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Delay of Surgery in Men With Low Risk Prostate Cancer

Delay of Surgery in Men With Low Risk Prostate Cancer

Purpose

Treatment options for patients with low risk prostate cancer include radical prostatectomy, radiation therapy, and active surveillance. Among patients treated with radical prostatectomy, prior studies have demonstrated significantly higher biochemical progression rates with surgical delays of 6 months or greater. We determined the impact of surgical delay on radical prostatectomy outcomes specifically in low risk patients.

Materials and Methods

From our radical prostatectomy database we identified men who fulfilled the D’Amico low risk criteria (clinical stage T1c/T2a, prostate specific antigen less than 10 ng/ml, and biopsy Gleason 6 or less). Pathological tumor features and biochemical progression rates were compared between men with and without surgical delay. We used Cox proportional hazards models to examine predictors of biochemical progression.

Results

Of 1,111 men who fulfilled the D’Amico low risk criteria, those with a surgical delay of 6 months or more were significantly older, had a higher proportion of African American men, and a lower proportion of clinical stage T2a (vs T1). A surgical delay of 6 months or more was associated with a greater risk of high grade disease at prostatectomy (p = 0.001) and biochemical progression (p = 0.04). The progression-free survival rate was significantly lower among men with a surgical delay. On multivariate analysis with prostate specific antigen and clinical stage, surgical delays of 6 months or more were significantly and independently associated with time to biochemical progression.

Conclusions

In men who met the D’Amico low risk criteria, a surgical delay of 6 months or more was associated with significantly worse radical prostatectomy outcomes, including more pathology upgrading and a higher rate of biochemical progression. Low risk patients choosing to defer initial definitive therapy should be counseled regarding the possibility of worse treatment outcomes at a later date.

Key Words: prostatic neoplasms, prostatectomy, disease progression

Abbreviations and Acronyms: ERSPC, European Randomized Study of Screening for Prostate Cancer, PSA, prostate specific antigen, RP, open retropubic radical prostatectomy, SEARCH, Shared Equal Access Regional Cancer Hospital

 

 

Men with a recently diagnosed low risk prostate cancer have many management options, including RP, radiation therapy and active surveillance.1, 2 Although there is evidence from a prospective, randomized clinical trial that RP provides better cancer specific and overall survival than watchful waiting for clinically localized prostate cancer,3, 4 there are no prospective randomized studies comparing the results of surgery to radiation or current active surveillance protocols. The American Urological Association2 and National Comprehensive Cancer Network1 guidelines suggest that all 3 options are reasonable for men with low risk disease.

Among men who ultimately elect to undergo RP, several factors may influence the time from biopsy to treatment. These include increasing initial use of active surveillance protocols, additional staging biopsies, scheduling issues, and time spent on acquiring information about management options.

Data are conflicting regarding the impact of surgical delay on outcomes after radical prostatectomy. Whereas studies from Johns Hopkins,5 Memorial Sloan-Kettering,6 the ERSPC and a population based study from Sweden7 suggest that there are no significant differences in outcomes for men with low risk prostate cancer managed with delayed surgery, a Canadian study8 and recent analyses from the SEARCH database9 suggest an increased risk of biochemical recurrence in men who had surgery greater than 6 months after diagnosis. The aim of our study was to determine the impact of delaying radical prostatectomy for 6 months or more on surgical pathology and biochemical recurrence rates in a contemporary population of men with low risk prostate cancer.

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Methods 

From 1989 to 2009, 1,900 men underwent radical prostatectomy by a single surgeon (WJC), using standardized technique. From this population we identified 1,111 men with D’Amico low risk prostate cancer (biopsy Gleason score 6 or less, clinical stage T2a or less, preoperative PSA 10 ng/ml or less).10 The remaining patients had D’Amico intermediate risk (718 with clinical stage T2b or biopsy Gleason score 7 or preoperative PSA 10 to 20 ng/ml) or high risk disease (71 with clinical stage T2c or greater, or biopsy Gleason 8 or greater, or preoperative PSA greater than 20 ng/ml). We compared pathological tumor features and biochemical recurrence rates (defined as a confirmed serum PSA 0.2 ng/ml or greater) in patients with low risk prostate cancer treated within 6 months of diagnosis vs those with a treatment delay of 6 months or more. The followup protocol included a postoperative serum PSA measurement 1 month after surgery, then every 6 months thereafter.

Student’s t test and the chi-square test were used to compare clinicopathological characteristics between the early and delayed groups. We used Kaplan-Meier curves to examine progression-free survival, and comparisons were made with the log rank test. Finally, multivariable Cox proportional hazards models were used to identify predictors of biochemical progression including the variables PSA (continuous variable), clinical stage (T1 vs greater than T1) and surgical delay (less than 6 vs 6 months or more). Gleason score was not included since all patients by definition had Gleason 6 or less according to the D’Amico low risk criteria. Statistical significance was defined as p <0.05.

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Results 

The clinical and pathology characteristics of the study population are shown in table 1. Of the 1,111 men 1,052 were treated less than 6 months after diagnosis and 59 were treated at 6 months or more. Although preoperative PSA was similar between the groups, men in the delayed surgery group were proportionately older, and a greater proportion was African-American. A greater proportion of men with palpable disease (cT2) were treated within 6 months of diagnosis (p = 0.02).

Table 1. Clinicopathological findings and biochemical recurrence rates
  Surgical Delay Less Than 6 Mos Surgical Delay 6 Mos or More p Value
Mean age 59 61 0.05
% African-American 2.2 6.8 0.05
Mean preop PSA (ng/ml) 4.7 5.0 0.30
% Clinical stage T2 or greater 18.9 6.8 0.02
Mean mos from diagnosis to surgery 2.4 15.6 <0.0001
% Organ confined 90 85 0.27
% Extracapsular extension 9 10 0.80
% Pos surgical margins 10 9 0.99
% Seminal vesicle invasion 1 2 0.48
% Lymph node metastases 0 0
% Prostatectomy Gleason score 7 or greater 27 47 0.001
Mean mos postop followup (range) 43(1–159) 38(1–222) 0.17
% Biochemical recurrence 5 12 0.04

There were no significant differences between the early and delayed surgery groups in the rates of organ confined disease, extracapsular tumor extension, positive surgical margins, seminal vesicle invasion or lymph node metastases. However, a surgical delay of 6 months or more was associated with a significantly greater proportion upgraded to Gleason 7–10. Specifically a prostatectomy Gleason score of 7 or greater was found in 27% of men treated within 6 months vs 47% of those treated 6 months or more after diagnosis (p <0.001).

A delay in surgery of 6 months or more was also associated with a proportionately greater risk of biochemical recurrence, despite a similar followup interval for the groups (p = 0.17). Biochemical recurrence occurred in 5% of men treated within 6 months vs 12% in the delayed surgery group (p = 0.04).

The figure shows the actuarial 5-year progression-free survival curves stratified by the timing of radical prostatectomy. Men were considered progression-free if postoperative PSA had not increased to 0.2 ng/ml or greater at last followup. A surgical delay of 6 months or more was associated with a significantly lower 5-year progression-free survival rate (p = 0.009). Table 2 shows the results of multivariable analysis to predict biochemical recurrence. After controlling for PSA and clinical stage, a surgical delay of 6 months or more was associated with a 2.9-fold increased risk of biochemical recurrence in these low risk patients (p = 0.017).

Table 2. Multivariate Cox model to predict biochemical recurrence
  HR p Value
PSA 1.2 0.024
Clinical stage greater than T1 1.9 0.029
Surgical delay 6 mos or more 2.9 0.017

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Discussion 

A delay from prostate cancer diagnosis to radical prostatectomy may occur for several reasons. A patient with newly diagnosed low risk disease is presented a broad range of potential management options, including surgery, radiotherapy or active surveillance. Even for those who elect radical prostatectomy, delays in surgery may occur as the patient obtains second opinions or from scheduling issues. Other patients choose to defer initial therapy and enroll in active surveillance. However, a proportion of these patients ultimately undergo surgery due to anxiety from living with untreated prostate cancer, increases in PSA, or histological evidence of greater tumor volume or higher grade disease on repeat biopsy.

Surgical delay has been shown to influence treatment outcomes in several types of genitourinary malignancy, including bladder and renal cancers.11, 12 However, low risk prostate cancer has a long natural history and may not impact survival for many years.13 As discussed above, active surveillance protocols have emerged in an attempt to find a balance between quality of life and oncologic control.14 However, the appropriate patient selection for active surveillance may be challenging, and the optimal triggers for intervention during the window for curability are controversial.

Prior studies have examined the relationship between surgical delay and RP outcomes with conflicting results. Nam et al performed a retrospective review of 645 men.8 Using biochemical recurrence and metastasis as end points, men were divided into 2 groups using a shorter time interval than our study (less than 3, or 3 months or more surgical delay). The adjusted analysis suggested a trend toward an increased risk of biochemical progression with surgical delay greater than 3 months (HR 1.46, p = 0.09).

Subsequently a study from Johns Hopkins analyzed 926 men with less stringent inclusion criteria than our study (clinical stage T1c–T3a with no restrictions on PSA or Gleason score).5 The majority (764) of patients in this study had surgery greater than 2 months after diagnosis (including 119 of 764 after 6 months). Using Kaplan-Meier analysis no significant differences in biochemical recurrence rates were observed between the early and late groups. However, there was a significantly higher proportion of clinical stage T1c and Gleason 6 or less disease in the group with the longest surgical delay (more than 150 days), suggesting selection bias in those with surgical delay.

Vickers et al examined a series of 3,149 patients who underwent radical prostatectomy within a year of diagnosis.6 Although the study population included men with poorly differentiated tumors and locally advanced disease, they used a multivariate regression model to control for disease severity. The end point of the study was biochemical recurrence at 3, 5, 8 and 10 years. They found no significant difference in biochemical recurrence rates between men who had surgery at less than 6 months vs 6 to 12 months after diagnosis, although the confidence intervals were wide and there were few patients (20) with surgical delays longer than 9 months.

More recently van den Bergh et al retrospectively compared men from the Swedish arm of the ERSPC with low risk prostate cancer (T1c/T2, PSA less than 10 ng/ml, Gleason 6, 1 to 2 positive biopsies) who chose immediate RP vs those on expectant management who ultimately underwent surgery.15 There was no significant difference in Gleason score, positive margin rate, or biochemical progression rate between the groups. However, there was a nonsignificant trend for a higher rate of capsular perforation by the tumor in the delayed surgery group (OR 2.45, p = 0.091). Nevertheless, there was heterogeneity in the groups, with some men in the immediate group not undergoing surgery for as long as 1 year after diagnosis (range 0.1 to 1.1 year).

In a study using a design similar to our own, Freedland et al examined 895 men from the SEARCH database who met the D’Amico low risk criteria.9 In accordance with prior studies, men with surgical delays of more than 3 months were at similar risk for biochemical recurrence as those with delays less than 3 months (RR 1.1, 95% CI 0.70–1.71). However, delays of greater than 6 months were associated with a significantly higher risk for biochemical recurrence (RR 2.73, 95% CI 1.51–4.94).

Interestingly in our study we did not find a significant difference in biochemical recurrence rates with delays of 3 months or more (data not shown). However, we found a statistically significant 2.9-fold increased risk of biochemical progression in D’Amico low risk patients with longer surgical delays 6 months or more on multivariable analysis. Additionally, we observed a higher rate of Gleason upgrading with delays 6 months or more in RP.

Although a delay is more likely to result in Gleason upgrading, whether this influences prostate cancer specific survival has not yet been demonstrated. In a recent population based study in Sweden,7 222 men who deferred treatment for a median of 19.2 months (10th to 90th percentile 9.2 to 45.5 months) were compared to men who immediately underwent radical prostatectomy (median 3.5 months, 10th to 90th percentile 1.6 to 7.2 months). Although this study did not find any difference in positive surgical margins or extraprostatic extension, men in the deferred group were more likely to have Gleason upgrading on final pathological examination compared to biopsy (p <0.001). Indeed the longer the delay, the greater likelihood of Gleason upgrading (p <0.05). Nevertheless, there was no significant difference in prostate cancer specific death between the deferred and immediate radical prostatectomy groups (0.9% vs 0.7%, respectively), although 8 years median followup is likely insufficient to evaluate prostate cancer specific mortality, particularly in lower risk patients.

A limitation of our study, as with other retrospective analyses, is an inherent selection bias. Patients who delay initial therapy may have systematic differences from those undergoing repeat treatment, and the reasons for delaying treatment were not known in all cases. In a single patient, a documented repeat biopsy revealed Gleason upgrading before surgery, potentially prompting the transition to surgical treatment. Although upgrading on a subsequent biopsy is therefore unlikely to account for the worse outcomes observed in the delayed group, these interval data were not uniformly reported.

Although our study only included men who met the D’Amico low risk criteria, unmeasured differences may have confounded the results. The results may have been different using more stringent criteria for low risk disease, such as fewer than 2 positive biopsy cores with a maximum of 50% core involvement.16 Finally, our followup was relatively short, precluding an assessment of the impact of surgical delay on long-term oncologic outcomes.

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Conclusions 

In a contemporary population of patients with low risk prostate cancer undergoing radical prostatectomy a delay in surgery of 6 months or more after diagnosis was associated with a significantly greater proportion of high grade disease and higher rates of biochemical progression. Men with low risk prostate cancer should be counseled that when they choose to initially postpone radical treatment and subsequently switch to radical prostatectomy, there is a possibility of worse pathological outcomes and biochemical recurrence-free survival when the delay is 6 months or greater. Further studies are necessary to ascertain whether these findings will translate into a difference in cancer specific and overall mortality rates.

 

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References 

  1. Mohler J, Bahnson RR, Boston B, et al. NCCN clinical practice guidelines in oncology: prostate cancer. J Natl Compr Canc Netw. 2010;8:162

  2. Thompson IM, Thrasher JB, Aus G, et al. Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol. 2007;177:2106

  3. Bill-Axelson A, Holmberg L, Filén F, et al. Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian prostate cancer group-4 randomized trial. J Natl Cancer Inst. 2008;100:1144

  4. Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 2005;352:1977

  5. Khan MA, Mangold LA, Epstein JI, et al. Impact of surgical delay on long-term cancer control for clinically localized prostate cancer. J Urol. 2004;172:1835

  6. Vickers AJ, Bianco FJ, Boorjian S, et al. Does a delay between diagnosis and radical prostatectomy increase the risk of disease recurrence?. Cancer. 2006;106:576