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Association of prostate size with urinary morbidity following mixed conformal neutron and photon irradiation
Int. J. Radiation Oncology Biol. Phys., Vol. 45, No. 4, pp. 871– 875, 1999 Copyright © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/99/$–see front matter
PII S0360-3016(99)00275-8
CLINICAL INVESTIGATION
Prostate
ASSOCIATION OF PROSTATE SIZE WITH URINARY MORBIDITY FOLLOWING MIXED CONFORMAL NEUTRON AND PHOTON IRRADIATION JEFFREY D. FORMAN, M.D., SAMEER KEOLE, B.S., SUE BOLTON, M.S., AND SAM TEKYI-MENSAH, PH.D. Gershenson Radiation Oncology Center of the Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI Purpose: This study was designed to characterize the relationship between the observed rate of postradiation genitourinary (GU) complications and the prostate gland size. Methods and Materials: Two hundred seventy-three patients received conformal neutron and photon irradiation to the prostate seminal vesicles. Data on post-treatment urinary morbidity were collected and examined in relationship to a number of clinical and technical factors. Results: With a median follow-up of 30 months (range 7– 61), the 4-year rate of Grade 2 or higher GU complications was 21%. On univariate analysis, the risk of complications was significantly associated with prostate size and neutron beam arrangement. On multivariate analysis, only the prostate size was significantly associated with the risk of GU morbidity. Patients with a preradiation prostate volume more than 74 cc had a two and a half fold increase in the risk of complications compared to patients with smaller glands. Conclusion: Patients with an enlarged prostate have a significantly higher risk of chronic GU complications. Although these data were obtained for patients receiving combined neutron and photon irradiation, it is likely that these data would also be applicable for those patients receiving photon irradiation as well. These observations may add an additional rationale for the study of preirradiation hormonal treatment. © 1999 Elsevier Science Inc. Prostate size, Urinary morbidity, Conformal radiation.
Radiotherapy (RT) has undergone a technological revolution in the last 15 years. Computerized tomographic (CT) scan– based treatment planning has allowed for the development and widespread application of three-dimensional treatment planning (3D-CRT) (1–5). The data generated from these 3D-CRT systems include the dose and volume interrelationships of normal tissues as well as tumors (1, 6, 7). Thus, the dose of radiation delivered to all or part of an organ can now be precisely quantified and displayed. In the treatment of prostate cancer, different combinations of radiation beams can be compared using these dose– volume histograms (DVH) to pick the “best” plan. Tumor control probabilities (TCP) and normal tissue complication probabilities (NTCP) can be estimated for each treatment plan based on the information provided in these DVH (8). Thus, if the TCP and NTCP estimates are accurate, an “optimal” treatment plan can be generated for each patient. Overall, the use of 3D-CRT has resulted in a reduction in the observed rate of acute and chronic complications, presumably secondary to reducing the volume of normal tissue irradiation (9 –12). This has allowed for investigation of radiation dose escalation programs in an attempt to improve
the TCP (1, 7, 9 –11). At Wayne State University, dose escalation has been accomplished through the use of conformal mixed photon and neutron irradiation (MNP) (13, 14). However, no correlation has been seen between the DVH for the bladder and rectum and the subsequent rate of chronic complications (15, 16). A complicated and laborintensive analysis of the dose to the surface of the rectum and bladder suggests a correlation with morbidity, but this system is quite cumbersome and impractical for routine use (16). A simple method of predicting and/or reducing morbidity is needed. Because the volume of the rectum and bladder receiving all or part of the radiation dose appears to be related to post-RT morbidity (6), and because this volume is directly related to the size of the target volume for RT, it is possible that reducing the size of the target may result in a reduction in toxicity. Preirradiation hormonal downsizing has been shown to reduce the prostate size, the volume of rectum and bladder receiving RT and to improve the predicted NTCP (17, 18). The volume of the prostate gland is a readily accessible parameter available in the majority of patients, and does not require a 3D system to calculate. This study was undertaken to identify if a correlation between the
Reprint requests to: Jeffrey Forman, M.D., FACR, Harper Hospital, 3990 John R Street, Detroit, MI 48201.
E-mail: [email protected] Accepted for publication 30 June 1999.
INTRODUCTION
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Table 1. Patient characteristics Median age Median pre-RT PSA level Race African American (men) Caucasian Gleason score Stage
67 years 8 ng/ml
(Range 45 to 82) (Range 0.6 to 314)
3–6 7–9 Missing T1 T2
96 (35%) 177 (65%) 145 (54%) 125 (46%) 3 96 (35%) 177 (65%)
rate of post-RT complications and the pre-RT size of the prostate gland exists. METHODS AND MATERIALS Two hundred seventy-three patients treated between 1994 and 1997 for adenocarcinoma of the prostate were selected for this analysis. Patients were treated on 3 consecutive institutional review board–approved treatment protocols using conformal mixed neutron and photon irradiation. All patients selected for analysis had organ-confined disease (Stage T1 or T2) and completed irradiation more than 18 months before analysis in order to adequately assess the rate of chronic complications. Patient characteristics are summarized in Table 1. All patients underwent a CT-based virtual simulation. The volume of irradiation included the prostate and seminal vesicles with a minimum of 1.5-cm margin from the gross tumor volume to the aperture edge. No patient received elective pelvic lymph node irradiation. Most patients (87%) received 10 Gy of neutrons (NGy) combined with 38 or 40 Gy of photons. The sequence of irradiation was under investigation and 159 patients (58%) received neutrons prior to photon irradiation whereas 114 (42%) received the 4 weeks of photon irradiation followed by 2 weeks of neutron irradiation. Daily doses were 1.0 NGy and 2.0 Gy for neutrons and photons, respectively. The first 175 patients had an eight-field treatment plan (4 neutron, 4 photon) whereas the next 98 patients had a 14-field plan (6 neutron, 8 photon). One hundred four patients (38%) received preradiation hormone treatment. The treatment parameters are summarized in Table 2. The prostate size was calculated from the 3D treatment Table 2. Treatment parameters Neutron dose Neutron sequence Field arrangement
Pre-RT hormones
9 NGy 10 NGy First 2 weeks Last 2 weeks 4-field neutron/4-field photon 6-field neutron/8-field photon No Yes
35 238 159 114
patients patients patients patients
(13%) (87%) (58%) (42%)
175 patients (64%) 98 patients (36%) 169 patients (62%) 104 patients (38%)
Volume 45, Number 4, 1999
planning system. The prostate was contoured on each axial CT image at 5-mm intervals. Intravesical and intraurethral contrast were used to optimize the delineation of the volume (19). Follow-up was at 1 month after radiation, every 3 months for the first year, every 4 months in the second and third years, and every 6 months in subsequent years. Urinary toxicity was classified according to the Radiation Therapy Oncology Group (RTOG) toxicity scale. Grade 2 toxicity included obstructive or irritative symptoms requiring medication, minimal incontinence not requiring a pad, and/or hematuria not requiring fulguration. The Grade 3 complications included symptoms that required a cystoscopy with fulguration of bleeding areas, significant incontinence requiring pad use, or obstructive and/or irritative symptoms not controlled by medication. Chronic complication was defined as a Grade 2 or higher toxicity occurring 6 or more months following the end of radiotherapy. The date of occurrence was noted for patients developing chronic complications. Complication-free survival time was defined as the length of time between the end of radiotherapy and the date of occurrence of Grade 2 or higher toxicity, date of death, or date of last follow-up, whichever occurred first. Complication-free survival times of patients not developing chronic genitourinary (GU) complications were considered censored at the time of death or time of last follow-up. It was assumed that the events of developing GU complications and of being censored were independent.
Statistical analysis BMDP statistical software (Version 7.0; BMDP Statistical Software, Inc., University of California Press, Los Angeles, CA) was used for statistical analysis of the data. Comparisons of prostate volume according to the categories of preclinical and treatment-related factors were achieved using either the Student’s t-test (for 2-level categories) or the analysis of variance (ANOVA) test (for multilevel categories). Complication-free survival curves were constructed using the product limit method of Kaplan-Meier, and the log-rank test was utilized for the comparison of survival curves (20). Cox’s proportional hazards model was used for carrying out univariate analysis of each factor. Preclinical and treatment factors under consideration included age (continuous), race (African-American vs. Caucasian), Gleason score (3– 6 vs. 7–9), stage (T1 vs. T2), neutron dose (7–9 vs. 10 –11 Gy), neutron sequence (first 2 weeks vs. last 2 weeks), field arrangement (4-field vs. 6-field), preradiation hormones (no vs. yes), prostate volume (continuous), pretreatment prostate-specific antigen (PSA) (continuous). Risk factors for urinary morbidity were identified using the stepwise Cox’s proportional hazards regression model approach. Definition of low- and high-risk groups of urinary morbidity based on prostate size required the partitioning of the range of values of prostate volume.
Prostate size and post-RT urinary morbidity
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Fig. 1. Chronic GU complication-free survival.
RESULTS The median follow-up was 30 months (range 7 to 61 months). Forty patients (14%) had Grade 2 or higher GU complications. The 4-year actuarial rate of Grade 2 or higher GU complications was 21% (Fig. 1). There were 30 Grade 2, 9 Grade 3, and 1 Grade 4 complications. The median prostate size was 52 cc (range 10 to 155 cc). African-American men had a significantly larger, average prostate volume of 64 vs. 53 cc, respectively (p ⫽ 0.0002). The patients with Stage T1 prostate cancer had larger prostate volumes than those with Stage T2. There was no difference in the size of the prostate as a function of grade, pretreatment PSA level, or the use of pre-RT hormones. Similarly, there was no difference in prostate size according Table 3a. Prostate volume as a function of various preclinical factors Clinical factor Race
Characteristic
African-American Caucasian Stage T1 T2 Pre-RT PSA 0–4 ⬎4–10 ⬎10–20 ⬎20 Gleason score 3–6 7–9 Pre-RT hormones No Yes
Average prostate p volume (cc) Value 64 53 62 54 48 57 61 58 57 58 57 58
0.0002
to radiation dose or sequence. However, patients treated with a nonaxial neutron beam arrangement had a significantly smaller prostate volume than those treated with a 6-field technique, 54 vs. 63 cc, respectively (p ⫽ 0.002). These results are summarized in Tables 3a and 3b. The risk of chronic GU complications was assessed according to the eight factors in Tables 3a and 3b as well as the prostate size and age of the patient. On univariate analysis only, the prostate size (p ⫽ 0.01) (Fig. 2) and neutron technique (p ⫽ 0.04) were significantly associated with the rate of complications. In addition, African-American men had a higher rate of Grade 2 or higher GU complications (p ⫽ 0.07). These results are summarized in Table 4. There was no significant difference in the observed rate of complications by stage, pre-RT hormones, neutron dose, or sequence. On multivariate analysis, only the size of the prostate was significantly associated with the risk of chronic GU morbidity. Preliminary evaluations of various partitioning schemes (deciles, quantiles, quartiles, etc.) of
Table 3b. Prostate volume as a function of treatment-related factors
0.004 Treatment factor
Characteristic
Average prostate volume (cc)
Neutron technique
4-field nonaxial 6-field axial First Last 7–9 Gy 10–11Gy
54 63 57 57 58 57
p Value
0.08 Neutron sequence 0.6 Neutron dose 0.6
0.002 0.8 0.7
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Volume 45, Number 4, 1999
Fig. 2. Chronic GU complication-free survival gross tumor volume ⱕ 74.6 vs. ⬎ 74.6 cc.
the range of prostate volume values revealed that patients with increased prostate size were at a relatively higher risk of GU morbidity. This observation suggested the formation of two groups, which, in turn, required the location of a cutpoint. The cutpoint was determined to be that point for which discrimination in the “survival” curves between the two risk groups formed was greatest. A partitioning of the range of prostate volume values (recursively) along the percentile points into two groups, with the restriction that a group should contain at least 40 patients, produced a cutpoint at the 80th percentile (74.6 cc). DISCUSSION The goal of planning radiation treatment for prostate cancer is to maximize the therapeutic ratio between local tumor eradication and chronic complications (21). Conformal treatment techniques based on CT-acquired anatomical Table 4. Four-year actuarial risk of Grade 2 or higher GU complications Factor
Characteristic
ⱕ74 cc ⬎74 cc Neutron technique 4-field nonaxial 6-field axial Neutron technique ⱕ74 cc (4-field nonaxial) ⬎74 cc Race African-American Caucasian Prostate size
* 30 m means at 30 months.
No.
4 year (%)*
p Value
218 55 175 98 147 28 96 177
19% 33% 11% (30 m) 35% (30 m) 10% (30 m) 17% (30 m) 25% 19%
0.01 0.04 0.2 0.07
data have done much to make these goals a reality (1, 4, 5, 7, 21). As a result of 3D-CRT, the risks of chronic complications have been reduced, modest dose-escalation has been safely accomplished, and the rates of tumor control have been enhanced (3, 9, 10 –12). Dose and volume data represented by DVHs allow for comparison and optimization of plans (9, 15, 20). However, despite these advances some patients remain at risk for chronic complications following treatment. In this study, the pre-RT size of the prostate gland was found to be an important predictor of chronic GU complications. The observation that the prostate volume was larger in AfricanAmerican men may be an explanation for why race was a factor in predicting for complications as well (Table 4). The association of prostate size with neutron technique is harder to explain. The neutron technique was switched from the nonaxial 4-field to 6-field technique approximately 21⁄2 years ago to reduce soft tissue complication rates (22, 23). Why the more recently treated patients would have significantly larger prostate volumes is most likely a chance observation. Fortunately prostate size is a modifiable variable. Previous studies have shown that significant prostate downsizing (30 – 40%) can occur through the use of preirradiation hormonal treatment. As a result the volume of rectum and bladder receiving various percentages of the prescription dose could be reduced. This reduction predicted for a reduction in NTCP (17, 18). However, no prospective study of downsizing has shown an association with prostate size with the observed rate of complications (24, 25). This study suggests that a benefit may be found in terms of risk reduction in patients with enlarged prostates, and would be
Prostate size and post-RT urinary morbidity
a valuable endpoint in prospective clinical studies, even if there is no clear evidence of a disease-free survival component. CONCLUSIONS In summary, patients with enlarged prostate glands have a two and a half fold increased risk of chronic GU compli-
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cations. Based on these observations as well as the fact that hormonal therapy can reduce the volume of the prostate, it follows that preradiation hormones could be used in patients with enlarged prostate to make the treatment safer. While it is very likely that these data would also be applicable for patients receiving photon irradiation only, it is important to realize that these data were obtained for patients receiving mixed conformal neutron and photon irradiation.
REFERENCES 1. Leibel SA, Heimann R, Kutcher GJ, Zelefsky MJ, Burman CM, Melian E, Orazem JP, Mohan R, LoSasso TJ, Lo Y, Wiseberg JA, Chapman DS, Ling CC, Fuks Z. Three dimensional conformal radiation therapy in locally advanced carcinoma of the prostate: Preliminary results of a phase I dose escalation study. Int J Radiat Oncol Biol Phys 1993;28:55– 65. 2. Pilepich MV, Perez CA, Prasad S. Computed tomography in definitive radiotherapy of prostatic carcinoma. Int J Radiat Oncol Biol Phys 1980;6:923–926. 3. Sandler HM, McLaughlin W, TenHaken RK, Addison H, Forman JD, Lichter AS. Three dimensional conformal radiotherapy for the treatment of prostate cancer: Low risk of chronic rectal morbidity observed in a large series of patients. Int J Radiat Oncol Biol Phys 1995;33:797– 801. 4. Simpson JF, Purda JA, Manolos JM, Pilepich MV, Burman C, Forman JD, Fuks Z, Cheng E, Chu J, Matthews J, Mohan R, Solin L, Tepper J, Urie M. Three dimensional treatment planning considerations for prostate cancer. Int J Radiat Oncol Biol Phys 1991;21:243–252. 5. Smith AR, Purdy JA. Three dimensional photon treatment planning: Report of the collaborative working group on the evaluation of treatment planning for external photon beam radiotherapy. Int J Radiat Oncol Biol Phys 1991;(Suppl.):21: 25–36. 6. Niemierko A, Goitein M. Modeling of normal tissue response to radiation: The critical volume model. Int J Radiat Oncol Biol Phys 1992;25:135–145. 7. Zelefsky MJ, Leibel SA, Gaudin PB, Kutcher GJ, Fleshner NE, Venkatramen ES, Reuter VE, Fair WR, Ling CC, Fuks Z. Dose escalation with three dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys 1998;41:491–500. 8. Hartford AC, Niemierko A, Adams JA, Urie MM, Shipley WU. Conformal irradiation of the prostate: Estimating longterm rectal bleeding risk using dose–volume histograms. Int J Radiat Oncol Biol Phys 1996;36:721–730. 9. Fukunaga-Johnson N, Sandler HM, McLaughlin PW, Strawderman MS, Grijalva KH, Kish KE, Lichter AS. Results of 3D conformal radiotherapy in the treatment of localized prostate cancer. Int J Radiat Oncol Biol Phys 1997;38:311–317. 10. Hanks GE, Hanlon AL, Schultheiss TE, Pinover WH, Movsas B, Epstein BE, Hunt MA. Dose escalation with 3D conformal treatment: Five year outcomes, treatment optimization and future directions. Int J Radiat Oncol Biol Phys 1998;41:501– 510. 11. Sandler HM, McShan DL, Lichter AS. Potential improvement in the results of irradiation for prostate carcinoma using improved dose distribution. Int J Radiat Oncol Biol Phys 1991; 22:361–367. 12. Soffen EM, Hanks GE, Hunt MA, Epstein BE. Conformal static field radiation therapy treatment of early prostate cancer versus non-conformal techniques: A reduction in acute morbidity. Int J Radiat Oncol Biol Phys 1992;24:485– 488. 13. Forman JD, Kocheril PG, Hart KB, Chuba PJ, Washington T, Orton CG, Porter AT. Estimating the RBE for pelvic neutron
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irradiation in patients treated for carcinoma of the prostate. J Brachyther Int 1997;13:29 –34. Forman JD, Duclos M, Sharma R, Chuba PJ, Hart KB, Yudelev M, Devi S, Court WS, Shamsa F, Littrup P, Grignon D, Porter AT, Maughan R. Conformal mixed neutron and photon irradiation in localized and locally advanced prostate cancer: Preliminary estimates of the therapeutic ratio. Int J Radiat Oncol Biol Phys 1996;35:259 –266. Bonta D, Lu Y, Chen GYT, Gilio J, Forman JD. Estimation of the normal tissue complication probability parameters for rectal complication following prostate irradiation. Int J Radiat Oncol Biol Phys. In press. Gilio JP, Lu Y, Chen GYT, Vijayakumar S, Halpern HJ, Forman JD. Dependence of late rectal complications from prostate radiotherapy on dose and surface area irradiation. (Abstr.) J Radiol 1997;(Suppl.):205P:169. Forman JD, Kumar R, Haas G, Montie J, Porter AT, Mesina CF. Neo-adjuvant hormonal downsizing of localized carcinoma of the prostate: Effects on the volume of normal tissue irradiation. Cancer Investiga 1995;13:8 –15. Zelefsky MJ, Leibel SA, Burman CM, Kutcher GJ, Harrison A, Happersett L, Fuks Z. Neo-adjuvant hormonal therapy improves the therapeutic ratio in patients with bulky prostatic cancer treated with three-dimensional conformal radiation therapy. Int J Radiat Oncol Biol Phys 1994;29:755–761. Sharma R, Duclos M, Chuba PJ, Shamsa F, Forman JD. Enhancement of prostate tumor volume definition with intravesical contrast: A three dimensional dosimetric evaluation. Int J Radiat Oncol Biol Phys 1997;38:575–582. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. JASA 1958;53:457– 481. Forman JD, Zinreich E, Lee D, Wharam MD, Baumgardner RA, Order SE. Improving the therapeutic ratio of external beam irradiation for carcinoma of the prostate. Int J Radiat Oncol Biol Phys 1985;11:2073–2080. Chuba PJ, Sharma R, Yudelev M, Duclos M, Shamsa F, Giacalone S, Orton CG, Maughan RL, Forman JD. Hip stiffness following mixed conformal neutron and photon radiotherapy: A dose–volume relationship. Int J Radiat Oncol Biol Phys 1996;35:693– 699. Soulen RL, Romero JA, Chuba PJ, Evelhoch JL, Simpson RE, Forman JD. Musculoskeletal complications of neutron therapy for prostate cancer. Radiat Oncol Invest 1997;5:81–91. Pilepich MV, Krall JM, Al-Sarraf M, John MJ, Doggett RLS, Sause WT, Lawton CA, Abrams RA, Rotman M, Rubin P, Shipley WU, Grignon D, Caplan R, Cox JD. Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: A randomized comparative trial of the Radiation Therapy Oncology Group. Urology 1995;45:616 – 622. Zietman AL, Shipley WU. Androgen deprivation and radiation therapy in prostate cancer: The evolving case for combination therapy. Int J Radiat Oncol Biol Phys 1997;37:245– 246.
PII S0360-3016(99)00275-8
CLINICAL INVESTIGATION
Prostate
ASSOCIATION OF PROSTATE SIZE WITH URINARY MORBIDITY FOLLOWING MIXED CONFORMAL NEUTRON AND PHOTON IRRADIATION JEFFREY D. FORMAN, M.D., SAMEER KEOLE, B.S., SUE BOLTON, M.S., AND SAM TEKYI-MENSAH, PH.D. Gershenson Radiation Oncology Center of the Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI Purpose: This study was designed to characterize the relationship between the observed rate of postradiation genitourinary (GU) complications and the prostate gland size. Methods and Materials: Two hundred seventy-three patients received conformal neutron and photon irradiation to the prostate seminal vesicles. Data on post-treatment urinary morbidity were collected and examined in relationship to a number of clinical and technical factors. Results: With a median follow-up of 30 months (range 7– 61), the 4-year rate of Grade 2 or higher GU complications was 21%. On univariate analysis, the risk of complications was significantly associated with prostate size and neutron beam arrangement. On multivariate analysis, only the prostate size was significantly associated with the risk of GU morbidity. Patients with a preradiation prostate volume more than 74 cc had a two and a half fold increase in the risk of complications compared to patients with smaller glands. Conclusion: Patients with an enlarged prostate have a significantly higher risk of chronic GU complications. Although these data were obtained for patients receiving combined neutron and photon irradiation, it is likely that these data would also be applicable for those patients receiving photon irradiation as well. These observations may add an additional rationale for the study of preirradiation hormonal treatment. © 1999 Elsevier Science Inc. Prostate size, Urinary morbidity, Conformal radiation.
Radiotherapy (RT) has undergone a technological revolution in the last 15 years. Computerized tomographic (CT) scan– based treatment planning has allowed for the development and widespread application of three-dimensional treatment planning (3D-CRT) (1–5). The data generated from these 3D-CRT systems include the dose and volume interrelationships of normal tissues as well as tumors (1, 6, 7). Thus, the dose of radiation delivered to all or part of an organ can now be precisely quantified and displayed. In the treatment of prostate cancer, different combinations of radiation beams can be compared using these dose– volume histograms (DVH) to pick the “best” plan. Tumor control probabilities (TCP) and normal tissue complication probabilities (NTCP) can be estimated for each treatment plan based on the information provided in these DVH (8). Thus, if the TCP and NTCP estimates are accurate, an “optimal” treatment plan can be generated for each patient. Overall, the use of 3D-CRT has resulted in a reduction in the observed rate of acute and chronic complications, presumably secondary to reducing the volume of normal tissue irradiation (9 –12). This has allowed for investigation of radiation dose escalation programs in an attempt to improve
the TCP (1, 7, 9 –11). At Wayne State University, dose escalation has been accomplished through the use of conformal mixed photon and neutron irradiation (MNP) (13, 14). However, no correlation has been seen between the DVH for the bladder and rectum and the subsequent rate of chronic complications (15, 16). A complicated and laborintensive analysis of the dose to the surface of the rectum and bladder suggests a correlation with morbidity, but this system is quite cumbersome and impractical for routine use (16). A simple method of predicting and/or reducing morbidity is needed. Because the volume of the rectum and bladder receiving all or part of the radiation dose appears to be related to post-RT morbidity (6), and because this volume is directly related to the size of the target volume for RT, it is possible that reducing the size of the target may result in a reduction in toxicity. Preirradiation hormonal downsizing has been shown to reduce the prostate size, the volume of rectum and bladder receiving RT and to improve the predicted NTCP (17, 18). The volume of the prostate gland is a readily accessible parameter available in the majority of patients, and does not require a 3D system to calculate. This study was undertaken to identify if a correlation between the
Reprint requests to: Jeffrey Forman, M.D., FACR, Harper Hospital, 3990 John R Street, Detroit, MI 48201.
E-mail: [email protected] Accepted for publication 30 June 1999.
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Table 1. Patient characteristics Median age Median pre-RT PSA level Race African American (men) Caucasian Gleason score Stage
67 years 8 ng/ml
(Range 45 to 82) (Range 0.6 to 314)
3–6 7–9 Missing T1 T2
96 (35%) 177 (65%) 145 (54%) 125 (46%) 3 96 (35%) 177 (65%)
rate of post-RT complications and the pre-RT size of the prostate gland exists. METHODS AND MATERIALS Two hundred seventy-three patients treated between 1994 and 1997 for adenocarcinoma of the prostate were selected for this analysis. Patients were treated on 3 consecutive institutional review board–approved treatment protocols using conformal mixed neutron and photon irradiation. All patients selected for analysis had organ-confined disease (Stage T1 or T2) and completed irradiation more than 18 months before analysis in order to adequately assess the rate of chronic complications. Patient characteristics are summarized in Table 1. All patients underwent a CT-based virtual simulation. The volume of irradiation included the prostate and seminal vesicles with a minimum of 1.5-cm margin from the gross tumor volume to the aperture edge. No patient received elective pelvic lymph node irradiation. Most patients (87%) received 10 Gy of neutrons (NGy) combined with 38 or 40 Gy of photons. The sequence of irradiation was under investigation and 159 patients (58%) received neutrons prior to photon irradiation whereas 114 (42%) received the 4 weeks of photon irradiation followed by 2 weeks of neutron irradiation. Daily doses were 1.0 NGy and 2.0 Gy for neutrons and photons, respectively. The first 175 patients had an eight-field treatment plan (4 neutron, 4 photon) whereas the next 98 patients had a 14-field plan (6 neutron, 8 photon). One hundred four patients (38%) received preradiation hormone treatment. The treatment parameters are summarized in Table 2. The prostate size was calculated from the 3D treatment Table 2. Treatment parameters Neutron dose Neutron sequence Field arrangement
Pre-RT hormones
9 NGy 10 NGy First 2 weeks Last 2 weeks 4-field neutron/4-field photon 6-field neutron/8-field photon No Yes
35 238 159 114
patients patients patients patients
(13%) (87%) (58%) (42%)
175 patients (64%) 98 patients (36%) 169 patients (62%) 104 patients (38%)
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planning system. The prostate was contoured on each axial CT image at 5-mm intervals. Intravesical and intraurethral contrast were used to optimize the delineation of the volume (19). Follow-up was at 1 month after radiation, every 3 months for the first year, every 4 months in the second and third years, and every 6 months in subsequent years. Urinary toxicity was classified according to the Radiation Therapy Oncology Group (RTOG) toxicity scale. Grade 2 toxicity included obstructive or irritative symptoms requiring medication, minimal incontinence not requiring a pad, and/or hematuria not requiring fulguration. The Grade 3 complications included symptoms that required a cystoscopy with fulguration of bleeding areas, significant incontinence requiring pad use, or obstructive and/or irritative symptoms not controlled by medication. Chronic complication was defined as a Grade 2 or higher toxicity occurring 6 or more months following the end of radiotherapy. The date of occurrence was noted for patients developing chronic complications. Complication-free survival time was defined as the length of time between the end of radiotherapy and the date of occurrence of Grade 2 or higher toxicity, date of death, or date of last follow-up, whichever occurred first. Complication-free survival times of patients not developing chronic genitourinary (GU) complications were considered censored at the time of death or time of last follow-up. It was assumed that the events of developing GU complications and of being censored were independent.
Statistical analysis BMDP statistical software (Version 7.0; BMDP Statistical Software, Inc., University of California Press, Los Angeles, CA) was used for statistical analysis of the data. Comparisons of prostate volume according to the categories of preclinical and treatment-related factors were achieved using either the Student’s t-test (for 2-level categories) or the analysis of variance (ANOVA) test (for multilevel categories). Complication-free survival curves were constructed using the product limit method of Kaplan-Meier, and the log-rank test was utilized for the comparison of survival curves (20). Cox’s proportional hazards model was used for carrying out univariate analysis of each factor. Preclinical and treatment factors under consideration included age (continuous), race (African-American vs. Caucasian), Gleason score (3– 6 vs. 7–9), stage (T1 vs. T2), neutron dose (7–9 vs. 10 –11 Gy), neutron sequence (first 2 weeks vs. last 2 weeks), field arrangement (4-field vs. 6-field), preradiation hormones (no vs. yes), prostate volume (continuous), pretreatment prostate-specific antigen (PSA) (continuous). Risk factors for urinary morbidity were identified using the stepwise Cox’s proportional hazards regression model approach. Definition of low- and high-risk groups of urinary morbidity based on prostate size required the partitioning of the range of values of prostate volume.
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Fig. 1. Chronic GU complication-free survival.
RESULTS The median follow-up was 30 months (range 7 to 61 months). Forty patients (14%) had Grade 2 or higher GU complications. The 4-year actuarial rate of Grade 2 or higher GU complications was 21% (Fig. 1). There were 30 Grade 2, 9 Grade 3, and 1 Grade 4 complications. The median prostate size was 52 cc (range 10 to 155 cc). African-American men had a significantly larger, average prostate volume of 64 vs. 53 cc, respectively (p ⫽ 0.0002). The patients with Stage T1 prostate cancer had larger prostate volumes than those with Stage T2. There was no difference in the size of the prostate as a function of grade, pretreatment PSA level, or the use of pre-RT hormones. Similarly, there was no difference in prostate size according Table 3a. Prostate volume as a function of various preclinical factors Clinical factor Race
Characteristic
African-American Caucasian Stage T1 T2 Pre-RT PSA 0–4 ⬎4–10 ⬎10–20 ⬎20 Gleason score 3–6 7–9 Pre-RT hormones No Yes
Average prostate p volume (cc) Value 64 53 62 54 48 57 61 58 57 58 57 58
0.0002
to radiation dose or sequence. However, patients treated with a nonaxial neutron beam arrangement had a significantly smaller prostate volume than those treated with a 6-field technique, 54 vs. 63 cc, respectively (p ⫽ 0.002). These results are summarized in Tables 3a and 3b. The risk of chronic GU complications was assessed according to the eight factors in Tables 3a and 3b as well as the prostate size and age of the patient. On univariate analysis only, the prostate size (p ⫽ 0.01) (Fig. 2) and neutron technique (p ⫽ 0.04) were significantly associated with the rate of complications. In addition, African-American men had a higher rate of Grade 2 or higher GU complications (p ⫽ 0.07). These results are summarized in Table 4. There was no significant difference in the observed rate of complications by stage, pre-RT hormones, neutron dose, or sequence. On multivariate analysis, only the size of the prostate was significantly associated with the risk of chronic GU morbidity. Preliminary evaluations of various partitioning schemes (deciles, quantiles, quartiles, etc.) of
Table 3b. Prostate volume as a function of treatment-related factors
0.004 Treatment factor
Characteristic
Average prostate volume (cc)
Neutron technique
4-field nonaxial 6-field axial First Last 7–9 Gy 10–11Gy
54 63 57 57 58 57
p Value
0.08 Neutron sequence 0.6 Neutron dose 0.6
0.002 0.8 0.7
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I. J. Radiation Oncology
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Volume 45, Number 4, 1999
Fig. 2. Chronic GU complication-free survival gross tumor volume ⱕ 74.6 vs. ⬎ 74.6 cc.
the range of prostate volume values revealed that patients with increased prostate size were at a relatively higher risk of GU morbidity. This observation suggested the formation of two groups, which, in turn, required the location of a cutpoint. The cutpoint was determined to be that point for which discrimination in the “survival” curves between the two risk groups formed was greatest. A partitioning of the range of prostate volume values (recursively) along the percentile points into two groups, with the restriction that a group should contain at least 40 patients, produced a cutpoint at the 80th percentile (74.6 cc). DISCUSSION The goal of planning radiation treatment for prostate cancer is to maximize the therapeutic ratio between local tumor eradication and chronic complications (21). Conformal treatment techniques based on CT-acquired anatomical Table 4. Four-year actuarial risk of Grade 2 or higher GU complications Factor
Characteristic
ⱕ74 cc ⬎74 cc Neutron technique 4-field nonaxial 6-field axial Neutron technique ⱕ74 cc (4-field nonaxial) ⬎74 cc Race African-American Caucasian Prostate size
* 30 m means at 30 months.
No.
4 year (%)*
p Value
218 55 175 98 147 28 96 177
19% 33% 11% (30 m) 35% (30 m) 10% (30 m) 17% (30 m) 25% 19%
0.01 0.04 0.2 0.07
data have done much to make these goals a reality (1, 4, 5, 7, 21). As a result of 3D-CRT, the risks of chronic complications have been reduced, modest dose-escalation has been safely accomplished, and the rates of tumor control have been enhanced (3, 9, 10 –12). Dose and volume data represented by DVHs allow for comparison and optimization of plans (9, 15, 20). However, despite these advances some patients remain at risk for chronic complications following treatment. In this study, the pre-RT size of the prostate gland was found to be an important predictor of chronic GU complications. The observation that the prostate volume was larger in AfricanAmerican men may be an explanation for why race was a factor in predicting for complications as well (Table 4). The association of prostate size with neutron technique is harder to explain. The neutron technique was switched from the nonaxial 4-field to 6-field technique approximately 21⁄2 years ago to reduce soft tissue complication rates (22, 23). Why the more recently treated patients would have significantly larger prostate volumes is most likely a chance observation. Fortunately prostate size is a modifiable variable. Previous studies have shown that significant prostate downsizing (30 – 40%) can occur through the use of preirradiation hormonal treatment. As a result the volume of rectum and bladder receiving various percentages of the prescription dose could be reduced. This reduction predicted for a reduction in NTCP (17, 18). However, no prospective study of downsizing has shown an association with prostate size with the observed rate of complications (24, 25). This study suggests that a benefit may be found in terms of risk reduction in patients with enlarged prostates, and would be
Prostate size and post-RT urinary morbidity
a valuable endpoint in prospective clinical studies, even if there is no clear evidence of a disease-free survival component. CONCLUSIONS In summary, patients with enlarged prostate glands have a two and a half fold increased risk of chronic GU compli-
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cations. Based on these observations as well as the fact that hormonal therapy can reduce the volume of the prostate, it follows that preradiation hormones could be used in patients with enlarged prostate to make the treatment safer. While it is very likely that these data would also be applicable for patients receiving photon irradiation only, it is important to realize that these data were obtained for patients receiving mixed conformal neutron and photon irradiation.
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