Incidence of Secondary Cancer Development After High-Dose Intensity-Modulated Radiotherapy and Image-Guided Brachytherapy for the Treatment of Localized Prostate Cancer

doi:10.1016/j.ijrobp.2011.08.034

International Journal of Radiation OncologyBiologyPhysics

Volume 83, Issue 3, 1 July 2012, Pages 953-959

https://doi.org/10.1016/j.ijrobp.2011.08.034 Get rights and content

Purpose

To report the incidence and excess risk of second malignancy (SM) development compared with the general population after external beam radiotherapy (EBRT) and brachytherapy to treat prostate cancer.

Methods and Materials

Between 1998 and 2001, 1,310 patients with localized prostate cancer were treated with EBRT (n = 897) or brachytherapy (n = 413). We compared the incidence of SMs in our patients with that of the general population extracted from the National Cancer Institute’s Surveillance, Epidemiology, and End Results data set combined with the 2000 census data.

Results

The 10-year likelihood of SM development was 25% after EBRT and 15% after brachytherapy (p = .02). The corresponding 10-year likelihood for in-field SM development in these groups was 4.9% and 1.6% (p = .24). Multivariate analysis showed that EBRT vs. brachytherapy and older age were the only significant predictors for the development of all SMs (p = .037 and p = .030), with a trend for older patients to develop a SM. The increased incidence of SM for EBRT patients was explained by the greater incidence of skin cancer outside the radiation field compared with that after brachytherapy (10.6% and 3.3%, respectively, p = .004). For the EBRT group, the 5- and 10-year mortality rate was 1.96% and 5.1% from out-of field cancer, respectively; for in-field SM, the corresponding mortality rates were 0.1% and 0.7%. Among the brachytherapy group, the 5- and 10-year mortality rate related to out-of field SM was 0.8% and 2.7%, respectively. Our observed SM rates after prostate RT were not significantly different from the cancer incidence rates in the general population.

Conclusions

Using modern sophisticated treatment techniques, we report low rates of in-field bladder and rectal SM risks after prostate cancer RT. Furthermore, the likelihood of mortality secondary to a SM was unusual. The greater rate of SM observed with EBRT vs. brachytherapy was related to a small, but significantly increased, number of skin cancers in the EBRT patients compared with that of the general population.

Introduction

The risk of an induced second malignancy (SM) resulting from the mutagenic potential of ionizing radiation is well recognized. For the treatment of highly virulent tumors associated with poor survival outcomes, the low risk of SM development is of less concern than the significantly greater risk of primary tumor progression. However, for more indolent tumors, such as prostate cancer, quantifying the SM risk becomes more important. Several studies have suggested that prostate cancer patients have a greater risk of developing SMs, such as bladder and rectal cancer, regardless of treatment 1, 2, 3, 4. Brenner et al. (5) reported that the increased relative risk of developing SMs after external beam radiotherapy (EBRT) for prostate cancer was 15% and 34% for patients surviving >5 and >10 years after treatment, respectively. However, these rates were derived using the registries of the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program from prostate cancer patients treated with RT during the 1970s and 1980s. The incidence of SMs for prostate cancer patients treated in the current era with modern techniques, such as intensity-modulated radiotherapy (IMRT), remains unclear. Several reports 4, 6, 7, 8, 9, 10, tracking the incidence of SMs after EBRT using conformal RT, showed lower rates than those reported by Brenner et al. (5). It is also unclear what the differences in the risk of SMs are for patients treated with brachytherapy, because the radiation dose might be more confined but is associated with greater dose deposition within irradiated tissue compared with EBRT 9, 11. Currently, younger patients are more often considering nonsurgical options for their prostate cancer; thus, quantification of the relative risk of induced SMs becomes increasingly important because it could affect therapy selection.

Previous single-institution studies 6, 10 analyzing the risk of SMs have been limited by the number of patients included and the length of follow-up available for those treated with sophisticated modern techniques. We report on a cohort of >1,300 patients treated with IMRT and permanent seed interstitial implantation using an intraoperative planning transrectal ultrasound-guided technique. We report on the respective incidence of SM development for IMRT and brachytherapy patients and also report the actual mortality rate due to a SM.

Section snippets

Methods and Materials

Between 1998 and 2001, 1,310 patients with clinically localized prostate cancer received EBRT (n = 897) or brachytherapy (n = 413). The patient characteristics are listed in Table 1. In general, EBRT patients were treated with IMRT using a five-field coplanar beam arrangement delivered to the prostate and seminal vesicles using 15 MV photons in daily 1.8-Gy fractions. The treatment planning and delivery were as previously described (12). The median EBRT prescribed dose was 81 Gy. Before EBRT,

Overall incidence and location of SM

A total of 130 EBRT (15%) and 41 brachytherapy (10%) patients developed SMs. The SM location, incidence, and stage at clinical presentation for each group are listed in Table 2, Table 3. Of those developing SMs, 22 (2%) and 6 (1%) EBRT and brachytherapy patients, respectively, developed IF SMs (p = .24). The percentage of rectal cancers in the EBRT and brachytherapy groups was 0.56% (5 of 897) and 0.5% (2 of 413), respectively. The percentage of bladder cancers in the EBRT and brachytherapy

Discussion

The present study is unique in that the SM incidence was evaluated in patients who had received the most current and sophisticated forms of high-dose EBRT and brachytherapy to treat prostate cancer. Previous studies often included patients treated with older techniques, in which a greater volume of normal tissues was exposed to radiation doses, potentially further increasing the risk of SM development. Although our follow-up does not extend beyond 10 years, important insights can be obtained

Conclusions

In contrast to other studies, we report low rates of IF bladder and rectal SM risks after prostate cancer RT using modern sophisticated treatment techniques. For EBRT patients, compared with the general population, we noted an increased excess risk of OOF skin cancers but not for the brachytherapy patients. When SMs developed, they were generally of an early stage, likely owing to early detection, and the incidence of SM-related mortality was low among these patients. This information would be

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European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2023 Guidelines
2024, European Urology
We present an overview of the updated 2023 European Association of Urology (EAU) guidelines for muscle-invasive and metastatic bladder cancer (MMIBC).
To provide practical evidence-based recommendations and consensus statements on the clinical management of MMIBC with a focus on diagnosis and treatment.
A broad and comprehensive scoping exercise covering all areas of the MMIBC guidelines has been performed annually since 2017. Searches cover the Medline, EMBASE, and Cochrane Libraries databases for yearly guideline updates. A level of evidence and strength of recommendation are assigned. The evidence cutoff date for the 2023 MIBC guidelines was May 4, 2022.
Patients should be counselled regarding risk factors for bladder cancer. Pathologists should describe tumour and lymph nodes in detail, including the presence of histological subtypes. The importance of the presence or absence of urothelial carcinoma (UC) in the prostatic urethra is emphasised. Magnetic resonance imaging (MRI) of the bladder is superior to computed tomography (CT) for disease staging, specifically in differentiating T1 from T2 disease, and may lead to a change in treatment approach in patients at high risk of an invasive tumour. Imaging of the upper urinary tract, lymph nodes, and distant metastasis is performed with CT or MRI; the additional value of flurodeoxyglucose positron emission tomography/CT still needs to be determined. Frail and comorbid patients should be evaluated by a multidisciplinary team. Postoperative histology remains the most important prognostic variable, while circulating tumour DNA appears to be an interesting predictive marker. Neoadjuvant systemic therapy remains cisplatin-based. In motivated and selected women and men, sexual organ–preserving cystectomy results in better functional outcomes without compromising oncological outcomes. Robotic and open cystectomy have comparable outcomes and should be combined with (extended) lymph node dissection. The diversion type is an individual choice after taking patient and tumour characteristics into account. Radical cystectomy remains a highly complex procedure with considerable morbidity and risk of mortality, although lower rates are observed for higher hospital volumes (>20 cases/yr). With proper patient selection, trimodal therapy (chemoradiation) has comparable outcomes to radical cystectomy. Adjuvant chemotherapy after surgery improves disease-specific survival and overall survival (OS) in patients with high-risk disease who did not receive neoadjuvant treatment, and is strongly recommended. There is a weak recommendation for adjuvant nivolumab, as OS data are not yet available. Health-related quality of life should be assessed using validated questionnaires at baseline and after treatment. Surveillance is needed to monitor for recurrent cancer and functional outcomes. Recurrences detected on follow-up seem to have better prognosis than symptomatic recurrences.
This summary of the 2023 EAU guidelines provides updated information on the diagnosis and treatment of MMIBC for incorporation into clinical practice.
The European Association of Urology guidelines panel on muscle-invasive and metastatic bladder cancer has released an updated version of the guideline containing information on diagnosis and treatment of this disease. Recommendations are based on studies published up to May 4, 2022. Surgical removal of the bladder and bladder preservation are discussed, as well as updates on the use of chemotherapy and immunotherapy in localised and metastatic disease.
Advances in radiotherapy and its impact on second primary cancer risk: A multi-center cohort study in prostate cancer patients
2023, Radiotherapy and Oncology
Modelling studies suggest that advanced intensity-modulated radiotherapy may increase second primary cancer (SPC) risks, due to increased radiation exposure of tissues located outside the treatment fields. In the current study we investigated the association between SPC risks and characteristics of applied external beam radiotherapy (EBRT) protocols for localized prostate cancer (PCa).
We collected EBRT protocol characteristics (2000–2016) from five Dutch RT institutes for the 3D-CRT and advanced EBRT era (N = 7908). From the Netherlands Cancer Registry we obtained patient/tumour characteristics, SPC data, and survival information. Standardized incidence ratios (SIR) were calculated for pelvis and non-pelvis SPC. Nationwide SIRs were calculated as a reference, using calendar period as a proxy to label 3D-CRT/advanced EBRT.
From 2000-2006, 3D-CRT with 68–78 Gy in 2 Gy fractions, delivered with 10–23 MV and weekly portal imaging was the most dominant protocol. By the year 2010 all institutes routinely used advanced EBRT (IMRT, VMAT, tomotherapy), mainly delivering 78 Gy in 2 Gy fractions, using various kV/MV imaging protocols. Sixteen percent (N = 1268) developed ≥ 1 SPC. SIRs for pelvis and non-pelvis SPC (all institutes, advanced EBRT vs 3D-CRT) were 1.17 (1.00–1.36) vs 1.39 (1.21–1.59), and 1.01 (0.89–1.07) vs 1.03 (0.94–1.13), respectively. Nationwide non-pelvis SIR was 1.07 (1.01–1.13) vs 1.02 (0.98–1.07). Other RT protocol characteristics did not correlate with SPC endpoints.
None of the studied RT characteristics of advanced EBRT was associated with increased out-of-field SPC risks. With constantly evolving EBRT protocols, evaluation of associated SPC risks remains important.
Normal Tissue Integral Dose as a Result of Prostate Radiation Therapy: A Quantitative Comparison Between High-Dose-Rate Brachytherapy and Modern External Beam Radiation Therapy Techniques
2023, Advances in Radiation Oncology
Quantification of integral radiation dose delivered during treatment for prostate cancer is lacking. We performed a comparative quantification of dose to nontarget body tissues delivered via 4 common radiation techniques: conventional volumetric modulated arc therapy, stereotactic body radiation therapy, pencil-beam scanning proton therapy, and high-dose-rate brachytherapy.
Plans for each radiation technique were generated for 10 patients with typical anatomy. For brachytherapy plans, virtual needles were placed to achieve standard dosimetry. Standard planning target volume margins or robustness margins were applied as appropriate. A “normal tissue” structure (entire computed tomography simulation volume minus planning target volume) was generated for integral dose computation. Dose-volume histogram parameters for targets and normal structures were tabulated. Normal tissue integral dose was calculated by multiplying normal tissue volume by mean dose.
Normal tissue integral dose was lowest for brachytherapy. Pencil-beam scanning protons, stereotactic body radiation therapy, and brachytherapy resulted in 17%, 57%, and 91% absolute reductions compared with standard volumetric modulated arc therapy, respectively. Mean nontarget tissues receiving 25%, 50%, and 75% of the prescription dose were reduced by 85%, 76%, and 83% for brachytherapy relative to volumetric modulated arc therapy, by 79%, 64%, and 74% relative to stereotactic body radiation therapy, and 73%, 60%, and 81% relative to proton therapy. All reductions observed using brachytherapy were statistically significant.
High-dose-rate brachytherapy is an effective technique for reducing dose to nontarget body tissues relative to volumetric modulated arc therapy, stereotactic body radiation therapy, and pencil-beam scanning proton therapy.
European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2020 Guidelines
2021, European Urology
This overview presents the updated European Association of Urology (EAU) guidelines for muscle-invasive and metastatic bladder cancer (MMIBC).
To provide practical evidence-based recommendations and consensus statements on the clinical management of MMIBC with a focus on diagnosis and treatment.
A broad and comprehensive scoping exercise covering all areas of the MMIBC guideline has been performed annually since its 2017 publication (based on the 2016 guideline). Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries, resulting in yearly guideline updates. A level of evidence and a grade of recommendation were assigned. Additionally, the results of a collaborative multistakeholder consensus project on advanced bladder cancer (BC) have been incorporated in the 2020 guidelines, addressing those areas where it is unlikely that prospective comparative studies will be conducted.
Variant histologies are increasingly reported in invasive BC and are relevant for treatment and prognosis. Staging is preferably done with (enhanced) computerised tomography scanning. Treatment decisions are still largely based on clinical factors. Radical cystectomy (RC) with lymph node dissection remains the recommended treatment in highest-risk non–muscle-invasive and muscle-invasive nonmetastatic BC, preceded by cisplatin-based neoadjuvant chemotherapy (NAC) for invasive tumours in “fit” patients. Selected men and women benefit from sexuality sparing RC, although this is not recommended as standard therapy. Open and robotic RC show comparable outcomes, provided the procedure is performed in experienced centres. For open RC 10, the minimum selected case load is 10 procedures per year. If bladder preservation is considered, chemoradiation is an alternative in well-selected patients without carcinoma in situ and after maximal resection. Adjuvant chemotherapy should be considered if no NAC was given. Perioperative immunotherapy can be offered in clinical trial setting. For fit metastatic patients, cisplatin-based chemotherapy remains the first choice. In cisplatin-ineligible patients, immunotherapy in Programmed Death Ligand 1 (PD-L1)-positive patients or carboplatin in PD-L1–negative patients is recommended. For second-line treatment in metastatic disease, pembrolizumab is recommended. Postchemotherapy surgery may prolong survival in responders. Quality of life should be monitored in all phases of treatment and follow-up. The extended version of the guidelines is available at the EAU website: https://uroweb.org/guideline/bladder-cancer-muscle-invasive-and-metastatic/.
This summary of the 2020 EAU MMIBC guideline provides updated information on the diagnosis and treatment of MMIBC for incorporation into clinical practice.
The European Association of Urology Muscle-invasive and Metastatic Bladder Cancer (MMIBC) Panel has released an updated version of their guideline, which contains information on histology, staging, prognostic factors, and treatment of MMIBC. The recommendations are based on the current literature (until the end of 2019), with emphasis on high-level data from randomised clinical trials and meta-analyses and on the findings of an international consensus meeting. Surgical removal of the bladder and bladder preservation are discussed, as well as the use of chemotherapy and immunotherapy in localised and metastatic disease.
Kilovoltage intrafraction monitoring during normofractionated prostate cancer radiotherapy
2020, Cancer/Radiotherapie
During radiotherapy (RT) for prostate cancer (PCa), interfraction and intrafraction movements can lead to decreased target dose coverage and unnecessary over-exposure of organs at risk. New image-guided RT techniques accuracy allows planning target volume (PTV) margins reduction. We aim to assess the feasibility of a kilovoltage intrafraction monitoring (KIM) to track the prostate during RT.
Between November 2017 and April 2018, 44 consecutive patients with PCa were included in an intrafraction prostate motion study using the Truebeam Auto Beam Hold® tracking system (Varian Medical Systems, United State) triggered by gold fiducials localization on kilovoltage (kV) imaging. A 5-mm PTV was considered. A significant gating event (SGE) was defined as the occurrence of an automatic beam interruption requiring patient repositioning following the detection of one fiducial outside a 5-mm target area around the marker during more than 45 seconds.
Six patients could not benefit from the KIM because of technical issues (loss of one fiducial marker = 1, hip prosthesis = 4, morbid obesity causing table movements = 1). The mean rate of SGE per patient was 14 ± 19%, and the fraction average delivery time was increased by 146 ± 86 seconds. For a plan of 39 fractions of 2 Gy, the additional radiation dose increased by 0.13 ± 0.09 Gy. The mean rates of SGE were 2% and 18% (P = 0.002) in patients with planned fraction < 90 and > 90 seconds respectively, showing that duration of the session strongly interfered with prostate intrafraction movements. No other significant clinical and technical parameter was correlated with the occurrence of SGE.
Automated intrafraction kV imaging can effectively perform autobeam holds due to intrafraction movement of the prostate in the large majority of patients. The additional radiation dose and delivery time are acceptable. This technique may be a cost-effective alternative to electromagnetic transponder guidance.
Les mouvements pendant et entre les fractions peuvent conduire à une diminution de la couverture tumorale et à une exposition des organes à risque durant la radiothérapie des cancers de la prostate. Les nouvelles techniques de radiothérapie guidée par l’image (IGRT) permettent de diminuer les marges du volume tumoral prévisionnel (PTV). Notre objectif était de tester la faisabilité d’une radiothérapie guidée par l’image utilisant un monitoring par imagerie de basse énergie (kV) pendant les fractions.
De novembre 2017 à avril 2018, 44 patients atteints d’un cancer de la prostate ont été inclus dans cette étude utilisant le système de tracking Auto Beam Hold® sur machine Truebeam (Varian Medical Systems, États-Unis), guidé par la détection de grains d’or sur imagerie kV. Une marge de PTV de 5 mm a été considérée. Un évènement significatif était défini par la survenue d’une interruption du faisceau nécessitant un repositionnement du patient provoqué par la détection d’un marqueur en dehors de la zone cible de 5 mm de rayon définie autour de chacun des marqueurs pendant une durée supérieure à 45 secondes.
Six patients n’ont pu bénéficier du monitoring par imagerie de basse énergie pendant les fractions pour des raisons techniques (perte d’un repère fiduciel = un, prothèse de hanche = quatre, obésité morbide provoquant des mouvements de table = un). Le taux moyen d’évènements significatifs par patient était de 14 ± 19 %, et la durée d’irradiation était augmentée en moyenne de 146 ± 86 secondes. Pour un traitement de 39 séances de 2 Gy, la dose additionnelle moyenne de rayonnement était de 0,13 ± 0,09 Gy. Le taux moyen d’évènements significatifs était de 2 et 18 % (p = 0,002) chez les patients dont la durée de séance planifiée initialement était inférieure versus supérieure à 90 secondes, respectivement, montrant que la durée de l’irradiation est corrélée aux mouvements intraprostatiques. Aucun autre paramètre clinique ou technique n’était corrélé à la survenue d’un évènement significatif.
L’imagerie de basse énergie automatique durant les fractions permet de suspendre l’irradiation efficacement en cas de mouvements pendant les fractions chez la majorité des patients. La dose de rayonnements additionnelle est faible et la durée de traitement acceptable. Cette technique paraît donc tout à fait faisable et peut représenter une alternative aux marqueurs électromagnétiques.
Hospital burden of long-term genitourinary and gastrointestinal toxicity after radical radiotherapy for prostate cancer
2018, Surgeon
Treatment options for prostate cancer (PCa) include radical radiotherapy (RT) and radical prostatectomy, both of which have comparable oncological outcomes. The aim of this study was to investigate the hospital burden of long-term genitourinary and gastrointestinal toxicity among patients with PCa who were treated with radiotherapy at our institution.
The radiotherapy department database was used retrospectively to identify all patients who underwent radiotherapy for PCa from January 2006 to January 2008. The patient administration system from each public hospital in the region was interrogated and all patient points of contact were recorded. Minimum follow up was 5 years. Individual patient charts were reviewed and factors that might influence outcomes were documented.
We identified 112 patients. The mean age at diagnosis was 66 (44–76) and the median PSA was 12.1 (3.2–38). The mean duration of follow-up was 7.8 yrs. Twenty-three patients (20%) presented to the Emergency Department (ED) with late onset toxicity. Nine patients had more than 2 ED attendances. Twenty-five patients (22%) were investigated for genitourinary toxicity. Forty-seven patients (42%) underwent investigation for gastrointestinal side-effects and 45% of these required argon therapy (21/47).
We found a significant hospital burden related to the management of gastrointestinal and genitourinary toxicity post radical radiotherapy for prostate cancer. As health care reforms gain momentum, policy makers must take into account the considerable longitudinal health care cost related to radiotherapy. It is also important that patients are counselled carefully in relation to potential long-term side-effects.

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Clinical InvestigationIncidence of Secondary Cancer Development After High-Dose Intensity-Modulated Radiotherapy and Image-Guided Brachytherapy for the Treatment of Localized Prostate Cancer

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Methods and Materials

Overall incidence and location of SM

Discussion

Conclusions

Semin Radiat Oncol

Radiother Oncol

J Urol

J Urol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

J Urol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

J Urol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Radiother Oncol

Clinical Investigation
Incidence of Secondary Cancer Development After High-Dose Intensity-Modulated Radiotherapy and Image-Guided Brachytherapy for the Treatment of Localized Prostate Cancer