HAROW: Care study for localized prostate cancer

HAROW is a study in the field of urological healthcare research and is also the largest study on localized prostate cancer (PCa) in Germany. The name is derived from the initial letters of the treatment options applicable to PCa: hormone therapy, active surveillance, radiotherapy, surgery, and watchful waiting. HAROW documents the course of the different treatment strategies under everyday conditions. It records medical data, information on communication between doctors and patients, side effects, treatment acceptance, and the costs of treatment under everyday conditions. A unique aspect of the study is that, for the first time in Germany, defensive strategies such as active surveillance and watchful waiting are included in the treatment comparison. The aim is to record the distribution across the different treatment arms, resource consumption and benefits, as well as the acceptance of the therapies under everyday conditions. The following article presents the concept and structure of the study and shares some of the evaluated results.

Prostate cancer (PCa) is the most common cancer in men. Due to PSA-based early detection and standardized serial biopsies, the incidence is increasing. The Robert Koch Institute (RKI) estimated 40,876 new cases in 1996 and 60,118 in 2006. This increasing frequency of diagnosis is associated with a corresponding rise in treatments and thus also in resource consumption. From 1990 to 2003, for example, the number of inpatient rehabilitation treatments for prostate cancer patients increased from 59,579 to 396,798 cases, more than sixfold. The increased effort in diagnosis and therapy is offset by side effects and, to date, no demonstrable benefit. The mortality rate of the disease has not changed. The Robert Koch Institute (RKI) reported 11,417 deaths from prostate cancer (PCa) in 1998 and 11,448 in 2007. A majority of newly diagnosed cases detected through screening are localized PCa with a low risk of progression. Many of these tumors remain stable for years. However, some progress early despite timely treatment. The benefit of curative treatment is limited to a relatively small proportion of newly diagnosed PCa cases. At the same time, there is a wide range of treatment options available, from invasive procedures like surgery and radiation therapy to minimally invasive therapies such as LDR brachytherapy, and watchful waiting strategies such as active surveillance. It is currently unclear who benefits from which level of invasiveness of treatment.
Scientifically oriented urologists call for these questions to be examined in prospective, randomized studies according to evidence-based criteria. Such studies recruit participants, for example, the American PIVOT (1994-2009), the British ProtecT (2001-2013), and the multinational START (2007-2023). The HAROW healthcare study is based on the continuous documentation of collected data, which can be evaluated at any time. The criteria for individual parameters are less precise compared to a randomized study, but aim to better reflect routine clinical practice. HAROW also aims to document and evaluate outcomes over five or ten years. The study management hopes that follow-up observation and thus continuous interim analyses will be possible.
Study design, structure and methodology
HAROW continuously documents the treatment measures and disease progression of locally confined prostate cancer (PCa) from the time of diagnosis. Data collection is divided into parameters of physician (physician documentation) and patient-related interest (patient documentation). Patients answer the questions posed to them independently, without consulting their treating physician. HAROW aims to depict the care of PCa patients primarily where treatment decisions are made – in urological practices – and not solely in specialized clinics. The study is aimed at office-based urologists and radiation oncologists; hospitals and specialized outpatient clinics can also participate. The semi-annual physician documentation includes information on the tumor, the patient and their comorbidities (Charlson Comorbidity Index), and the disease course. The tumor data allows for differentiation between patients with low, intermediate, and high risk of progression. Risk stratification within the study follows the CHISM criteria to facilitate comparison of the data with results from the Dutch PRIAS study. HAROW has entered into a cooperation agreement with PRIAS to enable joint data analysis at a later date. The Chism risk stratification differs from the well-known d'Amico classification (Table 1) in its consideration of palpation findings. The Gleason score and PSA ranges are weighted identically in both classifications.
Patient documentation is also requested every six months. The patient reports whether and to what extent they are informed about the disease, its course, treatment options, and supportive measures. They document any changes in their quality of life and possible side effects of their treatment. They also provide information on rehabilitation measures, hospital stays, medications, and the use of medical aids and assistive devices. The costs of treatment can be derived from this information. The data from the physician's and patient's documentation can be correlated with the five different treatment measures as well as with the progression risk categories: low, intermediate, and high risk. The Active Surveillance strategy is still not well established in Germany. At least some practicing urologists are uncertain about who is suitable for the strategy and how to implement it, even though the guideline explicitly addresses this. HAROW therefore offers consultations with a physician available by telephone. It is not the physician's role to influence the treatment decision.
HAROW is funded by Gazprom Germania. The corporation itself has no influence on the study. It has commissioned the Men's Health Foundation to conduct the study. The foundation maintains contact with the physicians and individual patients through a study office. The physicians' documentation costs are reimbursed. The company CSG, commissioned by the foundation, prepares the monthly status report and the annual interim analysis and organizes the study's logistics, such as sending study materials, providing logistical support to the participating study centers, quality control of the data, and data compilation and analysis. In addition, there is expert oversight provided by the scientific advisory board (chair: Prof. Dr. Dr. hc. Rübben; Prof. Dr. Wullich representing the German Society of Urology; Dr. Schröder representing the Professional Association of German Urologists; Mr. Fiebrandt representing the Federal Association of Prostate Cancer Self-Help Groups; and Dr. Dietrich from the field of public health). Two urologists are available to advise physicians on the active surveillance therapy strategy by telephone as needed. Data documentation can be done in paper or electronic form. The necessary documentation software was developed by Docxcellence Berlin.
The study began in 2008 and is scheduled to run for five years, until 2013. Three of the annual interim reports have been published so far. The following results are excerpts from the 2011 interim report.
Results
By April 2011, 240 physicians participating in the study had reported 2,042 patients. On average, 50 to 60 new patients were recruited each month. 1,038 (511 TP3T) opted for surgery, 270 (131 TP3T) for active surveillance, 239 (121 TP3T) for radiation therapy, 150 (71 TP3T) for hormone therapy, and 93 (51 TP3T) for watchful waiting. 71 TP3T of the patients underwent a combined treatment of hormone therapy and radiation or surgery, or surgery and radiation therapy. HAROW patients are on average 67.3 years old and have low comorbidity, with a mean Charlson Comorbidity Index of 0.5.
In the majority of cases, the tumor was detected due to elevated PSA and serial biopsy (531 T1c). In 7 T1 patients, it was diagnosed incidentally during transurethral resection (TURP) (T1a and T1b). Only 39 T1 patients had a palpable tumor (T2a, b, c). The diagnosis was established in most patients through serial biopsy of ≥ 12 individual biopsies. Only in a minority of 7 T1 patients was the diagnosis confirmed using the previous standard of a six-core biopsy. 72 T1 patients in the HAROW study have prostate cancer with a low risk of progression, 17 T1 patients have an intermediate risk, and 7 T1 patients have a high risk. Quality of life data was collected in general (EQ 5D), in general cancer-related (QLQ C30), and prostate cancer-specific (QLQ PR 25). A majority of patients report coping well with their illness and therapy, including its side effects. Patients experiencing limitations in their quality of life most frequently cite pain, insomnia/anxiety, urinary (incontinence), sexual (erectile dysfunction), and hormone-related side effects. Individual analysis reveals varying occurrences of side effects depending on the specific therapy. Patients overwhelmingly perceive and value the doctor-patient interaction positively. However, areas for improvement in communication can be identified.
discussion
The HAROW study is an example of a study that uses health services research approaches to design high-quality studies under real-life conditions. HAROW is a non-pharmacological and non-interventional study. Other study approaches, such as randomized controlled trials, would not adequately address the research question regarding different treatment methods, as these studies would not be able to accommodate the heterogeneity of the patients represented in the HAROW study.
A randomized controlled trial has clearly defined criteria for all standards, meaning all diagnostic and assessment procedures and classifications. Past experience has shown that in prostate cancer, all parameters relevant for assessment and decision-making change within a 10- to 15-year period. We see changes in PSA testing, in the assessment of the Gleason score, and in the number of biopsies deemed necessary. A randomized controlled trial must adhere to its defined criteria and is therefore unsustainable over a long period. Even when such a trial is completed, the results are no longer applicable to daily clinical practice. The ongoing documentation and evaluation of data from daily medical routine—thus, health services studies—accepts changes in diagnostics and is therefore sustainable.
Conclusion
The question of which patient with localized prostate cancer should be treated, at what time, and with what level of invasiveness can best be answered by studies addressing healthcare provision. These studies, which focus on healthcare provision, only yield reliable results for this type of tumor after a long observation period, which can also lead to further insights and treatment recommendations. Essential for the success of these study approaches are a long-term funding model, regular interim analyses, and continuous quality control of the data.