Severe late complications after radiotherapy for advanced cervical cancer with special emphasis on brachytherapy

Ved behandling av avansert livmorhalskreft spiller stråleterapi en avgjørende rolle og det gis både ekstern og intern behandling (brachyterapi). Stråleterapi er alltid en avveiing mellom dosen som kan gis til maligne områder og dosen som kan tillates gitt til friskvevet. For å oppnå lokal kontroll ved strålebehandling av avansert livmorhalskreft, må det gis relativt høye doser. Blærens og rektums anatomiske posisjon i forhold til livmorhalsen, fører til at disse organene alltid vil få en viss strålebelastning og uønskede bivirkninger kan forekomme. For å kunne minimalisere disse bivirkningene, er det viktig å etablere pålitelige dose-respons-sammenhenger, hvilket betyr at man må ha gode estimater på hvilken dose friskvevet absorberer. For å kunne beregne den absorberte dosen til svulsten og friskvevet er det derfor viktig å kartlegge hvordan brachyterapikateteret (applikatoren) og de radioaktive kildene ligger i forhold til det omkringliggende vevet. Tilstedeværelse av applikatoren kan endre de anatomiske forholdene og avbildningen må derfor skje med applikatoren og såkalte surrogatkilder, på plass i pasienten. For å kunne gjennomføre en doseberegning må applikatorens geometri vært kjent. Overføringen av denne informasjonen til doseplansystemet kalles ofte applikator rekonstruksjon. Applikator rekonstruksjonen kan gjennomføres vha flere ulike metoder. I publikasjon II er det vist at usikkerheten i doseberegningen som følge av usikkerhet i rekonstruksjonsprosessen maksimalt vil være på 4% (1SD) i ulike punkter rundt applikatoren. I publikasjon III er konsekvenser av rekonstruksjonsusikkerheter på DVH-parametre undersøkt. For 20 pasienter ble rekonstruksjonsfeil simulert ved å forskyve dosefordelingen ? 3 mm i transversal og ant-post retning, samt ? 3 mm og ? 5 mm langs uterinapplikatoren. Resultatene viste at konsekvensene av rekonstruksjonsusikkerheten var størst i ant-post retning for rektum og blære med et midlere endring på ca 5% i dosen til D2cc per mm forskyvning dosefordelingen. D2cc er definert som minimumsdosen til 2cm3 som får den høyeste strålebelastningen. Fra 1994 til 1999 ble alle pasienter med avansert livmorhalskreft ved Radiumhospitalet behandlet et en nordisk protokoll kalt NOCECA-protokollen. Pasientene ble fulgt nøye opp og bivirkninger ble registrert. I publikasjon I ble det inkludert alle pasientene som hadde fått 50 Gy med ekstern strålebehandling og enten 7 fraksjoner (120 pasienter) eller 8 (119 pasienter) á 4.2 Gy (til punktA) med brachyterapi. Kaplan-Meyer analyse viste ikke signifikant forskjell på den kumulative insidensen av alvorlige senskader (? grad3) for de pasientene som hadde fått 8 vs 7 brachyfraksjoner for verken blære eller rektum. Referansedosen til rektum varierte lite fra pasient til pasient og var ca 75% av punktA-dosen. DVH parametre for pasientene forlå ikke og i publikasjon IV ble det vist at D2cc for rektum kunne variere fra 15% til 123% av punktA-dosen selv om dosen til referansepunktet var tilnærmet likt. Dette betyr at mangelen på signifikante forsekjeller i publikasjon I kan skyldes at den reell dosebelastningen til rektum ikke foreligger. I publikasjon IV og V ble endringer i DVH-parametre for risikoorgan undersøkt fra fraksjon til fraksjon. 3D opptak med CT ble gjennomført ved 3-6 brachyfraksjoner for 14 pasienter. For hver pasient ble middelverdien og relativt standardavvik for en rekke DVH-parametre beregnet. For volumet av rektum og blære ble det midlere relative standardavviket beregnet til henholdsvis 23.3% og 44.1%. Det midlere relative standardavviket for D2cc var på 15.5% og 19.9% for henholdsvis rektum og blære. Dette betyr at de variasjonene i volumet av organene ikke ble etterfulgt av like store variasjoner for D2cc. NTCP-verdien (Normal Tissue Complication Probability) for denne pasientgruppen ble beregnet ved hjelp av Lyman-Kutcher-Burman-modellen (LKB-modellen) og disse verdiene ble sammenlignet med senskadedata fra en tilsvarende gruppe behandlet tidligere. For rektum ble NTCP beregnet til 19.7%, mens klinisk frekvens for alvorlige senskader var 13%. Denne forskjellen kunne forklares med usikkerheter i parametrene i LKB-modellen. For blære ble NTCP beregnet til 61.9%, mens den kliniske frekvensen var kun 14%. Denne store forskjellen kan mest sannsynlig forklares ved manglende kunnskap om blærens toleransedose og dermed manglende kunnskap om parametre i LKB-modellen

Dose deviations induced by respiratory motion for radiotherapy of lung tumors: Impact of CT reconstruction, plan complexity, and fraction size

A thorax phantom was used to assess radiotherapy dose deviations induced by respiratory motion of the target volume. Both intensity modulated and static, non‐modulated treatment plans were planned on CT scans of the phantom. The plans were optimized using various CT reconstructions, to investigate whether they had an impact on robustness to target motion during delivery. During irradiation, the target was programmed to simulate respiration‐induced motion of a lung tumor, using both patient‐specific and sinusoidal motion patterns in three dimensions. Dose was measured in the center of the target using an ion chamber. Differences between reference measurements with a stationary target and dynamic measurements were assessed. Possible correlations between plan complexity metrics and measured dose deviations were investigated. The maximum observed motion‐induced dose differences were 7.8% and 4.5% for single 2 Gy and 15 Gy fractions, respectively. The measurements performed with the largest target motion amplitude in the superior–inferior direction yielded the largest dosimetric deviations. For 2 Gy fractionation schemes, the summed dose deviation after 33 fractions is likely to be less than 2%. Measured motion‐induced dose deviations were significantly larger for one CT reconstruction compared to all the others. Static, non‐modulated plans showed superior robustness to target motion during delivery. Moderate correlations between the modulation complexity score applied to VMAT (MCSv) and measured dose deviations were found for 15 Gy SBRT treatment plans. Correlations between other plan complexity metrics and measured dose deviations were not found

GEC/ESTRO recommendations on high dose rate afterloading brachytherapy for localised prostate cancer:an update

AbstractBackground: HDR afterloading brachytherapy (HDRBT) for prostate cancer is now established as an effective technique to achieve dose escalation in the radical treatment of localized prostate cancer. The previous guidelines published in 2005 from GEC ESTRO and EAU have been updated to reflect the current and emerging roles for HDRBT in prostate cancer. Patients and method: The indications for HDRBT in dose escalation schedules with external beam are wide ranging with all patients having localized disease eligible for this technique. Exclusion criteria are few encompassing patients medically unfit for the procedure and those with significant urinary outflow symptoms. Results: Recommendations for patient selection, treatment facility, implant technique, dose prescription and dosimetry reporting are given. Conclusions: HDRBT in prostate cancer can be practiced effectively and safely within the context of these guidelines with the main indication being for dose escalation with external beam. HDRBT used alone is currently under evaluation and its role in focal treatment and recurrence will be areas of future development

GEC-ESTRO/ACROP recommendations for quality assurance of ultrasound imaging in brachytherapy

Ultrasound (US) is an important imaging modality in brachytherapy (BT). In particular for low-dose-rate (LDR) and high-dose-rate (HDR) prostate implants transrectal ultrasound (TRUS) is widespread. Besides the common use of US for prostate implants, US can also be applied in gynecological and anal cancer therapies as examples amongst others. The BRAPHYQS (BRAchytherapy PHYsics Quality assurance System) and UroGEC (urology) working groups of GEC-ESTRO (GEC: Groupe Européen de Curiethérapie, committee of ESTRO: European SocieTy for Radiotherapy & Oncology) elaborated upon guidelines describing quality assurance (QA) methods for US in BT. The total quality management (QM) for the unit includes acceptance testing, commissioning and periodic image testing. In 2008, the AAPM (American Association of Physicists in Medicine) published the TG (Task group) 128 report. Whereas the TG 128 focuses on US systems and prostate BT, the current recommendations also cover tests for stepping devices and include other interstitial or intracavitary treatment sites in BT, such as anal implants and gynecological BT. The recommendations presented herein do not replace regular maintenance for the US devices performed by the vendor. They are the QA of US in BT but are not sufficient for the whole maintenance of medical US devices. Moreover, national regulations and recommendations should also be followed. For the tests presented in this report tolerances or action limits are given. These recommendations explain practical test procedures of US devices in BT. They will help the clinics to perform a high level of quality in the use of US for BT in Europe

Ten-year survival after High-Dose-Rate Brachytherapy combined with External Beam Radiation Therapy in high-risk prostate cancer: A comparison with the Norwegian SPCG-7 cohort

Background: The survival benefit of dose-escalation with High-Dose-Rate brachytherapy (HDR-BT) combined with External Beam Radiotherapy (EBRT) for the treatment of high-risk prostate cancer (PCa) remains debatable. We investigated 10-year PCa-specific mortality (PCSM) and overall mortality (OM) in high-risk patients treated with HDR-BT/EBRT compared to EBRT alone. Methods: HDR-BT boosts were given followed by 50 Gy conformal EBRT to the prostate and seminal vesicles. The HDR-BT/EBRT group (N:325) received Androgen Deprivation Therapy for median 2 years. The historical control group (N:296), received a median dose of 70 Gy to the prostate and seminal vesicles with lifelong Anti-Androgen Treatment. For each treatment group, PCSM and OM were calculated using competing-risk and Kaplan-Meier analyses, respectively. Differences were assessed with the logrank test. OM and PCSM were computed using Cox and Fine & Grey regression. Significance level set to p<0.05. Patient-measured (PM) toxicity were assessed by EPIC-26 questionnaire at 5 years. Results: Median follow-up was 104 and 120 months for the HDR-BT/EBRT and the EBRT group respectively. A 3.6-fold decreased risk of PCSM (p<0.01) and a 1.6-fold decreased risk of OM (p=0.02) in the HDR-BT/EBRT cohort compared to the EBRT-only group were revealed. Ten year OM and PCSM rates were 16 % and 2.5% in the HDR-BT/EBRT group versus 23% and 8.2% in the EBRT-only group respectively. Treatment modality (SHR=3.58, 95%CI 1.40-9.14) and Gleason score (SHR=2.58, 95%CI 1.15 5.78) were associated with PCSM. Only treatment modality (HR=1.63, 95%CI=1.08-2.44) was significantly associated with OM. Conclusions: Men with high-risk PCa have a significantly reduced PCSM and OM rates when treated with dose-escalated radiotherapy achieved by HDR-BT/EBRT compared to EBRT alone (70 Gy). PM toxicity scores were acceptable and similar to the ProtecT study. A Gleason score of 8-10 was independently associated with increased risk of PCSM. Randomized studies in men with high-risk disease treated with dose-escalation are warranted

Ten-year survival after High-Dose-Rate Brachytherapy combined with External Beam Radiation Therapy in high-risk prostate cancer: A comparison with the Norwegian SPCG-7 cohort

Background The survival benefit of dose-escalation with High-Dose-Rate brachytherapy (HDR-BT) boost combined with External Beam Radiotherapy (EBRT) for the treatment of high-risk prostate cancer (PCa) remains debatable. We investigated 10-year PCa-specific mortality (PCSM) and overall mortality (OM) in high-risk patients treated with HDR-BT/EBRT (calculated EQD2 = 102 Gy) compared to EBRT alone (70 Gy). Methods HDR-BT boosts (10 Gy × 2) were given 2 weeks apart followed by 50 Gy conformal EBRT (2 Gy × 25) to the prostate and seminal vesicles. The HDR-BT/EBRT group (N:325) received Androgen Deprivation Therapy for a median duration of 2 years. The historical control group (N:296), received a median dose of 70 Gy (2 Gy × 35) to the prostate and seminal vesicles with lifelong Anti-Androgen Treatment. For each treatment group PCSM and OM were established by competing-risk analyses and Kaplan–Meier analyses respectively. Differences were evaluated by the logrank test. Independent associations were established by Cox regression analyses. Significance level set to p < 0.05. Results Median follow-up was 104 and 120 months for the HDR-BT/EBRT and the EBRT group respectively. A 3.6-fold decreased risk of PCSM (p < 0.01) and a 1.6-fold decreased risk of OM (p = 0.02) in the HDR-BT/EBRT cohort compared to the EBRT-only group were revealed. Ten-year OM and PCSM rates were 16% and 2.5% in the HDR-BT/EBRT group versus 23% and 8.2% in the EBRT-only group respectively. Both treatment modality (HR = 3.59, 95%CI 1.50–8.59) and Gleason score (HR = 2.48, 95%CI 1.18–5.21) were associated with PCSM. Only treatment modality (HR = 1.63, 95%CI = 1.08–2.44) was significantly associated with OM. Conclusions Men with high-risk PCa have a significantly reduced PCSM and OM rates when treated with dose-escalated radiotherapy achieved by HDR-BT/EBRT compared to EBRT alone (70 Gy). A Gleason score of 8–10 was independently associated with increased risk of PCSM. Randomized studies are warranted. Summary Observational study of 10-year survival in high-risk Prostate Cancer (PCa) after High-Dose-Rate brachytherapy combined with External Beam Radiation Therapy (HDR-BT/EBRT) compared to EBRT alone. The combined HDR-BT/EBRT treatment was found to give a 3.6-fold decrease in Prostate Cancer Specific Mortality (PCSM) and a 1.6-fold decrease in Overall Mortality (OM). Gleason score and type of treatment strongly influenced PCSM whereas only treatment modality was associated with OM. The observed benefits of dose-escalation warrant future randomized trials

Dose planning variations related to delineation variations in MRI-guided brachytherapy for locally advanced cervical cancer

Purpose: To examine the variability in prescribed dose due to contouring variations in intracavitary image-guided adaptive brachytherapy for cervical cancer. To identify correlations between dosimetric outcomes and delineation uncertainty metrics. Methods and materials: A data set from an EMBRACE sub-study on contouring uncertainties was used, consisting of magnetic resonance images of six patients with cervical cancer delineated by 10 experienced observers (target volumes and organs at risk). Two gold standard contours were generated, an expert consensus and the simultaneous truth and performance level estimation. Plans were individually optimised to all of the contour sets (12 in total). Plans were applied to the gold standard contour sets, and dose volume histogram parameters including D90, D98 and D2cm3 were determined. The variability between plans was assessed. Dose volume histogram parameters and delineation uncertainty metrics were correlated using the Spearman's non-parametric rank correlation. Results: There is a dosimetric variability between observers, patients and the gold standard contour used for analysis. Approximately 3 Gy D90 EQD210 variability (SD) was observed for the CTVHR and 1.2-3.6 Gy D2cm3 EQD23 for the organs at risk. The maximum geometric dimensions of the delineations are most commonly correlated with dosimetry changes. Although the correlations are similar across gold standards, the direction of these correlations differs, indicating that the dosimetric outcomes are dependent on the contour that the plan is optimised to. Conclusion: This study highlights the dosimetric differences interobserver uncertainty in contouring can have for cervical cancer brachytherapy. The importance of carefully choosing a gold standard from which to benchmark is reiterated