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International Journal of Urology (2014) 21, 572–577
doi: 10.1111/iju.12373
Original Article: Clinical Investigation
Salvage partial brachytherapy for prostate cancer recurrence after primary brachytherapy Hiroshi Sasaki,1 Masahito Kido,1 Kenta Miki,1 Hidetoshi Kuruma,1 Hiroyuki Takahashi,2 Manabu Aoki3 and Shin Egawa1 Departments of 1Urology, 2Pathology and 3Radiology, Jikei University School of Medicine, Tokyo, Japan
Abbreviations & Acronyms ADT = androgen deprivation therapy Ant = anterior BCR = biochemical recurrence CT = computed tomography CTV = clinical target volume DW = diffusion-weighted EBRT = external beam radiotherapy LDR-BT = low-dose rate brachytherapy Lt SV = left seminal vesicle MRI = magnetic resonance imaging NA = not available PSA = prostate-specific antigen PSADT = prostate-specific antigen doubling time Rec = recovery Rt SV = right seminal vesicle Sal BT = salvage regional low-dose-rate brachytherapy T2W = T2-weighted Tx = treatment Correspondence: Hiroshi Sasaki M.D., Department of Urology, Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan. Email: [email protected] Received 2 July 2013; accepted 17 November 2013. Online publication 23 December 2013
572
Objectives: To characterize local recurrence of prostate cancer and to assess the effect of salvage partial brachytherapy after primary 125-iodine low-dose rate brachytherapy with or without external beam radiotherapy in Japanese men. Methods: Between 2003 and 2010, a total of 616 consecutive patients underwent lowdose rate brachytherapy-based therapy for clinically localized prostate cancer at Jikei University Hospital in Tokyo, Japan. Biochemical recurrence occurred in 45 (7.3%) patients at a median of 30 months (range 11–93 months). A total of 20 patients subsequently underwent transperineal template prostatic biopsy; of those, eight had positive cores at the base of the prostate or at the seminal vesicles. These eight patients had underdosed areas identified at initial low-dose rate brachytherapy corresponding to the positive biopsy sites. All were confirmed to have only localized recurrence, and seven underwent salvage partial low-dose rate brachytherapy. Results: Median prostate-specific antigen nadir level in the eight patients with biopsyproven local recurrence after initial low-dose rate brachytherapy was 0.75 ng/mL (range 0.39–2.06). The seven retreated patients tolerated the salvage partial low-dose rate brachytherapy well, and showed a decrease in prostate-specific antigen level at follow up. Two patients later developed biochemical and clinical progression at 11 and 13 months, respectively. Prostate-specific antigen level continued to be low in the remaining five patients. No significant genitourinary or gastrointestinal toxicity was encountered. Conclusions: Salvage partial low-dose rate brachytherapy for biopsy-proven localized prostate cancer recurrence appears rational, technically feasible and safe. Optimal patient selection is of utmost importance for long-term success. Larger studies with longer follow up are warranted.
Key words: local recurrence, prostate cancer, salvage partial brachytherapy.
Introduction Selection of ideal treatment for localized prostate cancer recurrence after definitive radiotherapy is controversial, owing to the lack of evidence based on randomized controlled trials. According to guidelines from the National Comprehensive Cancer Network, local salvage therapy should be considered for patients with solitary local recurrence. Such therapy includes radical prostatectomy, cryosurgery and brachytherapy, and some authorities also recommend salvage highintensity focused ultrasound. However, because of the toxicities associated with these modalities, physicians often choose palliative treatment with ADT instead.1,2 Potentially curative treatment is thus withheld from many patients. Salvage LDR-BT can be a useful treatment option for localized prostate cancer.3–7 However, conventional salvage LDR-BT, with re-implantation of the entire prostate,2 might be associated with serious adverse events. Gastrointestinal or genitourinary grade ≥3 toxicity has been reported in up to 47% of patients, and can develop prostatic urethral fistulas requiring surgical repair, if proper dosimetric constraints are not applied.2,7 Salvage LDR-BT of the entire gland can be suboptimal if inappropriately applied. Localized persistence of prostate cancer after radiotherapy might result from radioresistant cell clones in the primary tumor. However, such persistence can more often be the result of inhomogeneous dosimetric distribution of irradiation within the prostate, so that the tumor does not incur uniformly lethal damage.2,7,8 In such cases, underdosed regions or “cold spots” would be expected to correspond to areas of local recurrence.8 The target volume could then be defined based on the initial dosimetric record, coupled with information from template-style biopsy © 2013 The Japanese Urological Association
Methods
0.78 2.06 0.39 1.69 0.49 0.75
PSA nadir after initial BT
mapping. We carried out the present study to test this hypothesis, in order to better define the safety and technical feasibility of salvage partial LDR-BT for undertreated areas.
1.20 0.72 0.48
Salvage partial brachytherapy
© 2013 The Japanese Urological Association
135.9 124.7 113.0 – 142.3 134.8 189.9 143.3 123.9 135.9† 38.0 41.8 30.7 31.0 19.7 30.4
86.8 84.6 99.1 – 89.0 87.1 98.1 89.8 94.8 89.0† 30.0 11.7 28.8
†Patient no. 3 excluded.
69 69 66 69 69 68.5 4 5 6 7 8 Median
7.9 13.8 14.8 6.8 12.2 12.0
T1c T1c T2a T1c T2a
3+3=6 3+4=7 4+3=7 3+3=6 4+3=7
1/6 5/6 3/8 2/8 3/8
Low Intermediate Intermediate Low Intermediate
I-125 I-125 I-125 EBRT I-125 I-125 I-125 I-125 I-125 Intermediate Low High 4/6 5/6 2/6 3+4=7 3+3=6 3+4=7 T1c T1c T1c 68 64 68 1 2 3
11.7 9.5 34.0
V100 Prostatic volume (cc) Source Risk stratification Biopsy cores no. positive/total Biopsy Gleason score Stage PSA (ng/mL) Age (years)
Demographics of patients at presentation who later developed local recurrence after 125-iodine LDR-BT-based radiotherapy
Patients
Table 1
Between October 2003 and April 2010, 616 Japanese patients underwent LDR-BT for localized prostate cancer at Jikei University Hospital. LDR-BT was administered using an ultrasound-guided technique with a Mick applicator as previously described.9 LDR-BT monotherapy was administered in 167 low-risk, 124 intermediate-risk and two high-risk patients as defined by D’Amico’s risk stratification. A total of 17 patients in the intermediate-risk and nine patients in the highrisk group received trimodality therapy consisting of LDR-BT, ADT, and EBRT. A total of 90 patients enrolled in the SHIP0804 randomized controlled trial for intermediate-risk prostate cancer had 3-month neoadjuvant ADT before LDRBT; none of them received EBRT. An additional 43 patients from the SHIP0804 study received 9-month adjuvant ADT.9 BCR was defined as a PSA increase of >2 ng/mL above the PSA nadir level (Phoenix definition).10 A total of 45 patients (7.3%) developed BCR after initial LDR-BT at a median of 30 months (range 11–93 months). Patients with BCR within 24 months had significant clinical progression or continuous increasing PSA levels, thus minimizing the possibility of PSA bounce phenomenon. Admittedly, this diagnosis is primarily made based on clinical judgment, as there are no solid diagnostic criteria available to exclude this possibility, especially during the early phase after LDR-BT. A total of 20 patients subsequently underwent template transperineal biopsy to confirm local recurrence as described by Satoh et al.11 A total of 22 tissue cores were obtained in general from the prostate; 16 from the mid-prostate to the base including seminal vesicles, and six cores from the distal half of the gland. All histology was reviewed by one pathologist (HT). The remaining patients did not undergo prostatic biopsy after BCR, either because distant metastases were diagnosed (n = 19) or because the patient refused the procedure (n = 6). These latter patients are currently followed without further treatment. Patients with positive biopsy results were further evaluated with the use of CT, MRI (T2W and DW at 1.5T, beginning in 2007) and bone scintigraphy to exclude the possibility of distant metastases. Local recurrence and its location within the prostate were visually evaluated using DW imaging. Eight patients had positive cores at the base of the prostate or the seminal vesicles (Table 1). Those eight patients were confirmed to have localized recurrence only. All eight patients had underdosed areas identified at initial LDR-BT, and those areas corresponded to the positive biopsy sites. Seven of the eight patients underwent salvage partial LDR-BT using 125-iodine with real-time transrectal ultrasound-guided transperineal loading. The eighth patient opted for surveillance. Median follow up after initial LDR-BT for these eight patients with isolated local recurrence was 88.5 months (range 36–108 months). No patients received ADT after initial LDR-BT before BCR. Seven patients had been initially treated with 144 Gy 125-iodine LDR-BT monotherapy, and the
D90
Patients
573
H SASAKI ET AL.
remaining patient had undergone combined modality therapy with partial-dose 110 Gy 125-iodine implantation and 45 Gy of EBRT. Median follow up after salvage partial LDR-BT for these seven patients with isolated local recurrence was 27 months (range 3–62 months).
Defining CTV at salvage partial prostate brachytherapy Salvage partial LDR-BT was designed to deliver 144 Gy to recurrent regions, defined as sites of positive biopsy corresponding to underdosed areas at initial LDR-BT. The term “underdosed” was understood to mean that the area received less than the prescribed dose of radioactivity. As fusion imaging was not available, the CTV was manually delineated as a region of local recurrence with biopsy positivity and initial underdosage according to the MRI imaging and the initial CT dosimetry. The treatment was deliberately designed to reduce rectal and urinary morbidity by positioning needles away from the urethra and rectal wall. Regions with sufficient coverage during initial LDR-BT were carefully avoided. The dose was prescribed to the isodose line covering the CTV. The planning target volume included the CTV plus a 5-mm margin (5-mm posterior margin). Prostatic MRI showed no abnormalities outside the targeted area.
Patient follow up All patients underwent a CT scan for post-implant dosimetry 1 month after salvage partial LDR-BT. Post-treatment follow up was quarterly for the first 2 years and semiannually thereafter, with PSA measurement and rectal examination at each visit. Toxicities were recorded using Common Toxicity Criteria version 3.0. Written informed consent was obtained from all patients. Multiple imaging studies, including chest X-ray, CT scan (chest, abdomen), bone scintigraphy and pelvic MRI, were carried out in cases of BCR (Phoenix definition) to search for clinical recurrence.
Results Characteristics of isolated local recurrent tumors after initial LDR-BT and/or EBRT Eight patients were histologically confirmed to have isolated local recurrence of prostate cancer (Table 1). The median time to BCR was 58.5 months. The median initial PSA was 12.0 ng/mL (range 6.8–34.0). At initial LDR-BT, median D90 and median V100 were 135.9 Gy (range 123.9–189.9) and 89.0% (range 84.6–98.1), respectively. Median nadir PSA level after initial LDR-BT was 0.75 ng/mL (range 0.39–2.06). Median PSA level at the time of BCR was 3.66 ng/mL (range 2.88–4.39). Of the 12 patients with negative biopsy, four patients had declined PSA over a median period of 21.5 months after biopsy (from a median of 3.58 to 0.63 ng/mL). The remaining patients still sustain rising PSA trend at last follow up. The median time to BCR in these 12 patients with negative biopsy was 26.0 months, and that for four patients with declining PSA after biopsy was 22.5 months, respectively. Positive biopsy sites were in the anterior base in five patients, posterior base in one patient and seminal vesicles in two patients. These regions corresponded precisely to the underdosed area at 574
dosimetry 1 month after initial LDR-BT. No anatomical variations, such as protruding median lobe, were observed in any of these cases. The number of positive cores ranged from 1 to 3 (median 2), located exclusively in the base (6 patients) and seminal vesicles (2 patients). The maximum cancer length ranged from 1 to 14 mm (median 7 mm). Only a mild radiation effect was noted histologically, as defined by Crook et al.12 Assigned Gleason scores were 6–7. MRI was carried out in six patients after histological confirmation of recurrence. In five of those six patients, MRI findings showed local recurrence of prostate cancer at the base and/or seminal vesicle (Table 2). These tumors typically appeared as low-intensity lesions on T2WI and high-intensity lesions on DWI, ranging from 10 to 18 mm in size. All of these lesions were located in underdosed areas with positive biopsy.
Quality assessment of salvage partial LDR-BT The median number of seeds for salvage partial LDR-BT was 50 (range 20–70). The activity of seeds was 0.29–0.33 mCi per seed. All patients tolerated the procedure well and showed decreased PSA (median 14.5% at 7 months) (Fig. 1). Two patients later developed biochemical and clinical progression at 11 and 13 months after salvage partial LDR-BT, respectively. The PSA response persisted in the remaining patients. Time to BCR after the initial LDR-BT in the two patients who developed clinical progression was shorter (18 and 27 months, respectively) than in the other five patients. The median PSADT before BCR was calculated as log × 2 / the slope of the log PSA line (the difference in the 2 log PSA value divided by the time between readings in months). For these patients, the median PSADT before BCR was 13.2 months (range 8.4– 32.3 months). The PSADT was 8.4 and 13.3 months, respectively, for the two patients with disease progression. No significant genitourinary or gastrointestinal toxicity was noted.
Case presentation A 69-year-old man with Gleason score 6, T1cN0M0 prostate cancer (patient no. 4 in Tables 1,2) had undergone initial LDR-BT in August 2004. A CT scan 4 weeks after the implant showed D90 to be 142.3 Gy and V100 to be 89.0%, and showed an underdosed area at the anterior base of the prostate (Fig. 2a). The PSA nadir after LDR-BT was 0.78 ng/mL. BCR was diagnosed in April 2011; the PSA level was 4.18 ng/mL, and one positive core was detected at the right anterior base of the prostate. On MRI, the recurrent tumor appeared as a lowintensity lesion on T2WI, and a high-intensity lesion on DWI at the base (Fig. 2b,c). Salvage partial LDR-BT was carried out in September 2011. The well-defined cold area was re-implanted with 50 seeds of 125-iodine (Fig. 2d). The post-salvage PSA level remained low at 0.06 ng/mL 13 months later. No significant genitourinary or gastrointestinal toxicity was noted.
Discussion Optimal patient selection is critical for the success of salvage therapy after definitive radiotherapy. Identification of candidates has been proposed on the basis of pretreatment clinical and pathological factors, as well as on post-treatment PSA kinetics, such as PSADT.13,14 Stock et al. have analyzed patterns © 2013 The Japanese Urological Association
16 2.12 4.6† 0.35 0.06 0.11† 0.14 0.70 –
14
PSA (ng/mL)
12
38 62 14 13 54 27 3 – 27
10 8 6 4
– + (11 m) – – –
– + (13 m)
Rec after sal BT
Follow up after sal BT (months)
PSA at last follow up (ng/mL)
Salvage partial brachytherapy
2 40
30 20 65 50 30 50 70 – 50
10 20 30 Time after salvage regional LDR-BT (months)
Changes of PSA with time after salvage regional LDR-BT. , Pt3; , Pt4; , Pt5; , Pt6; , Pt7.
, Pt1;
,
70 31 82 85 30 60 82 – 70 Sal BT Sal BT Sal BT Sal BT Sal BT Sal BT Sal BT Surveillance 1 8 7 7 14 6 5 8 7
© 2013 The Japanese Urological Association
†Patient no. 2 and no. 5 were given hormone therapy after the recurrence after salvage partial LDR-BT.
3+3 3+4 4+3 3+4 4+3 3+4 3+3 4+3 Rt SV Ant base Ant base Ant base Post base Lt SV Ant base Ant base 1/12 2/22 1/23 1/22 3/22 1/22 2/22 2/22 – NA + + NA + + + 13.1 8.4 18.4 10.3 13.3 16.4 32.3 9.0 13.2 3.90 2.88 3.10 4.18 4.39 3.41 3.92 3.13 3.66 1 2 3 4 5 6 7 8 Median
60 18 65 80 27 57 70 36 58.5
Biopsy Gleason score Biopsy positive location Biopsy cores no. positive/total MRI finding T2W and DW PSADT (months)
Fig. 1 Pt2;
PSA at BCR (ng/mL)
Time to BCR (months)
0
Patients
Table 2
Clinicopathological findings of patients with local recurrence after 125-iodine LDR-BT-based radiotherapy
Biopsy maximum cancer length (mm)
Tx after BCR
Time to sal BT after initial BT (months)
Sal BT, number of seeds
0
of failure after LDR-BT for localized prostate cancer,13 and suggested that time to BCR, Gleason score and PSADT were all predictive of distant metastases.13 Local therapy should be indicated for those with the highest probability of purely localized recurrence. Lee et al. reported that ideal candidates for salvage local therapy meet the following criteria: (i) low risk at initial treatment and prediagnostic PSA velocity 12 months and low absolute PSA value before initiating salvage local therapy (
International Journal of Urology (2014) 21, 572–577
doi: 10.1111/iju.12373
Original Article: Clinical Investigation
Salvage partial brachytherapy for prostate cancer recurrence after primary brachytherapy Hiroshi Sasaki,1 Masahito Kido,1 Kenta Miki,1 Hidetoshi Kuruma,1 Hiroyuki Takahashi,2 Manabu Aoki3 and Shin Egawa1 Departments of 1Urology, 2Pathology and 3Radiology, Jikei University School of Medicine, Tokyo, Japan
Abbreviations & Acronyms ADT = androgen deprivation therapy Ant = anterior BCR = biochemical recurrence CT = computed tomography CTV = clinical target volume DW = diffusion-weighted EBRT = external beam radiotherapy LDR-BT = low-dose rate brachytherapy Lt SV = left seminal vesicle MRI = magnetic resonance imaging NA = not available PSA = prostate-specific antigen PSADT = prostate-specific antigen doubling time Rec = recovery Rt SV = right seminal vesicle Sal BT = salvage regional low-dose-rate brachytherapy T2W = T2-weighted Tx = treatment Correspondence: Hiroshi Sasaki M.D., Department of Urology, Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan. Email: [email protected] Received 2 July 2013; accepted 17 November 2013. Online publication 23 December 2013
572
Objectives: To characterize local recurrence of prostate cancer and to assess the effect of salvage partial brachytherapy after primary 125-iodine low-dose rate brachytherapy with or without external beam radiotherapy in Japanese men. Methods: Between 2003 and 2010, a total of 616 consecutive patients underwent lowdose rate brachytherapy-based therapy for clinically localized prostate cancer at Jikei University Hospital in Tokyo, Japan. Biochemical recurrence occurred in 45 (7.3%) patients at a median of 30 months (range 11–93 months). A total of 20 patients subsequently underwent transperineal template prostatic biopsy; of those, eight had positive cores at the base of the prostate or at the seminal vesicles. These eight patients had underdosed areas identified at initial low-dose rate brachytherapy corresponding to the positive biopsy sites. All were confirmed to have only localized recurrence, and seven underwent salvage partial low-dose rate brachytherapy. Results: Median prostate-specific antigen nadir level in the eight patients with biopsyproven local recurrence after initial low-dose rate brachytherapy was 0.75 ng/mL (range 0.39–2.06). The seven retreated patients tolerated the salvage partial low-dose rate brachytherapy well, and showed a decrease in prostate-specific antigen level at follow up. Two patients later developed biochemical and clinical progression at 11 and 13 months, respectively. Prostate-specific antigen level continued to be low in the remaining five patients. No significant genitourinary or gastrointestinal toxicity was encountered. Conclusions: Salvage partial low-dose rate brachytherapy for biopsy-proven localized prostate cancer recurrence appears rational, technically feasible and safe. Optimal patient selection is of utmost importance for long-term success. Larger studies with longer follow up are warranted.
Key words: local recurrence, prostate cancer, salvage partial brachytherapy.
Introduction Selection of ideal treatment for localized prostate cancer recurrence after definitive radiotherapy is controversial, owing to the lack of evidence based on randomized controlled trials. According to guidelines from the National Comprehensive Cancer Network, local salvage therapy should be considered for patients with solitary local recurrence. Such therapy includes radical prostatectomy, cryosurgery and brachytherapy, and some authorities also recommend salvage highintensity focused ultrasound. However, because of the toxicities associated with these modalities, physicians often choose palliative treatment with ADT instead.1,2 Potentially curative treatment is thus withheld from many patients. Salvage LDR-BT can be a useful treatment option for localized prostate cancer.3–7 However, conventional salvage LDR-BT, with re-implantation of the entire prostate,2 might be associated with serious adverse events. Gastrointestinal or genitourinary grade ≥3 toxicity has been reported in up to 47% of patients, and can develop prostatic urethral fistulas requiring surgical repair, if proper dosimetric constraints are not applied.2,7 Salvage LDR-BT of the entire gland can be suboptimal if inappropriately applied. Localized persistence of prostate cancer after radiotherapy might result from radioresistant cell clones in the primary tumor. However, such persistence can more often be the result of inhomogeneous dosimetric distribution of irradiation within the prostate, so that the tumor does not incur uniformly lethal damage.2,7,8 In such cases, underdosed regions or “cold spots” would be expected to correspond to areas of local recurrence.8 The target volume could then be defined based on the initial dosimetric record, coupled with information from template-style biopsy © 2013 The Japanese Urological Association
Methods
0.78 2.06 0.39 1.69 0.49 0.75
PSA nadir after initial BT
mapping. We carried out the present study to test this hypothesis, in order to better define the safety and technical feasibility of salvage partial LDR-BT for undertreated areas.
1.20 0.72 0.48
Salvage partial brachytherapy
© 2013 The Japanese Urological Association
135.9 124.7 113.0 – 142.3 134.8 189.9 143.3 123.9 135.9† 38.0 41.8 30.7 31.0 19.7 30.4
86.8 84.6 99.1 – 89.0 87.1 98.1 89.8 94.8 89.0† 30.0 11.7 28.8
†Patient no. 3 excluded.
69 69 66 69 69 68.5 4 5 6 7 8 Median
7.9 13.8 14.8 6.8 12.2 12.0
T1c T1c T2a T1c T2a
3+3=6 3+4=7 4+3=7 3+3=6 4+3=7
1/6 5/6 3/8 2/8 3/8
Low Intermediate Intermediate Low Intermediate
I-125 I-125 I-125 EBRT I-125 I-125 I-125 I-125 I-125 Intermediate Low High 4/6 5/6 2/6 3+4=7 3+3=6 3+4=7 T1c T1c T1c 68 64 68 1 2 3
11.7 9.5 34.0
V100 Prostatic volume (cc) Source Risk stratification Biopsy cores no. positive/total Biopsy Gleason score Stage PSA (ng/mL) Age (years)
Demographics of patients at presentation who later developed local recurrence after 125-iodine LDR-BT-based radiotherapy
Patients
Table 1
Between October 2003 and April 2010, 616 Japanese patients underwent LDR-BT for localized prostate cancer at Jikei University Hospital. LDR-BT was administered using an ultrasound-guided technique with a Mick applicator as previously described.9 LDR-BT monotherapy was administered in 167 low-risk, 124 intermediate-risk and two high-risk patients as defined by D’Amico’s risk stratification. A total of 17 patients in the intermediate-risk and nine patients in the highrisk group received trimodality therapy consisting of LDR-BT, ADT, and EBRT. A total of 90 patients enrolled in the SHIP0804 randomized controlled trial for intermediate-risk prostate cancer had 3-month neoadjuvant ADT before LDRBT; none of them received EBRT. An additional 43 patients from the SHIP0804 study received 9-month adjuvant ADT.9 BCR was defined as a PSA increase of >2 ng/mL above the PSA nadir level (Phoenix definition).10 A total of 45 patients (7.3%) developed BCR after initial LDR-BT at a median of 30 months (range 11–93 months). Patients with BCR within 24 months had significant clinical progression or continuous increasing PSA levels, thus minimizing the possibility of PSA bounce phenomenon. Admittedly, this diagnosis is primarily made based on clinical judgment, as there are no solid diagnostic criteria available to exclude this possibility, especially during the early phase after LDR-BT. A total of 20 patients subsequently underwent template transperineal biopsy to confirm local recurrence as described by Satoh et al.11 A total of 22 tissue cores were obtained in general from the prostate; 16 from the mid-prostate to the base including seminal vesicles, and six cores from the distal half of the gland. All histology was reviewed by one pathologist (HT). The remaining patients did not undergo prostatic biopsy after BCR, either because distant metastases were diagnosed (n = 19) or because the patient refused the procedure (n = 6). These latter patients are currently followed without further treatment. Patients with positive biopsy results were further evaluated with the use of CT, MRI (T2W and DW at 1.5T, beginning in 2007) and bone scintigraphy to exclude the possibility of distant metastases. Local recurrence and its location within the prostate were visually evaluated using DW imaging. Eight patients had positive cores at the base of the prostate or the seminal vesicles (Table 1). Those eight patients were confirmed to have localized recurrence only. All eight patients had underdosed areas identified at initial LDR-BT, and those areas corresponded to the positive biopsy sites. Seven of the eight patients underwent salvage partial LDR-BT using 125-iodine with real-time transrectal ultrasound-guided transperineal loading. The eighth patient opted for surveillance. Median follow up after initial LDR-BT for these eight patients with isolated local recurrence was 88.5 months (range 36–108 months). No patients received ADT after initial LDR-BT before BCR. Seven patients had been initially treated with 144 Gy 125-iodine LDR-BT monotherapy, and the
D90
Patients
573
H SASAKI ET AL.
remaining patient had undergone combined modality therapy with partial-dose 110 Gy 125-iodine implantation and 45 Gy of EBRT. Median follow up after salvage partial LDR-BT for these seven patients with isolated local recurrence was 27 months (range 3–62 months).
Defining CTV at salvage partial prostate brachytherapy Salvage partial LDR-BT was designed to deliver 144 Gy to recurrent regions, defined as sites of positive biopsy corresponding to underdosed areas at initial LDR-BT. The term “underdosed” was understood to mean that the area received less than the prescribed dose of radioactivity. As fusion imaging was not available, the CTV was manually delineated as a region of local recurrence with biopsy positivity and initial underdosage according to the MRI imaging and the initial CT dosimetry. The treatment was deliberately designed to reduce rectal and urinary morbidity by positioning needles away from the urethra and rectal wall. Regions with sufficient coverage during initial LDR-BT were carefully avoided. The dose was prescribed to the isodose line covering the CTV. The planning target volume included the CTV plus a 5-mm margin (5-mm posterior margin). Prostatic MRI showed no abnormalities outside the targeted area.
Patient follow up All patients underwent a CT scan for post-implant dosimetry 1 month after salvage partial LDR-BT. Post-treatment follow up was quarterly for the first 2 years and semiannually thereafter, with PSA measurement and rectal examination at each visit. Toxicities were recorded using Common Toxicity Criteria version 3.0. Written informed consent was obtained from all patients. Multiple imaging studies, including chest X-ray, CT scan (chest, abdomen), bone scintigraphy and pelvic MRI, were carried out in cases of BCR (Phoenix definition) to search for clinical recurrence.
Results Characteristics of isolated local recurrent tumors after initial LDR-BT and/or EBRT Eight patients were histologically confirmed to have isolated local recurrence of prostate cancer (Table 1). The median time to BCR was 58.5 months. The median initial PSA was 12.0 ng/mL (range 6.8–34.0). At initial LDR-BT, median D90 and median V100 were 135.9 Gy (range 123.9–189.9) and 89.0% (range 84.6–98.1), respectively. Median nadir PSA level after initial LDR-BT was 0.75 ng/mL (range 0.39–2.06). Median PSA level at the time of BCR was 3.66 ng/mL (range 2.88–4.39). Of the 12 patients with negative biopsy, four patients had declined PSA over a median period of 21.5 months after biopsy (from a median of 3.58 to 0.63 ng/mL). The remaining patients still sustain rising PSA trend at last follow up. The median time to BCR in these 12 patients with negative biopsy was 26.0 months, and that for four patients with declining PSA after biopsy was 22.5 months, respectively. Positive biopsy sites were in the anterior base in five patients, posterior base in one patient and seminal vesicles in two patients. These regions corresponded precisely to the underdosed area at 574
dosimetry 1 month after initial LDR-BT. No anatomical variations, such as protruding median lobe, were observed in any of these cases. The number of positive cores ranged from 1 to 3 (median 2), located exclusively in the base (6 patients) and seminal vesicles (2 patients). The maximum cancer length ranged from 1 to 14 mm (median 7 mm). Only a mild radiation effect was noted histologically, as defined by Crook et al.12 Assigned Gleason scores were 6–7. MRI was carried out in six patients after histological confirmation of recurrence. In five of those six patients, MRI findings showed local recurrence of prostate cancer at the base and/or seminal vesicle (Table 2). These tumors typically appeared as low-intensity lesions on T2WI and high-intensity lesions on DWI, ranging from 10 to 18 mm in size. All of these lesions were located in underdosed areas with positive biopsy.
Quality assessment of salvage partial LDR-BT The median number of seeds for salvage partial LDR-BT was 50 (range 20–70). The activity of seeds was 0.29–0.33 mCi per seed. All patients tolerated the procedure well and showed decreased PSA (median 14.5% at 7 months) (Fig. 1). Two patients later developed biochemical and clinical progression at 11 and 13 months after salvage partial LDR-BT, respectively. The PSA response persisted in the remaining patients. Time to BCR after the initial LDR-BT in the two patients who developed clinical progression was shorter (18 and 27 months, respectively) than in the other five patients. The median PSADT before BCR was calculated as log × 2 / the slope of the log PSA line (the difference in the 2 log PSA value divided by the time between readings in months). For these patients, the median PSADT before BCR was 13.2 months (range 8.4– 32.3 months). The PSADT was 8.4 and 13.3 months, respectively, for the two patients with disease progression. No significant genitourinary or gastrointestinal toxicity was noted.
Case presentation A 69-year-old man with Gleason score 6, T1cN0M0 prostate cancer (patient no. 4 in Tables 1,2) had undergone initial LDR-BT in August 2004. A CT scan 4 weeks after the implant showed D90 to be 142.3 Gy and V100 to be 89.0%, and showed an underdosed area at the anterior base of the prostate (Fig. 2a). The PSA nadir after LDR-BT was 0.78 ng/mL. BCR was diagnosed in April 2011; the PSA level was 4.18 ng/mL, and one positive core was detected at the right anterior base of the prostate. On MRI, the recurrent tumor appeared as a lowintensity lesion on T2WI, and a high-intensity lesion on DWI at the base (Fig. 2b,c). Salvage partial LDR-BT was carried out in September 2011. The well-defined cold area was re-implanted with 50 seeds of 125-iodine (Fig. 2d). The post-salvage PSA level remained low at 0.06 ng/mL 13 months later. No significant genitourinary or gastrointestinal toxicity was noted.
Discussion Optimal patient selection is critical for the success of salvage therapy after definitive radiotherapy. Identification of candidates has been proposed on the basis of pretreatment clinical and pathological factors, as well as on post-treatment PSA kinetics, such as PSADT.13,14 Stock et al. have analyzed patterns © 2013 The Japanese Urological Association
16 2.12 4.6† 0.35 0.06 0.11† 0.14 0.70 –
14
PSA (ng/mL)
12
38 62 14 13 54 27 3 – 27
10 8 6 4
– + (11 m) – – –
– + (13 m)
Rec after sal BT
Follow up after sal BT (months)
PSA at last follow up (ng/mL)
Salvage partial brachytherapy
2 40
30 20 65 50 30 50 70 – 50
10 20 30 Time after salvage regional LDR-BT (months)
Changes of PSA with time after salvage regional LDR-BT. , Pt3; , Pt4; , Pt5; , Pt6; , Pt7.
, Pt1;
,
70 31 82 85 30 60 82 – 70 Sal BT Sal BT Sal BT Sal BT Sal BT Sal BT Sal BT Surveillance 1 8 7 7 14 6 5 8 7
© 2013 The Japanese Urological Association
†Patient no. 2 and no. 5 were given hormone therapy after the recurrence after salvage partial LDR-BT.
3+3 3+4 4+3 3+4 4+3 3+4 3+3 4+3 Rt SV Ant base Ant base Ant base Post base Lt SV Ant base Ant base 1/12 2/22 1/23 1/22 3/22 1/22 2/22 2/22 – NA + + NA + + + 13.1 8.4 18.4 10.3 13.3 16.4 32.3 9.0 13.2 3.90 2.88 3.10 4.18 4.39 3.41 3.92 3.13 3.66 1 2 3 4 5 6 7 8 Median
60 18 65 80 27 57 70 36 58.5
Biopsy Gleason score Biopsy positive location Biopsy cores no. positive/total MRI finding T2W and DW PSADT (months)
Fig. 1 Pt2;
PSA at BCR (ng/mL)
Time to BCR (months)
0
Patients
Table 2
Clinicopathological findings of patients with local recurrence after 125-iodine LDR-BT-based radiotherapy
Biopsy maximum cancer length (mm)
Tx after BCR
Time to sal BT after initial BT (months)
Sal BT, number of seeds
0
of failure after LDR-BT for localized prostate cancer,13 and suggested that time to BCR, Gleason score and PSADT were all predictive of distant metastases.13 Local therapy should be indicated for those with the highest probability of purely localized recurrence. Lee et al. reported that ideal candidates for salvage local therapy meet the following criteria: (i) low risk at initial treatment and prediagnostic PSA velocity 12 months and low absolute PSA value before initiating salvage local therapy (
