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British Journal of Radiology (2004) 77, 129-136
© 2004 British Institute of Radiology
doi: 10.1259/bjr/37893924
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Full Paper

Sparing of the penile bulb and proximal penile structures with intensity-modulated radiation therapy for prostate cancer

J Kao, MD 1 J Turian, MS 1 A Meyers, BS 1 R J Hamilton, PhD 2 B Smith, MSEE 1 S Vijayakumar, MD 3 and A B Jani, MD, MSEE 1

1 University of Chicago/University of Illinois at Chicago Department of Radiation Oncology, 5758 S. Maryland Avenue, MC 9006, Chicago, IL 60637, 2 University of Arizona, Department of Radiation Oncology, 1501 N. Campbell Avenue, Tucson, AZ 85724 and 3 University of California at Davis, Department of Radiation Oncology, 4501 X Street G126, Sacramento, CA 95817, USA

Correspondence: Dr Ashesh Jani


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Conclusion
 References
 
Quality of life is an important consideration in the treatment of early prostate cancer. Laboratory and clinical data suggest that higher radiation doses delivered to the bulb of penis and proximal penile structures correlates with higher rates of post-radiation impotence. The goal of this investigation was to determine if intensity-modulated radiation therapy (IMRT) spares dose to the penile bulb while maintaining coverage of the prostate. 10 consecutive patients with clinically organ confined prostate cancer were planned with 3D conformal radiation therapy (3D-CRT) or IMRT to give a dose of 74 Gy without specifically constraining the plans to spare the penile bulb. All 10 patients were ultimately treated with IMRT. Dose–volume histograms were evaluated and the doses to prostate, rectum, bladder and penile bulb were compared. IMRT reduced the mean penile bulb doses compared with 3D-CRT (33.2 Gy vs 48.9 Gy, p<0.001), the percentage of penile bulb receiving over 40 Gy (37.7% vs 67.2%, p<0.001) and the dose received by >95% of penile bulb (5.3 Gy vs 11.7 Gy, p=0.003). Maximum penile bulb doses were higher with IMRT (81.2 Gy vs 73.1 Gy, p<0.001) although the volume of this high dose region was small. Both methods resulted in similar coverage of the prostate. The volume of rectum receiving 70 Gy was significantly reduced with IMRT (18.4% vs 21.9%, p=0.003) but the volumes of bladder receiving 70 Gy were similar (p=0.3). IMRT may potentially reduce long term sexual morbidity by reducing the dose to the majority of the penile bulb.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Conclusion
 References
 
Prostate cancer is the most common non-cutaneous cancer diagnosed in American men [1]. For localized disease, external beam radiation therapy (EBRT), interstitial brachytherapy and radical prostatectomy produce equivalent rates of disease control [1]. Therefore, it has been suggested that treatments should be selected based on quality of life and complication data. Loss of sexual potency is the most common complication of radiotherapeutic or surgical management of prostate cancer [2, 3]. Although impotence is more common after radical prostatectomy (with or without nerve-sparing), it remains a significant problem after EBRT [2–4]. Approximately 50% of patients treated with EBRT will lose sexual potency [2, 3]. However, advances in radiological imaging and computer technology have allowed the implementation of sophisticated treatment planning and delivery techniques over the past decade [5]. These techniques include 3D conformal radiation therapy (3D-CRT) and more recently intensity-modulated radiation therapy (IMRT). Compared with conventional EBRT, 3D-CRT and IMRT reduces the dose delivered to the rectum, resulting in decreased complication rates [6–8]. There is significant interest in increasing the dose prescribed to the prostate with 3D-CRT or IMRT. The available data suggest increased freedom from prostate specific antigen (PSA) failure with dose escalation using conformal techniques, with equivalent or lower normal tissue toxicity than conventional radiation therapy treated to conventional doses [9, 10].

Published reports suggest that erectile dysfunction after radiotherapy is predominantly caused by vascular damage, most commonly arteriogenic [11, 12]. Further pre-clinical and clinical studies have correlated the dose to the bulb of penis with potency outcome [13–16]. A recent study suggested that the dose to the proximal penile crura may also be significant [17]. Some studies have correlated increasing prescribed dose to the prostate with poorer potency outcome [18, 19]. This may be due to higher doses delivered to potency determining structures, since no specific effort was made to limit doses to those structures. IMRT, and to a lesser degree, 3D-CRT are more successful in limiting the volume of normal rectum, bladder and femoral heads receiving high doses of radiation in the treatment of prostate cancer than conventional EBRT [7].

To maintain or improve the current therapeutic ratio when proceeding with dose escalation in EBRT, there is a need for improved techniques for maintaining sexual potency. Limiting the dose to penile structures is a promising approach to achieve this objective. A previous study from our department demonstrated that 6-field 3D-CRT decreased the dose to penile structures compared with two different 4-field techniques using 3D-CRT [20]. We expected that IMRT/inverse planning can generate highly conformal dose distributions resulting in significant sparing of the bulb of penis while maintaining adequate coverage of the target volume. Therefore, we initiated a planning study to determine whether IMRT or 3D-CRT better achieved these objectives.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Conclusion
 References
 
Patient selection and target definitions
The study population consists of 10 consecutive patients at our institution between February and June of 2002 with clinically staged T1–2 adenocarcinoma of the prostate with a less than 15% risk of lymph node metastasis [21]. Patients were positioned supine and immobilized using both upper and lower Alpha Cradles indexed to the treatment table (Alpha Cradle, Smithers Medical Products, Inc, Akron, OH). No special bladder or rectal emptying was employed. A CT scan (PQ5000, Marconi Medical Systems, Cleveland, OH) was obtained with approximately 80 images per patient from the level of the L4 vertebral body to 5 cm below the ischial tuberosities. The scan parameters consisted of a large field-of-view pelvic protocol with a 3 mm slice thickness/table index. Urethral and rectal contrast media were administered to aid in the delineation of the normal and target tissues. Following the International Commission on Radiation Units and Measurements (ICRU) Report No. 50 recommendations, a clinical target volume (CTV) was contoured on the individual axial CT slices of each patient [22]. For 3D-CRT, all planned target volumes (PTV) were framed using a beams eye view (BEV) with a 1 cm margin to block edge. These techniques have been described in earlier publications [20].

Briefly, for 3D-CRT, the CTV1 consisted of the entire prostate and seminal vesicles. The CTV1 was expanded by 1 cm circumferentially to account for organ motion and setup uncertainty. This volume, PTV1, was treated to a dose of 50 Gy in 2 Gy daily fractions. For the first boost volume, a PTV2 was created by expanding the prostate by 1 cm circumferentially, which was treated to a dose of 16 Gy. For PTV3, the prostate was framed with a 1 cm margin circumferentially except for a rectal margin, which was framed by 6 mm margin. This volume was treated for an additional 6 Gy in 2 Gy daily fractions. For the final 2 Gy boost, the prostate was expanded by 1 cm margin circumferentially except for the rectum, which was blocked completely using BEV for each beam. Thus the total dose delivered to the prostate minus the rectum was 74 Gy.

For IMRT, CTV1 and PTV1 are as described above. As in the case of 3D-CRT, the prescribed dose to PTV1 is 50 Gy. PTV2 is the prostate expanded by 1 cm in all dimensions except for a rectal margin of 6 mm. The total prescription dose to the prostate is 74 Gy. In both 3D-CRT and IMRT planning, dose was prescribed to the target volume, rather than the isocentre.

Outlining of critical structures
The rectum (from the ischial tuberosities to the peritoneal reflection), bladder, and the proximal penile tissues and bulb of penis were contoured for every patient. The penile structures included the proximal Corpora cavernosa and Bulbus spongiosum [20]. These structures are readily discernible on CT simulation [23]. Outlined structures are demonstrated on a 3D reconstruction in Figure 1Go. The CTV and normal tissue delineation required approximately 20–25 min for each patient.



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  		Figure 1. 3D reconstruction of prostate and adjacent structures. Prostate (red), seminal vesicles (white), bladder (yellow), rectum (purple) and penile bulb and proximal penile tissues (blue).

 
Field definition
The technique used for 3D-CRT was a six field co-planar (6FLD) arrangement with 45°, 90°, 135°, 225°, 270°, and 315° gantry angles. This technique was shown to be superior to a 4-field box technique and 4-field non-axial technique in a prior study in terms of dose delivered to the penile tissues [20]. Beam weightings were 0.75, 1.5, 0.75, 0.75, 1.5 and 0.75, respectively. Patients were treated with 18 MV photons. Dose calculations were done using Cad Plan (Varian Associates, Palo Alto, CA) treatment planning system normalized to the 95% isodose line.

IMRT to the prostate used a 5-field plan consisting of a posteroanterior (PA) and 4 oblique fields (45°, 135°, 180°, 225°, and 315°). Beam weightings were based on the optimization output. Patients were treated with 6 MV photons. Plans were optimized using a commercially available inverse planning software (Helios [version 6.2], Varian Associates, Palo Alto, CA), which uses a conjugate gradient optimization algorithm. The user defines the prescription dose and dose–volume constraints of target and normal tissues. For the IMRT plans, the goals were to generate a plan which conformed to the defined PTV while minimizing the dose delivered to the rectum. The plans were normalized to achieve adequate target coverage without excessive inhomogeneity. The initial constraints used for each phase are shown pictorially in Figure 2aGo [initial (50 Gy) phase], and Figure 2bGo [boost (24 Gy) phase]. These initial constraints were arrived at after multiple iterations on several cases at our institution and as with IMRT planning at any site, were individualized to generate the optimum plan for each patient based on accumulated understanding of the optimization algorithm of the IMRT system. The plans were evaluated both quantitatively with dose–volume histogram (DVH) analysis and qualitatively by visually inspecting isodose curves on axial slices. The PTV dose–volume histograms were evaluated to ensure that <10% of the PTV received >110% of the prescription dose and <1% received >115%. Hot spots along the anterior rectal and posterior bladder walls were not accepted except where they overlapped with PTV. For both 3D-CRT and IMRT, patients were treated with a Varian CL2100 EX accelerator (Varian Associates, Palo Alto, CA) equipped with a 120 multileaf collimator and automatic beam sequencing software. Treatment was delivered using the sliding window method. The accuracy of the setup was verified on days 1–5 of treatment and then weekly with amorphous silicon portal images.



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  		Figure 2. Dose volume constraints for intensity-modulated radiation therapy plans. (a) Initial (50 Gy) phase, and (b) boost (last 24 Gy) phase.

 
Comparisons of plans and dose–volume histograms
Dose–volume histograms for all plans were reviewed. Because the initial 50 Gy PTV1 was identical for both 3D-CRT and IMRT plans, a direct comparison of the two techniques for PTV1 coverage, and the doses to rectum, bladder and penile bulb could be made. Since the boost volumes, i.e. volumes receiving >50 Gy, were defined differently for 3D-CRT and IMRT, direct comparisons of PTV coverage is not possible. Therefore, for the summed plans, only prostate coverage and the doses to rectum, bladder and penile bulb were compared. Although the slightly different boost target volumes confound this analysis, this comparison provides a clinically relevant comparison of dose distributions achieved by 3D-CRT and IMRT as practiced in our department. The data were shown to exhibit a normal distribution; thus, pairwise comparisons using the two tailed paired student's t-test were performed. All 10 patients were ultimately treated with IMRT.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Conclusion
 References
 
The dose–volume histograms of the initial 3D-CRT and IMRT plans to 50 Gy were compared. Significant differences between the two plans were noted (Table 1GoGo). Maximum doses received by PTV1, rectum, bladder and bulb of penis were significantly higher for the IMRT plans suggesting greater inhomogeneity. A slightly higher dose was received by 95% of the PTV1 with 3D-CRT (50.5 Gy vs 49.3 Gy, p=0.002). The volume of PTV1 receiving the full prescription dose was also higher (97.6% vs 88.7%, p=0.007). The IMRT plans were significantly more conformal. This resulted in lower mean doses to the rectum and bulb of penis. Although mean bladder doses were lower with IMRT, this did not reach statistical significance. The percentage of rectum, bladder and bulb of penis receiving 45 Gy was significantly lower with the IMRT plans. Specifically IMRT reduced the mean penile bulb dose from 35 Gy to 21 Gy (p<0.001) and the volume receiving >45 Gy from 41% to 16% (p<0.001).


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  		Table 1. Comparison of dosimetric statistics for the initial 50 Gy volume for 3D conformal radiotherapy (CRT) and intensity-modulated radiation therapy (IMRT) plans

 

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  		Table 2. Comparison of composite rectal, bladder and prostate dose statistics for 3D conformal radiotherapy (CRT) and intensity-modulated radiation therapy (IMRT): mean values (±standard deviation)

 
Composite plans to 74 Gy were compared for both 3D-CRT and IMRT (Table 2Go). Dose–volume histograms for one representative patient are demonstrated in Figure 3Go. The mean rectal dose was 39.1 Gy for IMRT vs 49.2 Gy for 3D-CRT (p<0.001). The IMRT plan was superior to 3D-CRT in the percentage of rectum receiving >70 Gy (18.4% vs 21.9%, p=0.003) but higher maximum rectal doses (80.1 Gy vs 75.5 Gy, p<0.001) were delivered to a small volume. The mean bladder dose was 47.8 Gy for IMRT vs 48.7 Gy for 3D-CRT (p=0.4). While volumes receiving >70 Gy to the bladder were similar in the two groups, the maximum bladder dose was increased with IMRT. Prostate coverage was similar between IMRT and 3D-CRT in terms of dose received by 95% of the prostate and percentage of prostate receiving 76 Gy, although significantly higher maximum doses are delivered with IMRT when the prescription dose is identical.



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  		Figure 3. Composite dose–volume histograms for 3D conformal radiotherapy and intensity-modulated radiation therapy plans for a representative patient.

 
Data for doses received by the bulb of penis are shown in Table 3Go. The mean penile bulb dose was 33.2 Gy for IMRT vs 48.9 Gy for 3D-CRT (p<0.001). However, the maximum penile dose was 81.2 Gy for IMRT vs 73.1 Gy for 3D-CRT (p<0.001). To compare our results with published data demonstrating superior potency preservation with lower penile bulb doses, the percentage of penile bulb receiving 40 Gy and 70 Gy and dose received by >95% of penile bulb were analysed. IMRT significantly decreased the percentage of penile bulb receiving >40 Gy (37.7 Gy vs 67.2 Gy, p<0.001) while the percentage of volume receiving >70 Gy was nearly identical (15.0% vs 14.8%, p=0.71). The dose received by >95% of penile bulb was 5.3 Gy for IMRT vs 11.7 Gy for 3D-CRT (p=0.003).


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  		Table 3. Comparison of composite penile bulb dose statistics for 3D conformal radiotherapy (CRT) and intensity-modulated radiation therapy (IMRT): mean values (±standard deviation)

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Conclusion
 References
 
Prostate cancer remains an important cause of morbidity and mortality. There are data demonstrating that treatment of T1–2 prostate cancer with surgery will result in a higher disease specific survival and freedom from metastatic disease than observation [24]. However, these patients have a significantly higher rate of sexual impotence after radical prostatectomy [25]. EBRT is a non-invasive treatment which results in equal biochemical disease free survival when patients are stratified by clinical stage, biopsy Gleason score and pre-treatment PSA, and results in higher rates of potency preservation in comparative studies [1–4]. Therefore, radiation therapy is the preferred modality of treatment for selected subgroups of patients.

Both 3D-CRT and IMRT have demonstrated efficacy in sparing more normal tissues than conventional EBRT [6, 7]. Traditionally, rectal toxicity has been the dose limiting structure. High rates of late >= Grade 2 rectal toxicity occurs when a high percentage of rectum is treated to greater than 70 Gy [26]. When rectal volumes receiving greater than 70 Gy are low, dose escalation to doses as high as 86.4 Gy are possible, with acceptable late toxicity rates in preliminary reports [27].

One concern of dose escalation is that increased dose prescribed to the target volume will result in higher rates of potency loss [18, 19]. However, IMRT allows for improved conformality to the PTV compared with 3D-CRT [7]. Therefore, the penile bulb which lies caudal and anterior to the PTV may be better spared using IMRT.

Prostate coverage is comparable for 3D-CRT and IMRT, although IMRT has greater inhomogeneity. Therefore, even though the prescription dose is 74 Gy, on average, the IMRT plans in this study treated over half of the prostate to greater than 76 Gy. Directing these hotspots to higher risk portions of the prostate is under active investigation [28]. IMRT results in a significant reduction in the median rectal doses as well as percentage of rectum treated to over 70 Gy. This finding is in agreement with other investigators [7]. The maximum rectal dose to a small volume increases with IMRT due to overlap of rectum with PTV and the greater inhomogeneity. The long-term effect of this is unknown although early reports of IMRT treated to high doses resulted in less rectal toxicity than 3D-CRT to lower doses [7].

Because the bladder was entered as an avoidance structure, IMRT resulted in lower median bladder doses, similar volumes receiving 70 Gy but with higher maximum bladder doses than 3D-CRT. The clinical significance of these findings is unknown, although reports to date have not correlated bladder dose–volume histogram doses with urinary toxicity rates [6, 7]. Urinary toxicity may relate to urethra or bladder neck doses rather than whole bladder doses [29].

The clinical significance of limiting the dose to the penile bulb has been established by four clinical studies correlating penile bulb DVHs with potency outcome [14–17]. These studies established mean penile bulb dose, percentage of penile bulb volume receiving >40 Gy and >70 Gy and dose received by 95% of the penile bulb volume as clinically significant endpoints. Although no specific effort was made to spare the penile bulb, IMRT dramatically decreased the mean dose and the percentage of the volume receiving 40 Gy and the dose received by 95% of the penile bulb volume. There was no statistically significant difference in the volume receiving more than 70 Gy. Among 20 patients treated on the Radiation Therapy Oncology Group (RTOG) 9406 phase I/II 3D-CRT dose escalation protocol, a mean penile bulb dose of 52.5 Gy has been suggested as a tolerance dose with a hazard ratio of 5.7 for impotence at 2 years [16]. In our study, 0 of 10 patients planned with IMRT exceeded this threshold vs 5 of 10 patients planned with 3D-CRT. Although IMRT was superior in sparing the penile bulb at lower doses, IMRT resulted in an increase in the maximum dose. This occurred because there was some overlap between PTV and penile bulb contours and the IMRT plan had greater inhomogeneity. The long-term consequences of this effect are unknown. However, if the effect is volume-dependent, the consequences are likely to be small because, as with IMRT plans at many disease sites, the high inhomogeneity regions in the treatment plan are very small in absolute volume.

Our data are in agreement with data from other institutions documenting decreased mean and minimum penile bulb doses with IMRT compared with 7-field 3D-CRT [30, 31]. We suggest these findings demonstrate that decreased penile bulb doses at physiologically important dose levels with IMRT will reduce potency loss compared with 3D-CRT. One institution has reported that patients treated to a dose of 70 Gy in 2.5 Gy daily fractions with IMRT, using daily ultrasound localization, experienced better outcomes on a validated sexual function questionnaire than a similar cohort of patients treated to 78 Gy using standard fractionation with 3D-CRT [32]. Our data provide a pathophysiological explanation for this improvement in potency outcome among patients treated with IMRT.

The dominant mechanism for a loss of potency after radical prostatectomy is believed to be damage to neurovascular bundles [33]. At present, the effect of high doses to the neurovascular bundle with EBRT is not clearly established. In the brachytherapy literature, there are two published studies comparing neurovascular bundle doses in potent and impotent men after prostate brachytherapy [34, 35]. A small study in which 16 patients were treated with combined EBRT followed by high dose rate (HDR) brachytherapy demonstrated higher mean doses to the neurovascular bundles in the impotent cohort [34]. A larger study, however, did not confirm these findings among patients treated with permanent interstitial brachytherapy with or without EBRT [35].

The reduction in the dose to the bulb of the penis occurred in our investigation without specifically entering the penile bulb as an avoidance structure. Further gains may be possible if this structure is routinely incorporated into treatment planning. Although the results are not shown here, for one patient with a higher percentage of penile bulb receiving >70 Gy with IMRT than 3D-CRT, the penile bulb was entered as an additional avoidance structure. Maximum penile bulb dose and volume receiving >70 Gy were reduced with this technique without significantly increasing rectal doses or sacrificing target volume coverage. A formal dosimetric study should be undertaken to determine whether this technique is beneficial for a general population of prostate cancer patients. These plans were calculated on a single computer system and planning environment (Helios [version 6.2]) and it is not known whether other planning systems and optimization algorithms may result in different dose distributions. In our experience, more recent versions of commercially available IMRT planning systems have decreased inhomogeniety without sacrificing conformality (unpublished data).

Increasingly, radiotherapy is combined with hormonal therapy to improve the likelihood of eradication of prostate cancer [36]. Several studies demonstrate a PSA control and survival benefit for hormonal therapy in addition to radiotherapy for locally advanced prostate cancer [37–39]. Although retrospective data suggest a possible benefit in terms of PSA control for intermediate and high risk T1–2 prostate cancer, definitive results from randomized trials are lacking at present [36, 40]. There are conflicting data on the effect of hormonal therapy on long-term loss of potency from radiation therapy [18, 41]. However, since the mechanism of potency loss after hormonal therapy is endocrine, while the effect of radiotherapy is largely vascular, patients treated with hormonal therapy may also benefit from penile bulb sparing [3].

There are several weaknesses in our study. This paper is a theorectical planning study comparing 3D-CRT and IMRT. All patients were ultimately treated with IMRT and follow up is insufficient (9 to 13 months since completion of treatment) to determine safety and efficacy since the true incidence of sexual dysfunction and PSA failure with radiotherapy increase over time. The boost volumes and photon energy, as practised in our department, were different for 3D-CRT and IMRT. This reflects adaptations in practice based on the emergence of newer technologies. We have not routinely treated IMRT patients with 18 MV photons due to the satisfactory dose distributions achieved with 6 MV and concerns about neutron production with photon energies above 10 MV with the increased beam on times associated with IMRT. A comparison study of 6 MV and 18 MV photons for pelvic IMRT failed to demonstrate a significant difference in target or critical structure dose distributions, including bulb of penis with either energy [42]. This suggests that using 18 MV IMRT would not have significantly altered the conclusions of this study. In contrast, photon energies >=10 MV are preferred for pelvic targets using 3D-CRT [43].

The differences in the dose to the penile bulb between 3D-CRT and IMRT were demonstrated in both the composite plans (where PTVs were slightly different) and the initial PTV (where PTVs were identical). Therefore, the dosimetric advantages for the penile bulb demonstrated are the result of the method of treatment delivery and planning rather than the minor differences in the posterior margin in the boost volumes. Since the penile bulb lies inferior and anterior to the prostate, small differences in the posterior margin are unlikely to affect penile bulb doses significantly.

This investigation provides further dosimetric evidence that IMRT allows an increasing therapeutic ratio in prostate cancer by increasing the dose which can be safely prescribed without encountering excess rectal or sexual side effects. Other male patients receiving pelvic radiotherapy for anal canal, rectal cancer and bladder cancers may benefit from lower doses to the penile structures. However, long-term clinical data will be required to prove these hypotheses.


   Conclusion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusion
References
 
IMRT, as currently practiced in our institution, resulted in significant reductions in clinically significant doses to the penile bulb compared with 3D-CRT. Further improvement may be possible if the penile bulb is added as an additional avoidance structure. Carefully collected outcome data with long-term follow up are required to determine whether these dosimetric advantages will translate into clinical benefits.

Received for publication January 2, 2003. Revision received August 1, 2003. Accepted for publication August 29, 2003.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusion
 References
 

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