Stereotactic body radiotherapy for bone oligometastatic disease in prostate cancer.

PURPOSE: There are sparse data describing outcomes of bone-only oligometastatic prostate cancer in comparison with lymph node disease treated with stereotactic body radiotherapy (SBRT). The primary aim of this study was to report progression-free survival (PFS) data for patients with bone-only disease. Influence of hormone sensitivity and androgen deprivation therapy use was also assessed. METHODS: This is a single-centre retrospective cohort study. Hormone-sensitive and castrate-resistant patients with oligometastatic (≤ 3) bone-only prostate cancer treated with SBRT were included. Data were collected using electronic records. Kaplan-Meier survivor function, log rank test, as well as Cox regression were used to calculate PFS and overall survival. RESULTS: In total, 51 patients with 64 bone metastases treated with SBRT were included. Nine patients were castrate resistant and 42 patient's hormone sensitive at the time of SBRT. Median follow-up was 23 months. Median PFS was 24 months in hormone-sensitive patients and 3 months in castrate-resistant patients. No patients experienced grade 3 or 4 toxicities. There were three in-field recurrences. CONCLUSIONS: In this study, patients with bone oligometastatic disease showed potential benefit from SBRT with a median PFS of 11 months. Hormone-sensitive patients showed the greatest benefit, with results similar to that published for oligometastatic pelvic nodal disease treated with SBRT. Prospective randomised control trials are needed to determine the survival benefit of SBRT in oligometastatic bone-only prostate cancer and to determine prognostic indicators.

Trends in Management of Oligometastatic Hormone-Sensitive Prostate Cancer.

PURPOSE OF REVIEW: Systemic therapy for patients with hormone-sensitive oligometastatic prostate cancer is non-curative and associated with toxicities. Meanwhile, this population presents unique clinical opportunities to improve outcomes, including the demonstrated benefits of radiotherapy to the primary tumor or oligometastatic sites. RECENT FINDINGS: Recently published randomized studies have demonstrated benefits with the addition of radiotherapy to the primary disease or metastatic lesions in patients with synchronous or metachronous disease. The introduction of novel PET imaging has improved the sensitivity and specificity for detecting metastatic disease and provides an opportunity to better select patients who will benefit from local therapy. The data presented in this review supports revisiting practice guidelines for patients with hormone-sensitive metastatic prostate cancer, particularly in relation to the role of radiotherapy to the primary tumor and sites of oligometastatic disease. Future trials will aim to further establish the role of metastasis-directed therapies in metachronous, synchronous, and castrate-resistant disease.

Improving fiducial and prostate capsule visualization for radiotherapy planning using MRI.

BACKGROUND AND PURPOSE: Intraprostatic fiducial markers (FM) improve the accuracy of radiotherapy (RT) delivery. Here we assess geometric integrity and contouring consistency using a T2*-weighted (T2*W) sequence alone, which allows visualization of the FM. MATERIAL AND METHODS: Ten patients scanned within the Prostate Advances in Comparative Evidence (PACE) trial (NCT01584258) had prostate images acquired with computed tomography (CT) and Magnetic Resonance (MR) Imaging: T2-weighted (T2W) and T2*W sequences. The prostate was contoured independently on each imaging dataset by three clinicians. Interobserver variability was assessed using comparison indices with Monaco ADMIRE (research version 2.0, Elekta AB) and examined for statistical differences between imaging sets. CT and MR images of two test objects were acquired to assess geometric distortion and accuracy of marker positioning. The first was a linear test object comprising straight tubes in three orthogonal directions, the second was a smaller test object with markers suspended in gel. RESULTS: Interobserver variability for prostate contouring was lower for both T2W and T2*W compared to CT, this was statistically significant when comparing CT and T2*W images. All markers are visible in T2*W images with 29/30 correctly identified, only 3/30 are visible in T2W images. Assessment of geometric distortion revealed in-plane displacements were under 0.375 mm in MRI, and through plane displacements could not be detected. The signal loss in the MR images is symmetric in relation to the true marker position shown in CT images. CONCLUSION: Prostate T2*W images are geometrically accurate, and yield consistent prostate contours. This single sequence can be used to identify FM and for prostate delineation in a mixed MR-CT workflow.

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.

Comparison of prostate delineation on multimodality imaging for MR-guided radiotherapy.

OBJECTIVE:: With increasing incorporation of MRI in radiotherapy, we investigate two MRI sequences for prostate delineation in radiographer-led image guidance. METHODS:: Five therapeutic radiographers contoured the prostate individually on CT, T2 weighted (T2W) and T2* weighted (T2*W) imaging for 10 patients. Contours were analysed with Monaco ADMIRE (research v. 2.0) to assess interobserver variability and accuracy by comparison with a gold standard clinician contour. Observers recorded time taken for contouring and scored image quality and confidence in contouring. RESULTS:: There is good agreement when comparing radiographer contours to the gold-standard for all three imaging types with Dice similarity co-efficient 0.91-0.94, Cohen's κ 0.85-0.91, Hausdorff distance 4.6-7.6 mm and mean distance between contours 0.9-1.2 mm. In addition, there is good concordance between radiographers across all imaging modalities. Both T2W and T2*W MRI show reduced interobserver variability and improved accuracy compared to CT, this was statistically significant for T2*W imaging compared to CT across all four comparison metrics. Comparing MRI sequences reveals significantly reduced interobserver variability and significantly improved accuracy on T2*W compared to T2W MRI for DSC and Cohen's κ. Both MRI sequences scored significantly higher compared to CT for image quality and confidence in contouring, particularly T2*W. This was also reflected in the shorter time for contouring, measuring 15.4, 9.6 and 9.8 min for CT, T2W and T2*W MRI respectively. Conclusion: Therapeutic radiographer prostate contours are more accurate, show less interobserver variability and are more confidently and quickly outlined on MRI compared to CT, particularly using T2*W MRI. Advances in knowledge: Our work is relevant for MRI sequence choice and development of the roles of the interprofessional team in the advancement of MRI-guided radiotherapy.

Dosimetric Implications of Computerised Tomography-Only versus Magnetic Resonance-Fusion Contouring in Stereotactic Body Radiotherapy for Prostate Cancer.

Background: Magnetic resonance (MR)-fusion contouring is the standard of care in prostate stereotactic body radiotherapy (SBRT) for target volume localisation. However, the planning computerised tomography (CT) scan continues to be used for dose calculation and treatment planning and verification. Discrepancies between the planning MR and CT scans may negate the benefits of MR-fusion contouring and it adds a significant resource burden. We aimed to determine whether CT-only contouring resulted in a dosimetric detriment compared with MR-fusion contouring in prostate SBRT planning. Methods: We retrospectively compared target volumes and SBRT plans for 20 patients treated clinically with MR-fusion contouring (standard of care) with those produced by re-contouring using CT data only. Dose was 36.25 Gy in 5 fractions. CT-only contouring was done on two occasions blind to MR data and reviewed by a separate observer. Primary outcome was the difference in rectal volume receiving 36 Gy or above. Results: Absolute target volumes were similar: 63.5 cc (SD ± 27.9) versus 63.2 (SD ± 26.5), Dice coefficient 0.86 (SD ± 0.04). Mean difference in apex superior-inferior position was 1.1 (SD ± 3.5; CI: −0.4–2.6). Small dosimetric differences in favour of CT-only contours were seen, with the mean rectal V36 Gy 0.3 cc (95% CI: 0.1–0.5) lower for CT-only contouring. Conclusions: Prostate SBRT can be successfully planned without MR-fusion contouring. Consideration can be given to omitting MR-fusion from the prostate SBRT workflow, provided reference to diagnostic MR imaging is available. Development of MR-only work flow is a key research priority to gain access to the anatomical fidelity of MR imaging.

Stereotactic Body Radiotherapy for Primary Prostate Cancer.

Prostate cancer is the most common non-cutaneous cancer in males. There are a number of options for patients with localized early stage disease, including active surveillance for low-risk disease, surgery, brachytherapy, and external beam radiotherapy. Increasingly, external beam radiotherapy, in the form of dose-escalated and moderately hypofractionated regimens, is being utilized in prostate cancer, with randomized evidence to support their use. Stereotactic body radiotherapy, which is a form of extreme hypofractionation, delivered with high precision and conformality typically over 1 to 5 fractions, offers a more contemporary approach with several advantages including being non-invasive, cost-effective, convenient for patients, and potentially improving patient access. In fact, one study has estimated that if half of the patients currently eligible for conventional fractionated radiotherapy in the United States were treated instead with stereotactic body radiotherapy, this would result in a total cost savings of US$250 million per year. There is also a strong radiobiological rationale to support its use, with prostate cancer believed to have a low α/ß ratio and therefore being preferentially sensitive to larger fraction sizes. To date, there are no published randomized trials reporting on the comparative efficacy of stereotactic body radiotherapy compared to alternative treatment modalities, although multiple randomized trials are currently accruing. Yet, early results from the randomized phase III study of HYPOfractionated RadioTherapy of intermediate risk localized Prostate Cancer (HYPO-RT-PC) trial, as well as multiple single-arm phase I/II trials, indicate low rates of late adverse effects with this approach. In patients with low- to intermediate-risk disease, excellent biochemical relapse-free survival outcomes have been reported, albeit with relatively short median follow-up times. These promising early results, coupled with the enormous potential cost savings and implications for resource availability, suggest that stereotactic body radiotherapy will take center stage in the treatment of prostate cancer in the years to come.

Magnetic Resonance Imaging-Guided Adaptive Radiation Therapy: A "Game Changer" for Prostate Treatment?

Radiation therapy to the prostate involves increasingly sophisticated delivery techniques and changing fractionation schedules. With a low estimated α/ß ratio, a larger dose per fraction would be beneficial, with moderate fractionation schedules rapidly becoming a standard of care. The integration of a magnetic resonance imaging (MRI) scanner and linear accelerator allows for accurate soft tissue tracking with the capacity to replan for the anatomy of the day. Extreme hypofractionation schedules become a possibility using the potentially automated steps of autosegmentation, MRI-only workflow, and real-time adaptive planning. The present report reviews the steps involved in hypofractionated adaptive MRI-guided prostate radiation therapy and addresses the challenges for implementation.

Phase 1/2 Dose-Escalation Study of the Use of Intensity Modulated Radiation Therapy to Treat the Prostate and Pelvic Nodes in Patients With Prostate Cancer.

PURPOSE: To investigate the feasibility of dose escalation and hypofractionation of pelvic lymph node intensity modulated radiation therapy (PLN-IMRT) in prostate cancer (PCa). METHODS AND MATERIALS: In a phase 1/2 study, patients with advanced localized PCa were sequentially treated with 70 to 74 Gy to the prostate and dose-escalating PLN-IMRT at doses of 50 Gy (cohort 1), 55 Gy (cohort 2), and 60 Gy (cohort 3) in 35 to 37 fractions. Two hypofractionated cohorts received 60 Gy to the prostate and 47 Gy to PLN in 20 fractions over 4 weeks (cohort 4) and 5 weeks (cohort 5). All patients received long-course androgen deprivation therapy. Primary outcome was late Radiation Therapy Oncology Group toxicity at 2 years after radiation therapy for all cohorts. Secondary outcomes were acute and late toxicity using other clinician/patient-reported instruments and treatment efficacy. RESULTS: Between August 9, 2000, and June 9, 2010, 447 patients were enrolled. Median follow-up was 90 months. The 2-year rates of grade 2+ bowel/bladder toxicity were as follows: cohort 1, 8.3%/4.2% (95% confidence interval 2.2%-29.4%/0.6%-26.1%); cohort 2, 8.9%/5.9% (4.1%-18.7%/2.3%-15.0%); cohort 3, 13.2%/2.9% (8.6%-20.2%/1.1%-7.7%); cohort 4, 16.4%/4.8% (9.2%-28.4%/1.6%-14.3%); cohort 5, 12.2%/7.3% (7.6%-19.5%/3.9%-13.6%). Prevalence of bowel and bladder toxicity seemed to be stable over time. Other scales mirrored these results. The biochemical/clinical failure-free rate was 71% (66%-75%) at 5 years for the whole group, with pelvic lymph node control in 94% of patients. CONCLUSIONS: This study shows the safety and tolerability of PLN-IMRT. Ongoing and planned phase 3 studies will need to demonstrate an increase in efficacy using PLN-IMRT to offset the small increase in bowel side effects compared with prostate-only IMRT.

Nine-year Follow-up for a Study of Diffusion-weighted Magnetic Resonance Imaging in a Prospective Prostate Cancer Active Surveillance Cohort.

BACKGROUND: In active surveillance (AS) for prostate cancer there are few data on long-term outcomes associated with novel imaging markers. OBJECTIVE: To determine long-term outcomes with respect to the apparent diffusion coefficient (ADC) derived from diffusion-weighted magnetic resonance imaging (DW-MRI) in a prospective AS cohort. Early results have already been published; we now present findings with long-term follow-up. DESIGN, SETTING, AND PARTICIPANTS: A subset of patients (n=86) underwent pre-enrolment DW-MRI in a prospective AS study between 2002 and 2006. Inclusion criteria were untreated prostate cancer, clinical T1/T2a/N0M0, Gleason ≤ 3+4, and prostate-specific antigen (PSA) <15 ng/ml. Protocol follow-up was by biopsy at 18-24 mo and then every 24 mo, with regular PSA measurement. INTERVENTION: Men underwent baseline DW-MRI in addition to standard sequences. ADC was measured from the index lesion on T2-weighted images. To avoid influencing treatment decisions, DW-MRI sequence results were not available to the AS study investigators. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline ADC was analysed with respect to time to radical treatment (TRT) and time to adverse histology (TAH). Kaplan-Meier analysis and univariate and multivariate regression analyses were performed. RESULTS AND LIMITATIONS: The median follow-up was 9.5 yr (interquartile range 7.9-10.0 yr). On univariate analysis, ADC below the median was associated with shorter TAH (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.17-3.89; p<0.014) and TRT (HR 2.54, 95% CI 1.49-4.32; p<0.001). Median TRT was 9.3 yr (95% CI 7.0-11.6 yr) for patients with ADC above the median and only 2.4 yr (95% CI 1.5-6.0 yr) for ADC below the median. For TRT, addition of ADC to a multivariate model of baseline variables resulted in a significant improvement in model fit (HR 1.33, 95% CI 1.14-1.54; p<0.001). Receiver operating characteristic analysis for TRT revealed an area under the curve of 0.80 (95% CI 0.70-0.88). The number of variables included in the multivariate model was limited by sample size. CONCLUSIONS: Long-term follow-up for this study provides strong evidence that ADC is a useful marker when selecting patients for AS. Routine DW-MRI is now being evaluated in our ongoing AS study for initial assessment and as an alternative to repeat biopsy. PATIENT SUMMARY: Before entering a study of close monitoring for the initial management of prostate cancer, patients had a type of magnetic resonance imaging scan that looks at the movement of water within cancers. These scans may help in predicting whether patients should receive close monitoring or whether immediate treatment should be given.

Reducing treatment toxicities in the management of good prognosis testicular germ cell tumors.

Testicular germ cell tumors are the most frequent solid tumor to affect young adult males and are increasing in incidence for reasons that are poorly understood. Increasingly, patients present with localized disease where disease-specific survival approaches 100%. Even in the presence of metastatic disease, the majority of patients with good prognostic features should expect to be cured. However, toxicities from treatment are increasingly recognized, with patients experiencing increased rates of second malignancies, cardiovascular disease and a range of circulatory, neurological and endocrine sequelae. High cure rates in a young population make reducing this long-term treatment-related morbidity and mortality imperative. In stage I disease, options following orchidectomy range from surveillance to adjuvant therapy, in the form of carboplatin or para-aortic radiotherapy for seminoma, and combination chemotherapy for nonseminoma. Metastatic disease requires combination chemotherapy with the exception of low-volume para-aortic nodal disease in seminoma, where radiotherapy with or without carboplatin may be curative. These various treatment options are discussed with a focus on reducing long-term treatment-related toxicities while preserving the high rates of long-term disease control.

A study of diffusion-weighted magnetic resonance imaging in men with untreated localised prostate cancer on active surveillance.

BACKGROUND: Markers that predict the behaviour of localised prostate cancer are needed to identify patients that require treatment. OBJECTIVE: We have analysed the apparent diffusion coefficient (ADC) generated from diffusion-weighted magnetic resonance imaging (DW-MRI) with respect to repeat biopsy findings and time to radical treatment in patients in a prospective study of active surveillance. DESIGN, SETTING, AND PARTICIPANTS: Some 86 men recruited between 2002 and 2006 were followed for a median of 29 mo. Patients had clinical stage T1/T2a N0/Nx M0/Mx adenocarcinoma of the prostate, prostate-specific antigen (PSA) level<15 ng/ml, Gleason score≤7, primary Gleason grade≤3, and positive biopsy cores (pbc)≤50%. MEASUREMENTS: All patients had DW-MRI in addition to standard MRI sequences. Tumour regions of interest (ROIs) were identified using T2-weighted fast-spin echo images as focal areas of restricted diffusion. Univariate analyses including all clinical variables and tumour ADC data were performed with respect to repeat biopsy findings and time to radical treatment. Receiver operating curves (ROC) compared predictive variables. RESULTS AND LIMITATIONS: Patients in the study had a median age of 66 yr and a median initial PSA level of 6.7 ng/ml. Some 39 patients (45%) received deferred radical treatment, and 34 patients (40%) had adverse histology on repeat biopsy. According to univariate analysis, tumour ADC was a significant predictor of both adverse repeat biopsy findings (p<0.0001; hazard ratio [HR]: 1.3; 95% confidence interval [CI]: 1.1-1.6), and time to radical treatment (p<0.0001; HR: 1.5; 95% CI: 1.2-1.8). ROC curves for ADC showed an area under the curve (AUC) of 0.7 for prediction of adverse repeat biopsy findings and an AUC of 0.83 for prediction of radical treatment. CONCLUSIONS: In patients with low-risk, localised disease, tumour ADC on DW-MRI may be a useful marker of prostate cancer progression and may help to identify patients who stand to benefit from radical treatment. This possibility warrants further study.

Predicting the probability of deferred radical treatment for localised prostate cancer managed by active surveillance.

OBJECTIVES: Outcome data from a prospective study of active surveillance of localised prostate cancer were analysed to identify factors, present at the time of diagnosis, that predict subsequent radical treatment. METHODS: Eligible patients had clinical stage T1-T2a, N0-Nx, M0-Mx adenocarcinoma of the prostate with serum PSA<15 ng/ml, Gleason score 1 ng/ml/yr) or histological progression (primary Gleason grade >or= 4, or %pbc > 50%). Multivariate Cox regression analysis of baseline variables was performed with respect to time to radical treatment. RESULTS: The 326 men recruited from 2002 to 2006 have been followed for a median of 22 mo. Median age was 67 yr, and median initial PSA (iPSA) 6.4 ng/ml. Sixty-five patients (20%) had deferred radical treatment, 16 (5%) changed to watchful waiting because of increasing comorbidity, 7 (2%) died of other causes, and 238 (73%) remain on surveillance. On multivariate Cox regression analysis, the free/total PSA ratio (p<0.001) and clinical T stage (p=0.006) were independent determinants of time to radical treatment. CONCLUSIONS: In addition to established prognostic factors, the free/total PSA ratio may predict time to radical treatment in patients with untreated, localised prostate cancer managed by active surveillance. This possibility warrants further study.

Active surveillance with selective radical treatment for localized prostate cancer.

The challenge of managing localized prostate cancer is to distinguish patients with clinically relevant cancers, who may benefit from radical treatment, from the remainder who do not need any intervention. Active surveillance with selective radial intervention is a management strategy that offers patients the hope of avoiding "unnecessary" treatment without detriment to their long-term survival. Here we discuss the rationale for active surveillance, and the early results. There is no consensus on the optimum active surveillance protocol, with uncertainty regarding the interpretation of PSA kinetics, repeat biopsy results and prostate imaging. In the future, it is likely that molecular markers will revolutionize our ability to select patients who will benefit from definitive treatment. In the meantime, active surveillance provides an attractive way of reducing over treatment.