Peter Ostler

Stereotactic body radiotherapy for oligometastases

The management of metastatic solid tumours has historically focused on systemic treatment given with palliative intent. However, radical surgical treatment of oligometastases is now common practice in some settings. The development of stereotactic body radiotherapy (SBRT), building on improvements in delivery achieved by intensity-modulated and image-guided radiotherapy, now allows delivery of ablative doses of radiation to extracranial sites. Many non-randomised studies have shown that SBRT for oligometastases is safe and effective, with local control rates of about 80%. Importantly, these studies also suggest that the natural history of the disease is changing, with 2-5 year progression-free survival of about 20%. Although complete cure might be possible in a few patients with oligometastases, the aim of SBRT in this setting is to achieve local control and delay progression, and thereby also postpone the need for further treatment. We review published work showing that SBRT offers durable local control and the potential for progression-free survival in non-liver, non-lung oligometastatic disease at a range of sites. However, to test whether SBRT really does improve progression-free survival, randomised trials will be essential.

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.

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.

A Phase II Study of High-Dose-Rate Afterloading Brachytherapy as Monotherapy for the Treatment of Localized Prostate Cancer

PURPOSE A Phase II dose escalation study has been undertaken to evaluate high-dose-rate brachytherapy (HDRBT) monotherapy for prostate cancer. METHODS AND MATERIALS A total of 110 patients have been entered, all with locally advanced cancer. Three dose levels have been used; 34 Gy in four fractions, 36 Gy in four fractions, and 31.5 Gy in three fractions. These equate to 226Gy(1.5), 252Gy(1.5), and 252Gy(1.5), respectively. Thirty patients have received 34 Gy, 25 received 36 Gy, and 55 patients received 31.5 Gy. Acute and late toxicity was analyzed using the International Prostate Symptom Score, and urologic and rectal events were scored using the Radiation Therapy Oncology Group/Common Terminology Criteria scoring systems. RESULTS Seven patients required urethral catheterization at 2 weeks; 3 receiving 34 Gy, 1 receiving 36 Gy, and 3 receiving 31.5 Gy. Only 3 patients remained catheterized at 12 weeks. Radiation Therapy Oncology Group 1 and 2 gastrointestinal toxicity at 2 weeks was seen in 61%, 68%, and 77%, respectively. Grade 3 bladder toxicity was seen in 2 patients at 6 months, 1 each from the 36 Gy and 31.5 Gy arms. One patient from the 31.5-Gy cohort reported Grade 2 bowel toxicity at 6 months. Prostate-specific antigen (PSA), stratified for androgen deprivation therapy (ADT) and no-ADT patients ranged from 16.1-22.9 microg/L and 11.1-12.5 microg/L, respectively. This fell at 12 months to 0.2-0.6 microg/L and 0.5-1.4 microg/L, respectively. No PSA relapses have yet been seen with a median follow-up of 30 months (34 Gy), 18 months (36 Gy), and 11.8 months (31.5 Gy). CONCLUSIONS Early results suggest an excellent biochemical response with no differences seen in acute and late toxicity between doses of 34 Gy/four fractions, 36 Gy/four fractions, or 31.5 Gy/three fractions.

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.

Prostate Stereotactic Body Radiotherapy - First UK Experience

AIMS Stereotactic body radiotherapy (SBRT) combines image-guided radiotherapy with hypofractionation, both of which will probably result in improvements in patient outcomes in prostate cancer. Most clinical experience with this technique resides in North America. Here we present the first UK cohort to receive SBRT for prostate cancer. MATERIALS AND METHODS Fifty-one prostate cancer patients (10 low risk, 35 intermediate risk and 6 high risk) were treated with 36.25 Gy in five fractions over 1-2 weeks and gold seed image guidance. All patients had toxicity International Prostate Symptom score (IPSS) and Radiation Therapy Oncology Group recorded prospectively and prostate-specific antigen was measured 3-6 monthly during follow-up. RESULTS The median IPSS was 6, 11, 8 and 5 at baseline, 1-3 weeks, 4-6 weeks and 7-12 weeks after treatment. Radiation Therapy Oncology Group genitourinary and gastrointestinal toxicity of grade 2 was seen in 22% and 14%, respectively, at 1-3 weeks after treatment; no patient had grade 3+ toxicity at this time point, although two patients had grade 3 urinary frequency recorded during treatment. The median follow-up for the 42 patients who did not receive androgen deprivation was 14.5 months. Prostate-specific antigen at 13-18 months after treatment was 1.3 ng/ml. CONCLUSION Prostate SBRT is a promising treatment for organ-confined prostate cancer and is currently being investigated in a UK-led phase III trial.

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.

Epoetin alfa improves anemia and anemia-related, patient-reported outcomes in patients with breast cancer receiving myelotoxic chemotherapy: Results of a european, multicenter, randomized, controlled trial

This study evaluated the effects of epoetin alfa on patient-reported outcomes in patients with breast cancer receiving myelotoxic chemotherapy. Early intervention with epoetin alfa was well tolerated and improved anemia-related patient-reported outcomes.

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.