The Treatment of Localized Prostate Cancer in Everyday Practice in Germany
A multicenter prospective observational study (HAROW) in 2957 patients
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Background: Prostate cancer is now often diagnosed in the localized, well-differentiated stage. In the HAROW study, we investigated the care situation with respect to the various treatment options for localized prostate cancer in everyday clinical practice in Germany.
Method: Study physicians for this prospective, multicenter observational study were recruited through the Federation of German Urologists. At six-month intervals, clinical variables were recorded (T category, prostate-specific antigen [PSA], Gleason score, d’Amico risk profile, Charlson Comorbidity Index [CCI]) and patients filled out questionnaires (QLQ-C30) regarding their indication-related quality of life (QoL). Covariance analysis was used to adjust for the variable distribution of patient features among the treatment groups.
Results: Data from 2957 patients were available for analysis. The mean follow-up time was 28.4 months overall, and 47.6 months in the active surveillance (AS) group. Younger patients and patients with a CCI of 0 or 1 predominated in the AS and surgery groups; older patients and patients with a CCI of 2 or above predominated in the groups in which palliative treatment strategies such as hormone therapy (HT) and watchful waiting were applied. The HT group had the highest percentage of patients with a Gleason score of 8 or above (21.2%), while the AS group had the highest percentage of patients with a Gleason score of 6 or below (92.5%), as well as the lowest mean PSA value (5.8 ± 3.4 ng/mL) and the highest percentage of patients with a low-risk profile (82.5%). Of 468 patients in the AS group, 170 (36.3%) underwent a change of treatment strategy. After adjustment for the severity of disease, no significant difference with respect to the global quality of life was found between AS and the curative treatment options over the long term.
Conclusion: The study physicians drew a clear distinction between curative and palliative treatment strategies, and the inclusion criteria for AS were largely respected. The observed preference for surgery in low-risk patients indicates overtreatment in this patient group.
Prostate cancer (PCa) ranks third among the causes of cancer death in Germany, where 70 000 new cases occur each year (1). Over the past 20 years, the introduction of screening for PCa and the regular determination of prostate-specific antigen (PSA) has led to a stage shift from advanced carcinomas to localized, well-differentiated tumors that frequently have no impact on life expectancy (2, 3). The cancer-specific 15-year survival rate for initially conservatively treated patients over 65 years of age with a Gleason score ≤ 7 is 94.3% (4). Tumors with a Gleason score ≤ 6 do not change their grade of malignancy (5) and display neither metastatic potential nor tumor-specific mortality (6–8), unless biopsy sampling has missed a portion of the tumor with higher malignancy. According to a systematic review that embraced epidemiological, clinical, and autopsy studies, this results in rates of overdiagnosis and overtreatment ranging from 1.7 to 67% (9).
The current German S3 guideline (10) lists the following treatment options for localized PCa: for intermediate- and high-risk tumors, either prostatectomy (OP) or radiotherapy (RT) in the form of percutaneous irradiation or high-dose-rate (HDR) brachytherapy; for low-risk PCa, additional active surveillance (AS) and low-dose-rate (LDR) brachytherapy. In patients with poor general health or limited life expectancy, palliative strategies are indicated—long-term observation (watchful waiting, WW) and in special cases hormone withdrawal treatment (HT) (Table 1).
It is important to distinguish between the two non-invasive treatment options, AS and WW. AS is a curative strategy. The patient is closely monitored (digital rectal examination, PSA measurement, repeat biopsy), and if any signs of progression are noted, or the patient so wishes, invasive treatment is carried out. In contrast, WW is a palliative strategy with treatment of symptoms as required, usually by means of HT.
Studies comparing the treatment strategies seem to indicate equivalence (11, 12). Prospective randomized trials are problematic in that the low metastatic potential and the lack of cancer-specific mortality make it difficult to reach the patient numbers required for definitive conclusions. A two-armed study had to be discontinued for this reason (13), and a three-armed trial had to be continued with a lower number of cases (14).
Nevertheless, prospective randomized trials of several treatment strategies have recently been initiated. The German PREFERE study compares AS, OP, RT, and brachytherapy (15), while the British ProtecT trial is investigating AS, OP, and RT (14).
When the efficacy of different treatments is practically the same, other factors become much more important, such as treatment-related adverse effects, quality of life (QoL), the feasibility of the treatments in everyday practice, and cost–benefit considerations. Investigation of these aspects is the task of healthcare research (HCR), which examines “[...] the care of individuals and of the population [...] under everyday conditions” (16). HCR data can be used to assess the consequences for daily practice of results obtained in the rather artificial setting of randomized studies.
The HAROW study (HT, AS, RT, OP, WW) is the first urological study of the treatment of localized PCa in Germany (17). It describes the various treatment options in detail and examines the evolution of QoL over time. The AS group was observed with particular interest, because when the study began the strategy of AS was relatively unknown and not widely used.
The HAROW study is a multicenter prospective observational study. It was carried out over a 5-year period from July 2008 to July 2013. Of the 259 physicians involved in the study, 86% were urologists in private practice. The criterion for inclusion in HAROW was newly diagnosed cancer confined to the prostate (≤ cT2c) with no evidence of metastasis (N0, M0). Data from 2 957 patients were available for analysis.
Because HAROW was conceived as a non-interventional observational study, no restrictions were placed on the type of treatment or how it was carried out. The decision on how to proceed in each individual case was a matter for the patient and the treating physician.
At the outset of the study AS was a novel strategy with no guideline regulating its application. The indication for AS specified in the study protocol (≤ cT2c, PSA ≤ 10 ng/mL, Gleason score ≤ 6, PSA density ≤ 0.2 ng/mL2, ≤ 2 positive biopsies) reflected the then accepted criteria from the specialist literature (6, 18, 19) and the European PRIAS study (Prostate Cancer Research International Active Surveillance) (20), the largest published prospective study of AS at the time. These indications differ from the criteria now laid down in guidelines (10, 21) with regard to T category (HAROW: all cT2 tumors; guidelines: only ≤ cT2a), PSA density (guideline: not specified), and tumor volume (guideline: maximally 50% in both positive biopsy samples) (Table 1). The patients in the AS group were followed up every 3 months for the first 2 years. Thereafter, they underwent digital rectal examination and measurement of PSA concentration and PSA doubling time (PSA-DT) at 6-monthly intervals. Biopsy was repeated after 1 year and then every 3 years. The criteria for discontinuation of AS were: clinical findings (increased size on digital rectal examination or PSA increase with PSA-DT <3 years), histological evidence of progressive disease (upgrading on repeat biopsy), the patient's wish, or the treating physician's recommendation.
Data were acquired at the time of recruitment into the study and then at 6-monthly intervals. The physicians recorded clinical parameters, tumor characteristics (findings in digital rectal examination, PSA concentration, Gleason score, risk profile according to D'Amico ), details of treatment, disease course, and comorbidities (with the aid of the Charlson Comorbidity Index, CCI) (23).
The patients gave written answers to questions about communication by their physician, psychosocial care, and health-related QoL. The QoL was established using module C30 of the Quality of Life Questionnaire (QLQ–C30) of the European Organisation for Research and Treatment of Cancer (EORTC) (24, 25). This module, developed and validated for use in cancer patients, features a global scale for QoL (rated between 0 and 100) alongside scales for function and symptoms.
A detailed description of the methods can be found in the eBox.
The mean observation time was 28.4 months. Further questioning of the AS group up to April 2015 extended the mean observation time to 47.6 months.
The characteristics of the patients at the beginning of the study are shown in Table 2. The younger patients and those with the least comorbidities (CCI = 0–1) are concentrated predominantly in the AS and OP groups, while the older patients and those with the most comorbidities (CCI ≥ 2) are mostly in the palliative HT and WW groups. The non-invasively treated groups (AS and WW) are characterized by relatively low PSA concentrations (5.8 ± 3.4 ng/mL and 6.8 ± 4.9 ng/mL) and low proportions of patients with a Gleason score ≥ 8. The AS group contains most (92.5%) of the patients with a Gleason score ≥ 6 and the majority (82.5%) of those with a low risk profile. Among the patients with a low risk profile, 517/1151 (44.9%) underwent surgery, 14.7% were irradiated, and 37.0% were treated non-invasively (AS or WW).
At the end of the HAROW study in July 2013, 284 (60.7%) of the original 468 patients were still under AS, 112 (23.9%) had switched to another treatment strategy, and 72 (15.4%) had left the study (Figure 1). The reasons for changing treatment were: upgrading on repeat biopsy (n = 52), increased PSA concentration (n = 32), the patient's wish (n = 17), and the treating physician's recommendation (n = 6). In five cases no reason was given.
Follow-up of patients under AS was extended to April 2015. By that time a further 58 patients (12.4%) had switched to a different treatment strategy and 25 (5.3%) had left the study; the remaining 201 (42.9%) were still under AS. The treatments to which AS patients switched are shown in Figure 2. While OP predominated up to the end of the regular HAROW study, during the extended observation period changes to OP decreased in favor of WW.
Pathological data are available for 54 of the 65 patients who switched to OP before the end of the HAROW study: in 46 cases tumor growth was confined to the prostate, eight patients had a pT3a tumor, and none had a tumor ≥ pT3b. Twelve patients from the AS group died during this period—none of them from PCa.
Quality of life
The trends in global QoL—adjusted by patient characteristics—over a period of 3.5 years varied among the treatment groups (Figure 3). The AS group had the highest initial rating (75.56 points, 95% confidence interval [73.43; 77.69]) and maintained this level over time. Patients from the OP and RT groups had lower initial QoL (70.9 points, 95% CI [69.77; 72.03] and 72.82 points, 95% CI [70.52; 75.13] respectively), but over time they approached and eventually attained the level of the AS group. Significant differences between AS and OP were found only in the first year of the study (T0: p = 0.017 and T1: p = 0.018). Between AS and RT no significant differences were observed at all. HT patients had the lowest QoL score at the outset (65.52 points, 95% CI [61.92; 68.91]) and stayed practically constant over time. The QoL of patients in the WW group rose steadily up to T3 (1.5 years) but sank almost back to the initial level thereafter. Only at T3 was there a significant difference (p = 0.007) between WW and HT.
The role of invasive procedures in the treatment of localized PCa with a low risk profile remains to be clearly defined. The reasons for this lie in the biological characteristics of the tumor. Tumors with a Gleason score ≤ 6 appear to have hardly any potential for metastasis, so that OP or RT would represent overtreatment. Two studies, one from the 1980s and one from the 1990s, compared OP with non-intervention (WW) and came to different conclusions after observation for 10 and 13 years respectively. In the PIVOT study, carried out in the USA, the OP strategy achieved higher cancer-specific survival only in patients with an initial PSA concentration >10 ng/mL (11), while the Swedish SPCG-4 study demonstrated superiority of OP only in patients aged <65 years (12). More clinically apparent tumors were included in those studies than would be expected today, because now most tumors are detected by determination of PSA. In the SPCG-4 study 75% of the patients had a palpable tumor (≥ T2) and the mean PSA was 13.0 ng/mL. In comparison, the proportion of T2 tumors in the PRIAS study (recruiting only AS patients) is 14.9% (26) and in the HAROW study 39.1%; the mean PSA concentrations are 5.6 ng/mL and 9.4 ng/mL respectively.
HAROW: overall findings
The distribution of T category and the Gleason score in the HAROW study corresponds to the well-known stage shift: non-palpable tumors (≤ cT1c = 61.9%) with a Gleason score ≤ 6 (57.9%) predominate. This is comparable with data from other studies of localized PCa (14, 27). The allocation to the treatment groups shows correct differentiation between curative and palliative strategies, in that younger patients and those with a low CCI score were often treated with AS or OP, while the WW and HT groups are dominated by older patients with high CCI. The high proportion of patients with a low d'Amico risk profile in the AS group (82.5%) and the distinct differences in age and comorbidities between AS and WW seem to show that the participating physicians often selected the AS strategy in accordance with the S3 guideline or the HAROW recommendations. AS was chosen for 33.5% of the patients with a low risk profile, but the fact that OP was preferred for 44.9% of those in this risk category seems to support the overtreatment described in the literature (3, 9).
Insight into everyday practice is provided by the frequency with which patients switch from AS to other treatment strategies. In a systematic review of 10 clinical AS series embracing a total of more than 3 500 patients, 33% of the patients switched to invasive treatments within the first 5 years (28); in the HAROW study it was 36.3% in just under 4 years. An interesting observation in the HAROW study is the shift from AS to WW. Many study physicians switched patients who for particular reasons (age, comorbidities) were no longer suitable for curative treatment or no longer desired it from AS to the palliative WW strategy. In the first 28.5 months 6.3% of the patients switched to WW, and by 47.6 months the figure was 15.9% (27/170).
Quality of life
Assuming that the various treatment options are oncologically equivalent in low-risk PCa, the anticipated adverse effects and their impact on the patient's QoL become more important. The principal complications of OP are erectile dysfunction (29–100%) and stress incontinence (4–50%) (10), while RT is followed mainly by urogenital (34%) and gastrointestinal (30%) complications (29). Approximately 61% of patients treated with RT are affected by the late complication of erectile dysfunction within 2 years (30). In contrast, a recent systematic review found that patients treated by AS showed high QoL ratings in the absence of serious negative psychological consequences (31). An investigation into quality-adjusted life expectancy showed higher QoL for AS than for invasive forms of treatment (32). The HAROW study is the first in which QoL can be compared longitudinally across all five treatment options. Among the curative strategies, significantly lower QoL than in the AS group was found only for OP patients at T0 and T1, which can be explained by the intervention and the subsequent phase of convalescence. In the longer term, QoL did not differ significantly among the three curative treatments (AS, RT, OP).
Moreover, the lower QoL was significantly different only for OP patients at two time points (T0, T1). As for the palliative options, the pronounced increase in the QoL of patients in the WW group was seen particularly in the first 1.5 years. Thus, at least in the early phase of treatment there were distinct differences in QoL between WW and HT patients. The predominant lack of significance can be explained by the low case numbers of both groups. For this reason, early HT seems inappropriate in asymptomatic localized PCa, a view supported by the fact that a cohort study with 66 000 low-risk patients found no benefit of early HT in respect of cancer-specific survival (33). Only in patients with advanced PCa was immediate HT associated with improved progression-free survival.
In the AS group, the 88 patients who reached T7 had a QoL rating of 77.68 points at T0, higher than the mean QoL of all AS patients at T0 (75.56 points). This suggests positive selection (attrition bias), a problem that occurs mainly in groups with low numbers of patients. In the WW group, the 19 patients still left at T7 had a QoL rating of 72.22 points at T0 (mean for all WW patients at T0: 69.17 points). Attrition bias was also evident in the HT and RT groups.
On the one hand, HCR data consistently yield a lower level of evidence than data from randomized controlled trials (RCTs), largely because of less stringent inclusion criteria and the lack of comparison groups. On the other hand, HCR reflects more accurately the reality of healthcare, which cannot be simulated in RCTs (34). One limitation specific to HAROW is the observation period of 28.4 months (47.6 months for the AS group), relatively short when considering metastasis and tumor-specific mortality for a type of tumor with slow growth. The histological findings were not reviewed by a reference pathologist; however, this is rarely the case in everyday practice. The study physicians were not representative in that due to their participation in HAROW they were acquainted with the (then novel) AS strategy, meaning that bias cannot be excluded.
The results of the HAROW study show that the participating physicians differentiated clearly between curative and palliative treatment strategies. The preference for OP in the majority of tumors with a low risk profile clearly points to overtreatment. A treatment shift—away from OP towards AS—should be targeted in the near future. In addition to diagnosis and advice on management options, urologists in private practice are responsible for an essential part of the treatment in the form of AS. In this context, the revised S3 guideline recommends advancing the time of the first repeat biopsy from 12–18 months to 6 months (10). Since 2014, the British guidelines (35) stipulate multiparametric magnetic resonance imaging before AS.
In a situation where the outcomes of various treatment strategies can be assumed to be similar, non-ontological factors such as QoL, the practicability of treatments, and cost–benefit considerations assume special importance. Herein lies a task for HCR.
It remains to be seen whether the lack of differences in global QoL among the curative forms of treatment will be confirmed in the other dimensions of the EORTC QLQ-C30 (function and symptom scales).
Ethics committee approval
All investigations described in this article took place with the approval of the ethics committee of the Bavarian State Medical Association and adhered to German laws and the Helsinki Declaration of 1975 (current version). All participating patients gave written informed consent.
The HAROW study was initiated and conducted by the Foundation of Men's Health and financially supported by Gazprom Germania.
Conflict of interest statement
Prof. Weißbach has acted as a paid consultant for the Scientific Institute (WIdO) of the AOK health insurance provider. He has received study support (third-party funding) from Gazprom Germania.
The remaining authors declare that no conflict of interests exists.
Translated from the original German by David Roseveare.
Manuscript submitted on 31 July 2015, revised version accepted on
21 December 2015.
Dr. med. Jan Herden
Klinik und Poliklinik für Urologie und Kinderurologie
Kerpener Str. 62
50937 Köln, Germany
(last accessed on 21 March 2016).
Institute for Medical Sociology, Healthcare Research and Rehabilitation Science, Cologne University, Cologne: Jun. Prof. Ansmann, Jun. Prof. PD Ernstmann
Foundation of Men’s Health, Berlin: Dr. Schnell, Prof. Weißbach
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