Gerry Lowe

Randomised trial of external beam radiotherapy alone or combined with high-dose-rate brachytherapy boost for localised prostate cancer

BACKGROUND A randomised phase-III trial compared external beam radiotherapy (EBRT) alone with EBRT combined with high-dose-rate brachytherapy boost (HDR-BTb) in localised prostate adenocarcinoma. METHODS From December 1997 to August 2005, 218 patients were assigned to EBRT alone (n=108) or EBRT followed by a temporary high-dose-rate implant (n=110). Patients were stratified according to tumour stage, PSA, Gleason score and androgen deprivation therapy (ADT). Biochemical/clinical relapse-free survival (RFS) was the primary endpoint. Secondary endpoints were overall survival (OS), urinary and bowel toxicity. RESULTS RFS was significantly higher in patients treated with EBRT+HDR-BTb (log rank p=0.04). In multivariate analysis treatment arm, risk category and ADT were significant covariates for risk of relapse. Differences in OS were not significant. Incidence of severe late urinary and bowel morbidity was similar. CONCLUSIONS EBRT+HDR-BTb resulted in a significant improvement in RFS compared to EBRT alone with a 31% reduction in the risk of recurrence (p=0.01) and similar incidence of severe late urinary and rectal morbidity.

Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group: considerations and pitfalls in commissioning and applicator reconstruction in 3D image-based treatment planning of cervix cancer brachytherapy.

Image-guided brachytherapy in cervical cancer is increasingly replacing X-ray based dose planning. In image-guided brachytherapy the geometry of the applicator is extracted from the patient 3D images and introduced into the treatment planning system; a process referred to as applicator reconstruction. Due to the steep brachytherapy dose gradients, reconstruction errors can lead to major dose deviations in target and organs at risk. Appropriate applicator commissioning and reconstruction methods must be implemented in order to minimise uncertainties and to avoid accidental errors. Applicator commissioning verifies the location of source positions in relation to the applicator by using auto-radiography and imaging. Sectional imaging can be utilised in the process, with CT imaging being the optimal modality. The results from the commissioning process can be stored as library applicators. The importance of proper commissioning is underlined by the fact that errors in library files result in systematic errors for clinical treatment plans. While the source channel is well visualised in CT images, applicator reconstruction is more challenging when using MR images. Availability of commercial dummy sources for MRI is limited, and image artifacts may occur with titanium applicators. The choice of MR sequence is essential for optimal visualisation of the applicator. Para-transverse imaging (oriented according to the applicator) with small slice thickness (< or =5 mm) is recommended or alternatively 3D MR sequences with isotropic voxel sizes. Preferably, contouring and reconstruction should be performed in the same image series in order to avoid fusion uncertainties. Clear and correct strategies for the applicator reconstruction will ensure that reconstruction uncertainties have limited impact on the delivered dose. Under well-controlled circumstances the reconstruction uncertainties are in general smaller than other brachytherapy uncertainties such as contouring and organ movement.

Image guided brachytherapy in locally advanced cervical cancer: Improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study

PURPOSE Image guided brachytherapy (IGBT) for locally advanced cervical cancer allows dose escalation to the high-risk clinical target volume (HRCTV) while sparing organs at risk (OAR). This is the first comprehensive report on clinical outcome in a large multi-institutional cohort. PATIENTS AND METHODS From twelve centres 731 patients, treated with definitive EBRT±concurrent chemotherapy followed by IGBT, were analysed. Kaplan-Meier estimates at 3/5years were calculated for local control (LC, primary endpoint), pelvic control (PC), overall survival (OS), cancer specific survival (CSS). In 610 patients, G3-4 late toxicity (CTCAEv3.0) was reported. RESULTS Median follow up was 43months, percent of patients per FIGO stage IA/IB/IIA 22.8%, IIB 50.4%, IIIA-IVB 26.8%. 84.8% had squamous cell carcinomas; 40.5% lymph node involvement. Mean EBRT dose was 46±2.5Gy; 77.4% received concurrent chemotherapy. Mean D90 HRCTV was 87±15Gy (EQD210), mean D2cc was: bladder 81±22Gy, rectum 64±9Gy, sigmoid 66±10Gy and bowel 64±9Gy (all EQD23). The 3/5-year actuarial LC, PC, CSS, OS were 91%/89%, 87%/84%, 79%/73%, 74%/65%. Actuarial LC at 3/5years for IB, IIB, IIIB was 98%/98%, 93%/91%, 79%/75%. Actuarial PC at 3/5years for IB, IIB, IIIB was 96%/96%, 89%/87%, 73%/67%. Actuarial 5-year G3-G5 morbidity was 5%, 7%, 5% for bladder, gastrointestinal tract, vagina. CONCLUSION IGBT combined with radio-chemotherapy leads to excellent LC (91%), PC (87%), OS (74%), CSS (79%) with limited severe morbidity.

Justification for inter-fraction correction of catheter movement in fractionated high dose-rate brachytherapy treatment of prostate cancer

BACKGROUND AND PURPOSE Fractionated high dose-rate (HDR) brachytherapy in the treatment of prostate cancer relies on reproducible catheter positions for each fraction to ensure adequate tumour coverage while minimising dose to normal tissues. Peri-prostatic oedema may cause caudal displacement of the catheters relative to the prostate gland between fractions. This can be corrected for by changing source dwell positions or by physical re-advancement of catheters before treatment. MATERIALS AND METHODS Data for 20 consecutive monotherapy patients receiving three HDR fractions of 10.5 Gy per fraction over 2 days were analysed retrospectively. Pre-treatment CT scans were used to assess the effect of catheter movement between fractions on implant quality, with and without movement correction. Implant quality was evaluated using dosimetric parameters. RESULTS Compared to the first fraction (f1) the mean inter-fraction caudal movement relative to the prostate base was 7.9 mm (f2) (range 0-21 mm) and 3.9 mm (f3) (range 0-25.5 mm). PTV D90% was reduced without movement correction by a mean of 27.8% (f2) and 32.3% (f3), compared with 5.3% and 5.1%, respectively, with catheter movement correction. Dose to 2 cc of the rectum increased by a mean of 0.69 (f2) and 0.76 Gy (f3) compared with an increase of 0.03 and 0.04 Gy, respectively, with correction. The urethra V12 also increased by a mean of 0.36 (f2) and 0.39 Gy (f3) compared with 0.06 and 0.16 Gy, respectively, with correction. CONCLUSIONS Inter-fraction correction for catheter movement using pre-treatment imaging is critical to maintain the quality of an implant. Without movement correction there is significant risk of tumour under-dosage and normal tissue over-dosage. The findings of this study justify additional imaging between fractions in order to carry out correction.

High-dose-rate brachytherapy alone given as two or one fraction to patients for locally advanced prostate cancer: Acute toxicity

BACKGROUND To evaluate early urinary (GU) and gastrointestinal (GI) adverse events (AEs) after two or one fraction of high-dose rate brachytherapy (HDR-BT) in advanced prostate cancer. PATIENTS AND METHODS 165 patients were treated with 2 × 13 Gy (n=115), or a single dose of 19 Gy (n=24) or 20 Gy (n=26) HDR-BT. Early AEs were assessed using the RTOG scoring system and the International Prostate Symptom Score (IPSS). RESULTS Week-2 prevalence of severe IPSS symptoms was higher after 20 Gy than after 26 or 19 Gy but by 12 weeks all groups were at pre-treatment levels or less. Grade-3 GU toxicity was observed ≤9% of patients. No Grade 4 GU and no Grade 3 or 4 GI complications were observed. However, there was a significant increase in catheter use in the first 12 weeks after implant after 19 and 20 Gy compared with 2 × 13 Gy. CONCLUSION Single dose HDR-BT is feasible with acceptable levels of acute complications; tolerance may have been reached with the single 19 Gy schedule.

Applicator reconstruction for HDR cervix treatment planning using images from 0.35 T open MR scanner

BACKGROUND AND PURPOSES Magnetic resonance (MR) imaging is widely recognised as the modality of choice for imaging soft tissue such as the target volume and critical structures relevant to high dose rate (HDR) brachytherapy of the cervix. This work sets out to assess some of the issues faced when introducing this technique clinically compared to the more widely used computed tomography (CT). MR can be used either as the sole imaging modality, or in conjunction with CT. MATERIALS AND METHODS Distortion of the images produced by the MR scanner was assessed with a geometrical phantom. Distortion local to the titanium applicators, introduced by the susceptibility of the applicators themselves, was also measured. The technique used to reconstruct applicators is briefly described. An inter-operator study was performed to assess the variability of applicator reconstruction between operators when MR images are used alone to reconstruct the applicators. RESULTS A 14-cm cube within which distortion was less than 2mm at all points was identified. The inter-operator study showed some variability in applicator reconstruction with both MR and CT (median MR/CT 1.3mm/0.9 mm, range 0-3.6mm/0-3.3mm). Inter-operator variation in planning target volume (PTV) V 100% and PTV D 90% for MR/CT was 6.1%/3.0% and 7.4%/6.3%, respectively, and D(2cc) OAR doses varied by up to 1.0 Gy between operators for both MR and CT. CONCLUSIONS In this study distortion was minimal within a defined volume and inter-observer errors were comparable on MR and CT when used to define applicators and when applied to dose-volume histograms (DVHs). However this does not assure the technique is appropriate with other scanners and applicator sets without further commissioning.

Critical structure movement in cervix brachytherapy

BACKGROUND AND PURPOSE To investigate critical structure movement and subsequent dose received during conformal MR-guided cervix brachytherapy. MATERIALS AND METHODS 21 patients (36 HDR fractions) undergoing brachytherapy for cervical cancer underwent a second MR immediately prior to treatment (pre-treatment MR). Bowel (including sigmoid), bladder and rectum were outlined on both planning and pre-treatment MR scans and dosimetry compared. RESULTS No statistically significant differences were found between the volumes of the OAR doses across the two scans but there were large variations between patients with differences of up to 3.3 Gy observed. The percentage of fractions for which D2cc was within 10% of that planned was 61.1%, 41.7% and 47.2% for bladder, rectum and bowel, respectively. The average time between MR scans was found to be 4.75 h (SD±1.2; range 3.2-9.9 h), with no correlation found with critical structure movement within this range. CONCLUSIONS OAR movement is difficult to predict though significant changes occur in individual patients. In 61% of cases in our sample the D2cc dose changed by at least 10% for at least one OAR from that planned. Pre-treatment imaging with subsequent adjustment of dosimetry will minimise the impact of organ movement on delivered dose.

High-dose-rate brachytherapy with two or three fractions as monotherapy in the treatment of locally advanced prostate cancer

BACKGROUND To evaluate late urinary (GU) and gastrointestinal (GI) adverse events (AEs) and biochemical control of disease after high-dose rate brachytherapy (HDR-BT) in locally advanced prostate cancer. PATIENTS AND METHODS 227 consecutive patients were treated with 3 × 10.5 Gy (n = 109) or 2 × 13 Gy (n = 118) HDR-BT alone. Biochemical failure was assessed using the Phoenix definition of PSA nadir + 2 μg/l and late AEs using the RTOG scoring system and the International Prostate Symptom Score (IPSS). RESULTS Kaplan-Meier estimates and prevalence of late events indicate that urinary, bowel and IPSS symptoms are higher after 31.5 Gy than after 26 Gy, however differences are significant only for Grade 1 and 2 urinary toxicity. Kaplan-Meier estimates of morbidity are consistently and considerably higher than time-point estimates of prevalence; which reflects the transient nature of most symptoms. At 3 years 93% and 97% of patients treated with 26 and 31.5 Gy, respectively, were free from biochemical relapse (p = 0.5) and 91% for the latter regimen at 5 years. In univariate and multivariate analysis risk-category was the only significant predictor of relapse (p < 0.03). CONCLUSION These HDR-BT schedules achieved high levels of biochemical control of disease in patients with advanced prostate cancer with few severe complications seen throughout the first 3 years.

Single-dose high-dose-rate brachytherapy compared to two and three fractions for locally advanced prostate cancer

BACKGROUND Single-dose high-dose-rate brachytherapy (HDR-BT), in a Phase-II study, was compared to two or three fractions in intermediate and high-risk localized prostate cancer. PATIENTS AND METHODS 293 patients received 1×19Gy or 1×20Gy (A=49), 2×13Gy (B=138), or 3×10.5Gy (C=106) and assessed with prospective measures of serum PSA, late genitourinary (GU) and gastrointestinal (GI) morbidity using RTOG scales and the International Prostate Symptom Score (IPSS). RESULTS Median follow-up is 49, 63 and 108months (A, B and C, respectively). At 4years biochemical relapse free survival was 94% (A), 93% (B) and 91% (C) (p=0.54). Risk-category was the only significant independent predictor of relapse (p<0.0001). Kaplan-Meier 4-year-estimates of GU-3 were 2% (A and B) and 11% (C). GI-3 was 0% (A and B) and 1% (C). No GU or GI grade-4 events were observed. IPSS≥20 was 11% (A), 9% (B) and 16% (C) (p=0.9). Prevalence of GU-3 was ≤4% in the 3 groups at all times; GI-3 was low or non-existent. Prevalence of catheter use was ≤6% in all groups. CONCLUSIONS A single dose of 19-20Gy achieves similar rates of late morbidity and biochemical control compared to 2 and 3 fractions.

The Influence of Prostate Volume on Outcome After High-Dose-Rate Brachytherapy Alone for Localized Prostate Cancer

OBJECTIVE To determine whether late genitourinary toxicity, biochemical control of prostate cancer, and dosimetric parameters in patients with large prostate glands is different from those variables in men with smaller glands after treatment with high-dose-rate brachytherapy alone (HDR-BT). METHODS From November 2003 to July 2009, 164 patients with locally advanced prostate carcinoma were sequentially enrolled and treated with 34 or 36 Gy in 4 fractions and 31.5 Gy in 3 fractions of (192)Ir HDR-BT alone. The median follow-up time was 71 months. Gland size was not considered in the selection criteria for this study. Estimates of freedom from biochemical relapse (FFbR) and late morbidity, stratified by median clinical target volume (CTV), were obtained, and differences were compared. RESULTS The median CTV volume was 60 cc (range, 15-208 cc). Dose-volume parameters D90 and V100 (ie, minimum dose to 90% of the prostate volume and volume receiving 100% of the prescribed isodose) achieved in patients with glands ≥60 cc were not significantly different from those with glands <60 cc (P≥.2). Nonetheless, biochemical control in patients with larger CTV was significantly higher (91% vs 78% at 6 years; P=.004). In univariate and multivariate analysis, CTV was a significant predictor for risk of biochemical relapse. This was not at the expense of an increase in either moderate (P=.6) or severe (P=.3) late genitourinary toxicity. The use of hormonal therapy was 17% lower in the large gland group (P=.01). CONCLUSIONS Prostate gland size does not affect dosimetric parameters in HDR-BT assessed by D90 and V100. In patients with larger glands, a significantly higher biochemical control of disease was observed, with no difference in late toxicity. This improvement cannot be attributed to differences in dosimetry. Gland size should not be considered in the selection of patients for HDR-BT.