Prostatectomy Versus Observation for Localized Prostate Cancer: A Meta-Analysis

Abstract

Background and Aims:

Controversy exists regarding whether prostatectomy benefits localized prostate cancer patients; the aim of our study was to evaluate the role of prostatectomy in localized prostate cancer patients.

Materials and Methods:

A systematic search was conducted using PubMed and Web of Science through March 22, 2019, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to identify randomized studies reporting on prostatectomy for localized prostate cancer patients.

Results:

Of a total of 1827 studies, six were considered for evidence synthesis. A total of 2524 patients in 3 studies were included for survival analysis, where 1256 patients received prostatectomy and 1268 patients received no treatment but were regularly followed up. Three other studies were included for adverse effects analysis. Prostatectomy displayed a significantly decreased risk of death of 9% compared with that of observation for patients with localized prostate cancer (risk ratio = 0.91; 95% confidence interval, 0.85–0.97; p = 0.007). Pooled data indicated that prostatectomy reduced the risk of disease progression by 43% (risk ratio = 0.57; 95% confidence interval, 0.47–0.70; p < 0.00001). Anxiety, depressed mood, well-being, and sense of meaningfulness for patients were not different between the prostatectomy and observation groups. However, prostatectomy increased the risk of erectile dysfunction by 2.10-fold (risk ratio = 2.10; 95% confidence interval, 1.36–3.26; p = 0.0009) and the risk of urinary function problems by 2.02-fold (risk ratio = 2.02; 95% confidence interval, 1.15–3.54; p = 0.01).

Conclusion:

Prostatectomy prolonged survival and deferred disease progression compared to observation for patients with localized prostate cancer. Symptoms between the two groups were not significantly different except for erectile and urinary function. Patients should decide on prostatectomy after balancing the survival benefit and risk of erectile dysfunction.

Keywords

Prostatectomy observation prostate cancer survival erection dysfunction quality of life

Introduction

It was estimated that 174,650 new prostate cancer cases and 31,620 prostate cancer deaths will occur in the United States in 2019. Prostate cancer is expected to be the number one type of new cancer cases and the second leading cause of death in men (1). Treatment of prostate cancer includes active surveillance, chemotherapy, radiation therapy, endocrine therapy, and radical prostatectomy (2). The best management for patients with localized prostate cancer remains controversial. Guidelines emphasize the role of observation focused on serial serum PSA (prostate-specific antigen) measurements, digital rectal examinations, and repeated prostate biopsies to check for and identify pathological indications of tumor progression (3).

Several studies have compared prostatectomy and observation for patients with localized prostate cancer, but the results are conflicting (4 –7). Hamdy et al. (6) randomized 545 patients with localized prostate cancer who received active monitoring and 553 patients who received surgery between 1999 and 2009. Prostate cancer mortality was assessed at a median of 10 years of follow-up. There were 13 prostate cancer–specific deaths overall: 8 in the active monitoring group (1.5 deaths per 1000 person-years) and 5 in the surgery group (0.9 per 1000 person-years). However, no significant difference was observed among the groups. Another study performed by Wilt et al. (7) randomly assigned 731 men with localized prostate cancer to radical prostatectomy or observation from 1994 to 2002, and after nearly 20 years of follow-up, they concluded that surgery was not associated with significantly lower mortality than observation; however, surgery was associated with a higher frequency of adverse events than observation. Recently, Bill-Axelson et al. (5) reported the results of a 29-year follow-up study for localized prostate cancer patients who received radical prostatectomy or observation, and patients who received surgery gained a mean of 2.9 years of life. The aim of this meta-analysis was to compare the survival benefit and quality of life between prostatectomy and observation.

Materials and Methods

Search Strategy

The meta-analysis and systematic review were performed by searching the Web of Science and PubMed through March 22, 2019. Additional records were identified through other sources (by screening the references in the identified studies). Searches included the terms “localized prostate cancer” OR “early prostate cancer” AND “observation” OR “active surveillance” OR “watchful waiting” AND “prostatectomy” (see Appendix 1). The citations in the retrieved articles were reviewed to identify other potentially relevant studies.

Inclusion and Exclusion Criteria

Two investigators (X.L. and W.Y.) independently extracted the data, and an agreement was reached by discussion. Studies that met the following criteria were included in this meta-analysis: (1) all patients were pathologically diagnosed with localized prostate cancer, (2) the study was a randomized trial, (3) patients were regularly followed up, and (4) sufficient data were available for examining cancer-specific survival and the hazard ratio (HR) with its 95% confidence interval (95% CI). Major reasons for exclusion of studies were as follows: (1) patients had cancer metastases or prostate membrane infiltration; (2) incomplete data for the analysis; (3) conference abstracts, reviews, letters to editors/commentaries/editorials, and articles published in a language that cannot be translated; and (4) duplicate data (these were removed and only the updated data were selected).

Statistical Analysis

The risk ratio (RR) with its 95% CI was extracted from the included studies. The heterogeneity in the studies was evaluated using I² statistics (value ranged from 0% to 100%). We pooled the information with a random or fixed effect model according to the I² value. The fixed effects model method was used when I² < 50%, indicating low heterogeneity among studies. When the existence of heterogeneity was indicated, the random effects model was applied. Sensitivity analysis was performed to assess the stability of the results. Funnel plots were drawn to estimate publication bias, and whether the funnel plot was symmetrical was assessed with Egger’s test. When using Egger’s test to assess the publication bias, p < 0.05 statistically indicated publication bias (8). The statistical analysis was performed using Review Manager Software (version 3.6).

Results

Study Selection and Characteristics

A total of 1827 relevant studies were identified through the literature search. After excluding 1628 articles focused on benign prostatic hyperplasia and advanced prostate cancer, 48 articles were fully assessed. Many studies had duplicate data, such as research conducted by Wilt et al. (7 –13) and Bill-Axelson et al. (5, 14 –18), and only the most recent publication was selected. Finally, three studies that met the inclusion criteria were included in our meta-analysis; another three studies were also included for adverse effect analysis. (4 –7, 14, 19) (Fig. 1). Of these, three studies with a total of 2524 patients were included for survival analysis (5 –7). A total of 1256 patients received prostatectomy, and 1268 patients received no treatment but were regularly followed up. Quality of life was assessed by the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) investigators in a study, where 136 men in the radical prostatectomy group and 136 men in the watchful-waiting group answered the questionnaire (14). In another study, 545 patients were actively monitored, and 553 received radical prostatectomy; patient-reported outcomes were measured in the Prostate Testing for Cancer and Treatment (ProtecT) trial (19). The characteristics of the included studies analyzed for survival are listed in Table 1.

Fig. 1.

Flow diagram of the selection study process.

Table 1

Characteristics of enrolled studies.

Study	Year of publication	Country	Prostatectomy			Observation			Follow up (years)	Study design
Study	Year of publication	Country	Death from any cause	Death from PCa	Total number	Death from any cause	Death from PCa	Total number	Follow up (years)	Study design
Bill-Axelson	2018	European	261	71	347	292	110	348	29	RCT
Hamdy	2016	UK	55	5	545	59	8	553	10	RCT
Wilt	2017	USA	223	27	364	245	42	367	19.5	RCT

PCa: prostate cancer; RCT: randomized controlled trial.

Overall and Prostate Cancer–Specific Survival

Of the three studies, one study with 695 patients indicated a better prognosis associated with surgery compared to surveillance. These included 347 patients who received prostatectomy and 348 patients with observation (5). Another two studies with 1829 patients showed that no meaningful differences existed between prostatectomy and observation. These included 909 patients who received prostatectomy and 920 patients with observation (6, 7). In our meta-analysis, I² was 0%; therefore, the fixed effect model was used for the overall survival analysis, and the pooled RR was 0.91 (95% CI, 0.85–0.97; p = 0.007). Thus, prostatectomy displayed a significantly decreased risk of death of 9% compared with observation (Fig. 2). For prostate cancer–specific survival analysis, the pooled RR was 0.65 (95% CI, 0.52–0.81; p = 0.0001; Supplemental Fig. 1).

Fig. 2.

Meta-analysis and risk of bias of included studies for overall survival.

Disease Progression

Disease progression was defined as distant metastases, palpable extracapsular extension, or voiding obstruction that required intervention (5). Two studies with 900 patients who received surgery and 893 patients with observation were analyzed in our meta-analysis (5, 6). The fixed effect model was used, as I² was 0%. Pooled data indicated that prostatectomy reduced the risk of disease progression by 43% (RR = 0.57; 95% CI, 0.47–0.70; p < 0.00001; Fig. 3).

Fig. 3.

Meta-analysis of included studies for disease progression.

Patient-Reported Symptoms

Posttreatment symptom distress is an important consideration in determining whether surgery is the most appropriate course of treatment in patients with localized prostate cancer. Patient-reported symptoms were measured in four studies (4, 7, 14, 19). We concluded that the symptoms result from several aspects, including emotion, sexual function, and urinary function.

Anxiety

Two studies compared 601 patients who received prostatectomy with 594 patients who received observation (14, 19). Anxiety was less common among men treated with prostatectomy compared to that in the observation group in one study (14). Another study indicated that anxiety had a similar incidence for patients who received prostatectomy or observation (19). Pooled data showed that anxiety was not different between the prostatectomy and observation groups (RR = 0.78; 95% CI, 0.48–1.29; p = 0.34; Fig. 4).

Fig. 4.

Meta-analysis of included studies for different symptoms.

Depressed mood

A total of 595 patients who received prostatectomy and 600 patients who received observation completed depression questionnaires in two studies (14, 19). Seventy-two patients who received prostatectomy and 77 patients who received observation suffered from depression. No statistical significance was found between the populations (RR = 0.94; 95% CI, 0.70–1.27; p = 0.70; Fig. 4).

Well-Being and Sense of Meaningfulness

Bill-Axelson et al. evaluated the well-being and sense of meaningfulness for patients (14), and surgery did not influence these two types of emotion (Fig. 4).

Quality of life

Two studies compared quality of life in 522 patients who received prostatectomy with 530 patients who received observation (14, 19). A total of 110 patients in the prostatectomy group and 109 patients in the observation group complained of low quality of life, and there was no significant difference (RR = 1.02; 95% CI, 0.81–1.30; p = 0.85; Fig. 4).

Erectile function

Four studies evaluated erectile function (4, 7, 14, 19). A total of 919 of the 2480 men in the prostatectomy group and 305 of the 1369 men in the observation group had difficulties with erection. Our analysis indicated that surgery increased the risk of erectile dysfunction by 2.77-fold (RR = 2.10; 95% CI, 1.36–3.26; p = 0.0009; Fig. 4).

Urinary function

Incontinence was the main urinary function problem, and three studies with 2342 men in the prostatectomy group and 1260 men in the observation group were followed up for urinary function (4, 7, 19). Surgery did influence urinary function (RR = 2.02; 95% CI, 1.15–3.54; p = 0.01; Fig. 4).

Risk of Bias

Risk of bias were assessed for the included studies. Only one study cannot be assigned as a high quality of evidence (6). We then excluded that study to conduct the sensitivity meta-analysis and found that prostatectomy decreased the risk of death by 9% compared with the risk in the observation group (RR = 0.91; 95% CI, 0.85–0.97; p = 0.003; Supplemental Figure 2).

Publication Bias

Egger’s test and Begg’s funnel plots were used to assess the publication bias in this meta-analysis. Egger’s funnel plot test (p = 0.368) indicated that there was no publication bias among the included studies. In addition, Begg’s test (p = 0.602; Fig. 5) supported this conclusion.

Fig. 5.

Funnel plots of survival analysis.

Sensitivity Analysis

Studies were sequentially removed to investigate whether any study could have an influence on the pooled results (Fig. 6). The test suggested that the pooled result did not exhibit alterations when an individual study was excluded.

Fig. 6.

Sensitivity analysis of the “summary” OR of “survival.”

Discussion

Several systematic reviews have studied the role of prostatectomy in localized prostate cancer patients (20 –23). Randomized trials have shown a benefit of prostatectomy on mortality outcomes (23). Radical prostatectomy demonstrated an all-cause or cancer-specific mortality benefit compared to watchful waiting (22). Radical prostatectomy, external beam radiotherapy, or androgen-deprivation therapy can all be considered effective monotherapies for localized disease (20, 21); however, all treatments have unique adverse event profiles. The benefit of prostatectomy for localized prostate cancer patients was assessed compared with that of observation, and the adverse effects were also evaluated in our research.

In this meta-analysis, we included six studies that investigated the survival and symptoms of localized prostate cancer patients. Three studies with a total of 2524 patients were included for prostate cancer–specific survival analysis, and 103 of the 1256 men in the prostatectomy group and 160 of the 1268 men in the observation group died of prostate cancer. Two studies compared the disease progression between the groups. A total of 105 of the 900 men in the prostatectomy group and 183 of the 893 men in the observation group had cancer progression. Our meta-analysis indicated that prostatectomy contributed to prolonged survival and deferred disease progression. We note that in one study, the follow-up was 10 years (6), and the other two were 19.5 and 29 years (5, 7). Most patients survive within 10 years of follow-up despite prostatectomy or observation, and the effects of prostatectomy may not be observed. The 5-year overall survival rate and no biological evidence of disease rate for localized prostate cancer patients were 97.7% for patients undergoing prostatectomy and 92.4% for patient with observation (24). Thus, enough time for follow-up was necessary to compare the prostatectomy group and observation group.

The incidental discovery of low-grade prostate cancer patients is not likely to shorten survival or cause health problems during a man’s lifetime (25), and guidelines on the use of observation or active surveillance in men with clinically insignificant prostate cancer were described (26 –28). Risk stratification for localized prostate cancer patients is necessary. In our research, due to the lack of sufficient data, subgroup analysis was not performed. Patients should be stratified according to, for example, age, PSA value, and Gleason score. The included studies evaluated patients aged <65 or ⩾65 years old, and death from prostate cancer was decreased in the prostatectomy group in one study (5), while another study did not support these results (7). The PSA value or Gleason score did not affect the results in the study in which surgery was not associated with significantly lower prostate cancer mortality than that of observation (7). Currently, overtreatment is a well-recognized consequence of the diagnosis of low-risk prostate cancer in which patients are at a low risk of aggressive or lethal disease (28, 29). More randomized studies are needed to investigate the role of prostatectomy in low-, intermediate-, or high-risk prostate cancer patients.

Our meta-analysis indicated that prostatectomy would increase the survival of patients with localized prostate cancer, but adverse effects existed. Anxiety, depressed mood, well-being, and sense of meaningfulness for patients were not different between the prostatectomy and observation groups (Fig. 4). Erectile function and urinary control were the main concerns for clinicians and patients (30, 31). We found that erectile dysfunction and urinary symptoms were more common in the prostatectomy group (Fig. 4). It was noted that the prostatectomy performed in the included studies was many years ago, and the techniques for nerve-sparing were insufficient (32, 33). The management of erectile dysfunction post radical prostatectomy was diverse (34). Thus, it is significant to compare prostatectomy (with application of new nerve-sparing theories and techniques) with observation for localized prostate cancer in the new era.

There were some limitations worth noting. First, localized prostate cancer patients contained high-, medium-, and low-risk groups; subgroup analysis was not performed. Second, the total population was relatively small for survival analysis, and only four studies were included. Third, comparisons were not performed between radical prostatectomy, external beam radiotherapy, or androgen-deprivation therapy.

The high quality of the included studies ensured robust results of our meta-analysis; thus far, our research concluded from the available data that prostatectomy prolonged survival for localized prostate cancer patients without obvious adverse effects except for erectile dysfunction.

Conclusion

Our research indicated that prostatectomy prolonged survival and deferred disease progression compared to observation for localized prostate cancer patients. Symptoms between the two groups were not significantly different except for erectile and urinary function. Patients should decide on prostatectomy after balancing the survival benefit and risk of erectile dysfunction.

Supplemental Material

supplement_figure_1 – Supplemental material for Prostatectomy versus observation for localized prostate cancer: A Meta-Analysis

Supplemental material, supplement_figure_1 for Prostatectomy versus observation for localized prostate cancer: A Meta-Analysis by Xiaojin Luo, Meilian Yi, Qun Hu and Weihua Yin in Scandinavian Journal of Surgery

Supplemental Material

supplement_figure_2 – Supplemental material for Prostatectomy versus observation for localized prostate cancer: A Meta-Analysis

Supplemental material, supplement_figure_2 for Prostatectomy versus observation for localized prostate cancer: A Meta-Analysis by Xiaojin Luo, Meilian Yi, Qun Hu and Weihua Yin in Scandinavian Journal of Surgery

Footnotes

Appendix 1

“localized prostate cancer” [All Fields] OR “early prostate cancer” [All Fields] AND “observation” [All Fields] OR “active surveillance” [All Fields] OR “watchful waiting” [All Fields] AND “prostatectomy” [All Fields]

Author Contributions

W.Y. contributed to project development, manuscript editing, and study supervision; X.L. contributed to data collection or management and manuscript writing; M.Y. and Q.H. contributed to data analysis and interpretation.

Declaration of Conflicting Interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval

All procedures performed in included studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with human participants performed by any of the authors.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Informed Consent

Informed consent was obtained from all individual participants in the included study. For this study, formal consent is not required.

ORCID iD

Weihua Yin

Supplemental Material

Supplemental material for this article is available online.

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