- Email: [email protected]
Successful Treatment of Incidental Prostate Cancer by Radical Transurethral Resection of Prostate Cancer
Original Study
Successful Treatment of Incidental Prostate Cancer by Radical Transurethral Resection of Prostate Cancer Masaru Morita,1 Takeshi Matsuura2 Abstract It often seems difficult to decide how to manage patients with incidental prostate cancer. We analyzed our patients who underwent radical transurethral resection of prostate cancer (RTUR-PCa) and obtained satisfactory results that suggested RTUR-PCa could be an option for radical treatment against incidental cancer. Background: To evaluate the rationale for RTUR-PCa against pT1a/b cancer, we analyzed oncological and functional outcomes. Patients and Methods: Fifty-six patients with incidental prostate cancer were included and the age ranged from 66 to 91 years (mean, 76.6; median, 75.0). Preoperative prostate specific antigen (PSA) levels were between 0.70 and 44.1 ng/mL (mean, 5.90; median, 4.60). We performed 69 RTUR-PCa’s by resecting and fulgurating the residual prostate tissues after previous transurethral resection of the prostate. Prostate specific antigen nonrecurrence rate was calculated by Kaplan–Meier method. Results: Follow-up duration of 51 patients was mean ⫾ SD 64.1 ⫾ 21.6 months (median, 67.8 months; range, 13.8-99.8) excluding 5 patients that were lost to follow-up. Prostate specific antigen failure developed in 3 patients (5.9%). In the other 48 patients, PSA stabilized as follows: PSA ⱕ 0.01, 24 cases; ⱕ 0.02, 5 cases; ⱕ 0.03, 6 cases; ⱕ 0.04, 3 cases; ⱕ 0.1, 7 cases; and ⱕ 0.4, 3 cases. Prostate specific antigen nonrecurrence rates were 100% for pT2a and 91.3% for pT2b at the mean follow-up period of 64.1 months. Nonrecurrence rate grouped by D’Amico classification system were 100% in the low-risk group, 94.7% in the intermediate-risk group, and 88.2% in the high-risk group, respectively. Water intoxication did not develop and no patients required transfusion. Bladder neck contracture, which developed in 22 out of 51 patients (43.1%), was the most frequent postoperative complication. Postoperative incontinence was temporary and disappeared within 3 months in all patients. Conclusion: Satisfactory oncologic and functional results suggest that RTUR-PCa could be a promising option for radical treatment against incidental prostate cancer. Clinical Genitourinary Cancer, Vol. 11, No. 2, 94-9 © 2013 Elsevier Inc. All rights reserved. Keywords: Focal TUR-PCa, Incidental cancer, Radical TUR-PCa, T1a/b prostate cancer, TURP
Introduction Urologists might often believe it is difficult to manage patients with incidental prostate cancer (PCa), given several therapeutic options such as radical therapy, hormone therapy, or watchful waiting. Incidental cancer is usually low-grade, small-volume, and sometimes pT0, but such cancer might also have a risk to be progressive. What is more important, precise pathologic evaluation of cancer foci is also
1
Kounaizaka Clinic, Kochi, Japan Department of Urology, Matsubara Tokushukai Hospital, Osaka, Japan
2
Submitted: Aug 13, 2012; Revised: Sep 24, 2012; Accepted: Sep 26, 2012; Epub: Nov 6, 2012 Address for correspondence: Masaru Morita, MD, PhD, Kounaizaka Clinic, 1917-3 Asakura-Hei, Kochi 780-8063, Japan E-mail contact: [email protected]
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difficult especially in the peripheral zone where prostate cancer mainly arises, because the central and transition zones are the main targets of transurethral resection of the prostate (TURP) for benign prostate hyperplasia (BPH).1 In the tumor-nodes-metastasis (TNM) classification of 1997,2 T1 was subdivided into T1a (ⱕ 5% of tissue in resection for benign disease has cancer) and T1b (⬎ 5% of tissue in resection for benign disease has cancer, or poorly differentiated) based on a report published 30 years ago.3 Some recent reports mention that radical treatment is not necessary in patients with T1a disease, especially in patients 60 years or older,4 and it should be indicated only in patients younger than 60 years, namely in patients with expected survival of 10 years or more and in patients with T1b disease that can be progressive.5 On the other hand, other reports mention that the method of treatment should be decided based on the prostate specific antigen
1558-7673/$ - see frontmatter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2012.09.012
(PSA) values before and after TURP and Gleason scores (GS) because the decision could be difficult based on the T1a or T1b classification, and the reports also state that the staging system might need reassessment.6-8 There are other studies that investigated predictors for successful results in patients treated with radical prostatectomy for incidental cancer.6,9 Despite the controversial staging system of T1a and T1b, European Association of Urology (EAU) guidelines of 201210 still adopt the TNM classification system of 1997 and 2009. Patients with incidental cancer who are to receive radical prostatectomy must be informed preoperatively that oncologic outcome might be superior but functional outcome might be inferior compared with the patients with no history of TURP.11-15 Our transurethral radical approach against localized prostate cancer is specified because it is less invasive compared with radical prostatectomy.16,17 We here report the oncologic and functional outcomes of radical transurethral resection of prostate cancer (RTUR-PCa) against incidental prostate cancer.
Patients and Methods Patient Characteristics Between December 2005 and April 2009, a total of 69 RTURPCa were performed under spinal anesthesia in 56 patients who had been diagnosed to have incidental prostate cancer after TURP for BPH. We primarily take a policy to follow patients with T1 cancer by regular PSA measurement. The candidates of the present study include patients whose PSA became elevated during the follow-up periods with or without hormone therapy and patients who hoped to undertake radical surgical therapy instead of hormonal therapy or watchful waiting. We informed the patients that the procedure was not a standard radical surgery, and those who did not agree with the procedure were excluded from the study. We also excluded patients who might not tolerate standard TURP because of underlying diseases. Patients who provided written informed consent were eligible to participate in the transurethral resection of prostate cancer (TUR-PCa) program, which was approved by the institutional review board after a preliminary study. Patients ranged from 66 to 91 years old (mean ⫾ SD, 76.6 ⫾ 5.0; median, 75.0) and preoperative PSA, 0.70 to 44.1 (mean ⫾ SD, 5.90 ⫾ 6.25; median, 4.60). Seven patents were diagnosed to have T1a disease and 49 patients, T1b (TNM classification of 1997). After the diagnosis of incidental PCa, 38 patients with T1b disease were taking hormone therapy using chlormadinone acetate for a mean period of 87 weeks with the longest period being 12 years. Fifty-one patients were included in the present study excluding 5 patients who were lost to follow-up. We preoperatively performed ultrasound-guided transrectal biopsy taking 14 samples because our procedure needed precise information about cancer localization.
Operative Procedure One authorized urologist (M.M.) performed all the surgeries. We used a standard TURP setup with an irrigation pressure of 80 cm H2O and an irrigation rate of 250 mL per minute using D-sorbitol solution. We tried to resect and fulgurate the residual peripheral zone completely, especially where cancer was detected by biopsy. We continued the resection until adipose tissue, venous sinus, or the external sphincter was identified. Instead of resecting more deeply, we aggressively fulgurated the prostate bed next to the area where adipose
tissue or venous sinus was exposed because the remaining prostate tissue could be a thin layer there. We especially paid attention not to distend the bladder too much preventing a high irrigation pressure and a resultant transurethral resection (TUR) syndrome. Special attention was also paid to avoid injuries to Santorini’s plexus and the rectum. The procedure was started from the 12 o’clock position, dividing the prostate into 6 parts, and resected specimens were collected separately to examine the distribution of cancer. The seminal vesicle was partially resected at its attached part to the prostate between the 4 and 8 o’clock positions to determine the invasion of cancer. The verumontanum was finally resected to achieve complete resection.
Follow-Up Postoperative PSA was measured every 2 months starting 2 months after the surgery. PSA failure was suspected when PSA showed a consecutive rise more than 0.2 ng/mL. If the PSA level reached a plateau between 0.2 and 1.0 ng/mL, we did not immediately think treatment failure had occurred in these patients. These were also applied to the indication of the second RTUR-PCa. We evaluated stress urinary incontinence by asking patients about the postoperative status of urinary leak on cough or sneeze and needs for urinary pads.
Results Overall Follow-Up Results Out of 56 patients, the mean follow-up period of 51 patients was 64.1 ⫾ 21.6 (mean ⫾ SD) months (median, 67.8; range, 13.8-99.8 months). The mean operation time was 74 minutes (range, 60-90 minutes) and the mean resected weight was 8.7 g (range, 4-17 g). The preoperative mean PSA value was 5.90 ⫾ 6.25 ng/mL (median, 4.60; range, 0.70-44.1 ng/mL) with 2 patients of unknown PSA. Of 5 patients who were lost to follow-up, 4 patients went to other hospitals and 1 refused the second transurethral surgery. Pathologic stages and GS were as follows: pT2a, 27 cases; pT2b, 23 cases; pT3, 1 case (Table 1), and GS 5, 3 cases; GS 6, 15 cases; GS 7, 19 cases; GS 8,7 cases; and GS 9, 7 cases (Table 2). Five patients died 14 to 79 months (mean, 35.8 months) after the surgery with low PSA values of 0.001 to 0.054 ng/mL. The causes of death were myelodysplastic syndrome, malignant lymphoma, cerebrovascular accident, pneumonia, and cardiac arrest. No patient died of prostate cancer.
Second Surgery Thirty-nine patients with incidental PCa had low and stable PSA after the first RTUR-PCa. The second surgery was performed in 11 patients after a mean period of 20.6 months (range, 9-33 months). No cancer was detected by pathologic examination in 2 patients. The second surgery was necessary in 8 (31.8%) of 21 patients before May 2006 but 3 (10.0%) of 30 patients after that time, suggesting a learning curve effect.
Latest Clinical Results and Nonrecurrent Rate Prostate specific antigen finally stabilized in 48 patients (94.1%) as follows: PSA ⱕ 0.01 ng/mL, 24 patients; ⱕ 0.02, 5 patients; ⱕ 0.03, 6 patients; ⱕ 0.04, 3 patients; ⱕ 0.1, 7 patients; and ⱕ 0.4, 3 patients. Prostate specific antigen failure was diagnosed in 3 patients: 2 patients with pT2b disease and 1 patient with pT3. Prostate spe-
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Treatment of T1a/b Prostate Cancer by Radical TUR Table 1 Results of RTUR-PCa Grouped by Pathologic Stage Total Patients Pathologic Stage
Patients Treated With 1 Surgery Patients With Stable PSA After TUR Patients, Patients, Latest PSA/Mean (ⴞSD)/ n n Median (Range)
Patients Treated With 2 Surgeries Patients With Stable PSA After TUR PSA Patients, Patients, Latest PSA/Mean (ⴞSD)/ Failure, n n n Median (Range)
Patients, n
Preoperative PSA, Mean (ⴞSD)/Median (Range)
pT2a
27
4.90 (2.88)/4.65 (0.70-11.60)
22
22
0.038 (0.081)/0.009 (0.001-0.319)
0
pT2b
23
7.01 (8.64)/4.47 (1.40-44.10)
17
17
0.023 (0.026)/0.013 (0.001-0.085)
0
pT3
1
7.3
1
1
—
1
5
PSA Failure, n
5
0.068 (0.097)/0.021 (0.003-0.258)
0
6
4
0.032 (0.032)/0.018 (0.005-0.087)
2
—
—
—
—
PSA, prostate specific antigen; RTUR-PCa, radical transurethral resection of prostate cancer; TUR, transurethral resection.
Table 2 Results of RTUR-PCa Grouped by Gleason Score Total Patients Gleason Score
Patients Treated With 1 Surgery
Patients Treated With 2 Surgeries
Patients With Stable PSA After TUR
Patients With Stable PSA After TUR
Patients, Preoperative PSA, Mean Patients, Patients, n (ⴞSD)/Median (Range) n n
Latest PSA/Mean (ⴞSD)/ Median (Range)
Latest PSA/Mean (ⴞSD)/ Median (Range)
PSA Failure, n
5
3
4.32 (3.24)/2.17 (1.90-8.90)
2
2
0.009 (0.007)/0.009 (0.002-0.016)
0
1
1
0.013
0
6
15
3.96 (1.74)/3.90 (1.50-7.30)
12
12
0.040 (0.066)/0.021 (0.001-0.253)
0
3
3
0.037 (0.036)/0.021 (0.003-0.087)
0
7
19
6.25 (3.47)/5.70 (1.40-14.90)
15
15
0.015 (0.022)/0.005 (0.001-0.074)
0
4
3
0.010 (0.009)/0.005 (0.003-0.022)
1
8
7
3.81 (2.04)/4.33 (0.70-7.30)
6
5
0.004 (0.004)/0.002 (0.001-0.012)
1
1
0
—
1
9
7
11.95 (13.36)/6.50 (3.50-44.10)
5
5
0.093 (0.116)/0.033 (0.001-0.319)
0
2
2
0.156 (0.102)/0.156 (0.054-0.258)
0
cific antigen nonrecurrent rates were 100.0% in pT2a and 91.3% in pT2b at a mean postoperative follow-up period of 64.1 months (Figure 1). Nonrecurrence rates according to D’Amico’s risk group18 were 100.0% in the low-risk group (stage T1c, T2a, and PSA level ⱕ 10 ng/mL and Gleason score ⱕ 6; 15 patients), 94.7% in the intermediate-risk group (stage T2b or Gleason score of 7 or 10 ⬍ PSA level ⱕ 20 ng/mL; 19 patients) and 88.2% in the high-risk group (stage T2c or PSA level ⬎ 20 ng/mL or Gleason score ⱖ 8; 17 patients) (Figure 2). The patient with a high preoperative PSA value of 44.1 ng/mL had urinary retention at the time of PSA measurement and pathologic stage was pT2b. He has a low PSA value of 0.001 ng/mL at 51 months.
Complications Approximately half of the patients experienced stress urinary incontinence immediately after the removal of a balloon catheter on the third postoperative day. Incontinence gradually improved and disappeared at 3 months postoperatively. Bladder neck contracture developed in 22 patients (43.1%) usually 3 to 4 months after the surgery. Other complications were rectourethral fistula in 1 case and acute epididymitis in 1 case. Erectile function was not evaluated because many of the patients were taking hormonal therapy after the diagnosis of incidental prostate cancer.
Discussion There appears to be some important issues that must be solved concerning the treatment of incidental prostate cancer. Incidental cancer might have a tendency to lead overdiagnosis and overtreatment, so as is cancer found by PSA mass screening. Moreover, surgical treatment, either open or laparoscopic prostatectomy, is technically more difficult in patients after TURP.11-15 In the present
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PSA Patients, Patients, Failure, n n n
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study, the surgical procedure could be completed only by resecting and fulgurating the residual peripheral zone after previous TURP. The procedure seems less invasive judging from a mean surgery time of 74 minutes and the fact that no patient needed transfusion, and it can be applied to elderly patients. As RTUR-PCa is a repeatable procedure, then theoretically, cancer foci are possible to be eradicated and the procedure is also a low-cost one. Some urologists tend to choose watchful waiting or active surveillance19,20 to avoid issues about overdiagnosis and overtreatment related to PSA screening. The policy, however, has not be accepted widely so far. Patients might hope to be treated with a standard treatment because of the fear of having cancer. Because RTUR-PCa might be less invasive and have low occurrence rate of postoperative incontinence, it might be possible to solve the problems of overdiagnosis and overtreatment relevant to incidental prostate cancer as well as PSA screening. In addition, PSA nonrecurrence rate of the present procedure was comparable to the reports of other surgical treatment12-15 at the mean follow-up period of 64.1 months (median, 67.8 months). Dissemination of cancer cells during TUR-PCa is another disputable point and remains to be solved.21-24 Considering our clinical results of RTUR-PCa with a mean follow-up period of 5.3 years (the longest, 8.3 years in 1 case), dissemination of cancer cells might be minimum or almost ignored though longer follow-up period with more patients will be necessary to obtain a definite conclusion. Continence rate after radical prostatectomy of T1a and T1b patients are reported between 86% and 93%, which is not statistically significant compared with the continence rate of other stages.11-15 During our transurethral surgery, we can clearly identify the external sphincter and minimize the injury to the supporting structures surrounding the prostate. Incontinence after RTUR-PCa was tempo-
Masaru Morita, Takeshi Matsuura Figure 1 Actuarial Biochemical Nonrecurrence Rate of Each Pathologic Stage
Non-Recurrence Rate (Pathological stage) pT2a
93M 1.0
1.0 pT2b
24M 0.96
0.9
99M 0.91
55M 0.91
0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1
N = 27 (pT2a) N = 23 (pT2b) 10
20
30
40 50 60 70 Time after Operation (months)
80
90
100
Figure 2 Actuarial Biological Nonrecurrence Rate of Each Risk Group
99M 1.0
Non-Recurrence Rate (Risk group) Low-risk group
1.0 0.9
55M 0.95
12M 0.94 24M 0.88
0.8
93M Intermediate-risk group 0.95 High-risk group 93M 0.88
0.7 0.6 0.5 0.4 0.3 0.2 0.1
N = 15 (Low-risk group) N = 19 (Intermediate-risk group) N = 17 (High-risk group) 10
20
30
40 50 60 70 Time after Operation (months)
rary and disappeared within 3 months in all patients and the frequency can be theoretically considered as same as that of TURP for BPH, which is reported to be 0.4% to 3.3%.25,26 Extravasation of irrigation fluid is sure to occur during the operation, but no patients experienced water intoxication or electrolyte abnormality with lower irrigation pressure, and no patients needed blood transfusion. These suggest that the procedure can be performed safely, but much safer surgery is possible with a bipolar TUR system using saline as an irrigation fluid. The most
80
90
100
frequent postoperative complication was bladder neck contracture that occurred in 43.1% of patients 3 to 4 months after surgery (grade IIIa by Clavien classification). This had been anticipated because of aggressive bladder neck resection to achieve radicality. It was easily treated by optical urethrotomy under caudal block on a day surgery basis. Erectile function cannot be evaluated because of preoperative antiandrogen treatment. We previously reported that erectile function was preserved in 67.7% of patients by our procedure.16 Neurovascular bundle reserving
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Treatment of T1a/b Prostate Cancer by Radical TUR TUR to preserve erectile function might be possible by less aggressive resection at the 4 and/or 8 o’clock position based on biopsy information,27 because TUR-PCa is possible to repeat if postoperative PSA starts to rise. Other postoperative complications that we experienced were 1 case (1.8%) of rectourethral fistula and 1 case (1.8%) of acute epididymitis. There are many reports of perioperative complications relating to prostate surgery. Many reported complications of TURP for BPH are as follows: erectile problems (10%), bladder neck contracture/stricture (1.5%-7.0%), significant hematuria (6%), infection (0.49%-6.0%), transfusion (3.9%-8.0%), and mortality (0.2%).25,26,28 The following are reported as complications of open prostatectomy for prostate cancer: erectile dysfunction (21.9%100%), rectourethral fistula (1.5%-2.1%), bladder neck stricture (1.2%-9.1%), urine leakage (6.0%-26.1%), lymphocele (1.0%7.3%), transfusion/major bleeding (3.0%-6.6%) and mortality (0%2.1%).11-14,29 According to the data of the Healthcare Cost and Utilization Project,30 mean charge of open prostatectomy for prostate cancer (number of discharges, 74,006; mean age, 61) and TURP for BPH (number of discharges, 41,790; mean age, 72) are $38,187 and $21,203, respectively. Frequency of the above complications might be acceptable and both procedures can be performed safely. However, transurethral procedure compared with open prostatectomy appears less invasive and cost-effective by such reasons as no need for general anesthesia, less severe complications, lower cost, and no need for specific devices. The standard to treat T1 cancer seems greatly different among institutions though most of the patients with T1 cancer have a lowstage disease. We take a surveillance policy with regular PSA measurement and we usually select a hormone therapy in patients who want anticancer therapy. The present study, therefore including many patients who were taking hormone therapy preoperatively, might not be a well-designed one and the effect of chlormadinone acetate on postoperative PSA must be considered. We could not find any reports that describe the duration of the suppressive effect of chlormadinone acetate in patients with prostate cancer. In patients with prostate hyperplasia and taking 50 mg per day of chlormadinone acetate for 16 weeks, PSA levels are reported to return to the baseline levels 32 weeks after discontinuation.31 In the present study the effect of preoperative hormone therapy on the most recent PSA levels can be minimal or negligible.
Conclusion Treatment of incidental cancer diagnosed after surgery for BPH has some specific issues to be considered. Radical open surgery can be technically more difficult in patients with previous surgery. Our procedure, RTUR-PCa, is thought to be less invasive and we obtained a satisfactory PSA nonrecurrence rate. Prolonged stress incontinence was not observed. RTUR-PCa can be an option for radical surgical treatment against incidental prostate cancer.
Clinical Practice Points ●
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Management of patients with incidental prostate cancer seems difficult because it is usually low-grade, small-volume, but such cancer also has a risk to be progressive.
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●
●
●
●
●
Radical prostatectomy might result in superior oncologic outcome but inferior functional outcome compared with the patients with no history of TURP. Our transurethral radical approach against localized prostate cancer is specified because it is less invasive compared with radical prostatectomy. Prostate specific antigen nonrecurrence rate using the present procedure was comparable with the reports of other surgical treatment. The most frequent postoperative complication was bladder neck contracture (43.1%, grade IIIa by Clavien classification), which is treated easily by cold incision of the bladder neck. Prolonged stress incontinence was not observed. RTUR-PCa can be an option for radical surgical treatment against incidental prostate cancer with a lower rate of complications.
Disclosure The authors have stated that they have no conflicts of interest.
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Successful Treatment of Incidental Prostate Cancer by Radical Transurethral Resection of Prostate Cancer Masaru Morita,1 Takeshi Matsuura2 Abstract It often seems difficult to decide how to manage patients with incidental prostate cancer. We analyzed our patients who underwent radical transurethral resection of prostate cancer (RTUR-PCa) and obtained satisfactory results that suggested RTUR-PCa could be an option for radical treatment against incidental cancer. Background: To evaluate the rationale for RTUR-PCa against pT1a/b cancer, we analyzed oncological and functional outcomes. Patients and Methods: Fifty-six patients with incidental prostate cancer were included and the age ranged from 66 to 91 years (mean, 76.6; median, 75.0). Preoperative prostate specific antigen (PSA) levels were between 0.70 and 44.1 ng/mL (mean, 5.90; median, 4.60). We performed 69 RTUR-PCa’s by resecting and fulgurating the residual prostate tissues after previous transurethral resection of the prostate. Prostate specific antigen nonrecurrence rate was calculated by Kaplan–Meier method. Results: Follow-up duration of 51 patients was mean ⫾ SD 64.1 ⫾ 21.6 months (median, 67.8 months; range, 13.8-99.8) excluding 5 patients that were lost to follow-up. Prostate specific antigen failure developed in 3 patients (5.9%). In the other 48 patients, PSA stabilized as follows: PSA ⱕ 0.01, 24 cases; ⱕ 0.02, 5 cases; ⱕ 0.03, 6 cases; ⱕ 0.04, 3 cases; ⱕ 0.1, 7 cases; and ⱕ 0.4, 3 cases. Prostate specific antigen nonrecurrence rates were 100% for pT2a and 91.3% for pT2b at the mean follow-up period of 64.1 months. Nonrecurrence rate grouped by D’Amico classification system were 100% in the low-risk group, 94.7% in the intermediate-risk group, and 88.2% in the high-risk group, respectively. Water intoxication did not develop and no patients required transfusion. Bladder neck contracture, which developed in 22 out of 51 patients (43.1%), was the most frequent postoperative complication. Postoperative incontinence was temporary and disappeared within 3 months in all patients. Conclusion: Satisfactory oncologic and functional results suggest that RTUR-PCa could be a promising option for radical treatment against incidental prostate cancer. Clinical Genitourinary Cancer, Vol. 11, No. 2, 94-9 © 2013 Elsevier Inc. All rights reserved. Keywords: Focal TUR-PCa, Incidental cancer, Radical TUR-PCa, T1a/b prostate cancer, TURP
Introduction Urologists might often believe it is difficult to manage patients with incidental prostate cancer (PCa), given several therapeutic options such as radical therapy, hormone therapy, or watchful waiting. Incidental cancer is usually low-grade, small-volume, and sometimes pT0, but such cancer might also have a risk to be progressive. What is more important, precise pathologic evaluation of cancer foci is also
1
Kounaizaka Clinic, Kochi, Japan Department of Urology, Matsubara Tokushukai Hospital, Osaka, Japan
2
Submitted: Aug 13, 2012; Revised: Sep 24, 2012; Accepted: Sep 26, 2012; Epub: Nov 6, 2012 Address for correspondence: Masaru Morita, MD, PhD, Kounaizaka Clinic, 1917-3 Asakura-Hei, Kochi 780-8063, Japan E-mail contact: [email protected]
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difficult especially in the peripheral zone where prostate cancer mainly arises, because the central and transition zones are the main targets of transurethral resection of the prostate (TURP) for benign prostate hyperplasia (BPH).1 In the tumor-nodes-metastasis (TNM) classification of 1997,2 T1 was subdivided into T1a (ⱕ 5% of tissue in resection for benign disease has cancer) and T1b (⬎ 5% of tissue in resection for benign disease has cancer, or poorly differentiated) based on a report published 30 years ago.3 Some recent reports mention that radical treatment is not necessary in patients with T1a disease, especially in patients 60 years or older,4 and it should be indicated only in patients younger than 60 years, namely in patients with expected survival of 10 years or more and in patients with T1b disease that can be progressive.5 On the other hand, other reports mention that the method of treatment should be decided based on the prostate specific antigen
1558-7673/$ - see frontmatter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2012.09.012
(PSA) values before and after TURP and Gleason scores (GS) because the decision could be difficult based on the T1a or T1b classification, and the reports also state that the staging system might need reassessment.6-8 There are other studies that investigated predictors for successful results in patients treated with radical prostatectomy for incidental cancer.6,9 Despite the controversial staging system of T1a and T1b, European Association of Urology (EAU) guidelines of 201210 still adopt the TNM classification system of 1997 and 2009. Patients with incidental cancer who are to receive radical prostatectomy must be informed preoperatively that oncologic outcome might be superior but functional outcome might be inferior compared with the patients with no history of TURP.11-15 Our transurethral radical approach against localized prostate cancer is specified because it is less invasive compared with radical prostatectomy.16,17 We here report the oncologic and functional outcomes of radical transurethral resection of prostate cancer (RTUR-PCa) against incidental prostate cancer.
Patients and Methods Patient Characteristics Between December 2005 and April 2009, a total of 69 RTURPCa were performed under spinal anesthesia in 56 patients who had been diagnosed to have incidental prostate cancer after TURP for BPH. We primarily take a policy to follow patients with T1 cancer by regular PSA measurement. The candidates of the present study include patients whose PSA became elevated during the follow-up periods with or without hormone therapy and patients who hoped to undertake radical surgical therapy instead of hormonal therapy or watchful waiting. We informed the patients that the procedure was not a standard radical surgery, and those who did not agree with the procedure were excluded from the study. We also excluded patients who might not tolerate standard TURP because of underlying diseases. Patients who provided written informed consent were eligible to participate in the transurethral resection of prostate cancer (TUR-PCa) program, which was approved by the institutional review board after a preliminary study. Patients ranged from 66 to 91 years old (mean ⫾ SD, 76.6 ⫾ 5.0; median, 75.0) and preoperative PSA, 0.70 to 44.1 (mean ⫾ SD, 5.90 ⫾ 6.25; median, 4.60). Seven patents were diagnosed to have T1a disease and 49 patients, T1b (TNM classification of 1997). After the diagnosis of incidental PCa, 38 patients with T1b disease were taking hormone therapy using chlormadinone acetate for a mean period of 87 weeks with the longest period being 12 years. Fifty-one patients were included in the present study excluding 5 patients who were lost to follow-up. We preoperatively performed ultrasound-guided transrectal biopsy taking 14 samples because our procedure needed precise information about cancer localization.
Operative Procedure One authorized urologist (M.M.) performed all the surgeries. We used a standard TURP setup with an irrigation pressure of 80 cm H2O and an irrigation rate of 250 mL per minute using D-sorbitol solution. We tried to resect and fulgurate the residual peripheral zone completely, especially where cancer was detected by biopsy. We continued the resection until adipose tissue, venous sinus, or the external sphincter was identified. Instead of resecting more deeply, we aggressively fulgurated the prostate bed next to the area where adipose
tissue or venous sinus was exposed because the remaining prostate tissue could be a thin layer there. We especially paid attention not to distend the bladder too much preventing a high irrigation pressure and a resultant transurethral resection (TUR) syndrome. Special attention was also paid to avoid injuries to Santorini’s plexus and the rectum. The procedure was started from the 12 o’clock position, dividing the prostate into 6 parts, and resected specimens were collected separately to examine the distribution of cancer. The seminal vesicle was partially resected at its attached part to the prostate between the 4 and 8 o’clock positions to determine the invasion of cancer. The verumontanum was finally resected to achieve complete resection.
Follow-Up Postoperative PSA was measured every 2 months starting 2 months after the surgery. PSA failure was suspected when PSA showed a consecutive rise more than 0.2 ng/mL. If the PSA level reached a plateau between 0.2 and 1.0 ng/mL, we did not immediately think treatment failure had occurred in these patients. These were also applied to the indication of the second RTUR-PCa. We evaluated stress urinary incontinence by asking patients about the postoperative status of urinary leak on cough or sneeze and needs for urinary pads.
Results Overall Follow-Up Results Out of 56 patients, the mean follow-up period of 51 patients was 64.1 ⫾ 21.6 (mean ⫾ SD) months (median, 67.8; range, 13.8-99.8 months). The mean operation time was 74 minutes (range, 60-90 minutes) and the mean resected weight was 8.7 g (range, 4-17 g). The preoperative mean PSA value was 5.90 ⫾ 6.25 ng/mL (median, 4.60; range, 0.70-44.1 ng/mL) with 2 patients of unknown PSA. Of 5 patients who were lost to follow-up, 4 patients went to other hospitals and 1 refused the second transurethral surgery. Pathologic stages and GS were as follows: pT2a, 27 cases; pT2b, 23 cases; pT3, 1 case (Table 1), and GS 5, 3 cases; GS 6, 15 cases; GS 7, 19 cases; GS 8,7 cases; and GS 9, 7 cases (Table 2). Five patients died 14 to 79 months (mean, 35.8 months) after the surgery with low PSA values of 0.001 to 0.054 ng/mL. The causes of death were myelodysplastic syndrome, malignant lymphoma, cerebrovascular accident, pneumonia, and cardiac arrest. No patient died of prostate cancer.
Second Surgery Thirty-nine patients with incidental PCa had low and stable PSA after the first RTUR-PCa. The second surgery was performed in 11 patients after a mean period of 20.6 months (range, 9-33 months). No cancer was detected by pathologic examination in 2 patients. The second surgery was necessary in 8 (31.8%) of 21 patients before May 2006 but 3 (10.0%) of 30 patients after that time, suggesting a learning curve effect.
Latest Clinical Results and Nonrecurrent Rate Prostate specific antigen finally stabilized in 48 patients (94.1%) as follows: PSA ⱕ 0.01 ng/mL, 24 patients; ⱕ 0.02, 5 patients; ⱕ 0.03, 6 patients; ⱕ 0.04, 3 patients; ⱕ 0.1, 7 patients; and ⱕ 0.4, 3 patients. Prostate specific antigen failure was diagnosed in 3 patients: 2 patients with pT2b disease and 1 patient with pT3. Prostate spe-
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Treatment of T1a/b Prostate Cancer by Radical TUR Table 1 Results of RTUR-PCa Grouped by Pathologic Stage Total Patients Pathologic Stage
Patients Treated With 1 Surgery Patients With Stable PSA After TUR Patients, Patients, Latest PSA/Mean (ⴞSD)/ n n Median (Range)
Patients Treated With 2 Surgeries Patients With Stable PSA After TUR PSA Patients, Patients, Latest PSA/Mean (ⴞSD)/ Failure, n n n Median (Range)
Patients, n
Preoperative PSA, Mean (ⴞSD)/Median (Range)
pT2a
27
4.90 (2.88)/4.65 (0.70-11.60)
22
22
0.038 (0.081)/0.009 (0.001-0.319)
0
pT2b
23
7.01 (8.64)/4.47 (1.40-44.10)
17
17
0.023 (0.026)/0.013 (0.001-0.085)
0
pT3
1
7.3
1
1
—
1
5
PSA Failure, n
5
0.068 (0.097)/0.021 (0.003-0.258)
0
6
4
0.032 (0.032)/0.018 (0.005-0.087)
2
—
—
—
—
PSA, prostate specific antigen; RTUR-PCa, radical transurethral resection of prostate cancer; TUR, transurethral resection.
Table 2 Results of RTUR-PCa Grouped by Gleason Score Total Patients Gleason Score
Patients Treated With 1 Surgery
Patients Treated With 2 Surgeries
Patients With Stable PSA After TUR
Patients With Stable PSA After TUR
Patients, Preoperative PSA, Mean Patients, Patients, n (ⴞSD)/Median (Range) n n
Latest PSA/Mean (ⴞSD)/ Median (Range)
Latest PSA/Mean (ⴞSD)/ Median (Range)
PSA Failure, n
5
3
4.32 (3.24)/2.17 (1.90-8.90)
2
2
0.009 (0.007)/0.009 (0.002-0.016)
0
1
1
0.013
0
6
15
3.96 (1.74)/3.90 (1.50-7.30)
12
12
0.040 (0.066)/0.021 (0.001-0.253)
0
3
3
0.037 (0.036)/0.021 (0.003-0.087)
0
7
19
6.25 (3.47)/5.70 (1.40-14.90)
15
15
0.015 (0.022)/0.005 (0.001-0.074)
0
4
3
0.010 (0.009)/0.005 (0.003-0.022)
1
8
7
3.81 (2.04)/4.33 (0.70-7.30)
6
5
0.004 (0.004)/0.002 (0.001-0.012)
1
1
0
—
1
9
7
11.95 (13.36)/6.50 (3.50-44.10)
5
5
0.093 (0.116)/0.033 (0.001-0.319)
0
2
2
0.156 (0.102)/0.156 (0.054-0.258)
0
cific antigen nonrecurrent rates were 100.0% in pT2a and 91.3% in pT2b at a mean postoperative follow-up period of 64.1 months (Figure 1). Nonrecurrence rates according to D’Amico’s risk group18 were 100.0% in the low-risk group (stage T1c, T2a, and PSA level ⱕ 10 ng/mL and Gleason score ⱕ 6; 15 patients), 94.7% in the intermediate-risk group (stage T2b or Gleason score of 7 or 10 ⬍ PSA level ⱕ 20 ng/mL; 19 patients) and 88.2% in the high-risk group (stage T2c or PSA level ⬎ 20 ng/mL or Gleason score ⱖ 8; 17 patients) (Figure 2). The patient with a high preoperative PSA value of 44.1 ng/mL had urinary retention at the time of PSA measurement and pathologic stage was pT2b. He has a low PSA value of 0.001 ng/mL at 51 months.
Complications Approximately half of the patients experienced stress urinary incontinence immediately after the removal of a balloon catheter on the third postoperative day. Incontinence gradually improved and disappeared at 3 months postoperatively. Bladder neck contracture developed in 22 patients (43.1%) usually 3 to 4 months after the surgery. Other complications were rectourethral fistula in 1 case and acute epididymitis in 1 case. Erectile function was not evaluated because many of the patients were taking hormonal therapy after the diagnosis of incidental prostate cancer.
Discussion There appears to be some important issues that must be solved concerning the treatment of incidental prostate cancer. Incidental cancer might have a tendency to lead overdiagnosis and overtreatment, so as is cancer found by PSA mass screening. Moreover, surgical treatment, either open or laparoscopic prostatectomy, is technically more difficult in patients after TURP.11-15 In the present
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PSA Patients, Patients, Failure, n n n
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study, the surgical procedure could be completed only by resecting and fulgurating the residual peripheral zone after previous TURP. The procedure seems less invasive judging from a mean surgery time of 74 minutes and the fact that no patient needed transfusion, and it can be applied to elderly patients. As RTUR-PCa is a repeatable procedure, then theoretically, cancer foci are possible to be eradicated and the procedure is also a low-cost one. Some urologists tend to choose watchful waiting or active surveillance19,20 to avoid issues about overdiagnosis and overtreatment related to PSA screening. The policy, however, has not be accepted widely so far. Patients might hope to be treated with a standard treatment because of the fear of having cancer. Because RTUR-PCa might be less invasive and have low occurrence rate of postoperative incontinence, it might be possible to solve the problems of overdiagnosis and overtreatment relevant to incidental prostate cancer as well as PSA screening. In addition, PSA nonrecurrence rate of the present procedure was comparable to the reports of other surgical treatment12-15 at the mean follow-up period of 64.1 months (median, 67.8 months). Dissemination of cancer cells during TUR-PCa is another disputable point and remains to be solved.21-24 Considering our clinical results of RTUR-PCa with a mean follow-up period of 5.3 years (the longest, 8.3 years in 1 case), dissemination of cancer cells might be minimum or almost ignored though longer follow-up period with more patients will be necessary to obtain a definite conclusion. Continence rate after radical prostatectomy of T1a and T1b patients are reported between 86% and 93%, which is not statistically significant compared with the continence rate of other stages.11-15 During our transurethral surgery, we can clearly identify the external sphincter and minimize the injury to the supporting structures surrounding the prostate. Incontinence after RTUR-PCa was tempo-
Masaru Morita, Takeshi Matsuura Figure 1 Actuarial Biochemical Nonrecurrence Rate of Each Pathologic Stage
Non-Recurrence Rate (Pathological stage) pT2a
93M 1.0
1.0 pT2b
24M 0.96
0.9
99M 0.91
55M 0.91
0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1
N = 27 (pT2a) N = 23 (pT2b) 10
20
30
40 50 60 70 Time after Operation (months)
80
90
100
Figure 2 Actuarial Biological Nonrecurrence Rate of Each Risk Group
99M 1.0
Non-Recurrence Rate (Risk group) Low-risk group
1.0 0.9
55M 0.95
12M 0.94 24M 0.88
0.8
93M Intermediate-risk group 0.95 High-risk group 93M 0.88
0.7 0.6 0.5 0.4 0.3 0.2 0.1
N = 15 (Low-risk group) N = 19 (Intermediate-risk group) N = 17 (High-risk group) 10
20
30
40 50 60 70 Time after Operation (months)
rary and disappeared within 3 months in all patients and the frequency can be theoretically considered as same as that of TURP for BPH, which is reported to be 0.4% to 3.3%.25,26 Extravasation of irrigation fluid is sure to occur during the operation, but no patients experienced water intoxication or electrolyte abnormality with lower irrigation pressure, and no patients needed blood transfusion. These suggest that the procedure can be performed safely, but much safer surgery is possible with a bipolar TUR system using saline as an irrigation fluid. The most
80
90
100
frequent postoperative complication was bladder neck contracture that occurred in 43.1% of patients 3 to 4 months after surgery (grade IIIa by Clavien classification). This had been anticipated because of aggressive bladder neck resection to achieve radicality. It was easily treated by optical urethrotomy under caudal block on a day surgery basis. Erectile function cannot be evaluated because of preoperative antiandrogen treatment. We previously reported that erectile function was preserved in 67.7% of patients by our procedure.16 Neurovascular bundle reserving
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Treatment of T1a/b Prostate Cancer by Radical TUR TUR to preserve erectile function might be possible by less aggressive resection at the 4 and/or 8 o’clock position based on biopsy information,27 because TUR-PCa is possible to repeat if postoperative PSA starts to rise. Other postoperative complications that we experienced were 1 case (1.8%) of rectourethral fistula and 1 case (1.8%) of acute epididymitis. There are many reports of perioperative complications relating to prostate surgery. Many reported complications of TURP for BPH are as follows: erectile problems (10%), bladder neck contracture/stricture (1.5%-7.0%), significant hematuria (6%), infection (0.49%-6.0%), transfusion (3.9%-8.0%), and mortality (0.2%).25,26,28 The following are reported as complications of open prostatectomy for prostate cancer: erectile dysfunction (21.9%100%), rectourethral fistula (1.5%-2.1%), bladder neck stricture (1.2%-9.1%), urine leakage (6.0%-26.1%), lymphocele (1.0%7.3%), transfusion/major bleeding (3.0%-6.6%) and mortality (0%2.1%).11-14,29 According to the data of the Healthcare Cost and Utilization Project,30 mean charge of open prostatectomy for prostate cancer (number of discharges, 74,006; mean age, 61) and TURP for BPH (number of discharges, 41,790; mean age, 72) are $38,187 and $21,203, respectively. Frequency of the above complications might be acceptable and both procedures can be performed safely. However, transurethral procedure compared with open prostatectomy appears less invasive and cost-effective by such reasons as no need for general anesthesia, less severe complications, lower cost, and no need for specific devices. The standard to treat T1 cancer seems greatly different among institutions though most of the patients with T1 cancer have a lowstage disease. We take a surveillance policy with regular PSA measurement and we usually select a hormone therapy in patients who want anticancer therapy. The present study, therefore including many patients who were taking hormone therapy preoperatively, might not be a well-designed one and the effect of chlormadinone acetate on postoperative PSA must be considered. We could not find any reports that describe the duration of the suppressive effect of chlormadinone acetate in patients with prostate cancer. In patients with prostate hyperplasia and taking 50 mg per day of chlormadinone acetate for 16 weeks, PSA levels are reported to return to the baseline levels 32 weeks after discontinuation.31 In the present study the effect of preoperative hormone therapy on the most recent PSA levels can be minimal or negligible.
Conclusion Treatment of incidental cancer diagnosed after surgery for BPH has some specific issues to be considered. Radical open surgery can be technically more difficult in patients with previous surgery. Our procedure, RTUR-PCa, is thought to be less invasive and we obtained a satisfactory PSA nonrecurrence rate. Prolonged stress incontinence was not observed. RTUR-PCa can be an option for radical surgical treatment against incidental prostate cancer.
Clinical Practice Points ●
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Management of patients with incidental prostate cancer seems difficult because it is usually low-grade, small-volume, but such cancer also has a risk to be progressive.
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●
●
●
●
●
Radical prostatectomy might result in superior oncologic outcome but inferior functional outcome compared with the patients with no history of TURP. Our transurethral radical approach against localized prostate cancer is specified because it is less invasive compared with radical prostatectomy. Prostate specific antigen nonrecurrence rate using the present procedure was comparable with the reports of other surgical treatment. The most frequent postoperative complication was bladder neck contracture (43.1%, grade IIIa by Clavien classification), which is treated easily by cold incision of the bladder neck. Prolonged stress incontinence was not observed. RTUR-PCa can be an option for radical surgical treatment against incidental prostate cancer with a lower rate of complications.
Disclosure The authors have stated that they have no conflicts of interest.
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