primary objective of the phase 1 study was to determine the maximum tolerated dose to CTV2, which will be further tested in the phase 2 study.ResultsEleven patients showed increasing IMPT dose levels without acute dose limiting toxicities that prevented dose escalation to maximum tolerated dose. Acute toxicity was generally mild with no radiation interruptions. No unexpected perioperative morbidity was noted. Eight months postoperatively, one patient developed hydronephrosis that was treated by stent with ureter dissected off tumor and received 57.5 GyRBE. Retained ureter(s) was (were) subsequently constrained to 50.4 GyRBE without further problem. With an 18-month median follow-up, there were no local recurrences.ConclusionsIMPT dose escalation to CTV2 to 63 GyRBE was achieved without acute dose limiting toxicities. The phase 2 study of IMPT will accrue patients to that dose. Parallel intensity modulated radiation therapy phase 1 arm is currently accruing at the initial dose level. Ureters that undergo a high dose radiation and/or surgery are at risk for late hydro-ureter. Future studies will constrain retained ureters to 50.4 GyRBE to avoid ureteral stricture.

Carbon ion radiotherapy for unresectable localized axial soft tissue sarcoma

“…Progress in the technology associated with various perioperative RT modalities has strengthened their potential in the surgical treatment of axial STS, especially along with margin setting. 22,23 However, for cases of unresectable axial STSs, there are still not enough data concerning the efficacy of each of the modalities. At this stage, CIRT could be a treatment option for unresectable localized axial STSs.…”

Definitive radiotherapy in the management of non-resectable or residual retroperitoneal sarcomas: institutional cohort analysis and systematic review

“…In a case series by Yoon et al (2010) preoperative proton-beam radiation therapy in RPS was shown to allow marked sparing of OARs in comparison to IMRT [44]. In a prospective, phase 1 clinical trial of preoperative intensity modulated proton therapy for RPS, a dose escalation to 63 GyE was achieved with only mild acute toxicities and one late grade-3 hydronephrosis [45]. However, results of a parallel phase 1 study of the IMRT have not yet been published.…”

Radiation therapy in retroperitoneal sarcoma management

“…This is typically the region of tumor abutting the posterior abdominal wall, vertebral bodies, and great vessels. Early reports for this technique are encouraging, but further data for both safety and efficacy are warranted before this approach can become standard practice . Mature results of a Massachusetts General Hospital‐led multi‐center Phase I‐II trial of proton and photon dose escalation are eagerly awaited .…”

“…Intensity modulated protons (IMPT) achieves dose conformality comparable to that of IMRT but with the additional benefit of a lower integral dose . As noted above, the ability to selectively increase the radiation dose with either IMRT or IMPT offers the attractive possibility of dose escalation to selected areas of the target such as the posterior abdominal wall, aorta, and vertebral bodies where it may be hardest to achieve an adequate surgical margin …”

“…37 As noted above, the ability to selectively increase the radiation dose with either IMRT or IMPT offers the attractive possibility of dose escalation to selected areas of the target such as the posterior abdominal wall, aorta, and vertebral bodies where it may be hardest to achieve an adequate surgical margin. 25,27 The dose painting approach with IMRT or IMPT may reduce some of the late toxicity reported with IORT such as neuropathy because of the lower radiation fraction size. The concept of selective dose escalation with IMPT or IMRT is currently being tested in a multicenter Phase I/II study (NCT01659203) to initially determine whether selective dose escalation to the high risk posterior target volume (defined jointly by the surgeon and the radiation oncologist) can be achieved to a dose of 63 Gy in 28 fractions (while the larger moderate risk volume receives 50.4 Gy in 28 fractions.…”