Risk adapted dose-intensified postoperative radiation therapy in prostate cancer patients using a simultaneous integrated boost technique applied with helical Tomotherapy

Background Postoperative adjuvant radiation therapy (ART) in T3 and R1 prostate cancer as well as salvage radiation therapy (SRT) in case of postoperative biochemical failure (BF) are established treatments. Dose- intensified postoperative radiation therapy (RT) schemes have shown superior biochemical control accompanied by increased toxicity rates. In our study we evaluate a novel risk adapted dose-intensified postoperative RT scheme. Methods A consecutive series of prostate cancer patients receiving postoperative RT after radical prostatectomy using helical Tomotherapy between 04/2012 and 04/2015 was analyzed retrospectively. RT was administered using a simultaneous integrated boost (SIB) to the area at risk (37 fractions of 1.9 Gy, total dose: 70.3 Gy) being defined based on histopathological findings (T3/R1 region) and in few cases according to additional diagnostic imaging. The whole prostate bed was treated with a dose of 66.6 Gy (37 fractions of 1.8 Gy). Primary endpoints were acute and late genitourinary (GU) and gastrointestinal (GI) toxicities. Secondary endpoints included patient reported outcome as assessed by the International Prostate Symptom Score (IPSS), the International Consultation on Incontinence questionnaire (ICIQ) and prostate cancer specific Quality of Life questionnaire QLQ-PR25, as well as rates of BF. Results A total of 69 patients were analyzed. Sixteen patients underwent ART and 53 patients SRT, respectively. The median follow-up was 20 months (range, 8–41 months). Seven (10.1%) and four (5.8%) patients experienced acute grade 2 GU and GI toxicity. Two patients (2.9%) had late grade 2 GU toxicity, whereas no late grade 2 GI nor any grade 3 acute or late GU or GI events were observed. When compared to the baseline IPSS scores (p = 1.0) and ICIQ scores (p = 0.87) were not significantly different at the end of follow-up. Patient reported Quality of life (QoL) showed also no significant difference. A total of seven patients (10.1%) experienced a biochemical recurrence with the 2-year biochemical progression-free survival (bPFS) being 91%. Conclusions Postoperative RT for prostate cancer patients with a risk adapted dose-intensified SIB using helical tomotherapy is feasible and associated with favorable acute and late GU and GI toxicity rates, no significant change of IPSS-, ICIQ scores and patient reported QoL and results in promising bPFS rates

Image-guided dose-escalated radiation therapy for prostate cancer with helical tomotherapy

Einführung: Primäre und postoperative Strahlentherapie sind etablierte Behandlungsoptionen des lokalisierten Prostatakarzinoms. Das onkologische Ergebnis kann durch Dosiseskalation verbessert werden. Damit einhergehende erhöhte Nebenwirkungsraten können durch die nebenwirkungsärmere bildgeführte Strahlentherapie (IGRT) kompensiert werden. Diese Dissertation umfasst Publikationen von Wust et al., Barelkowski et al. und Beck et al., welche die dosiseskalierte primäre und postoperative IGRT des lokalisierten Prostatakarzinoms am Tomotherapie-System retrospektiv untersucht haben. Methoden: 1) Wust et al. unternahmen einen Vergleich der Bestrahlungsgenauigkeit der primären IGRT basierend auf Megavoltcomputertomographien (MVCT) bzw. implantierten Markern. 2) Barelkowski et al. analysierten die klinischen Ergebnisse einer Kohorte, welche mit primärer MVCT-basierter IGRT behandelt wurde. Die verschriebene Dosis in der Prostata betrug bei niedrigem und günstigem intermediärem Risiko 80 Gy in 40 Fraktionen und bei ungünstigem intermediärem und hohem Risiko 84 Gy in 42 Fraktionen. 3) Beck et al. analysierten die klinischen Ergebnisse einer Kohorte, welche mit postoperativer MVCT-basierter IGRT behandelt wurde. Die verschriebene Dosis im Risikogebiet betrug 70,3 Gy in 37 Fraktionen. Ergebnisse: 1) Die Berechnungen erfolgten anhand eines repräsentativen Datensatzes von Patienten, welche mit MVCT- (n = 43) bzw. markerbasierter (n = 15) IGRT behandelt wurden. Insbesondere in vertikaler Richtung ergaben sich bei der MVCT-basierten Einstellung größere residuelle interfraktionelle Verschiebungen und Sicherheitssäume. Dies führte allerdings nur zu moderaten dosimetrischen Nachteilen (D95% im CTV: 76,5 Gy vs. 78,4 Gy). Die Dosisbelastung in den Risikoorganen lag bei beiden Gruppen weit unter üblichen Grenzwerten. 2) Achtundachtzig konsekutive Patienten wurden mit primärer Strahlentherapie behandelt, davon 11,4% mit niedrigem, 50% mit intermediärem und 38,6% mit hohem Risiko nach D’Amico. Die mediane Nachbeobachtungszeit betrug 66 Monate (Spannweite 8 - 83 Monate). Für Patienten mit niedrigem, intermediärem und hohem Risiko ergab sich ein biochemisch rezidivfreies Überleben nach 5 Jahren von 100%, 92,8%, und 70,4%. Folgende Grad 2 und 3 Nebenwirkungsraten wurden jeweils verzeichnet: urogenital akut 39,8% und 1,1%, gastrointestinal akut 12,5% und 0%, urogenital spät 19,3% und 4,5% sowie gastrointestinal spät 4,5% und 1,1%. Nebenwirkungen >Grad 3 traten nicht auf. 3) Neunundsechzig konsekutive Patienten wurden mit postoperativer Strahlentherapie behandelt. Bei einer medianen Nachbeobachtungszeit von 20 Monate (Spannweite 8 - 41 Monate) ergab sich ein biochemisch rezidivfreies Überleben nach 2 Jahren von 91% sowie folgende Grad 2 Nebenwirkungsraten: urogenital akut 10,1%, gastrointestinal akut 5,8%, urogenital spät 2,9% und gastrointestinal spät 0%. Nebenwirkungen >Grad 2 traten nicht auf. Schlussfolgerung: Das Tomotherapie-System ermöglicht die effektive und sichere dosiseskalierte primäre und postoperative Strahlentherapie des lokalisierten Prostatakarzinoms.Introduction: Primary and postoperative radiation therapy are established treatments of localized prostate cancer. Dose escalation improves oncological outcome. Resulting higher rates of toxicity can be reduced with image-guided radiation therapy (IGRT). This dissertation is comprised of publications by Wust et al., Barelkowski et al. and Beck et al. who retrospectively analyzed dose-escalated primary and postoperative IGRT of localized prostate cancer on the Tomotherapy® System. Methods: 1) Wust et al. compared primary IGRT based on megavoltage computed tomography (MVCT) or fiducial markers with regards to accuracy of delivery. 2) Barelkowski et al. assessed the clinical outcome of a cohort treated with primary MVCT-based IGRT. The prescribed dose to prostate was 80 Gy in 40 fractions for low- and favorable intermediate-risk patients and 84 Gy in 42 fractions for unfavorable intermediate-risk and high-risk patients. 3) Beck et al. assessed the clinical outcome of a cohort treated with postoperative MVCT-based IGRT. The prescribed dose to area at risk was 70.3 Gy in 37 fractions. Results: 1) A representative set of data of patients treated with MVCT- (n = 43) or marker-based (n = 15) IGRT was included. Particularly in the vertical direction, residual interfractional positioning errors were larger for MVCT-based IGRT, resulting in larger safety margins, but only moderate dosimetric inferiority (D95% in CTV: 76.5 Gy vs. 78.4 Gy). Dose to organs at risk was well below common constraints for both groups. 2) Eighty-eight consecutive patients were treated with primary radiation therapy. Of these 11.4% were low-risk, 50% intermediate-risk, and 38.6% high-risk patients according to D’Amico criteria. Median follow-up was 66 months (range 8–83 months). Five-year biochemical-recurrence free survival was 100%, 92.8%, and 70.4% for low-, intermediate-, and high-risk patients, respectively. Grade 2 and 3 toxicity occurred at the following rates: acute genitourinary toxicity 39.8% and 1.1%, acute gastrointestinal toxicity 12.5% and 0%, late genitourinary toxicity 19.3% and 4.5%, and late gastrointestinal toxicity 4.5% and 1.1% of patients. No toxicity >grade 3 was observed. 3) Sixty-nine consecutive patients were treated with postoperative radiation therapy. Median follow-up was 20 months (range 8–41 months). Two-year biochemical-recurrence free survival was 91%. Grade 2 toxicity occurred at the following rates: acute genitourinary toxicity 10.1%, acute gastrointestinal toxicity 5.8%, late genitourinary toxicity 2.9%, late gastrointestinal toxicity 0%. No toxicity >grade 2 was observed. Conclusion: The Tomotherapy® System allows for effective and safe dose-escalated primary and postoperative radiation therapy of localized prostate cancer

Role of Dose Intensification for Salvage Radiation Therapy after Radical Prostatectomy

For primary radiation therapy of prostate cancer dose intensification is established as standard of care. Less is known on the role of dose intensification in the post-prostatectomy setting for salvage radiation therapy. Thus, we aimed to identify and summarize the existing literature. In retrospective analyses dose intensified salvage radiation therapy showed a superior biochemical control compared to standard dose salvage radiation with favorable acute and late gastrointestinal and genitourinary toxicity rates, especially when modern radiation techniques such as intensity modulated radiation therapy were applied. We identified one randomized phase III trial addressing the potential benefits of dose intensified salvage radiation therapy (SAKK 09/10). Recently, acute gastrointestinal and genitourinary toxicities and early quality of life data of this trial were reported and no significant difference in acute toxicities between both treatment arms were found; however, a significant worsening of genitourinary quality of life was noted in the dose intensified treatment arm. Whereas dose intensified salvage radiation therapy appears to be feasible and well tolerated, the improved biochemical control rates using dose intensified radiation therapy as suggested by retrospective analyses have yet to be validated by prospective trials