A prospective observational study to analyse the influence of bladder and rectal volume changes on prostate radiotherapy using IMRT

AimTo analyse the interfractional bladder and rectal volume changes and the influence on prostate position.BackgroundInterfractional displacement of prostate due to variation in bladder and rectal volume is usual. It is only rational to study the bladder and rectal volume changes and their effects on prostate position during intensity modulated radiotherapy of prostate cancer.Materials and MethodsA prospective study was conducted on twenty patients with localized prostate cancer during the first phase of radiotherapy, where 50 gray in 25 fractions was delivered by the IMRT technique with daily cone beam computed tomography Bladder and rectum volumes were delineated on CBCT images and their volumes were noted. Prostate position was noted on each set of CBCT images with respect to specific reference points defined on the ileum and coccyx, and daily prostate displacement was noted.ResultsMean setup errors in vertical, longitudinal and lateral directions were noted as 1.49, 0.498 and 0.17 cm, respectively. Mean change in bladder and rectal volumes in daily CBCT images with respect to that on the first day CT images was noted as 101.94 and 10.22, respectively. Mean lateral and vertical displacement in prostate position was noted as 0.53 and 0.49 cm respectively. No considerable changes in dosimetric parameters were observed because of bladder and rectal volume changes.ConclusionsDaily CBCT should be done for accurate treatment delivery by the IMRT technique for prostate radiotherapy as prostate shifts physiologically with changes in rectal and bladder volumes.     

Implementation of intensity modulated radiotherapy for prostate cancer in a private radiotherapy service in Mexico

Intensity modulated radiation therapy (IMRT) allows physicians to deliver higher conformal doses to the tumour, while avoiding adjacent structures. As a result the probability of tumour control is higher and toxicity may be reduced. However, implementation of IMRT is highly complex and requires a rigorous quality assurance (QA) program both before and during treatment. The present article describes the process of implementing IMRT for localized prostate cancer in a radiation therapy department. In our experience, IMRT implementation requires careful planning due to the need to simultaneously implement specialized software, multifaceted QA programs, and training of the multidisciplinary team. Establishing standardized protocols and ensuring close collaboration between a multidisciplinary team is challenging but essential.     

Outcome modeling techniques for prostate cancer radiotherapy: Data,models, and validation

Prostate cancer is a frequently diagnosed malignancy worldwide and radiation therapy is a first-line approach in treating localized as well as locally advanced cases. The limiting factor in modern radiotherapy regimens is dose to normal structures, an excess of which can lead to aberrant radiation-induced toxicities. Conversely, dose reduction to spare adjacent normal structures risks underdosing target volumes and compromising local control. As a result, efforts aimed at predicting the effects of radiotherapy could invaluably optimize patient treatments by mitigating such toxicities and simultaneously maximizing biochemical control. In this work, we review the types of data, frameworks and techniques used for prostate radiotherapy outcome modeling. Consideration is given to clinical and dose-volume metrics, such as those amassed by the QUANTEC initiative, and also to newer methods for the integration of biological and genetic factors to improve prediction performance. We furthermore highlight trends in machine learning that may help to elucidate the complex pathophysiological mechanisms of tumor control and radiation-induced normal tissue side effects.     

Predicting toxicity in radiotherapy for prostate cancer

This comprehensive review addresses most organs at risk involved in planning optimization for prostate cancer. It can be considered an update of a previous educational review that was published in 2009 (Fiorino et al., 2009).The literature was reviewed based on PubMed and MEDLINE database searches (from January 2009 up to September 2015), including papers in press; for each section/subsection, key title words were used and possibly combined with other more general key-words (such as radiotherapy, dose-volume effects, NTCP, DVH, and predictive model). Publications generally dealing with toxicity without any association with dose–volume effects or correlations with clinical risk factors were disregarded, being outside the aim of the review.A focus was on external beam radiotherapy, including post-prostatectomy, with conventional fractionation or moderate hypofractionation (<4 Gy/fraction); extreme hypofractionation is the topic of another paper in this special issue. Gastrointestinal and urinary toxicity are the most investigated endpoints, with quantitative data published in the last 5 years suggesting both a dose–response relationship and the existence of a number of clinical/patient related risk factors acting as dose–response modifiers. Some results on erectile dysfunction, bowel toxicity and hematological toxicity are also presented.     

Finite element simulation of interactions between pelvic organs: Predictive model of the prostate motion in the context of radiotherapy

The setting up of predictive models of the pelvic organ motion and deformation may prove an efficient tool in the framework of prostate cancer radiotherapy, in order to deliver doses more accurately and efficiently to the clinical target volume (CTV). A finite element (FE) model of the prostate, rectum and bladder motion has been developed, investigating more specifically the influence of the rectum and bladder repletions on the gland motion. The required organ geometries are obtained after processing the computed tomography (CT) images, using specific softwares. Due to their structural characteristics, a 3D shell discretization is adopted for the rectum and the bladder, whereas a volume discretization is adopted for the prostate. As for the mechanical behavior modelling, first order Ogden hyperelastic constitutive laws for both the rectum and bladder are identified. The prostate is comparatively considered as more rigid and is accordingly modelled as an elastic tissue undergoing small strains. A FE model is then created, accounting for boundary and contact conditions, internal and applied loadings being selected as close as possible to available anatomic data.The order of magnitude of the prostate motion predicted by the FE simulations is similar to the measurements done on a deceased person, accounting for the delineation errors, with a relative error around 8%. Differences are essentially due to uncertainties in the constitutive parameters, pointing towards the need for the setting up of direct measurement of the organs mechanical behavior.     

Evaluating the predictive value of quantec rectum tolerance dose suggestions on acute rectal toxicity in prostate carcinoma patients treated with IMRT

AimTo investigate the predictive value of convenience of rectum dosimetry with Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) dose limits, maximum rectum dose (Dmax), total rectal volume (TVrectum), rectal volume included in PTV (VrectumPTV) on Grade 2–3 acute rectal toxicity for utilization in clinical practice.BackgroundNumerous previous data have reported frequent acute proctitis after external-beam RT of prostate cancer. Predicting toxicity limited with dose information is inadequate in clinical practice due to comorbidities and medications used.Materials and MethodSixty-four non-metastatic prostate cancer patients treated with IMRT were enrolled. Patients were treated to a total dose of 70–76 Gy. Rectal dose volume histograms (DVH) of all patients were evaluated retrospectively, and a QUANTEC Score between 0 and 5 was calculated for each patient. The correlation between the rectal DVH data, QUANTEC score, TVrectum, VrectumPTV, rectum Dmax and Grade 2–3 rectal toxicity was investigated.ResultsIn the whole group grade 1, 2 and 3 acute rectal toxicities were 25%, 18.8% and 3.1%, respectively. In the DVH data, rectum doses of all patients were under RTOG dose limits. Statistically significant correlation was found between grade 2–3 rectal toxicity and TVrectum (p = 0,043); however. It was not correlated with QUANTEC score, VrectumPTV and Dmax.ConclusionOur results were not able to show any significant correlation between increasing convenience with QUANTEC limits and lower rectal toxicity. Conclusively, new dosimetric definitions are warranted to predict acute rectal toxicity more accurately in prostate cancer patients during IMRT treatment.     

Multiparametric magnetic resonance imaging-guided salvage radiotherapy in prostate cancer

AimTo analyse the efficacy and toxicity of postprostatectomy SRT in patients with a BCR evaluated with mpMRI.BackgroundMultiparametric magnetic resonance imaging (mpMRI) has the ability to detect the site of pelvic recurrence in patients with biochemical recurrence (BCR) after radical prostatectomy (RP). However, we do not know the oncological outcomes of mpMRI-guided savage radiotherapy (SRT).ResultsLocal, lymph node, and pelvic bone recurrence was observed in 13, 4 and 2 patients, respectively. PSA levels were significantly lower in patients with negative mpMRI (0.4 ng/mL [0.4]) vs. positive mpMRI (2.2 ng/mL [4.1], p = 0.003). Median planning target volume doses in patients with visible vs. non-visible recurrences were 76 Gy vs. 70 Gy. Overall, mean follow-up was 41 months (6–81). Biochemical relapse-free survival (bRFS) at 3 years was 82.3% and 82.5%, respectively, for the negative and positive mpMRI groups (p = 0.800). Three-year rates of late grade ≥2 urinary and rectal toxicity were 14.8% and 1.9%, respectively; all but one patient recovered without sequelae.ConclusionSRT to the macroscopic recurrence identified by mpMRI is a feasible and well-tolerated option. In this study, there were no differences in bRFS between MRI-positive and MRI-negative patients, indicating effective targeting of MRI-positive lesions.     

Radiosensitization effects by bismuth oxide nanorods of different sizes in megavoltage external beam radiotherapy

BackgroundNanotechnology application has successfully reached numerous scientific breakthroughs including in radiotherapy. However, the clinical application of nanoparticles requires more diligent research primarily on the crucial parameters such as nanoparticle sizes. This study is aimed to investigate the influence of bismuth oxide nanorod (Bi₂O₃-NR) sizes on radiosensitization effects on MCF-7 and HeLa cell lines for megavoltage photon and electron beam radiotherapy.Materials and methodsMCF-7 and HeLa cells were treated with and without 0.5 μMol/L of Bi₂O₃-NR of varying sizes (60, 70, 80, and 90 nm). The samples, including the control groups, were exposed to different radiation doses (0–10 Gy), using photon (6 MV and 10 MV), and electron beam (6 MeV and 12 MeV) radiotherapy. Clonogenic assay was performed, and sensitization enhancement ratio (SER) was determined from linear quadratic based cell survival curves.ResultsThe results depicted that 60 nm Bi₂O₃-NR yields the most excellent SER followed by 70 nm Bi₂O₃-NR. Meanwhile, the 80 and 90 nm Bi₂O₃-NR showed an insignificant difference between treated and untreated cell groups. This study also found that MCF-7 was subjected to more cell death compared to HeLa.Conclusion60 nm Bi₂O₃-NR was the optimal Bi₂O₃-NR size to induce radiosensitization effects for megavoltage external beam radiotherapy. The SER in photon beam radiotherapy marked the highest compared to electron beam radiotherapy due to decreased primary radiation energy from multiple radiation interaction and higher Compton scattering.     

Results of combined radiotherapy and hormonal treatment of prostate cancer patients with initial PSA value >40 ng/ml

AimTo evaluate the outcome of prostate cancer patients with initial PSA value >40 ng/ml.BackgroundThe outcome of prostate cancer patients with very high initial PSA value is not known and patients are frequently treated with palliative intent. We analyzed the outcome of radical combined hormonal treatment and radiotherapy in prostate cancer patients with initial PSA value >40 ng/ml.MethodsBetween January 2003 and December 2007 we treated, with curative intent, 56 patients with non-metastatic prostate cancer and initial PSA value >40 ng/ml. The treatment consisted of two months of neoadjuvant hormonal treatment (LHRH analog), radical radiotherapy (68–78 Gy, conformal technique) and an optional two-year adjuvant hormonal treatment.ResultsThe median time of follow up was 61 months. 5-Year overall survival was 90%. 5-Year biochemical disease free survival was 62%. T stage, Gleason score, PSA value, and radiotherapy dose did not significantly influence the outcome. Late genitourinal and gastrointestinal toxicity was acceptable.ConclusionRadical treatment in combination with hormonal treatment and radiotherapy can be recommended for this subgroup of prostate cancer patients with good performance status and life expectancy.     

Lower urinary tract infections from external beam radiation therapy in prostate cancer: A single institution experience

External beam radiation therapy (EMRT) is effective for the treatment of localized prostate cancer. Lower urinary tract infections (LUTIs) are considered one of the main possible adverse events related to External beam radiation therapy. Here we analyzed the incidence of LUTI during EMRT. Urinary tract infection was assumed when the findings of bacteriuria exceeded 100,000 units/mL, accompanied by specific cystitis symptoms. Among the total 540 analyzed patient, 208 (38.5%) developed a LUTI. E. coli was the main microorganism involved in LUTIs (102, 49.04%) with 8 cases of a combination between E. coli and another germ. In conclusion, a risk of urinary infections in cancer patients treated with pelvic radiotherapy was observed, in order to reduce the use of antibiotic resistance, preventive treatment with non-antibiotic agents 5 are warranted.     

A comparison of a moderately hypofractionated IMRT planning technique used in a randomised UK external beam radiotherapy trial with an in-house technique for localised prostate cancer

AimTo compare the radiotherapy technique used in a randomised trial with VMAT and an in-house technique for prostate cancer.BackgroundTechniques are evolving with volumetric modulated arc therapy (VMAT) commonly used. The CHHiP trial used a 3 PTV forward planned IMRT technique (FP_CH). Our centre has adopted a simpler two PTV technique with locally calculated margins.Materials and methods25 patients treated with FP_CH to 60 Gy in 20 fractions were re-planned with VMAT (VMAT_CH) and a two PTV protocol (VMAT_60/52 and VMAT_60/48). Target coverage, conformity index (CI), homogeneity index (HI), monitor units (MU) and dose to the rectum, bladder, hips and penile bulb were compared.ResultsPTV coverage was high for all techniques. VMAT_CH plans had better CI than FP_CH (p ≤  0.05). VMAT_60/52/48 plans had better CI than VMAT_CH. FP_CH had better HI and fewer MU than VMAT (p ≤  0.05). More favourable rectum doses were found for VMAT _CH than FP_CH (V_48.6, V_52.8, V₅₇, p ≤  0.05) with less difference for bladder (p ≥  0.05). Comparing VMAT_CH to VMAT_60/52/48 showed little differences for the bladder and rectum but VMAT_CH had larger penile bulb doses (V_40.8, V_48.6, mean, D_2, p ≤  0.05). Femoral head doses (V_40.8) were similarly low for all techniques (p = ≥ 0.05).ConclusionVMAT produced more conformal plans with smaller rectum doses compared to FP_CH albeit worse HI and more MU. VMAT_60/52 and VMAT_60/48 plans had similar rectal and bladder doses to VMAT_CH but better CI and penile bulb doses which may reduce toxicity.     

The role of medical physics in prostate cancer radiation therapy

Medical physics, both as a scientific discipline and clinical service, hugely contributed and still contributes to the advances in the radiotherapy of prostate cancer. The traditional translational role in developing and safely implementing new technology and methods for better optimizing, delivering and monitoring the treatment is rapidly expanding to include new fields such as quantitative morphological and functional imaging and the possibility of individually predicting outcome and toxicity. The pivotal position of medical physicists in treatment personalization probably represents the main challenge of current and next years and needs a gradual change of vision and training, without losing the traditional and fundamental role of physicists to guarantee a high quality of the treatment. The current focus issue is intended to cover traditional and new fields of investigation in prostate cancer radiation therapy with the aim to provide up-to-date reference material to medical physicists daily working to cure prostate cancer patients. The papers presented in this focus issue touch upon present and upcoming challenges that need to be met in order to further advance prostate cancer radiation therapy. We suggest that there is a smart future for medical physicists willing to perform research and innovate, while they continue to provide high-quality clinical service. However, physicists are increasingly expected to actively integrate their implicitly translational, flexible and high-level skills within multi-disciplinary teams including many clinical figures (first of all radiation oncologists) as well as scientists from other disciplines.     

Investigation of cellular movement in the prostate epithelium using an agent-based model

Experimental patterns of epithelial cell proliferation in the prostate suggest that cell movement may play an important role in prostate epithelial homeostasis, and genes known to regulate cell movement are commonly mutated or deleted in prostate carcinomas. However, the nature of cell movement within the prostate epithelium remains unknown. Here, the role of cellular movement in the prostate epithelium was explored by developing an agent-based model of the prostate duct. Prostatic adult stem cells, transit amplifying/intermediate cells (TA/ICs), and luminal cells were individually modeled within a three-dimensional reconstruction of a prostate duct. Different movement behaviors for TA/ICs and luminal cells were assessed by their ability to recreate experimental patterns of prostate cell proliferation and epithelial morphology. Strongly directed TA/IC movement toward the distal region of the prostate duct combined with weakly directed luminal cell movement toward the proximal region of the prostate duct was able to best recreate experimental patterns of prostate proliferation and morphology. The effects on cell mobility from abnormalities in PTEN and thymosin β15 (Tβ15), genes which are commonly altered in prostate cancer, were simulated in the model. These simulations show that altering prostate stem cell movement can dysregulate epithelial homeostasis and lead to excessive cell growth, suggesting that disruption of cell movement may contribute to prostate carcinogenesis.     

Late rectal and bladder toxicity following radiation therapy for prostate cancer: Predictive factors and treatment results

Aim

This study aimed at investigating factors associated to late rectal and bladder toxicity following radiation therapy and the effectiveness of Hyperbaric Oxygen Therapy (HBOT) when toxicity is grade ≥2.

Background

Radiation is frequently used for prostate cancer, but a 5–20% incidence of late radiation proctitis and cystitis exists. Some clinical and dosimetric factors have been defined without a full agreement. For patients diagnosed of late chronic proctitis and/or cystitis grade ≥2 treatment is not well defined. Hyperbaric Oxygen Therapy (HBOT) has been used, but its effectiveness is not well known.

Materials and methods

257 patients were treated with radiation therapy for prostate cancer. Clinical, pharmacological and dosimetric parameters were collected. Patients having a grade ≥2 toxicity were treated with HBOT. Results of the intervention were measured by monitoring toxicity by Common Toxicity Criteria v3 (CTCv3).

Results

Late rectal toxicity was related to the volume irradiated, i.e. V50 > 53.64 (p = 0.013); V60 > 38.59% (p = 0.005); V65 > 31.09% (p = 0.002) and V70 > 22.81% (p = 0.012). We could not correlate the volume for bladder. A total of 24 (9.3%) patients experienced a grade ≥2. Only the use of dicumarinic treatment was significant for late rectal toxicity (p = 0.014). A total of 14 patients needed HBOT. Final percentage of patients with a persistent toxicity grade ≥2 was 4.5%.

Conclusion

Rectal volume irradiated and dicumarinic treatment were associated to late rectal/bladder toxicity. When toxicity grade ≥2 is diagnosed, HBOT significantly ameliorate symptoms.     

Evaluation of combining bony anatomy and soft tissue position correction strategies for IMRT prostate cancer patients

Background

Radiotherapy treatment requires delivering high homogenous dose to target volume while sparing organs at risk. That is why accurate patient positioning is one of the most important steps during the treatment process. It reduces set-up errors which have a strong influence on the doses given to the target and surrounding tissues.

Aim

The aim of this study was to investigate the efficiency of combining bony anatomy and soft tissue imaging position correction strategies for patients with prostate cancer.

Materials and methods

The study based on pre-treatment position verification results determined for 10 patients using kV images and CBCT match. At the same patients’ position, two orthogonal kV images and set of CT scans were acquired. Both verification methods gave the information about patients’ position changes in vertical, longitudinal and lateral directions.

Results

For 93 verifications, the mean values of kV shifts in vertical, longitudinal and lateral directions equaled: −0.11 ± 0.54 cm, 0.26 ± 0.38 cm and −0.06 ± 0.47 cm, respectively. The same values achieved for CBCT matching equaled: 0.07 ± 0.62 cm, 0.22 ± 0.36 cm and −0.02 ± 0.45 cm. Statistically significant changes between the values of shifts received during the first week of treatment and the rest time of the irradiation process were found for 2 patients in the lateral direction and 2 patients in vertical direction among kV results and for 3 patients in the longitudinal direction among CBCT results. A significant difference between kV and CBCT match results was found in the vertical direction.

Conclusions

In clinical practice, CBCT combined with kV or even portal imaging improves precision and effectiveness of prostate cancer treatment accuracy.     

Retrospective comparison of rectal toxicity between carbon-ion radiotherapy and intensity-modulated radiation therapy based on treatment plan,normal tissue complication probability model,and clinical outcomes in prostate cancer

This retrospective study assessed the treatment planning data and clinical outcomes for 152 prostate cancer patients: 76 consecutive patients treated by carbon-ion radiation therapy and 76 consequtive patients treated by moderate hypo-fractionated intensity-modulated photon radiation therapy. These two modalities were compared using linear quadratic model equivalent doses in 2 Gy per fraction for rectal or rectal wall dose–volume histogram, 3.6 Gy per fraction-converted rectal dose–volume histogram, normal tissue complication probability model, and actual clinical outcomes. Carbon-ion radiation therapy was predicted to have a lower probability of rectal adverse events than intensity-modulated photon radiation therapy based on dose–volume histograms and normal tissue complication probability model. There was no difference in the clinical outcome of rectal adverse events between the two modalities compared in this study.     

SBRT and extreme hypofractionation: A new era in prostate cancer treatments?

AimRadiation therapy (RT) is a standard therapeutic option for prostate cancer (PC). In the last decades, several innovative technology applications have been introduced. 3-Dimensional conformal RT, volumetric/rotational intensity modulated RT associated or not with image-guided RT, are becoming largely diffused in the treatment of PC.BackgroundConsidering that PC could have a low α/β ratio, similar to late-reacting normal tissues, it could also be highly responsive to fraction size. Thus, the reduction of the number of fractions and the increase of the dose/fraction seem to be reasonable choices in the treatment of this cancer. This review reported the technology evolution, the radiobiological and the clinical data about the role of extreme hypofractionated RT in the treatment approach of PC patients.Materials and methodsMedline search and analysis of published studies containing key words: prostate cancer, radiotherapy, stereotactic radiotherapy.ResultsRecent technological developments, combined with an improved knowledge of the radiobiological models in favor of a high sensitivity of PC to larger fraction sizes are opening a new scenario in its treatment, reporting favorable efficacy and acceptable toxicity, despite short follow-up.ConclusionThus, thanks to technological improvement and the recent radiobiological data, “extreme hypofractionated RT” has been strongly introduced in the last years as a potential solid treatment option for PC.     

Metformin and statins: a possible role in high-risk prostate cancer

Aim and backgroundThere is increasing evidence that statins and oral anti-diabetic drugs, such as metformin, can have a favorable role in advanced prostate cancer treatment.Metformin has been shown to inhibit proliferation of tumor cells in vitro and statins inhibit carcinogenesis by suppressing angiogenesis/invasion mechanisms. However, clinical evidence on the protective effect of these drugs is still weak.The purpose of this study is to analyze if these drugs have an impact on Biochemical-Failure-Free-Survival (BFFS) and on Distant-Failure-Free-Survival (DFFS) in localized high-risk prostate cancer.Material and MethodsFrom 2002–2016, 447 patients with histologically confirmed high-risk prostate cancer were retrospectively evaluated. All patients received radiotherapy and androgen deprivation therapy. Biochemical recurrence was determined by the Phoenix criteria and metastatic patients were defined by the presence of radiological metastasis. Survival analysis was performed using the Kaplan-Meier method.Results175 patients were treated with statins (65.3 % with a dose ≤ 20 mg/day) and 70 with metformin (75.7 % with a dose ≤ 1700 mg/day). Median follow-up was 88 months (1–194) with no differences in BFFS and DFFS between metformin and non-metformin patients (77.4 % versus 80 %, p = 0.91 and 89.4 % versus 88.7 %, p = 0.56, respectively). We did not find a statistical difference in BFFS and DFFS in patients taking higher doses of those drugs.ConclusionMetformin and statins were not associated with BFFS or DFFS improvement in our analysis. However, the small number of patients treated with these drugs limits the reliability of the results and prospective studies are needed.