It is unclear whether immediate adjuvant radiotherapy for high-risk disease at prostatectomy (capsule perforation, seminal vesicle invasion, and/or positive surgical margins) is equivalent to delayed ...salvage radiotherapy at biochemical recurrence. We performed a matched case analysis comparing high-dose adjuvant intensity modulated radiotherapy (A-IMRT) with salvage IMRT (S-IMRT).
One hundred forty-four patients with high-risk disease at prostatectomy were referred for A-IMRT, and 134 patients with high-risk disease were referred at biochemical recurrence (rising prostate-specific antigen PSA, following prostatectomy, above 0.2 ng/ml) for S-IMRT. Patients were matched in a 1:1 ratio according to preoperative PSA level, Gleason score, and pT stage. Median doses of 74 Gy and 76 Gy were prescribed for A-IMRT and S-IMRT, respectively. We report biochemical relapse free survival (bRFS) rates using the Kaplan-Meier method. Univariate and multivariate analyses were used to examine tumour- and treatment-related factors.
A total of 178 patients were matched (89:89). From the end of radiotherapy, the median follow-up was 36 months for both groups. The 3-year bRFS rate for the A-IMRT group was 90% compared to 65% for the S-IMRT group (p < 0.05). On multivariate analysis, S-IMRT, Gleason grades of ≥ 4+3, perineural invasion, preoperative PSA level of ≥ 10 ng/ml, and omission of androgen deprivation (AD) were independent predictors for a reduced bRFS (p < 0.05). From the date of surgery, the median follow-up was 43 and 60 months for A-IMRT and S-IMRT, respectively. The 3-year bRFS rate for A-IMRT was 91% compared to 79% for S-IMRT (p < 0.05). On multivariate analysis, Gleason grades of ≥ 4+3, perineural invasion, and omission of AD were independent predictors for a reduced bRFS (p < 0.05). S-IMRT was no longer an independent prognostic factor (p = 0.08).
High-dose A-IMRT significantly improves 3-year bRFS compared to S-IMRT. Gleason grades of ≥ 4+3, perineural invasion, and omission of AD were independent prognostic factors for a decreased bRFS, both from the dates of surgery and from radiotherapy.
Summary Renal-cell carcinoma is considered to be a radioresistant tumour, but this notion might be wrong. If given in a few (even single) fractions, but at a high fraction dose, stereotactic body ...radiotherapy becomes increasingly important in the management of renal-cell carcinoma, both in primary settings and in treatment of oligometastatic disease. There is an established biological rationale for the radiosensitivity of renal-cell carcinoma to stereotactic body radiotherapy based on the ceramide pathway, which is activated only when a high dose per fraction is given. Apart from the direct effect of stereotactic body radiotherapy on renal-cell carcinoma, stereotactic body radiotherapy can also induce an abscopal effect. This effect, caused by immunological processes, might be enhanced when targeted drugs and stereotactic body radiotherapy are combined. Therefore, rigorous, prospective randomised trials involving a multidisciplinary scientific panel are needed urgently.
Patients with high-risk prostate cancer treated with curative intent are at an increased risk of biochemical recurrence, metastatic progression and cancer-related death compared with patients treated ...for low-risk or intermediate-risk disease. Thus, these patients often need multimodal therapy to achieve complete disease control. Over the past two decades, multiple studies on the use of neoadjuvant treatment have been performed using conventional androgen deprivation therapy, which comprises luteinizing hormone-releasing hormone agonists or antagonists and/or first-line anti-androgens. However, despite results from these studies demonstrating a reduction in positive surgical margins and tumour volume, no benefit has been observed in hard oncological end points, such as cancer-related death. The introduction of potent androgen receptor signalling inhibitors (ARSIs), such as abiraterone, apalutamide, enzalutamide and darolutamide, has led to a renewed interest in using neoadjuvant hormonal treatment in high-risk prostate cancer. The addition of ARSIs to androgen deprivation therapy has demonstrated substantial survival benefits in the metastatic castration-resistant, non-metastatic castration-resistant and metastatic hormone-sensitive settings. Intuitively, a similar survival effect can be expected when applying ARSIs as a neoadjuvant strategy in high-risk prostate cancer. Most studies on neoadjuvant ARSIs use a pathological end point as a surrogate for long-term oncological outcome. However, no consensus yet exists regarding the ideal definition of pathological response following neoadjuvant hormonal therapy and pathologists might encounter difficulties in determining pathological response in hormonally treated prostate specimens. The neoadjuvant setting also provides opportunities to gain insight into resistance mechanisms against neoadjuvant hormonal therapy and, consequently, to guide personalized therapy.
Abstract Context The introduction of novel imaging modalities has increased the detection of oligometastatic prostate cancer (PCa) recurrence, potentially justifying the use of a metastasis-directed ...therapy (MDT) with surgery or radiotherapy (RT) rather than a systemic approach. Objective To perform a systematic review of MDT for oligometastatic PCa recurrence. Evidence acquisition This systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. We searched the Medline and Embase databases from 1946 to February 2014 for studies reporting on biochemical or clinical progression and/or toxicity or complications of MDT (RT or surgery). Reports were excluded if these end points could not be ascertained or separately analysed, or if insufficient details were provided. Methodological quality was assessed using an 18-item validated quality appraisal tool for case series. Evidence synthesis Fifteen single-arm case series reporting on a total of 450 patients met the inclusion criteria. Seven studies were considered of acceptable quality. Oligometastatic PCa recurrence was diagnosed with positron emission tomography with coregistered computed tomography in most of the patients (98%). Nodal, bone, and visceral metastases were treated in 78%, 21%, and 1%, respectively. Patients were treated with either RT (66%) or lymph node dissection (LND) (34%). Adjuvant androgen deprivation was given in 61% of patients ( n = 275). In the case of nodal metastases, prophylactic nodal irradiation was administered in 49% of patients ( n = 172). Overall, 51% of patients were progression free 1–3 yr after salvage MDT, with most of them receiving adjuvant treatment. For RT, grade 2 toxicity was observed in 8.5% of patients, with one case of grade 3 toxicity. In the case of LND, 11% and 12% of grade 2 and grade 3 complications, respectively, were reported. Conclusions MDT is a promising approach for oligometastatic PCa recurrence, but the low level of evidence generated by small case series does not allow extrapolation to a standard of care. Patient summary We performed a systematic review to assess complications and outcomes of treating oligometastatic prostate cancer recurrence with surgery or radiotherapy. We concluded that although this approach is promising, it requires validation in randomised controlled trials.
Abstract The literature on metastasis-directed therapy for oligometastatic prostate cancer (PCa) recurrence consists of small heterogeneous studies. This study aimed to reduce the heterogeneity by ...pooling individual patient data from different institutions treating oligometastatic PCa recurrence with stereotactic body radiotherapy (SBRT). We focussed on patients who were treatment naive, with the aim of determining if SBRT could delay disease progression. We included patients with three or fewer metastases. The Kaplan-Meier method was used to estimate distant progression-free survival (DPFS) and local progression-free survival (LPFS). Toxicity was scored using the Common Terminology Criteria for Adverse Events. In total, 163 metastases were treated in 119 patients. The median DPFS was 21 mo (95% confidence interval, 15–26 mo). A lower radiotherapy dose predicted a higher local recurrence rate with a 3-yr LPFS of 79% for patients treated with a biologically effective dose ≤100 Gy versus 99% for patients treated with >100 Gy ( p = 0.01). Seventeen patients (14%) developed toxicity classified as grade 1, and three patients (3%) developed grade 2 toxicity. No grade ≥3 toxicity occurred. These results should serve as a benchmark for future prospective trials. Patient summary This multi-institutional study pools all of the available data on the use of stereotactic body radiotherapy for limited prostate cancer metastases. We concluded that this approach is safe and associated with a prolonged treatment progression-free survival.
To report on the acute toxicity of a third escalation level using intensity-modulated radiotherapy for prostate cancer (PCa) and the acute toxicity resulting from delivery of a simultaneous ...integrated boost (SIB) to an intraprostatic lesion (IPL) detected on magnetic resonance imaging (MRI), with or without spectroscopy.
Between January 2002 and March 2007, we treated 230 patients with intensity-modulated radiotherapy to a third escalation level as primary therapy for prostate cancer. If an IPL (defined by MRI or MRI plus spectroscopy) was present, a SIB was delivered to the IPL. To report on acute toxicity, patients were seen weekly during treatment and 1 and 3 months after treatment. Toxicity was scored using the Radiation Therapy Oncology Group toxicity scale, supplemented by an in-house-developed scoring system.
The median dose to the planning target volume was 78 Gy. An IPL was found in 118 patients. The median dose to the MRI-detected IPL and MRI plus spectroscopy-detected IPL was 81 Gy and 82 Gy, respectively. No Grade 3 or 4 acute gastrointestinal toxicity developed. Grade 2 acute gastrointestinal toxicity was present in 26 patients (11%). Grade 3 genitourinary toxicity was present in 15 patients (7%), and 95 patients developed Grade 2 acute genitourinary toxicity (41%). No statistically significant increase was found in Grade 2-3 acute gastrointestinal or genitourinary toxicity after a SIB to an IPL.
The results of our study have shown that treatment-induced acute toxicity remains low when intensity-modulated radiotherapy to 80 Gy as primary therapy for prostate cancer is used. In addition, a SIB to an IPL did not increase the severity or incidence of acute toxicity.
Summary Since its introduction more than a decade ago, intensity-modulated radiotherapy (IMRT) has spread to most radiotherapy departments worldwide for a wide range of indications. The technique has ...been rapidly implemented, despite an incomplete understanding of its advantages and weaknesses, the challenges of IMRT planning, delivery, and quality assurance, and the substantially increased cost compared with non-IMRT. Many publications discuss the theoretical advantages of IMRT dose distributions. However, the key question is whether the use of IMRT can be exploited to obtain a clinically relevant advantage over non-modulated external-beam radiation techniques. To investigate which level of evidence supports the routine use of IMRT for various disease sites, we did a review of clinical studies that reported on overall survival, disease-specific survival, quality of life, treatment-induced toxicity, or surrogate endpoints. This review shows evidence of reduced toxicity for various tumour sites by use of IMRT. The findings regarding local control and overall survival are generally inconclusive.
Several retrospective and a few prospective studies have shown that metastasis-directed therapy (MDT) could delay clinical progression and postpone the initiation of systemic treatment in ...oligorecurrent prostate cancer (PCa) patients. However, these endpoints are strongly influenced by variables such as concomitant use of androgen deprivation therapy (ADT) and follow-up imaging protocols. The aim of this manuscript was to assess palliative ADT- and metastatic castration-resistant prostate cancer (mCRPC)-free survival as long-term oncological outcomes in oligorecurrent PCa treated by MDT. We retrospectively identified consecutive post-prostatectomy oligorecurrent PCa patients treated by MDT (salvage lymphadenectomy, radiotherapy, or metastasectomy) at our tertiary referral center. Patients were eligible for inclusion if they developed recurrence following radical prostatectomy, had ≤5 metastatic lesions on imaging and had a serum testosterone >50 ng/dL or a testosterone suppression therapy-free interval of >2 years prior to the first MDT as an assumption of recovered serum testosterone (if no testosterone measurement available). Patients with castration-resistant or synchronous oligometastatic PCa at the time of first MDT were excluded. Repeated MDTs were allowed, as well as a period of concomitant ADT. Kaplan-Meier analyses were performed to assess palliative ADT-free and mCRPC-free survival. We identified 191 eligible patients who underwent MDT. Median follow-up from first MDT until last follow-up or death was 45 months (IQR 27-70; mean 51 months). Estimated median palliative-ADT free survival was 66 months (95% CI 58-164) and estimated median mCRPC-free survival was not reached (mean 117 months, 95% CI 103-132). In total, 314 MDTs were performed and 25 patients (13%) received ≥3 MDTs. This study demonstrated that (repeated) MDT is feasible and holds promise in terms of palliative ADT-free and mCRPC-free survival for patients with oligorecurrent PCa. However, these findings should be confirmed in prospective randomized controlled trials.
Context
There is an urgent need to develop novel treatment strategies in patients with unfavorable intermediate- and high-risk localized prostate cancer (PCa) to optimize the outcome of these ...patients. Androgen receptor signaling inhibitors (ARSI) have demonstrated a survival benefit in metastatic hormonesensitive and castration-resistant PCa. A similar benefit might be expected in the localized setting.
Objective
To perform a systematic review about the role of neoadjuvant ARSI in unfavorable intermediate and high-risk localized PCa.
Evidence acquisition
We performed a systematic review of the following databases: MEDLINE (PubMed), EMBASE, Cochrane Library and Web of Science. Publications of ASCO were consulted to identify meeting abstract with early results of ongoing trials. This systematic review was performed and reported in accordance with the PRISMA guidelines.
Evidence synthesis
Pathological complete response (pCR) following neoadjuvant ARSI treatment was observed in 4%–13% of the patients. Minimal residual disease response ranged from 36% to 73.9% when defined as residual cancer burden < 0.25 cm
3
at final pathology and from 8% to 20% when defined as the diameter of the remaining tumor < 5 mm. Despite intense neoadjuvant ARSI treatment, residual pT3 disease was observed in 48%–76% of the patients. In contrast, positive surgical margins (PSM) were present in only 5%–22%. Only one trial reported BCR following neoadjuvant ARSI therapy (44% BCR at a median follow-up of 4 years).
Conclusion
Despite intense neoadjuvant ARSI therapy, pCR is rarely attained and high proportions of pT3 disease are still observed at final pathology. In contrast, promising results are obtained in terms of PSMs. Long-term survival outcomes are eagerly awaited.
Abstract Purpose To assess the ability of combined whole-prostate magnetic resonance imaging and magnetic resonance spectroscopy imaging (MRI + MRSI) to predict the presence or absence of high grade ...(Gleason 4 + 3 or higher) prostate carcinoma in men with elevated PSA. Materials and methods Between March 2002 and September 2007, 356 subjects (mean serum PSA 11.5 ng/ml, range 0.4–133.0 ng/ml) were examined with fast-T2-weighted magnetic resonance imaging (MRI) and 3D-magnetic resonance spectroscopy imaging (MRSI) on a 1.5 T scanner. Prostate cancer was histopathologically proven in 220 patients (41 with high grade and 179 with lower grade cancer) and non-evidence of cancer was determined after at least 12 months (mean 21 months) clinical follow-up in 136 subjects. The sensitivity, false positive rate, and negative predictive value of MRI + MRSI were calculated using histopathology and follow-up results as reference standard. Results MRI + MRSI had a significantly higher sensitivity for high grade tumors (92.7%) than for lower grade tumors (67.6%), and was false positive in only 7.4% of patients with non-evidence of prostate cancer. For exclusion of a high grade tumor, MRI + MRSI had a negative predictive value of 98.4%. Conclusions MRI + MRSI holds great potential for predicting presence or absence of high grade tumors in men with elevated PSA. This can be important in the selection of patients for active surveillance, or in the decision to rebiopsy patients with prior negative biopsies.
PDF
