Evolving Prostate Cancer Radiotherapy: Exploring Gonadal Doses in 3DCRT and IMRT with Testicular Shielding

Objective: To compare the dosimetry of IMRT versus 3DCRT in prostate cancer, with a focus on testicular dose using lead testicular shielding. Materials and Methods: From January 2021 to January 2022, twenty patients with localized prostate cancer underwent IMRT treatment. Plans for 3DCRT were generated for each patient. Comparison was made between 3D-CRT and IMRT regarding target volume dose uniformity, sparing of critical organs, and testicular doses. Results: Significant differences were observed in dose uniformity and sparing of critical organs between the two modalities (p<0.005), demonstrating the superiority of IMRT over 3DCRT. However, with lead testicular shielding, comparable testicular doses were achieved with both techniques. Conclusion: IMRT offers superior dosimetric advantages compared to 3DCRT. Nevertheless, the testicular dose remains nearly equivalent between the two techniques when utilizing lead testicular shielding.

 Introduction

Over the past two decades, there has been notable progress in radiation therapy for prostate cancer. The treatment has evolved from simple X-ray fields based on bony structures to more advanced approaches like dose-escalated radiation therapy with image guidance and IMRT. According to the National Comprehensive Cancer Network (NCCN) guidelines, radiotherapy is recommended for patients across all risk groups, either as primary treatment or as part of a multimodal approach [1]. The goal of conformal radiotherapy is to deliver a high dose to the tumor while minimizing radiation exposure to surrounding organs [2].

IMRT, a significant technological advancement in conformal radiotherapy, offers unique capabilities due to its inverse planning feature. This technique involves using intensity-modulated beams with varying intensity levels for each beam direction and source position. Clinical studies have shown the benefits of escalated radiation doses in the radical treatment of localized prostate cancer [3, 4]. However, achieving a high dose to the prostate while minimizing radiation to adjacent organs, and reducing both immediate and long-term gastrointestinal side effects, remains challenging.

With 3DCRT technology, radiation doses of up to 72–74 Gy can be administered. Both historical and prospective data indicate that increased radiation therapy doses improve outcomes in clinically localized prostate cancer [5]. Nonetheless, the dose to the gonads poses a limitation when considering escalated doses for curative intent in locally advanced prostate cancer.

Prostate cancer patients often experience long-term effects of androgen suppression therapy, including various hormone-induced side effects such as an elevated risk of cardiac events, osteoporosis, metabolic syndrome, and diminished sexual function [6, 7]. While the impact of incidental testicular radiation on Leydig cell activity and testosterone production is well-known, the extent and clinical significance of testosterone decline following exclusive radiotherapy remain largely uncertain [8, 9].

In this study, we aim to compare testicular doses during 3DCRT and IMRT with lead testicular shielding. Our goal is to gain insight into incidental testicular irradiation and radiation-induced hypogonadism during prostate cancer treatment.

 Materials and Methods

The current study is an institutional retrospective cohort review. Twenty prostate tumors with localized illness were included in the investigation. Lead testicular shielding (Figure 1) was used in all the patients at the time of simulation, treatment planning, and treatment execution.

Between January 2021 and January 2022, the study was conducted. Prior to treatment, a thorough history and physical examination were performed on every patient. According to the Gleason score, T stage, and initial PSA of the patient, the group was divided into low, middle, and high risk. Patients who had metastases, a history of prostatectomy, chemotherapy, or cancer were disqualified from participating in this study. IMRT was used to treat every patient. Plans for each patient’s 3DCRT were created. Regarding target volume dose homogeneity and critical organ doses, the 3D-CRT and IMRT designs were compared. Additionally the testicular doses received by the patients in the two techniques were noted and compared.

Before the simulation, patients were told to drink water, and whenever they felt a need for speed, computed tomography (CT) images with a 3 mm slice thickness were taken. The body’s contouring for the neighboring delicate organs was both automatic and manual. The Clinical Target Volume (CTV) included only prostate in low-risk and prostate+seminal vesicle in intermediate-high risk patients. The planned target volume (PTV), with the exception of the posterior edge, which extended for just 5 mm, was represented by an 8 mm expansion of the CTV in all directions. In this work, we compared the critical organ sparing in general and testicular dose in particular, besides the dose homogeneity of the conventional dose (IMRT 70 Gy) with that of the 3D-CRT. For 7-field IMRT, dosimetric planning was done for the following treatment angles: 0, 51, 102, 153, 204, 255, and 306 degrees. For 4-field 3DCRT, dosimetric planning was done at treatment angles of 0, 90, 180, and 270 degrees. Apart from testicular dose, the mean doses of the femoral heads and the values of PTV maximum, PTV minimum, V25 (the volume receiving 25 Gy), V40, and V60 of the rectum and bladder were examined. The goal of this study was to assess the reduction of testicular dose by using the lead testicular shield while treating the malignancy with the best target volume dose uniformity and minimal critical organ irradiation. For this aim, mean values of V25, V40, and V60 of the testes, rectum and bladder as well as mean doses of the femoral heads were computed for 2 different procedures, and the data extracted from DVH’s were statistically analyzed.

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Statistical analyses were performed in SPSS version 22.0 software (Chicago, ILL, USA) and SAS version 9.4. Significance level was set at P <0.01. As this was an observational study, no ethical clearance was sought.

Results

The IMRT and 3DCRT plans were dosimetrically evaluated. Dose coverage to PTVs in both the techniques achieved the constraint that 95% of the volume is covered by more than 95% of the prescribed dose. Dose homogeneity within the various PTV’s was compared.

There was a statistically significant difference between both techniques in average dose volume (p<0.001), proving IMRT to be better with respect to 3DCRT as the doses in IMRT are closer to the mean dose of 70 Gy (Table 1).

PTV IMRT (Gy) 3DCRT (Gy) p-value
PTV minimum 67 65 0.001
PTV maximum 72.5 74.2 0.001
Mean Dose 70 70.4 0.001

Significantly lower doses to the entire OAR were achieved using IMRT (Table 2).

Parameters IMRT (Gy) (mean±SD) 3DCRT (Gy) (mean±SD) p-value
Rectum V25 74±2.4 78.4±4.27 0.001
Rectum V40 48.2±7.2 52.55±8.4 0.001
Rectum V60 12.55±6.3 27.70±9.3 0.001
Bladder V25 52.4±12.3 65.9±13.4 0.001
Bladder V40 32.6±14.2 51.3±15.2 0.001
Bladder V60 6.45±4.5 29.4±11.8 0.001
Left femoral head 17.7±5.67 28.5±4.3 0.001
Right femoral head 15.7±4.7 33.7±3.3 0.001

Moreover, the maximum, minimum and average (mean) doses received by the testes were compared. Testicular doses received by the patients in 3DCRT and IMRT techniques are presented in Table 3.

Patient RT Technique RT Dose (Gy) Actual Testes Dose (Gy) Testes Dose with Shield (%) p-value
1 3DCRT 70 1.26 1.8 <0.01
  IMRT 70 3.43 4.9 <0.01
2 3DCRT 70 1.4 2 <0.01
  IMRT 70 3.36 4.8 <0.01
3 3DCRT 70 1.47 2.1 <0.01
  IMRT 70 0.18 0.25 <0.01
4 3DCRT 70 1.05 1.5 <0.01
  IMRT 70 0.22 0.32 <0.01
5 3DCRT 70 1.33 1.9 <0.01
  IMRT 70 3.29 4.7 <0.01
6 3DCRT 70 1.19 1.7 <0.01
  IMRT 70 3.15 4.5 <0.01
7 3DCRT 70 1.12 1.6 <0.01
  IMRT 70 3.36 4.8 <0.01
8 3DCRT 70 1.33 1.9 <0.01
  IMRT 70 3.22 4.6 <0.01
9 3DCRT 70 1.26 1.8 <0.01
  IMRT 70 3.29 4.7 <0.01
10 3DCRT 70 1.4 2 <0.01
  IMRT 70 3.15 4.5 <0.01
11 3DCRT 70 1.54 2.2 <0.01
  IMRT 70 0.2 0.28 <0.01
12 3DCRT 70 1.12 1.6 <0.01
  IMRT 70 0.2 0.29 <0.01
13 3DCRT 70 1.19 1.7 <0.01
  IMRT 70 3.22 4.6 <0.01
14 3DCRT 70 1.26 1.8 <0.01
  IMRT 70 3.08 4.4 <0.01
15 3DCRT 70 1.05 1.5 <0.01
  IMRT 70 3.29 4.7 <0.01
16 3DCRT 70 1.26 1.8 <0.01
  IMRT 70 3.15 4.5 <0.01
17 3DCRT 70 1.19 1.7 <0.01
  IMRT 70 3.29 4.7 <0.01
18 3DCRT 70 1.33 1.9 <0.01
  IMRT 70 3.22 4.6 <0.01
19 3DCRT 70 1.26 1.8 <0.01
  IMRT 70 3.08 4.4 <0.01
20 3DCRT 70 1.26 1.8 <0.01
  IMRT 70 3.08 4.4 <0.01

The dose received by the testes was marginally higher in IMRT as compared to 3DCRT.

Discussion

The increased risk of acute and long-term gastrointestinal and genitourinary complications associated with high radiation doses is a significant concern in prostate cancer treatment. Therefore, it is essential to assess dosimetric factors, dose volume guidelines, and constraints for critical structures like the rectum and bladder, which are considered organs at risk. Additionally, individuals with prostate cancer commonly experience enduring adverse effects of androgen suppression therapy, including a heightened risk of cardiovascular events, osteoporosis, metabolic syndrome, and reduced sexual function.

In this study, we compared IMRT and 3D-CRT plans in terms of dose distribution and critical structure doses in patients with low- and intermediate-high risk prostate cancer, with a focus on gonadal doses. Our findings revealed that IMRT outperformed 3D-CRT in terms of dose uniformity and lower critical organ doses. However, IMRT showed a slightly higher gonadal dose compared to 3D-CRT. IMRT has long been established as the standard of care for prostate cancer treatment, serving as a viable alternative to surgery. In a similar comparison study by Zelefsky et al., IMRT was found to be more effective than 3D-CRT in prostate cancer treatment, with lower doses to critical structures contributing to the improved uniformity of radiation delivery [10].

Consistent with our results, other studies by Lee et al. and Zhu et al. also demonstrated the advantages of IMRT in terms of dose homogeneity and critical organ doses [11, 12]. Additionally, Wolff et al. found that IMRT resulted in lower rectal V40 compared to 3D-CRT, with further support from Vaarkamp et al. who reported decreased rectal V60 with IMRT [13, 14]. Moreover, increasing beam numbers in IMRT positively impacted dose homogeneity and reduced critical organ doses, as observed in the study by Vaarkamp et al., where patients received successful IMRT treatment without increased acute toxicity [14].

In the RTOG 0126 trial, patients receiving high-dose IMRT showed significantly reduced volumes of the bladder and rectum compared to those receiving 3D-CRT, supporting the advantages of IMRT in minimizing critical organ exposure [15, 16]. Similarly, in another study, patients treated with high doses of IMRT experienced less gastrointestinal toxicity compared to those receiving lower doses of 3D-CRT. Notably, the frequency of late toxicities increased with the volume of rectum receiving high radiation doses, as demonstrated in the MD Anderson study [17, 18].

Despite dose escalation, IMRT has been shown to have less late toxicity than 3D-CRT in various institutional datasets. Overall, higher radiation doses are now considered the standard therapy for clinically localized prostate cancer.

Several researchers [20-28] have examined the testicular dose across various techniques, including 3DCRT, IMRT, and SBRT (Table 4).

Study Number of patients Age (years) RT dose(median) RT technique ADT Follow-up (months) Testiculardose Hormonal levels Sexual function
Grigsbyet al. [20] 59 NS 65–70 Gy 3D-CRT NR 24 4.5–6 Gy Similar testosterone levels.Increased levels of LH and FSH after RT NR
Tomić et al. [21] 31 65 58–71 Gy 3D-CRT NR 20 Ranging between1 Gy to > 10 Gy Lower testosterone levels at 1 week and 3 months after RT.Testosterone levels returned to baseline 6–12 months after RT NR
Zagars et al. [5] 85 68 68–76 Gy 3D-CRT No ADT 3 1.8–2.4 Gy Lower testosterone levels at 3 months after RT (9%) NR
Pickleset al. [9] 666 72 65 Gy 3D-CRT 3 months ADT(neoadjuvant or adjuvant) 6 2.2 Gy Lower testosterone levels at 3 months after RT (83% of the baseline level).Recovery to baseline levels for 60% of the patients, within 18 months after RT. NR
Ishiyamaet al. [6] 39 64 76 Gy IMRT No ADT 36 5.3 Gy Lower testosterone levels at 12, 24, 30, 36 months NR
Markovinaet al. [8] 51(prostate gland: 41; prostate bed: 10) 64 Prostate gland: 73.8 GyProstate bed:64.8 Gy IMRT No ADT 24 0.31–2.4 Gy Lower testosterone levels at 6 months after RT (–33 ng/dL)Testosterone levels returned to baseline 12 months after RT NR
Pompe et al. [7] 248 71 70 Gy IMRT No ADT 72 NR Lower testosterone levels for 75% of the patients after RT (median decrease: 30%) NR
Oermann et al. [19] 26 69 36.25 Gy/5 fx SBRT(CyberKnife) No ADT 15 2.1 Gy Lower testosterone levels for69% of the patients after RT(median decrease: 3.3 nmol/L)No difference in proportion of patients experiencing hypogonadism (before RT/ after RT) Non-significantdecrease in EPICsexual score:Baseline: 66.71-year after RT: 60.1(p = 0.34)
Yuan et al. [10] 636 69 35–40 Gy/5 fx 38 Gy/4 fx SBRT No ADT 24 NR Lower testosterone levels afterRT (median decrease: 3–6 months: −13.4%, 7–12 months: −12.2%, 13–18 months: −11.2% 19–24 months: - 5.0%) No significantdecrease in EPICsexual score on thewhole periodSignificant decreasein EPIC sexual scorebetween 19 and 24months (10.9 pointsdecline)

Our investigation uncovered a notable reduction in testicular dose when employing a lead testicular shield. Specifically, we observed a slightly lower testicular dose in 3DCRT compared to IMRT. This discrepancy may be attributed to the higher number of beams in IMRT, leading to increased tissue exposure and integral dose, consequently resulting in greater scatter dose to the testes.

In conclusion, our study highlights the advantages and considerations associated with different radiation therapy techniques in prostate cancer management. Intensity-modulated radiation therapy (IMRT) emerges as a superior choice due to its enhanced dose homogeneity, superior conformity to the target volume, and efficient sparing of organs at risk (OARs). IMRT’s capability to optimize dose distribution offers a significant benefit in minimizing radiation-related toxicity while ensuring effective tumor control. Conversely, 3-dimensional conformal radiation therapy (3DCRT) exhibits a noteworthy advantage in terms of lower testicular doses compared to IMRT. This aspect underscores the importance of evaluating not only target coverage and critical organ sparing but also potential impacts on gonadal health, particularly given the long-term concerns associated with androgen suppression in prostate cancer patients.

Funding

Nil

Conflict of Interest

Nil

Ethical Approval

Not Required

References January 2018 NCCN Guidelines Version 1.2018. Prostate cancer. 3 09 239-250 64 2002 10.1016/s0167-8140(02)00184-6 Brundage M Lukka H Crook J Warde P Bauman G Catton C Markman BR Charette M Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology The use of conformal radiotherapy and the selection of radiation dose in T1 or T2 low or intermediate risk prostate cancer - a systematic review 01 1 01 67-74 70 2008 10.1016/j.ijrobp.2007.06.054 Kuban DA Tucker SL Dong L Starkschall G Huang EH Cheung MR Lee AK Pollack A International Journal of Radiation Oncology, Biology, Physics Long-term results of the M. D. Anderson randomized dose-escalation trial for prostate cancer 15 4 07 1056-1063 80 2011 10.1016/j.ijrobp.2010.03.049 Beckendorf V Guerif S Le Prisé E Cosset J Bougnoux Agnes Chauvet B Salem N et al International Journal of Radiation Oncology, Biology, Physics 70 Gy versus 80 Gy in localized prostate cancer: 5-year results of GETUG 06 randomized trial 01 5 08 1405-1418 74 2009 10.1016/j.ijrobp.2008.10.091 Viani GA Stefano EJ Afonso SL International Journal of Radiation Oncology, Biology, Physics Higher-than-conventional radiation doses in localized prostate cancer treatment: a meta-analysis of randomized, controlled trials 10 17 06 2420-2425 25 2007 10.1200/JCO.2006.09.3369 D'Amico AV Denham JW Crook J Chen M Goldhaber SZ Lamb DS Joseph D et al Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions 1 03 46-52 6 2008 10.3816/CGC.2008.n.008 Bruchovsky N Klotz L Crook J Phillips N Abersbach J Goldenberg SL Clinical Genitourinary Cancer Quality of life, morbidity, and mortality results of a prospective phase II study of intermittent androgen suppression for men with evidence of prostate-specific antigen relapse after radiation therapy for locally advanced prostate cancer 3 09 665-678 59 1974 Rowley M. J. Leach D. R. Warner G. A. Heller C. G. Radiation Research Effect of graded doses of ionizing radiation on the human testis 1 01 1-8 34 1995 10.1016/0167-8140(94)01501-s Izard M. A. Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology Leydig cell function and radiation: a review of the literature 3 06 241-249 55 2000 10.1016/s0167-8140(99)00100-0 Zelefsky M. J. Fuks Z. Happersett L. Lee H. J. Ling C. C. Burman C. M Hunt M et al Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology Clinical experience with intensity modulated radiation therapy (IMRT) in prostate cancer 6 12 618-625 28 2005 10.1097/01.coc.0000172281.32437.d4 Lee CT Dong L Ahamad AW Choi H Cheung R Lee AK Horne DF Breaux AJ Kuban DA American Journal of Clinical Oncology Comparison of treatment volumes and techniques in prostate cancer radiation therapy 6 12 398-404 10 2005 10.1007/s10147-005-0519-4 Zhu S Mizowaki T Nagata Y Takayama K Norihisa Y Yano S Hiraoka M International Journal of Clinical Oncology Comparison of three radiotherapy treatment planning protocols of definitive external-beam radiation for localized prostate cancer 2 11 226-233 93 2009 10.1016/j.radonc.2009.08.011 Wolff D Stieler F Welzel G Lorenz F Abo-Madyan Y Mai S Herskind C et al Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology Volumetric modulated arc therapy (VMAT) vs. serial tomotherapy, step-and-shoot IMRT and 3D-conformal RT for treatment of prostate cancer 1 10 65-72 73 2004 10.1016/j.radonc.2004.07.015 Vaarkamp J Adams EJ Warrington AP Dearnaley DP Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology A comparison of forward and inverse planned conformal, multi segment and intensity modulated radiotherapy for the treatment of prostate and pelvic nodes 15 14 07 2422-2430 121 2015 10.1002/cncr.29362 Bruner DW Hunt D Michalski JM Bosch WR Galvin JM Amin M Xiao C et al Cancer Preliminary patient-reported outcomes analysis of 3-dimensional radiation therapy versus intensity-modulated radiation therapy on the high-dose arm of the Radiation Therapy Oncology Group (RTOG) 0126 prostate cancer trial 15 4 07 769-776 86 2013 10.1016/j.ijrobp.2013.03.018 Vanasek J Odrazka K Dolezel M Kolarova I Jarkovsky J Pavlik T Hlavka A Dusek L International Journal of Radiation Oncology, Biology, Physics Statistical analysis of dose-volume profiles and its implication for radiation therapy planning in prostate carcinoma 01 5 08 1097-1105 53 2002 10.1016/s0360-3016(02)02829-8 Pollack A Zagars GK Starkschall G Antolak JA Lee JJ Huang E Eschenbach AC Kuban DA Rosen I International Journal of Radiation Oncology, Biology, Physics Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial 01 02 82-6 10 2007 10.1038/sj.pcan.4500910 Jani A Su A Correa D Gratzle J Prostate cancer and prostatic diseases Comparison of late gastrointestinal and genitourinary toxicity of prostate cancer patients undergoing intensity-modulated versus conventional radiotherapy using localized fields 1 01 102-107 57 2001 10.1016/s0090-4295(00)00890-6 Shu H. K. Lee T. T. Vigneauly E. Xia P. Pickett B. Phillips T. L. Roach M. Urology Toxicity following high-dose three-dimensional conformal and intensity-modulated radiation therapy for clinically localized prostate cancer 01 1 08 85-89 39 1997 10.1016/s0360-3016(97)00311-8 Zagars G. K. Pollack A. International Journal of Radiation Oncology, Biology, Physics Serum testosterone levels after external beam radiation for clinically localized prostate cancer 15 2 01 362-367 94 2002 10.1002/cncr.10219 Pickles T Agranovich A Berthelet E Duncan GG Keyes M Kwan W McKenzie MR Morris WJ Cancer Testosterone recovery following prolonged adjuvant androgen ablation for prostate carcinoma 173-7 2 1 2012 Ishiyama H Teh BS Paulino AC Yogeswaren S Mai WY Xu Bo et al J Radiat Oncol Serum testosterone level after intensity-modulated radiotherapy in low-risk prostate cancer patients: does testicular dose correlate with testosterone level? 6 12 4 2014 10.1016/j.prro.2014.02.004 Markovina S Weschenfelder Dc Gay H McCandless A Carey B DeWees T Knutson N Michalski J Practical radiation oncology Low incidence of new biochemical hypogonadism after intensity modulated radiation therapy for prostate cancer 7 07 876-882 14 2017 10.1016/j.jsxm.2017.04.675 Pompe RS Karakiewicz PI Zaffuto E Smith A Bandini M Marchioni M Tian Z et al The Journal of Sexual Medicine External Beam Radiotherapy Affects Serum Testosterone in Patients With Localized Prostate Cancer 27 03 12 4 2011 10.1186/1756-8722-4-12 Oermann EK Suy S Hanscom HN Kim JS Lei S Yu X Zhang G et al Journal of Hematology & Oncology Low incidence of new biochemical and clinical hypogonadism following hypofractionated stereotactic body radiation therapy (SBRT) monotherapy for low- to intermediate-risk prostate cancer 01 1 09 149-154 105 2019 10.1016/j.ijrobp.2019.05.014 Yuan Y Aghdam N King CR Fuller DB Weng J Chu F Mardirossian G et al International Journal of Radiation Oncology, Biology, Physics Testosterone Levels and Sexual Quality of Life After Stereotactic Body Radiation Therapy for Prostate Cancer: A Multi-Institutional Analysis of Prospective Trials 4 04 726-727 135 1986 10.1016/s0022-5347(17)45831-9 Grigsby P. W. Perez C. A. The Journal of Urology The effects of external beam radiotherapy on endocrine function in patients with carcinoma of the prostate 2 08 287-289 130 1983 10.1016/s0022-5347(17)51110-6 Tomić R. Bergman B. Damber J. E. Littbrand B. Löfroth P. O The Journal of Urology Effects of external radiation therapy for cancer of the prostate on the serum concentrations of testosterone, follicle-stimulating hormone, luteinizing hormone and prolactin