- Email: [email protected]
II dose-escalation study
Int. J. Radiation Oncology Biol. Phys., Vol. 60, No. 5, pp. 1351–1356, 2004 Copyright © 2004 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/04/$–see front matter
doi:10.1016/j.ijrobp.2004.05.026
CLINICAL INVESTIGATION
Prostate
PENILE BULB DOSE AND IMPOTENCE AFTER THREE-DIMENSIONAL CONFORMAL RADIOTHERAPY FOR PROSTATE CANCER ON RTOG 9406: FINDINGS FROM A PROSPECTIVE, MULTI-INSTITUTIONAL, PHASE I/II DOSE-ESCALATION STUDY
JAMES
MACK ROACH, M.D.,* KATHRYN WINTER, PH.D.,† JEFFREY M. MICHALSKI, M.D.,‡ D. COX, M.D.,§ JAMES A. PURDY, PH.D.,储 WALTER BOSCH, D.SC.,储 XIAO LIN, M.D.,储 WILLIAM S. SHIPLEY, M.D.¶
AND
*University of California San Francisco, San Francisco, CA; †Radiation Therapy Oncology Group, Philadelphia, PA; ‡Washington University, St. Louis, MO; §3D Quality Assurance Center at Washington University St. Louis, MO; 储The University of Texas M. D. Anderson Cancer Center, Houston, TX; ¶Massachusetts General Hospital, Boston MA Purpose: To assess the relationship between the dose to the bulb of the penis and the risk of impotence in men treated on Radiation Therapy Oncology Group (RTOG) 9406. Methods and Materials: Men enrolled on a Phase I/II dose-escalation study, RTOG 9406, who were reported to be potent at entry and evaluable (n ⴝ 158) were selected for inclusion. Follow-up evaluations were scheduled every 3, 4, and 6 months for the first, second, and the third through fifth years, then annually. At each follow-up visit an assessment of potency status was made. Penile structures were defined by a single observer blinded to the potency status, using Web-based, on-line software. The dosimetry for penile structures was calculated at the Quality Assurance Center at Washington University and provided to RTOG Statistical Headquarters to determine whether there was a relationship between dose and impotence. Results: Patients whose median penile dose was >52.5 Gy had a greater risk of impotence compared with those receiving <52.5 Gy (p ⴝ 0.039). In a multivariate analysis neither age, the dose to the prostate, nor the use of hormonal therapy correlated with the risk of impotence. Conclusions: Dose to the bulb of the penis seems to be associated with the risk of radiation-induced impotence. © 2004 Elsevier Inc. Prostate cancer, Three-dimensional conformal radiotherapy, Impotence.
Among the many controversial issues surrounding the treatment of clinical localized prostate cancer is the impact of various treatment options on sexual function. Although most comparative studies give an edge to radiotherapy in terms of the likelihood of preserving sexual function compared with surgery, not all studies are in agreement on this matter (1, 2). Complicating this issue is the fact that most studies reported to date have had short follow-up, are retrospective in nature, and are based on patients treated with older techniques to lower doses of radiation. The shortcomings of these studies are particularly relevant given the fact that numerous recent studies have demonstrated that higher doses result in a reduction in the risk of recurring after radiotherapy (3–5). The higher doses used in these series might be expected to compromise sexual function because in general, radiation-induced complications
depend primarily on dose. Might the use of higher doses cause impotence to be an unavoidable consequence of curative radiotherapy? Radiation Therapy Oncology Group (RTOG) 9406 is a landmark, multi-institutional Phase I/II study that set out to demonstrate that patients could be safely treated to higherthan-conventional doses with three-dimensional conformal radiotherapy (3D-CRT). Thus far, we have shown that late Grade 3 toxicity can be substantially reduced compared with historic controls (6 – 8). However, we have not previously reported on the impact of dose escalation on sexual function. To our knowledge, this represents the first large, prospective, multicenter study to assess the impact of increased doses of radiotherapy guided by 3D conformal planning software on sexual function. Several recent retrospective studies suggest that the dose
Reprint requests to: Mack Roach III, M.D., Department of Radiation Oncology, University of California San Francisco, Comprehensive Cancer Center, 1600 Divisadero Street, Suite H1031, San Francisco, CA 94143-1708. Tel: (415) 353-7175; Fax: (415) 353-9883; E-mail: [email protected]
Supported by grants RTOG U10CA 215661, CCOP U10CA37422, and Stat U10CA 32115 from the National Cancer Institute. Received Dec 31, 2003, and in revised form Apr 29, 2004. Accepted for publication May 11, 2004.
INTRODUCTION
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● Biology ● Physics
of radiation to the proximal penis might be a predictor of radiation-induced impotence (9, 10). This finding is not surprising, given that all other radiation-associated late normal tissue complications are related to dose and volume. RTOG 9406 provides an opportunity to clarify whether radiation-induced impotence is an unavoidable consequence of dose escalation or an avoidable, technique-dependent complication. Could awareness of this dose–volume relationship allow radiation oncologist to reduce the risk of impotence despite delivering high-dose radiation to the prostate? METHODS AND MATERIALS In 1994, the National Cancer Institute initially funded nine institutions with 3D-CRT capabilities to determine the feasibility of conducting a large dose-escalation study in men with localized prostate cancer. After 1995, the protocol was opened to other qualifying RTOG institutions. Each participating institution was required to provide details of their 3D-CRT treatment-planning systems and demonstrate their ability to exchange protocol-compliant treatment-planning data electronically with the Quality Assurance Center at Washington University in St. Louis, MO. All patients entered were done so after institutional review board approval, in accordance with the Helsinki Declaration of 1975, as revised in 1983. Study design RTOG 9406 was a Phase I/II dose-escalation study for men with localized prostate cancer (T1–T3) treated with 3D-CRT with curative intent. The details of the study, radiation prescription, and quality assurance have been previously described (6). The primary objective of this clinical trial was to define the maximally tolerated dose that can be delivered to the prostate gland and the surrounding normal tissues with 3D-CRT and to determine normal tissue toxicity rates (normal tissue complication probability). Neoadjuvant hormone therapy, if given, had to be initiated 2– 6 months before registration. All institutions were required to accrue 2 cases to the first dose level (68.4 Gy) and to demonstrate protocol compliance before subsequent dose escalation to the level being studied at the time of their initial participation. Patient eligibility Previously untreated patients with American Joint Committee on Cancer clinical stages T1, T2, and T3 prostate carcinoma were eligible (11). Patients thought to be at very low risk of recurrence and death after treatment with conventional doses were excluded because of concern about putting them at risk for complications without a high likelihood of benefit from higher doses. This latter group included stages T1a and T1b-c or T2a-b with Gleason score ⱕ5 and prostate-specific antigen (PSA) level ⱕ4 ng/mL. Patients with a PSA level ⱖ70 ng/mL were also ineligible. There were 203 men enrolled on RTOG 9406 at dose
Volume 60, Number 5, 2004
levels I (68.4 Gy) and II (73.8 Gy) who were reported to be potent at study entry. According to an unbiased (with respect to penile bulb dose) definition of potency after treatment, 39 patients were reported to be always potent. Fiftyfive patients were potent on all follow-up examinations except the last one, at which it was reported that the patient was either not sexually active or the information was unknown. Sixty-four patients were reported first to be potent but then impotent. Forty-five patients were excluded because they were always reported to be impotent (n ⫽ 23), to have variable potency (n ⫽ 5), or to be unevaluable owing to lack of information about potency at follow-up (n ⫽ 17). This analysis is based on the first three groups of patients (n ⫽ 158). The first and second groups were combined to define the potent group; the third group (patients who became impotent) was defined as the impotent group. Treatment planning Standard nomenclature as published by the International Commission on Radiation Units and Measurements was used (12). Patients were stratified into three treatment groups according to their risk of seminal vesicle (SV) involvement (percent SV risk ⫽ PSA ⫹ ([Gleason score ⫺6] ⫻ 10)) (13, 14). Group 1 comprised those patients with clinically organ-confined (Stages T1 and T2) disease whose estimated risk of SV invasion was ⱕ15%. Group 2 comprised those with T1 and T2 tumors but with a risk of SV invasion of ⬎15%. Group 3 comprised those with locally advanced prostate cancer with tumor spread beyond the capsule or gross SV involvement (T3). Patient positioning, target volume, and critical normal tissue definitions All patients were simulated in a supine position with an individual immobilization device. Treatment planning CT scans from the level of the iliac crest down to the perineum were obtained, including all tissue to be irradiated. Thickness of the CT slices was required to be ⱕ0.5 cm through the target volume region and ⱕ1 cm outside of the target volume. A urethrogram was required for verification of the most inferior extent of prostatic apex (15). The gross target volume (GTV) corresponded to the prostate with or without the SVs. The GTV was defined by the treating physicians with the planning CT scans and retrograde urethrogram. The most inferior extent of the GTV was defined as 5 mm superior to the tip of the urethral dye column. The clinical target volume (CTV) was defined as corresponding to the GTV plus areas at risk for microscopic extension, and the planning target volume (PTV) was defined as corresponding to the CTV plus a margin for set-up error and organ movement. Group 1 patients were treated to the CTV volume encompassing the prostate only. Group 2 patients were treated to the initial CTV volume (CTV1), including the prostate and bilateral SVs, for a minimum dose of 55.8 Gy, followed by a second CTV volume (CTV2) encompassing the prostate. The minimum PTV margin was allowed to vary from 5 to 10 mm in all
Radiation to the penis and impotence
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Fig. 1. An example of one case included in this study is shown by isodose lines from inside out at 6000, 5250, 4500, and 3500 cGy respectively. The penile bulb is also shown with a dotted line in the lower three panels.
directions, such that ultimately the most inferior edge of the field was determined at the discretion of the treating physician, as long as the minimum margin requirement was met. When RTOG 9406 was designed, the penis was not explicitly defined as an avoidance structure, thus for the purposes this study the proximal portion of the penis was defined by a single observer (M.R.) without knowledge of the potency status or the radiation dose distribution. 3D treatment planning and verification Treatment was given to the PTV with 3D conformal fields shaped to exclude as much of the bladder and rectum as possible, but there were no specific requirements to avoid penile structures. The treatment technique was left to the discretion of the participating institution, thus a variety of techniques was used. Dose volume histograms were generated for PTV, GTV, bladder, rectum, bilateral femora, and
unspecified tissues. Figure 1 demonstrates the normal anatomy for the prostate and proximal portion of the penile structures. Figure 2 provides an example of the dose distribution delivered to a patient treated on this trial who re-
Fig. 2. Graphic display of the dose–volume relationship for the bulb of the penis for the example shown in Fig. 1.
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ceived a relatively high dose of radiation to the bulb of the penis. On the first day, port films or portal images of each field were required. Twice-weekly verification films or images of orthogonal views (anterior–posterior and lateral projections) were obtained during the first 2 weeks of radiation therapy. Beginning the third week, port films were obtained weekly. Quality assurance of treatment planning and delivery The 3D Quality Assurance (QA) Center (St. Louis, MO) reviewed the PTV, CTV, and GTV, and designated critical structures on all cases submitted in this study, as previously described (6). For the purposes of this study, the critical anatomy (penile structures) were defined by a single observer (M.R.) using Web-based, on-line software made available through the QA Center. As previously noted, this observer was blinded to the potency status of the patients and the associated dose distribution. The dosimetry for each patient’s penile structures were then calculated at the QA Center, and this information was then provided to RTOG Statistical Headquarters to determine whether there was a relationship between dose and impotence. Follow-up schedule and toxicity scoring Follow-up evaluations after completion of treatment were scheduled every 3 months for the first year, every 4 months for the second year, and every 6 months for the third through fifth years, then annually thereafter. At each follow-up visit, digital rectal examination, PSA evaluation, and assessment of specific genitourinary parameters, including potency status and gastrointestinal morbidity, were performed. Side effects occurring within 120 days from the start of therapy were considered acute radiation morbidity. These were scored according to the RTOG acute radiation morbidity scoring criteria. Late effects were defined as gastrointestinal, rectal, bladder, or other genitourinary complications occurring or persisting ⬎120 days after start of treatment. These were scored according to the RTOG late radiation morbidity scoring scale. Statistical considerations For this study, the relationship between the dose to the bulb of the penis and impotence was queried with a break point based on the prior work of investigators (9, 16). Associations between pretreatment characteristics and potency were assessed by chi-squared analysis. Cut-point and regression analyses for being impotent were performed with logistic regression methods. Time to radiation-induced impotence was estimated by the cumulative incidence method (17), and dose effects were compared with Gray’s test (18). Multivariate analyses for time to radiation-induced impotence were performed with Cox regression analysis methods (19). RESULTS One hundred and fifty-eight patients were identified who were recorded as being potent at registration and evaluable
Volume 60, Number 5, 2004
Table 1. Posttreatment potency status by penile bulb doses
Potency status Always potent Potent then impotent
Mean penile bulb dose (Gy)
Median penile bulb dose (Gy)
Total
43.6 46.4
49.8 60.3
94 64
for potency status with subsequent follow-up. The median age of these patients was 68 years (range, 42–79 years). The disease group distribution was 46%, 40%, and 14% for disease groups 1, 2, and 3, respectively. The distribution of dose level for primary tumor was 31% at 68.4 Gy and 69% at 73.8 Gy. There was no association between age and potency or between disease group and potency. The mean and median doses received by patients who maintained potency and those who did not are shown in Table 1. Patients with a lower mean and median dose to the penis tended to have a greater likelihood of maintaining sexual function. Dose to the bulb of the penis was found to correlate with radiation-induced impotence, as shown in Table 2. Patients whose median penile dose was ⱖ52.5 Gy had an association with a greater risk of radiation-induced impotence, compared with those receiving a dose of ⬍52.5 Gy (p ⫽ 0.039, odds ratio ⫽ 1.98, 95% CI 1.03–3.78). Twenty-four percent of the patients in the low- (18 of 75, ⬍52.5 Gy) and high-bulb-dose (20 of 83, ⱖ52.5 Gy) groups received short-term induction hormones. In a multivariate analysis neither age, dose of radiation to the prostate, nor use of neoadjuvant hormonal therapy correlated with the risk of radiation-induced impotence (data not shown). There was a trend in favor of an association between primary tumor dose level and potency (p ⫽ 0.08), though not in the direction one might expect. A higher percentage of the 73.8-Gy patients tended to retain their potency compared with those receiving lower doses (see “Discussion” section). Figure 3 shows the relationship between dose to the bulb of the penis and the actuarial risk of radiation-induced impotence over time. At 5 years, the estimated incidence of radiation-induced impotence approached 50% in men receiving ⱖ52.5 Gy to the penis but was approximately 25% for those whose penile bulb received ⬍52.5 Gy (p ⫽ 0.048). The multivariate analyses for time to radiation-induced impotence showed no association with age, dose of radiation to the prostate, or neoadjuvant hormonal therapy. Table 2. Posttreatment potency status by penile bulb doses
Always potent Potent then impotent Total
Median dose to penile bulb ⬍52.5 Gy (%)
Median dose to penile bulb ⱖ52.5 Gy (%)
Total
51 (68) 24 (32)
43 (52) 40 (48)
94 64
75 (100)
83 (100)
158
Radiation to the penis and impotence
Fig. 3. Time to impotence after external beam radiotherapy in 158 men treated to dose levels I and II on RTOG 9406.
DISCUSSION At the time that RTOG 9406 was started, it was common to place the inferior border of the radiation field at the lower border of the ischial tuberosities (15). When this is done, much of the penis is incidentally included within the radiation field. One study demonstrated that “locating the inferior border of the external beam fields at the ischial tuberosity adequately treats at least 95.4% of all prostate patients with a margin of 1.5 centimeters or more below the prostate apex,” arguing for this practice to continue (20). However, extending the inferior border of the field well below the prostate results in a substantial increase in the dose of radiation incidentally received by the penis. This is the first prospective, multi-institutional study to demonstrate that the proximal portion of the penis represents an important avoidance structure for patients treated with 3D-CRT. Other important findings include the fact that avoidance of high doses to the penis was not directly linked to the dose to the prostate but probably reflected a lack of physician awareness about the value of avoiding the penis or perhaps a difference in the anatomy of patients. The trend for a higher percentage of patients treated to 73.8 Gy to retain their potency suggests the possibility of a learning curve in sparing the bulb and the former rather than the latter possibility. These data, combined with the results of several other studies, provide a strong rationale for encouraging radiation oncologists to give special attention to penile anatomy when planning treatment for prostate cancer (9, 16). This study supports the notion that the therapeutic advantages associated with higher doses can be had without
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unnecessarily irradiating the penis to a high dose. This study does not directly address the mechanism of radiation-induced impotence. It could well be that the blood supply or nerves immediately adjacent to the penis are more critical than the penis itself. However, because penile structures are immediately below the prostate and much easier to identify on CT than the other structures, it seems to be a convenient surrogate. Of note, this analysis was based on the doses planned, not necessarily the doses delivered to normal structures. This distinction arises owing to problems with organ movement and set-up error (21). Because of these problems, it is likely that the dose of radiation actually delivered to surrounding normal tissues is slightly higher than estimated (21). Because of the shape of the dose distribution, a 5-mm error away from normal tissues has a smaller effect on the planned dose than does a 5-mm move toward an adjacent normal structure (such as the penis) (22). This occurs because the radiation dose gradient is much steeper as you approach the center of the field (or PTV) and flattens and widens as you leave the edge of the PTV. The addition of electronic portal imaging to treatment delivery should enhance the promise of potency sparing, because smaller margins can be more accurately used, thus further reducing the potential for complications to normal tissues surrounding the prostate (23–25). The use of modern technology to reduce errors due to set-up and organ movement should provide an opportunity to consistently guarantee that the dose of radiation to critical normal tissues is minimized. Although the potential use of sildenafil was not accounted for in this study, many of the patients were treated before its availability, and there is no reason to expect that patients with lower bulb doses would be more likely to take the drug. In fact, impotent patients might be more likely to take sildenafil, perhaps obscuring a portion of the beneficial impact of sparing the bulb. A large, multicenter Phase III study is currently underway in the RTOG, and (based in part on these findings) the penis is routinely being incorporated as an avoidance structure. The use of compounds that selectively protect normal tissues but not tumor might create an additional opportunity to reduce the risk of radiationinduced impotence (26). This concept is also currently under study in the RTOG and elsewhere. We believe that the findings from this study provide a basis for additional optimism regarding our ability to cure prostate cancer with less morbidity than in the past.
REFERENCES 1. Robinson JW, Moritz S, Fung T. Meta-analysis of rates of erectile function after treatment of localized prostate carcinoma. Int J Radiat Oncol Biol Phys 2002;54:1063–1068. 2. Litwin MS, Flanders SC, Pasta DJ, et al. Sexual function and bother after radical prostatectomy or radiation for prostate cancer: Multivariate quality-of-life analysis from CaPSURE. Cancer of the Prostate Strategic Urologic Research Endeavor. Urology 1999;54:503–508.
3. Roach M, Meehan S, Kroll S, et al. Radiotherapy (XRT) for high-grade (HG) clinically localized adenocarcinoma of the prostate (CAP). J Urol 1996;156:1719 –1723. 4. Kupelian PA. Improvement in survival for patients with localized prostate cancer treated with higher than standard radiation doses [Abstract]. Proc Am Soc Clin Oncol 1999;18: 319a. 5. Pollack A, Zagars GK, Smith LG, et al. Preliminary results of
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a randomized radiotherapy dose-escalation study comparing 70 Gy with 78 Gy for prostate cancer. J Clin Oncol 2000;18:3904 –3911. Michalski JM, Purdy JA, Winter K, et al. Preliminary report of toxicity following 3D radiation therapy for prostate cancer on 3DOG/RTOG 9406. Int J Radiat Oncol Biol Phys 2000;46: 391– 402. Michalski JM, Winter K, Purdy JA, et al. Trade-off to lowgrade toxicity with conformal radiation therapy for prostate cancer on Radiation Therapy Oncology Group 9406. Semin Radiat Oncol 2002;12:75– 80. Ryu JK, Winter K, Michalski JM, et al. Interim report of toxicity from 3D conformal radiation therapy (3D-CRT) for prostate cancer on 3DOG/RTOG 9406, level III (79.2 Gy). Int J Radiat Oncol Biol Phys 2002;54:1036 –1046. Fisch BM, Pickett B, Weinberg V, et al. Dose of radiation received by the bulb of the penis correlates with risk of impotence after three-dimensional conformal radiotherapy for prostate cancer. Urology 2001;57:955–959. Merrick GS, Butler WM, Wallner KE, et al. The importance of radiation doses to the penile bulb vs. crura in the development of postbrachytherapy erectile dysfunction. Int J Radiat Oncol Biol Phys 2002;54:1055–1062. Greene FL, Page DL, Fleming ID, et al., eds. AJCC cancer staging manual. 6th ed. New York: Springer; 2002. International Commission on Radiation Units and Measurements. Prescribing, recording, and reporting photon beam therapy. ICRU Rep 1993;50:1– 8. Roach M. Re: The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol 1993;150:1923–1924. Diaz AZ, Roach M, Marquez C, et al. Indications for and significance of including the seminal vesicles during 3-D conformal radiotherapy in men with clinically localized prostate cancer. Int J Radiation Oncol Biol Phys 1994;30: 323–329. Roach M, Pickett B, Holland J, et al. The role of the urethro-
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gram during simulation for localized prostate cancer. Int J Radiat Oncol Biol Phys 1993;25:299 –307. Merrick GS, Wallner K, Butler WM, et al. A comparison of radiation dose to the bulb of the penis in men with and without prostate brachytherapy-induced erectile dysfunction. Int J Radiat Oncol Biol Phys 2001;50:597– 604. Kalbfleish JD PR. The statistical analysis of failure time data. New York: John Wiley & Sons; 1980. Gray R. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988;16:1141– 1154. Cox DR. Regression models and life tables. J R Stat Soc 1972;34:187–202. Wilson LD, Ennis R, Percarpio B, et al. Location of the prostatic apex and its relationship to the ischial tuberosities. Int J Radiat Oncol Biol Phys 1994;29:1133–1138. Langen KM, Jones DT. Organ motion and its management. Int J Radiat Oncol Biol Phys 2001;50:265–278. Pickett B, Roach M. The impact of isocenter placement errors associated with dose distributions used in irradiating prostate cancer. Med Dosim 1996;21:61–72. Pouliot J, Aubin M, Langen KM, et al. (Non)-migration of radiopaque markers used for on-line localization of the prostate with an electronic portal imaging device. Int J Radiat Oncol Biol Phys 2003;56:862– 866. Langen KMPJ, Angzinos C, Aubin M, et al. Evaluation of ultrasound-based prostate localization for image-guided radiotherapy. Int J Radiat Oncol Biol Phys 2003;57:635– 644. Aubin M, Liu Y, Langen KM, et al. Set-up verification using portal images of implanted prostate markers: An inter-observer study. Int J Radiat Oncol Biol Phys 2002;54(Suppl): 269. Athanassiou H, Antonadou D, Coliarakis N, et al. Protective effect of amifostine during fractionated radiotherapy in patients with pelvic carcinomas: Results of a randomized trial. Int J Radiat Oncol Biol Phys 2003;56:1154 –1160.
doi:10.1016/j.ijrobp.2004.05.026
CLINICAL INVESTIGATION
Prostate
PENILE BULB DOSE AND IMPOTENCE AFTER THREE-DIMENSIONAL CONFORMAL RADIOTHERAPY FOR PROSTATE CANCER ON RTOG 9406: FINDINGS FROM A PROSPECTIVE, MULTI-INSTITUTIONAL, PHASE I/II DOSE-ESCALATION STUDY
JAMES
MACK ROACH, M.D.,* KATHRYN WINTER, PH.D.,† JEFFREY M. MICHALSKI, M.D.,‡ D. COX, M.D.,§ JAMES A. PURDY, PH.D.,储 WALTER BOSCH, D.SC.,储 XIAO LIN, M.D.,储 WILLIAM S. SHIPLEY, M.D.¶
AND
*University of California San Francisco, San Francisco, CA; †Radiation Therapy Oncology Group, Philadelphia, PA; ‡Washington University, St. Louis, MO; §3D Quality Assurance Center at Washington University St. Louis, MO; 储The University of Texas M. D. Anderson Cancer Center, Houston, TX; ¶Massachusetts General Hospital, Boston MA Purpose: To assess the relationship between the dose to the bulb of the penis and the risk of impotence in men treated on Radiation Therapy Oncology Group (RTOG) 9406. Methods and Materials: Men enrolled on a Phase I/II dose-escalation study, RTOG 9406, who were reported to be potent at entry and evaluable (n ⴝ 158) were selected for inclusion. Follow-up evaluations were scheduled every 3, 4, and 6 months for the first, second, and the third through fifth years, then annually. At each follow-up visit an assessment of potency status was made. Penile structures were defined by a single observer blinded to the potency status, using Web-based, on-line software. The dosimetry for penile structures was calculated at the Quality Assurance Center at Washington University and provided to RTOG Statistical Headquarters to determine whether there was a relationship between dose and impotence. Results: Patients whose median penile dose was >52.5 Gy had a greater risk of impotence compared with those receiving <52.5 Gy (p ⴝ 0.039). In a multivariate analysis neither age, the dose to the prostate, nor the use of hormonal therapy correlated with the risk of impotence. Conclusions: Dose to the bulb of the penis seems to be associated with the risk of radiation-induced impotence. © 2004 Elsevier Inc. Prostate cancer, Three-dimensional conformal radiotherapy, Impotence.
Among the many controversial issues surrounding the treatment of clinical localized prostate cancer is the impact of various treatment options on sexual function. Although most comparative studies give an edge to radiotherapy in terms of the likelihood of preserving sexual function compared with surgery, not all studies are in agreement on this matter (1, 2). Complicating this issue is the fact that most studies reported to date have had short follow-up, are retrospective in nature, and are based on patients treated with older techniques to lower doses of radiation. The shortcomings of these studies are particularly relevant given the fact that numerous recent studies have demonstrated that higher doses result in a reduction in the risk of recurring after radiotherapy (3–5). The higher doses used in these series might be expected to compromise sexual function because in general, radiation-induced complications
depend primarily on dose. Might the use of higher doses cause impotence to be an unavoidable consequence of curative radiotherapy? Radiation Therapy Oncology Group (RTOG) 9406 is a landmark, multi-institutional Phase I/II study that set out to demonstrate that patients could be safely treated to higherthan-conventional doses with three-dimensional conformal radiotherapy (3D-CRT). Thus far, we have shown that late Grade 3 toxicity can be substantially reduced compared with historic controls (6 – 8). However, we have not previously reported on the impact of dose escalation on sexual function. To our knowledge, this represents the first large, prospective, multicenter study to assess the impact of increased doses of radiotherapy guided by 3D conformal planning software on sexual function. Several recent retrospective studies suggest that the dose
Reprint requests to: Mack Roach III, M.D., Department of Radiation Oncology, University of California San Francisco, Comprehensive Cancer Center, 1600 Divisadero Street, Suite H1031, San Francisco, CA 94143-1708. Tel: (415) 353-7175; Fax: (415) 353-9883; E-mail: [email protected]
Supported by grants RTOG U10CA 215661, CCOP U10CA37422, and Stat U10CA 32115 from the National Cancer Institute. Received Dec 31, 2003, and in revised form Apr 29, 2004. Accepted for publication May 11, 2004.
INTRODUCTION
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● Biology ● Physics
of radiation to the proximal penis might be a predictor of radiation-induced impotence (9, 10). This finding is not surprising, given that all other radiation-associated late normal tissue complications are related to dose and volume. RTOG 9406 provides an opportunity to clarify whether radiation-induced impotence is an unavoidable consequence of dose escalation or an avoidable, technique-dependent complication. Could awareness of this dose–volume relationship allow radiation oncologist to reduce the risk of impotence despite delivering high-dose radiation to the prostate? METHODS AND MATERIALS In 1994, the National Cancer Institute initially funded nine institutions with 3D-CRT capabilities to determine the feasibility of conducting a large dose-escalation study in men with localized prostate cancer. After 1995, the protocol was opened to other qualifying RTOG institutions. Each participating institution was required to provide details of their 3D-CRT treatment-planning systems and demonstrate their ability to exchange protocol-compliant treatment-planning data electronically with the Quality Assurance Center at Washington University in St. Louis, MO. All patients entered were done so after institutional review board approval, in accordance with the Helsinki Declaration of 1975, as revised in 1983. Study design RTOG 9406 was a Phase I/II dose-escalation study for men with localized prostate cancer (T1–T3) treated with 3D-CRT with curative intent. The details of the study, radiation prescription, and quality assurance have been previously described (6). The primary objective of this clinical trial was to define the maximally tolerated dose that can be delivered to the prostate gland and the surrounding normal tissues with 3D-CRT and to determine normal tissue toxicity rates (normal tissue complication probability). Neoadjuvant hormone therapy, if given, had to be initiated 2– 6 months before registration. All institutions were required to accrue 2 cases to the first dose level (68.4 Gy) and to demonstrate protocol compliance before subsequent dose escalation to the level being studied at the time of their initial participation. Patient eligibility Previously untreated patients with American Joint Committee on Cancer clinical stages T1, T2, and T3 prostate carcinoma were eligible (11). Patients thought to be at very low risk of recurrence and death after treatment with conventional doses were excluded because of concern about putting them at risk for complications without a high likelihood of benefit from higher doses. This latter group included stages T1a and T1b-c or T2a-b with Gleason score ⱕ5 and prostate-specific antigen (PSA) level ⱕ4 ng/mL. Patients with a PSA level ⱖ70 ng/mL were also ineligible. There were 203 men enrolled on RTOG 9406 at dose
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levels I (68.4 Gy) and II (73.8 Gy) who were reported to be potent at study entry. According to an unbiased (with respect to penile bulb dose) definition of potency after treatment, 39 patients were reported to be always potent. Fiftyfive patients were potent on all follow-up examinations except the last one, at which it was reported that the patient was either not sexually active or the information was unknown. Sixty-four patients were reported first to be potent but then impotent. Forty-five patients were excluded because they were always reported to be impotent (n ⫽ 23), to have variable potency (n ⫽ 5), or to be unevaluable owing to lack of information about potency at follow-up (n ⫽ 17). This analysis is based on the first three groups of patients (n ⫽ 158). The first and second groups were combined to define the potent group; the third group (patients who became impotent) was defined as the impotent group. Treatment planning Standard nomenclature as published by the International Commission on Radiation Units and Measurements was used (12). Patients were stratified into three treatment groups according to their risk of seminal vesicle (SV) involvement (percent SV risk ⫽ PSA ⫹ ([Gleason score ⫺6] ⫻ 10)) (13, 14). Group 1 comprised those patients with clinically organ-confined (Stages T1 and T2) disease whose estimated risk of SV invasion was ⱕ15%. Group 2 comprised those with T1 and T2 tumors but with a risk of SV invasion of ⬎15%. Group 3 comprised those with locally advanced prostate cancer with tumor spread beyond the capsule or gross SV involvement (T3). Patient positioning, target volume, and critical normal tissue definitions All patients were simulated in a supine position with an individual immobilization device. Treatment planning CT scans from the level of the iliac crest down to the perineum were obtained, including all tissue to be irradiated. Thickness of the CT slices was required to be ⱕ0.5 cm through the target volume region and ⱕ1 cm outside of the target volume. A urethrogram was required for verification of the most inferior extent of prostatic apex (15). The gross target volume (GTV) corresponded to the prostate with or without the SVs. The GTV was defined by the treating physicians with the planning CT scans and retrograde urethrogram. The most inferior extent of the GTV was defined as 5 mm superior to the tip of the urethral dye column. The clinical target volume (CTV) was defined as corresponding to the GTV plus areas at risk for microscopic extension, and the planning target volume (PTV) was defined as corresponding to the CTV plus a margin for set-up error and organ movement. Group 1 patients were treated to the CTV volume encompassing the prostate only. Group 2 patients were treated to the initial CTV volume (CTV1), including the prostate and bilateral SVs, for a minimum dose of 55.8 Gy, followed by a second CTV volume (CTV2) encompassing the prostate. The minimum PTV margin was allowed to vary from 5 to 10 mm in all
Radiation to the penis and impotence
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Fig. 1. An example of one case included in this study is shown by isodose lines from inside out at 6000, 5250, 4500, and 3500 cGy respectively. The penile bulb is also shown with a dotted line in the lower three panels.
directions, such that ultimately the most inferior edge of the field was determined at the discretion of the treating physician, as long as the minimum margin requirement was met. When RTOG 9406 was designed, the penis was not explicitly defined as an avoidance structure, thus for the purposes this study the proximal portion of the penis was defined by a single observer (M.R.) without knowledge of the potency status or the radiation dose distribution. 3D treatment planning and verification Treatment was given to the PTV with 3D conformal fields shaped to exclude as much of the bladder and rectum as possible, but there were no specific requirements to avoid penile structures. The treatment technique was left to the discretion of the participating institution, thus a variety of techniques was used. Dose volume histograms were generated for PTV, GTV, bladder, rectum, bilateral femora, and
unspecified tissues. Figure 1 demonstrates the normal anatomy for the prostate and proximal portion of the penile structures. Figure 2 provides an example of the dose distribution delivered to a patient treated on this trial who re-
Fig. 2. Graphic display of the dose–volume relationship for the bulb of the penis for the example shown in Fig. 1.
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ceived a relatively high dose of radiation to the bulb of the penis. On the first day, port films or portal images of each field were required. Twice-weekly verification films or images of orthogonal views (anterior–posterior and lateral projections) were obtained during the first 2 weeks of radiation therapy. Beginning the third week, port films were obtained weekly. Quality assurance of treatment planning and delivery The 3D Quality Assurance (QA) Center (St. Louis, MO) reviewed the PTV, CTV, and GTV, and designated critical structures on all cases submitted in this study, as previously described (6). For the purposes of this study, the critical anatomy (penile structures) were defined by a single observer (M.R.) using Web-based, on-line software made available through the QA Center. As previously noted, this observer was blinded to the potency status of the patients and the associated dose distribution. The dosimetry for each patient’s penile structures were then calculated at the QA Center, and this information was then provided to RTOG Statistical Headquarters to determine whether there was a relationship between dose and impotence. Follow-up schedule and toxicity scoring Follow-up evaluations after completion of treatment were scheduled every 3 months for the first year, every 4 months for the second year, and every 6 months for the third through fifth years, then annually thereafter. At each follow-up visit, digital rectal examination, PSA evaluation, and assessment of specific genitourinary parameters, including potency status and gastrointestinal morbidity, were performed. Side effects occurring within 120 days from the start of therapy were considered acute radiation morbidity. These were scored according to the RTOG acute radiation morbidity scoring criteria. Late effects were defined as gastrointestinal, rectal, bladder, or other genitourinary complications occurring or persisting ⬎120 days after start of treatment. These were scored according to the RTOG late radiation morbidity scoring scale. Statistical considerations For this study, the relationship between the dose to the bulb of the penis and impotence was queried with a break point based on the prior work of investigators (9, 16). Associations between pretreatment characteristics and potency were assessed by chi-squared analysis. Cut-point and regression analyses for being impotent were performed with logistic regression methods. Time to radiation-induced impotence was estimated by the cumulative incidence method (17), and dose effects were compared with Gray’s test (18). Multivariate analyses for time to radiation-induced impotence were performed with Cox regression analysis methods (19). RESULTS One hundred and fifty-eight patients were identified who were recorded as being potent at registration and evaluable
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Table 1. Posttreatment potency status by penile bulb doses
Potency status Always potent Potent then impotent
Mean penile bulb dose (Gy)
Median penile bulb dose (Gy)
Total
43.6 46.4
49.8 60.3
94 64
for potency status with subsequent follow-up. The median age of these patients was 68 years (range, 42–79 years). The disease group distribution was 46%, 40%, and 14% for disease groups 1, 2, and 3, respectively. The distribution of dose level for primary tumor was 31% at 68.4 Gy and 69% at 73.8 Gy. There was no association between age and potency or between disease group and potency. The mean and median doses received by patients who maintained potency and those who did not are shown in Table 1. Patients with a lower mean and median dose to the penis tended to have a greater likelihood of maintaining sexual function. Dose to the bulb of the penis was found to correlate with radiation-induced impotence, as shown in Table 2. Patients whose median penile dose was ⱖ52.5 Gy had an association with a greater risk of radiation-induced impotence, compared with those receiving a dose of ⬍52.5 Gy (p ⫽ 0.039, odds ratio ⫽ 1.98, 95% CI 1.03–3.78). Twenty-four percent of the patients in the low- (18 of 75, ⬍52.5 Gy) and high-bulb-dose (20 of 83, ⱖ52.5 Gy) groups received short-term induction hormones. In a multivariate analysis neither age, dose of radiation to the prostate, nor use of neoadjuvant hormonal therapy correlated with the risk of radiation-induced impotence (data not shown). There was a trend in favor of an association between primary tumor dose level and potency (p ⫽ 0.08), though not in the direction one might expect. A higher percentage of the 73.8-Gy patients tended to retain their potency compared with those receiving lower doses (see “Discussion” section). Figure 3 shows the relationship between dose to the bulb of the penis and the actuarial risk of radiation-induced impotence over time. At 5 years, the estimated incidence of radiation-induced impotence approached 50% in men receiving ⱖ52.5 Gy to the penis but was approximately 25% for those whose penile bulb received ⬍52.5 Gy (p ⫽ 0.048). The multivariate analyses for time to radiation-induced impotence showed no association with age, dose of radiation to the prostate, or neoadjuvant hormonal therapy. Table 2. Posttreatment potency status by penile bulb doses
Always potent Potent then impotent Total
Median dose to penile bulb ⬍52.5 Gy (%)
Median dose to penile bulb ⱖ52.5 Gy (%)
Total
51 (68) 24 (32)
43 (52) 40 (48)
94 64
75 (100)
83 (100)
158
Radiation to the penis and impotence
Fig. 3. Time to impotence after external beam radiotherapy in 158 men treated to dose levels I and II on RTOG 9406.
DISCUSSION At the time that RTOG 9406 was started, it was common to place the inferior border of the radiation field at the lower border of the ischial tuberosities (15). When this is done, much of the penis is incidentally included within the radiation field. One study demonstrated that “locating the inferior border of the external beam fields at the ischial tuberosity adequately treats at least 95.4% of all prostate patients with a margin of 1.5 centimeters or more below the prostate apex,” arguing for this practice to continue (20). However, extending the inferior border of the field well below the prostate results in a substantial increase in the dose of radiation incidentally received by the penis. This is the first prospective, multi-institutional study to demonstrate that the proximal portion of the penis represents an important avoidance structure for patients treated with 3D-CRT. Other important findings include the fact that avoidance of high doses to the penis was not directly linked to the dose to the prostate but probably reflected a lack of physician awareness about the value of avoiding the penis or perhaps a difference in the anatomy of patients. The trend for a higher percentage of patients treated to 73.8 Gy to retain their potency suggests the possibility of a learning curve in sparing the bulb and the former rather than the latter possibility. These data, combined with the results of several other studies, provide a strong rationale for encouraging radiation oncologists to give special attention to penile anatomy when planning treatment for prostate cancer (9, 16). This study supports the notion that the therapeutic advantages associated with higher doses can be had without
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unnecessarily irradiating the penis to a high dose. This study does not directly address the mechanism of radiation-induced impotence. It could well be that the blood supply or nerves immediately adjacent to the penis are more critical than the penis itself. However, because penile structures are immediately below the prostate and much easier to identify on CT than the other structures, it seems to be a convenient surrogate. Of note, this analysis was based on the doses planned, not necessarily the doses delivered to normal structures. This distinction arises owing to problems with organ movement and set-up error (21). Because of these problems, it is likely that the dose of radiation actually delivered to surrounding normal tissues is slightly higher than estimated (21). Because of the shape of the dose distribution, a 5-mm error away from normal tissues has a smaller effect on the planned dose than does a 5-mm move toward an adjacent normal structure (such as the penis) (22). This occurs because the radiation dose gradient is much steeper as you approach the center of the field (or PTV) and flattens and widens as you leave the edge of the PTV. The addition of electronic portal imaging to treatment delivery should enhance the promise of potency sparing, because smaller margins can be more accurately used, thus further reducing the potential for complications to normal tissues surrounding the prostate (23–25). The use of modern technology to reduce errors due to set-up and organ movement should provide an opportunity to consistently guarantee that the dose of radiation to critical normal tissues is minimized. Although the potential use of sildenafil was not accounted for in this study, many of the patients were treated before its availability, and there is no reason to expect that patients with lower bulb doses would be more likely to take the drug. In fact, impotent patients might be more likely to take sildenafil, perhaps obscuring a portion of the beneficial impact of sparing the bulb. A large, multicenter Phase III study is currently underway in the RTOG, and (based in part on these findings) the penis is routinely being incorporated as an avoidance structure. The use of compounds that selectively protect normal tissues but not tumor might create an additional opportunity to reduce the risk of radiationinduced impotence (26). This concept is also currently under study in the RTOG and elsewhere. We believe that the findings from this study provide a basis for additional optimism regarding our ability to cure prostate cancer with less morbidity than in the past.
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