- Email: [email protected]
Morbidity effect of the time gap between supplemental beam radiation and Pd-103 prostate brachytherapy
Brachytherapy 2 (2003) 108–113
Morbidity effect of the time gap between supplemental beam radiation and Pd-103 prostate brachytherapy Jacques Corriveau1, Kent Wallner1,2,*, Gregory Merrick3, Lawrence True4, William Cavanagh1,2, Steven Sutlief1,2, Wayne Butler3 1
Abstract
Radiation Oncology, Puget Sound Health Care System, Department of Veterans Affairs, Seattle, WA 2 Department of Radiation Oncology, University of Washington, Seattle, WA 3 Department of Radiation Oncology, Schiffler Cancer Center, Wheeling, WV 4 Department of Pathology, University of Washington, Seattle, WA
Purpose: To determine if gap time variations between prostate brachytherapy and supplemental beam radiation (EBRT) affect postimplant morbidity. Materials and Methods: Ninety-one patients with 1997 AJC clinical stage T1c-T2a prostatic carcinoma, Gleason grade 7–9, or PSA 10–20 ng/ml, were randomized to implantation with 90 Gy Pd-103 versus 115 Gy (NIST-1999) with 44 Gy versus 20 Gy preimplant supplemental beam radiation, respectively. Pd-103 implantation was performed by standard techniques, using a modified peripheral loading pattern. Beam radiation was delivered with a four-field arrangement, designed to cover the prostate and seminal vesicles with a 2-cm margin, reduced to 1.0 cm posteriorly. A postimplant computed tomography (CT) scan was obtained on the same day. Dosimetric parameters analyzed included the V100 – the percent of the postimplant prostate or rectal volume covered by the prescription dose, and the D90 – the dose that covers 90% of the post-implant prostate or rectal volume. For EBRT rectal D90s, the rectal volume included slices 0.9 cm above and below the seminal vesicles and apex, respectively. Treatment-related morbidity was monitored by mailed questionnaires, using standard American Urologic Association (AUA) and Radiation Therapy Oncology Group (RTOG) criteria at 1, 3, 6, 12, 18, and 24 months. Use of alpha-blockers to relieve obstructive symptoms was not controlled for, but was noted at each follow-up point. Median followup at the time of this analysis was 21 months, with a range of 18–26 months. Results: Variability in the total radiation delivery time within each treatment arm was due almost exclusively to gap time variability. Patients receiving 20 Gy EBRT completed their beam radiation over an average of 12 days (⫾1 day). Patients receiving 44 Gy did so over an average of 31 days (⫾ 2 days). The median gap interval for patients receiving 20 Gy EBRT was 5 days (range: 1–40 days) versus 9 days (range: 0–15 days) for patients receiving 44 Gy EBRT. Urinary morbidity, measured by a change in the AUA score from baseline (∆AUA) was greater at 1-month postimplant in patients who had shorter gap intervals. The effect of gap time on AUA score changes was lost by 6 months. When looking at the treatment arms separately, the dependence on gap interval was limited to those patients receiving 44 Gy beam radiation. No patient has developed RTOG grade 3 rectal morbidity, and no patient has required invasive therapy for rectal bleeding. There was no relationship between gap interval and rectal morbidity at any time point. There was no relationship between beam doses and RTOG rectal morbidity scores.
Received 25 October 2002; received in revised form 22 April 2003; accepted 29 April 2003. * Corresponding author. Radiation Oncology (#174), Department of Veterans Affairs, 1660 S. Columbian Way, Seattle, WA 98108-1597. Tel.: 206-768-5356; fax: 206-768-5331. E-mail address: [email protected] (K. Wallner). 1538-4721/03/$ – see front matter 쑖 2003 American Brachytherapy Society. All rights reserved. doi:10.1016/S 1 5 38 - 4 7 21 ( 0 3) 0 0 09 9 - 0
J. Corriveau et al. / Brachytherapy 2 (2003) 108–113
109
Conclusions: The findings reported here are suggestive that short gap times are safe. American Brachytherapy Society. All rights reserved. Keywords:
쑖
2003
Prostatic carcinoma; Brachytherapy; Time
Table 1 Modified RTOG morbidity criteria
Introduction Transperineal prostate brachytherapy has grown rapidly throughout North America over the past 10 years. Although data regarding longer-term outcomes are accumulating, there is still surprisingly little literature regarding optimal treatment parameters. Current practice regarding such essential parameters as dose, treatment margins, and homogeneity are based on limited clinical data (1, 2). Brachytherapy alone is typically used for patients with a pretreatment PSA ⬍ 10 and Gleason score of 6 or less. Supplemental external beam radiation has traditionally been added for patients with higher PSAs or Gleason scores, the rationale being that brachytherapy eradicates large central tumor masses while beam radiation eradicates microscopic disease outside of the implant volume (3). Beam radiation is usually delivered first, followed 2–6 weeks later by brachytherapy (4). Although the clinical outcomes with combined brachytherapy and supplemental beam radiation for higher risk patients are encouraging, there are little data regarding the optimal way to combine the modalities (3).
Rectal morbidity Grade 0
Grade 1
Grade 2
Grade 3
Normal
Bowel movements 3–5 times daily; slight rectal discharge or bleeding
Bowel movements ⬎5/day; excessive mucous or intermittent bleeding
Obstruction or bleeding requiring surgery
RTOG ⫽ Radiation Therapy Oncology Group.
One area of clinical concern when combining brachytherapy with beam radiation is the time interval (gap) between modalities. An interval of 2–6 weeks has typically been recommended, but with little data to support short versus longer gap intervals (2). In fact, we are unaware of any data regarding a relationship between gap interval and cancer control rates or morbidity. Of concern, there is mounting evidence that prolonged overall treatment times typical of longer gap
Fig. 1. Patients treated with 20 or 44 Gy supplemental external beam radiation, arranged by increasing gap times.
110
J. Corriveau et al. / Brachytherapy 2 (2003) 108–113
to determine if gap time variations affect postimplant morbidity.
Methods Study design
Fig. 2. Mean gap days for patients treated with 20 Gy versus 44 Gy supplemental beam radiation.
intervals are associated with lower tumor control rates in other cancer types (5, 6). We are currently conducting a prospective randomized trial comparing different dose combinations of Pd-103 and supplemental beam radiation in intermediate risk patients (PSA 10–20 or Gleason ⱖ7). The protocol, as originally written, called for a gap interval of 1–3 weeks, in accordance with widely quoted recommendations (2). However, in the course of routine clinical practice, the time interval for protocol patients has often been shortened, due to travel constraints for out-of-state patients. Gap intervals were not dependent on patients’ acute tolerance to beam radiation. As part of our interest in treatment planning optimization grounded in clinical outcomes data, we have analyzed urinary and rectal morbidity in the first 18 postimplant months
As of December 2000, 91 of a planned total of 600 patients with 1997 AJC clinical stage T1c-T2a prostatic carcinoma, Gleason grade 7–9, and/or PSA 10–20 ng/mL were randomized to implantation with Pd-103 (90 versus 115 Gy, NIST-1999) with 44 Gy versus 20 Gy preimplant supplemental beam radiation, respectively. Patients undergo standard pretherapy evaluation, including complete history and physical examination and serum prostatic specific antigen (PSA). All prostate biopsies are reviewed for Gleason score by one of the investigators (L.T.). Pd-103 implantation was performed by standard techniques, using a modified peripheral loading pattern (7). Beam radiation was delivered with a four-field arrangement, designed to cover the prostate and seminal vesicles with a 2-cm margin, reduced to 1.0-cm posteriorly. A postimplant computed tomography (CT) scan was obtained on the same day. The CT-derived postimplant target volume was determined as previously described, using 5-mm images (8). The contoured images and sources were entered into a Varian treatment planning system (Charlottesville, VA). A redundancy check was performed on seed localization to prevent seed duplication. Dose volume histograms of the prostate and rectum were calculated using the outer margin identified on CT scan. Dosimetric parameters analyzed included the V100–the percent of the post-implant prostate or rectal volume covered by the prescription dose,
Fig. 3. The change in American Urologic Association (∆AUA) scores at 1 and 6 months postimplant, versus gap interval.
J. Corriveau et al. / Brachytherapy 2 (2003) 108–113
111
Fig. 4. The change in American Urologic Association (∆AUA) scores at 1 month postimplant in patients who received 20 Gy or 44 Gy supplemental beam radiation.
and the D90–the dose that covers 90% of the postimplant prostate or rectal volume. D90s are expressed as a percent of the prescription doses, since the prescription doses were different between the two randomization arms. For EBRT rectal D90s, the rectal volume included slices 0.9 cm above and below the seminal vesicles and apex, respectively. Treatment-related morbidity was monitored by mailed questionnaires, using standard AUA and Radiation Therapy Oncology Group (RTOG) criteria at 1, 3, 6, 12, 18, and 24 months (Table 1; (9)). Use of alpha-blockers to relieve obstructive symptoms was not controlled for, but was noted at each follow-up point. Median follow-up at the time of this analysis was 21 months, with a range of 18–26 months. Follow-up information was complete in over 90% of patients, at each time interval. Cancer status, not included in this report, is monitored by annual serum PSA.
Results Variability in the total radiation delivery time within each treatment arm was due almost exclusively to gap time variability. Patients receiving 20 Gy EBRT completed their beam Table 2 Multivariate analysis of effect of radiation parameters on ∆AUA score at 1 month postimplant Variable
20 Gy
44 Gy
Gap V100 D90
.97 .43 .76
.07 .31 .28
∆AUA ⫽ change in American Urologic Association score.
radiation over an average of 12 days (⫾1 day). Patients receiving 44 Gy did so over an average of 31 days (⫾2 days). The median gap interval for patients receiving 20 Gy EBRT was 5 days (range: 1–40 days) versus 9 days (range: 0–15 days) for patients receiving 44 Gy EBRT (Figs. 1 and 2). Urinary morbidity, measured by a change in the AUA score from baseline (∆AUA) was slightly greater at 1-month post-implant in patients who had shorter gap intervals (Fig. 3 left). The effect of gap time on AUA score changes was lost by 6 months (Fig. 3, right). When looking at the treatment arms separately, the dependence on gap interval was limited to those patients receiving 44 Gy beam radiation (Fig. 4). On multivariate analysis including gap times, V100s and D90s as continuous variables for each treatment arm, gap interval was related to 1 month ∆AUA score only in patients receiving 44 Gy (Table 2). No patient has developed RTOG grade 3 rectal morbidity, and no patient has required invasive therapy for rectal bleeding (Table 3). There was no relationship between gap interval and rectal morbidity at any time point (Figure 5). Rectal V100 ranged from 0.0–3.2 ml (median: 0.41 ml). In multivariate Table 3 Overall incidence of grades 1–3 rectal morbidities Months after therapy
Grade 0
Grade 1
Grade 2
0 1 3 6 12 18
92% 71% 86% 91% 84% 88%
8% 26% 13% 1% 13% 10%
0% 2% 1% 0% 4% 3%
112
J. Corriveau et al. / Brachytherapy 2 (2003) 108–113
Fig. 5. Rectal morbidity scores versus increasing gap duration.
analysis including gap times, V100s, and D90s as continuous variables for each treatment arm, there was no association between rectal morbidity and gap interval or rectal volume receiving greater than the implant prescription dose (Table 4). Dosimetry data regarding rectal EBRT doses was available only for 61 patients treated at Schiffler Cancer Center. Rectal D90s ranged from 8% to 25% (median: 20%). On multivariate analysis including gap times and rectal parameters as continuous variables for each treatment arm, there was Table 4 Multivariate analysis of effect of radiation parameters on rectal morbidity scores at 12 months postimplant Variable
20 Gy
44 Gy
Gap V100 D90
.68 .39 .33
.64 .66 .92
no relationship between beam doses and RTOG rectal morbidity scores (Table 5). Discussion Despite prostate brachytherapy’s rapid, widespread promulgation, there have been remarkably few studies critically Table 5 Multivariate analysis of effect of rectal radiation parameters, including rectal beam doses, on rectal morbidity scores 12 months postimplant in 61 patients for whom EBRT dosimetry is available Variable
20 Gy
44 Gy
Gap Rectal V100 Rectal D90 Rectal D50
.58 .72 .2 .61
.72 .81 .14 .58
EBRT ⫽ external beam radiation therapy.
J. Corriveau et al. / Brachytherapy 2 (2003) 108–113
comparing treatment techniques and policies. The timing of brachytherapy combined with external beam radiation is a case in point – we are unaware of any evidence regarding the effect of gap interval on morbidity or cancer control rates. One argument for longer gap times is that they may decrease morbidity. In fact, there is a suggestion in the data summarized here that short-term urinary morbidity, as measured by the ∆AUA score, may be slightly worse in patients treated with shorter gap times. However, such differences appear short-lived, and are probably of minimal clinical significance. Similarly, there was no apparent relationship between rectal morbidity and gap times for patients treated with low- or high-dose supplemental beam radiation. There is mounting clinical evidence from other tumor types that greater overall therapy times, including gap time, may lead to lower tumor control rates (5, 6, 10). Data regarding overall treatment times and prostate cancer cure rates are mixed (11,12). We intend to address this issue with our own patients in the future.
Conclusion We present this data as preliminary guidance for other investigators who are questioning the proper timing of combined brachytherapy and beam radiation. While not definitive, the findings reported here are strongly suggestive that short gap times are safe. While it is possible that the findings will change with longer follow-up of a larger number of patients, most cases of persistent radiation-related rectal bleeding occur within 18 months of therapy, so that our lack of more serious morbidity with a minimum follow-up of 18 months is fairly reassuring (13, 14). It should also be noted, however, that late genitourinary morbidity could be exacerbated by short gap times, a possibility that will be addressed when longer follow-up is available. In the meantime, based on the data reported here, we continue to use shorter gap times than the typical 2–4 weeks used in previously published series. We expect that shorter gap times will ultimately be shown to decrease the likelihood of cancer recurrence.
113
References [1] Blasko JC, Grimm PD, Sylvester JE, et al. Palladium-103 brachytherapy for prostate carcinoma. Int J Radiat Oncol Biol Phys 2000;46: 839–850. [2] Nag SN, Beyer D, Friedland J, et al. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999;44:789–799. [3] Blasko JC, Grimm PD, Sylvester JE, et al. The role of external beam radiotherapy with I-125/Pd-103 brachytherapy for prostate carcinoma. Radiother Oncol 2000;57:273–278. [4] Wallner K, Blasko J, Dattoli M. Supplemental beam radiation. In: Dattoli M, ed. Prostate brachytherapy made complicated. Second edition. Seattle, WA: SmartMedicine Press, 2001, 11.1–11.23. [5] Ang KK, Trotti A, Brown BW, et al. Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001;51:571–578. [6] Weber DC, Kurtz JM, Allal AS. The impact of gap duration on local control in anal canal carcinoma treated by split-course radiotherapy and concomitant chemotherapy. Int J Radiat Oncol Biol Phys 2001; 50:675–680. [7] Merrick GS, Butler WM. Modified uniform seed loading for prostate brachytherapy: Rationale, design, and evaluation. Techn Urol 2000; 6:78–84. [8] Badiozamani KR, Wallner KE, Cavanagh W, et al. Comparability of CT-based and TRUS-based prostate volumes. Int J Radiat Oncol Biol Phys 1999;43:375–378. [9] Barry MJ, Fowler FJ, O’Leary MP, et al. The American Urologic Association symptom index for benign prostatic hyperplasia. J Urol 1992;148:1549. [10] Lanciano RM, Pajak TF, Martz K, et al. The influence of treatment time on outcome for squamous cell cancer of the uterine cervix treated with radiation: A patterns-of-care study. Int J Radiat Oncol Biol Phys 1993;25:391–397. [11] Amdur RJ, Parsons JT, Fitzgerald LT, et al. The effect of overall treatment time on local control in patients with adenocarcinoma of the prostate treated with radiation therapy. Int J Radiat Oncol Biol Phys 1990;19:1377–1382. [12] Lai PP, Pilipich MV, Krall JM, et al. The effect of overall treatment time on the outcome of definitive radiotherapy for localized prostate carcinoma: The Radiation Therapy Oncology Group 75-06 and 7706 experience. Int J Radiat Oncol Biol Phys 1991;21:925–933. [13] Hu K, Wallner K. Clinical course of rectal complications following I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 1998;41: 263–265. [14] Snyder KM, Stock RG, Hong SM, et al. Defining the risk of developing grade 2 proctitis following 125-I prostate brachytherapy using a rectal dose-volume histogram analysis. Int J Radiat Oncol Biol Phys 2001; 50:335–341.
Morbidity effect of the time gap between supplemental beam radiation and Pd-103 prostate brachytherapy Jacques Corriveau1, Kent Wallner1,2,*, Gregory Merrick3, Lawrence True4, William Cavanagh1,2, Steven Sutlief1,2, Wayne Butler3 1
Abstract
Radiation Oncology, Puget Sound Health Care System, Department of Veterans Affairs, Seattle, WA 2 Department of Radiation Oncology, University of Washington, Seattle, WA 3 Department of Radiation Oncology, Schiffler Cancer Center, Wheeling, WV 4 Department of Pathology, University of Washington, Seattle, WA
Purpose: To determine if gap time variations between prostate brachytherapy and supplemental beam radiation (EBRT) affect postimplant morbidity. Materials and Methods: Ninety-one patients with 1997 AJC clinical stage T1c-T2a prostatic carcinoma, Gleason grade 7–9, or PSA 10–20 ng/ml, were randomized to implantation with 90 Gy Pd-103 versus 115 Gy (NIST-1999) with 44 Gy versus 20 Gy preimplant supplemental beam radiation, respectively. Pd-103 implantation was performed by standard techniques, using a modified peripheral loading pattern. Beam radiation was delivered with a four-field arrangement, designed to cover the prostate and seminal vesicles with a 2-cm margin, reduced to 1.0 cm posteriorly. A postimplant computed tomography (CT) scan was obtained on the same day. Dosimetric parameters analyzed included the V100 – the percent of the postimplant prostate or rectal volume covered by the prescription dose, and the D90 – the dose that covers 90% of the post-implant prostate or rectal volume. For EBRT rectal D90s, the rectal volume included slices 0.9 cm above and below the seminal vesicles and apex, respectively. Treatment-related morbidity was monitored by mailed questionnaires, using standard American Urologic Association (AUA) and Radiation Therapy Oncology Group (RTOG) criteria at 1, 3, 6, 12, 18, and 24 months. Use of alpha-blockers to relieve obstructive symptoms was not controlled for, but was noted at each follow-up point. Median followup at the time of this analysis was 21 months, with a range of 18–26 months. Results: Variability in the total radiation delivery time within each treatment arm was due almost exclusively to gap time variability. Patients receiving 20 Gy EBRT completed their beam radiation over an average of 12 days (⫾1 day). Patients receiving 44 Gy did so over an average of 31 days (⫾ 2 days). The median gap interval for patients receiving 20 Gy EBRT was 5 days (range: 1–40 days) versus 9 days (range: 0–15 days) for patients receiving 44 Gy EBRT. Urinary morbidity, measured by a change in the AUA score from baseline (∆AUA) was greater at 1-month postimplant in patients who had shorter gap intervals. The effect of gap time on AUA score changes was lost by 6 months. When looking at the treatment arms separately, the dependence on gap interval was limited to those patients receiving 44 Gy beam radiation. No patient has developed RTOG grade 3 rectal morbidity, and no patient has required invasive therapy for rectal bleeding. There was no relationship between gap interval and rectal morbidity at any time point. There was no relationship between beam doses and RTOG rectal morbidity scores.
Received 25 October 2002; received in revised form 22 April 2003; accepted 29 April 2003. * Corresponding author. Radiation Oncology (#174), Department of Veterans Affairs, 1660 S. Columbian Way, Seattle, WA 98108-1597. Tel.: 206-768-5356; fax: 206-768-5331. E-mail address: [email protected] (K. Wallner). 1538-4721/03/$ – see front matter 쑖 2003 American Brachytherapy Society. All rights reserved. doi:10.1016/S 1 5 38 - 4 7 21 ( 0 3) 0 0 09 9 - 0
J. Corriveau et al. / Brachytherapy 2 (2003) 108–113
109
Conclusions: The findings reported here are suggestive that short gap times are safe. American Brachytherapy Society. All rights reserved. Keywords:
쑖
2003
Prostatic carcinoma; Brachytherapy; Time
Table 1 Modified RTOG morbidity criteria
Introduction Transperineal prostate brachytherapy has grown rapidly throughout North America over the past 10 years. Although data regarding longer-term outcomes are accumulating, there is still surprisingly little literature regarding optimal treatment parameters. Current practice regarding such essential parameters as dose, treatment margins, and homogeneity are based on limited clinical data (1, 2). Brachytherapy alone is typically used for patients with a pretreatment PSA ⬍ 10 and Gleason score of 6 or less. Supplemental external beam radiation has traditionally been added for patients with higher PSAs or Gleason scores, the rationale being that brachytherapy eradicates large central tumor masses while beam radiation eradicates microscopic disease outside of the implant volume (3). Beam radiation is usually delivered first, followed 2–6 weeks later by brachytherapy (4). Although the clinical outcomes with combined brachytherapy and supplemental beam radiation for higher risk patients are encouraging, there are little data regarding the optimal way to combine the modalities (3).
Rectal morbidity Grade 0
Grade 1
Grade 2
Grade 3
Normal
Bowel movements 3–5 times daily; slight rectal discharge or bleeding
Bowel movements ⬎5/day; excessive mucous or intermittent bleeding
Obstruction or bleeding requiring surgery
RTOG ⫽ Radiation Therapy Oncology Group.
One area of clinical concern when combining brachytherapy with beam radiation is the time interval (gap) between modalities. An interval of 2–6 weeks has typically been recommended, but with little data to support short versus longer gap intervals (2). In fact, we are unaware of any data regarding a relationship between gap interval and cancer control rates or morbidity. Of concern, there is mounting evidence that prolonged overall treatment times typical of longer gap
Fig. 1. Patients treated with 20 or 44 Gy supplemental external beam radiation, arranged by increasing gap times.
110
J. Corriveau et al. / Brachytherapy 2 (2003) 108–113
to determine if gap time variations affect postimplant morbidity.
Methods Study design
Fig. 2. Mean gap days for patients treated with 20 Gy versus 44 Gy supplemental beam radiation.
intervals are associated with lower tumor control rates in other cancer types (5, 6). We are currently conducting a prospective randomized trial comparing different dose combinations of Pd-103 and supplemental beam radiation in intermediate risk patients (PSA 10–20 or Gleason ⱖ7). The protocol, as originally written, called for a gap interval of 1–3 weeks, in accordance with widely quoted recommendations (2). However, in the course of routine clinical practice, the time interval for protocol patients has often been shortened, due to travel constraints for out-of-state patients. Gap intervals were not dependent on patients’ acute tolerance to beam radiation. As part of our interest in treatment planning optimization grounded in clinical outcomes data, we have analyzed urinary and rectal morbidity in the first 18 postimplant months
As of December 2000, 91 of a planned total of 600 patients with 1997 AJC clinical stage T1c-T2a prostatic carcinoma, Gleason grade 7–9, and/or PSA 10–20 ng/mL were randomized to implantation with Pd-103 (90 versus 115 Gy, NIST-1999) with 44 Gy versus 20 Gy preimplant supplemental beam radiation, respectively. Patients undergo standard pretherapy evaluation, including complete history and physical examination and serum prostatic specific antigen (PSA). All prostate biopsies are reviewed for Gleason score by one of the investigators (L.T.). Pd-103 implantation was performed by standard techniques, using a modified peripheral loading pattern (7). Beam radiation was delivered with a four-field arrangement, designed to cover the prostate and seminal vesicles with a 2-cm margin, reduced to 1.0-cm posteriorly. A postimplant computed tomography (CT) scan was obtained on the same day. The CT-derived postimplant target volume was determined as previously described, using 5-mm images (8). The contoured images and sources were entered into a Varian treatment planning system (Charlottesville, VA). A redundancy check was performed on seed localization to prevent seed duplication. Dose volume histograms of the prostate and rectum were calculated using the outer margin identified on CT scan. Dosimetric parameters analyzed included the V100–the percent of the post-implant prostate or rectal volume covered by the prescription dose,
Fig. 3. The change in American Urologic Association (∆AUA) scores at 1 and 6 months postimplant, versus gap interval.
J. Corriveau et al. / Brachytherapy 2 (2003) 108–113
111
Fig. 4. The change in American Urologic Association (∆AUA) scores at 1 month postimplant in patients who received 20 Gy or 44 Gy supplemental beam radiation.
and the D90–the dose that covers 90% of the postimplant prostate or rectal volume. D90s are expressed as a percent of the prescription doses, since the prescription doses were different between the two randomization arms. For EBRT rectal D90s, the rectal volume included slices 0.9 cm above and below the seminal vesicles and apex, respectively. Treatment-related morbidity was monitored by mailed questionnaires, using standard AUA and Radiation Therapy Oncology Group (RTOG) criteria at 1, 3, 6, 12, 18, and 24 months (Table 1; (9)). Use of alpha-blockers to relieve obstructive symptoms was not controlled for, but was noted at each follow-up point. Median follow-up at the time of this analysis was 21 months, with a range of 18–26 months. Follow-up information was complete in over 90% of patients, at each time interval. Cancer status, not included in this report, is monitored by annual serum PSA.
Results Variability in the total radiation delivery time within each treatment arm was due almost exclusively to gap time variability. Patients receiving 20 Gy EBRT completed their beam Table 2 Multivariate analysis of effect of radiation parameters on ∆AUA score at 1 month postimplant Variable
20 Gy
44 Gy
Gap V100 D90
.97 .43 .76
.07 .31 .28
∆AUA ⫽ change in American Urologic Association score.
radiation over an average of 12 days (⫾1 day). Patients receiving 44 Gy did so over an average of 31 days (⫾2 days). The median gap interval for patients receiving 20 Gy EBRT was 5 days (range: 1–40 days) versus 9 days (range: 0–15 days) for patients receiving 44 Gy EBRT (Figs. 1 and 2). Urinary morbidity, measured by a change in the AUA score from baseline (∆AUA) was slightly greater at 1-month post-implant in patients who had shorter gap intervals (Fig. 3 left). The effect of gap time on AUA score changes was lost by 6 months (Fig. 3, right). When looking at the treatment arms separately, the dependence on gap interval was limited to those patients receiving 44 Gy beam radiation (Fig. 4). On multivariate analysis including gap times, V100s and D90s as continuous variables for each treatment arm, gap interval was related to 1 month ∆AUA score only in patients receiving 44 Gy (Table 2). No patient has developed RTOG grade 3 rectal morbidity, and no patient has required invasive therapy for rectal bleeding (Table 3). There was no relationship between gap interval and rectal morbidity at any time point (Figure 5). Rectal V100 ranged from 0.0–3.2 ml (median: 0.41 ml). In multivariate Table 3 Overall incidence of grades 1–3 rectal morbidities Months after therapy
Grade 0
Grade 1
Grade 2
0 1 3 6 12 18
92% 71% 86% 91% 84% 88%
8% 26% 13% 1% 13% 10%
0% 2% 1% 0% 4% 3%
112
J. Corriveau et al. / Brachytherapy 2 (2003) 108–113
Fig. 5. Rectal morbidity scores versus increasing gap duration.
analysis including gap times, V100s, and D90s as continuous variables for each treatment arm, there was no association between rectal morbidity and gap interval or rectal volume receiving greater than the implant prescription dose (Table 4). Dosimetry data regarding rectal EBRT doses was available only for 61 patients treated at Schiffler Cancer Center. Rectal D90s ranged from 8% to 25% (median: 20%). On multivariate analysis including gap times and rectal parameters as continuous variables for each treatment arm, there was Table 4 Multivariate analysis of effect of radiation parameters on rectal morbidity scores at 12 months postimplant Variable
20 Gy
44 Gy
Gap V100 D90
.68 .39 .33
.64 .66 .92
no relationship between beam doses and RTOG rectal morbidity scores (Table 5). Discussion Despite prostate brachytherapy’s rapid, widespread promulgation, there have been remarkably few studies critically Table 5 Multivariate analysis of effect of rectal radiation parameters, including rectal beam doses, on rectal morbidity scores 12 months postimplant in 61 patients for whom EBRT dosimetry is available Variable
20 Gy
44 Gy
Gap Rectal V100 Rectal D90 Rectal D50
.58 .72 .2 .61
.72 .81 .14 .58
EBRT ⫽ external beam radiation therapy.
J. Corriveau et al. / Brachytherapy 2 (2003) 108–113
comparing treatment techniques and policies. The timing of brachytherapy combined with external beam radiation is a case in point – we are unaware of any evidence regarding the effect of gap interval on morbidity or cancer control rates. One argument for longer gap times is that they may decrease morbidity. In fact, there is a suggestion in the data summarized here that short-term urinary morbidity, as measured by the ∆AUA score, may be slightly worse in patients treated with shorter gap times. However, such differences appear short-lived, and are probably of minimal clinical significance. Similarly, there was no apparent relationship between rectal morbidity and gap times for patients treated with low- or high-dose supplemental beam radiation. There is mounting clinical evidence from other tumor types that greater overall therapy times, including gap time, may lead to lower tumor control rates (5, 6, 10). Data regarding overall treatment times and prostate cancer cure rates are mixed (11,12). We intend to address this issue with our own patients in the future.
Conclusion We present this data as preliminary guidance for other investigators who are questioning the proper timing of combined brachytherapy and beam radiation. While not definitive, the findings reported here are strongly suggestive that short gap times are safe. While it is possible that the findings will change with longer follow-up of a larger number of patients, most cases of persistent radiation-related rectal bleeding occur within 18 months of therapy, so that our lack of more serious morbidity with a minimum follow-up of 18 months is fairly reassuring (13, 14). It should also be noted, however, that late genitourinary morbidity could be exacerbated by short gap times, a possibility that will be addressed when longer follow-up is available. In the meantime, based on the data reported here, we continue to use shorter gap times than the typical 2–4 weeks used in previously published series. We expect that shorter gap times will ultimately be shown to decrease the likelihood of cancer recurrence.
113
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