Long-term oncologic and functional outcomes in men undergoing robot assisted radical prostatectomy for prostate cancer

Prostate cancer (PCa) is a common malignancy, with approximately 10,500 men diagnosed each year in Sweden. About one fifth of all men will receive the diagnosis during their lifetime. Most men who are diagnosed will at some point require active treatment and roughly one third undergo curative therapy either radical prostatectomy (RP) or radiotherapy (RT). RP is an effective curative treatment for PCa with trials demonstrating a survival benefit of 2.9 years compared with watchful waiting (SPCG-4). During RP the entire prostate gland is removed. Because of its anatomical location, adjacent sensitive structures such as the external urethral sphincter and neurovascular bundles may be affected, leading to postoperative side effects. The most common adverse effects are urinary incontinence (UI) and erectile dysfunction (ED), affecting approximately 20% and 70% of men, respectively, at 24-month follow-up, depending on the definitions used. Since PCa typically grows slowly and life expectancy continues to increase, many treated men will live for a long time with side effects of varying severity. There has therefore been a need to refine surgical approach, both through improved anatomical understanding and through the development of different operative approaches. In the late 1990s, minimally invasive surgery became increasingly popular, and in the early 2000s robot-assisted radical prostatectomy (RARP) was introduced in urology. Enhanced instrument manoeuvrability compared with conventional laparoscopy, together with improved 3D visualisation as opposed to poor optics in open radical prostatectomy (RRP), made RARP a more attractive option. Over the following decade, RARP became the most used technique for PCa surgery in the Western world. However, despite its wide adoption, long-term data on oncological outcomes were still lacking. As with the disease itself, RP is heterogeneous in its execution. To minimise functional side effects, surgeons may dissect closer to the prostate to preserve important structures. Surgical planning is based on the available preoperative information about the tumour. It is acknowledged that a closer dissection increases the risk of leaving residual cancer, possibly resulting in a positive surgical margin (PSM). This, in turn, may result in persistent or recurrent disease and the need for additional treatment. Thus, there is a constant trade-off when choosing the surgical plane, and the operation is customized according to the preoperative findings. In this thesis, long-term oncological and functional outcomes after RARP are evaluated. Studies 1 and 3 investigate biochemical recurrence (BCR), PCa- specific mortality, and the risk of salvage treatment during postoperative follow-up exceeding 10 years. Study 3 further investigates differences in oncological outcomes according to the presence of a PSM and its extent (focal or extensive) within different risk groups. Study 2 compares UI after RARP versus RRP, with additional stratification by risk group and analysis of oncological endpoints. Study 4 evaluates the correlation between preoperative MRI findings and final histopathology after RP. In Study 1, we analysed 889 men who underwent RARP at Karolinska University Hospital between 2002 and 2006. 10-year BCR-free survival and cancer-specific survival were estimated using Cox regression models. We found BCR-free survival of 81.8% (95% CI 79.1-84.2) and cancer-specific survival of 98.5% (95% CI 97.4-99.1). These results are comparable to outcomes reported in larger long-term series of traditional RRP. In Study 2, we analysed 2,650 men who underwent either RRP (n=805) or RARP (n=1845) within the LAPPRO-trial. Using binominal logistic regression, we estimated the relative risk of urinary continence recovery after RRP versus RARP. Differences were mainly observed in the high-risk group, RARP was associated with a higher risk of UI but lower rates of PSMs compared with RRP (UI: 60.5% vs 66.1%; RR 0.85, 95% CI 0.73-0.99; PSM: 23.5% vs 46.8%; RR 1.56, 95% Cl 1.10-2.21). Overall, there was a small difference in BCR at 24 months between RRP and RARP (6.6% vs 9.8%; RR 1.43, 95% CI 1.08-1.89). In Study 3, we analysed 1,039 men who underwent RARP at Karolinska University Hospital between 2002 and 2007 for localised PCa. In this cohort, 227 patients (21.8%) had a PSM. Using Cox regression models, we estimated the hazard ratios (HR) for BCR, salvage radiotherapy (SRT), androgen deprivation therapy (ADT), and PCa-specific mortality associated with focal or extensive PSMs, compared with negative margins. Analyses were stratified according to CAPRA risk groups. Compared with negative margins, an extensive PSM was associated with increased risks of BCR in the low-, intermediate-, and high-risk groups (HR 2.16, 95% CI 2.09-8.29; HR 3.76 95% CI 2.33-6.06, and HR 2.35 95% CI 1.03-5.38, respectively). Similarly, the risk of receiving SRT was higher for patients with extensive PSMs across the corresponding CAPRA strata (HR 3.75, 95% CI 1.45- 9.7; HR 4.57, 95% CI 2.47-8.43; and HR 9.32, 95% CI 1.06-14.82). In Study 4, the proportion of preoperatively undetected clinically significant cancer was lower with combined assessment than with MRI or systematic biopsies alone (12.3% vs 19.8 and 31.0%, respectively). Overall, this thesis indicates that RARP achieves long-term oncological outcomes comparable to those reported for RRP, including high 10-year cancer-specific survival and acceptable biochemical control. Evaluating outcomes after RP is best performed through risk-group stratification since the surgical approach is influenced by preoperative tumour characteristics. In theory, the risk of PSM increases when the dissection plane is closer to the prostate capsule. In our data, an extensive PSM was associated with a higher risk of BCR and the need for SRT across all risk groups, whereas a focal margin did not appear to have the same impact in the low- and intermediate-risk groups. This may suggest that a more tissue-preserving dissection could be acceptable in these patients, potentially improving functional outcomes without substantially compromising oncological safety. These findings highlight the importance of accurate preoperative assessment, as surgical decision- making relies heavily on the quality of available diagnostic information. Further refinement of preoperative evaluation methods may therefore enhance individualised surgical planning. There is a need for further research to better characterise and optimise the balance between oncological and functional outcomes in RARP. Future work should focus on identifying surgical strategies and preoperative risk-stratification tools that enable durable cancer control and low PSM rates without necessarily compromising postoperative continence and sexual function. Such advancements would support the notion that oncological radicality and functional preservation do not always have to be competing goals. List of scientific papers I. Rajan P, Hagman A, Sooriakumaran P, Nyberg T, Wallerstedt A, Adding C, Akre O, Carlsson S, Hosseini A, Olsson M, Egevad L, Wiklund F, Steineck G, Wiklund NP. Oncologic Outcomes After Robot-assisted Radical Prostatectomy: A Large European Single-centre Cohort with Median 10-Year Follow-up. Eur Urol Focus. 2018 Apr;4(3):351-359. https://doi.org/10.1016/j.euf.2016.10.007 II. Hagman A, Lantz A, Carlsson S, Höijer J, Stranne J, Tyritzis SI, Haglind E, Bjartell A, Hugosson J, Akre O, Steineck G, Wiklund P. Urinary continence recovery and oncological outcomes after surgery for prostate cancer analysed by risk category: results from the LAParoscopic prostatectomy robot and open trial. World J Urol. 2021 Sep;39(9):3239-3249. https://doi.org/10.1007/s00345-021-03662-0 III. Hagman A, Lantz A, Grannas D, Carlsson S, Akre O, Olsson M, Egevad L, Höijer J, Wiklund P. Positive surgical margin and oncological outcomes after robot- assisted radical prostatectomy in different Cancer of the Prostate Risk Assessment risk groups. BJU Int. 2025 Jul;136(1):135-142. https://doi.org/10.1111/bju.16732 IV. Hagman A, Pellegrino F, Egevad L, Jäderling F, Joo G, Font Peradejordi M, Falagario U, Proietti F, Brasetti A, Akre O, Lantz A, Wiklund P Assessing the Role of MRI in Omitting Systematic Biopsies Prior to Radical Prostatectomy [Manuscript]