Treatment outcome

In patients treated for low- or favourable intermediate-risk prostate cancer, survival does not represent an adequate parameter for treatment outcome. Therefore, several groups decided to choose BCR as the primary endpoint in this situation. ^{Reference Kindts, Stellamans and Billiet16,Reference Badakhshi, Graf and Budach17} In order to compare our data with literature, we also decided to evaluate this endpoint as defined by ASTRO Phoenix consensus. ^{Reference Roach, Hanks and Thames15}

Our data confirm the results of other groups for freedom from BCR. ^{Reference Kindts, Stellamans and Billiet16–Reference Goldner, Pötter and Battermann18} All papers report about 95% or more freedom from BCR over more than 5 years. Differences in outcome between the individual reports in literature may be due to patient selection, follow-up time, brachytherapy technique or operator experience.

Brachytherapy technique

IOR planning has been shown to be advantageous in brachytherapy for prostate cancer. ^{Reference Pons-Llanas, Roldan-Ortega and Celada-Alvarez10,Reference Goldner, Pötter and Battermann18,Reference Raben, Chen and Grebler19} One other study was also performed in a single institution and directly compared different brachytherapy planning techniques. ^{Reference Pons-Llanas, Roldan-Ortega and Celada-Alvarez10} This study did not find a significantly better biochemical control in patients treated with 160 Gy and IOR than in patients treated with 145 Gy and preoperative planning. Further, no increase in side effect rates despite the dose escalation of 15 Gy was found. This is explained by keeping and still meeting the dose limitations for urethra and rectum. In our study, IOR and the possibilities of directly responding to volume changes improved therapy outcome in both tumour control and therapy side effects. These results can be explained by strictly respecting the dose limitations for urethra and rectum (Table 1) and better geometric mapping. For example, this means to intraoperatively observe and respect the changes in the shape of the prostate or the position of the urethra directly caused by inserting the needles and thus bulging the prostate (Figure 3: ‘Second series’: Recontouring and planning).

Another point to be discussed is the use of stranded seeds in the IOR method. Compared to individual seeds, stranded seeds keep their position more precisely over time and, therefore, are likely to follow the plan prediction more accurately. ^{Reference Karius, Lotter and Kreppner20}

Better results for the patients with IOR planning may also be explained by a shorter learning curve with the IOR method. Compared to PPT, in IOR planning additional, onsite teaching by experienced physicians and physicists was carried out (Figure 2).

Still, our data might be characterised by a time bias with parts of the team being already more experienced in brachytherapy when starting with the IOR method (Figure 2). All of this may explain the weak results of the PPT group in freedom from BCR compared to other data in literature generated with preplanning techniques. ^{Reference Pons-Llanas, Roldan-Ortega and Celada-Alvarez10}

Gleason score

Consistent with other results in the literature, ^{Reference Kindts, Stellamans and Billiet16,Reference Badakhshi, Graf and Budach17,Reference Martell, Meyer and Sia21,Reference Morris, Keyes and Spadinger22} the Gleason score grading of the patients’ prostate cancer did not have a significant impact on the freedom from BCR outcome. Localised prostate tumours could be treated efficiently with the prescribed dose of 145 or 160 Gy, irrespective of grading. The few patients (n = 10) with a Gleason score of 7b and thus at higher risk of advanced prostate cancer did not significantly differ from the patients with Gleason score of <7a or 7a (Figure 4D).

Blood PSA levels

For our patients, blood PSA levels at diagnosis, as well as post-therapeutic decrease of PSA over time, did not influence freedom from BCR outcome (Figure 4C, Table 3). This may be due to PSA response being additionally dependent on parameters other than BCR. ^{Reference Martell, Meyer and Sia21}

In contrast, the reached PSA nadir level under PSA nadir of 0·2 ng/mL was a strong predictor for freedom from BCR (Figure 4B). All patients reaching a blood PSA level of <0·1 ng/mL (mean PSA nadir) did not suffer from BCR. Therefore, the absolute PSA blood level, not its rate of decrease, turned out to be a better measure for follow-up of prostate cancer patients treated with LDR brachytherapy.

Side effects

Consistent with other studies, ^{Reference Emara, Chadwick and Nobes23,Reference Ash, Bottomley and Al-Qaisieh24} our patients reported mild side effects. It could be shown that patients with higher grades of dysuria and urge to urinate had significantly higher total implanted activity corresponding with prostate volume (Figure 6). For the LDR brachytherapy of a prostate with a big volume of >40–50 mL, seeds with a higher activity have to be used. This results in difficulties with dose modulation at the organs at risk and, therefore, in potentially increased side effects. ^{Reference Delouya, Bahary and Carrier25–Reference Wust, von Borczyskowski and Henkel27} Furthermore, in some cases with a large prostate and pelvic bone interference, implantation of seeds to the most lateral parts of the organ is hampered. Then, in the process of aiming at an acceptable dose distribution within the prostate, the sphincter, urethra, and central and medial zone of the prostate turn out to be overdosed. Our data confirm reasonable clinical practice regarding LDR prostate brachytherapy patient selection with prostate volumes less than 40–50 mL to avoid side effects. ^{Reference Martell, Meyer and Sia21}

Limitations

The main limitation of this study is the retrospective, single-centre setting, which is prone to selection bias and a lack of data completeness. Comparing demographic, tumour and therapy data with literature, a wide consistency is found. ^{Reference Rodrigues, Yao and Loblaw6,Reference Pons-Llanas, Roldan-Ortega and Celada-Alvarez10} This means that there was no unexpected selection of patients. Further, the selection of treatment technique (PPT versus IOR) is based on the history of the two independent brachytherapy teams working at the centre with patients randomly allocated by different urologists (Figure 2).

In a clinical therapeutic retrospective study, side effects are difficult to evaluate. However, the study was based on patient records of follow-up visits without a specified trial structure. The clinical description of the side effects in these records was converted into the clinical toxicity criteria score by a radiation oncologist. The highest grade of every side effect reported was evaluated for each patient. Patient records may be incomplete by patients not attending follow-up visits or not reporting their symptoms or by physicians not documenting the side effects appropriately. Nevertheless, the data seem to be acceptably accurate to show the patients’ clinically relevant urological problems after brachytherapy.

Future possibilities

Several groups consistently found monotherapy LDR brachytherapy a highly effective treatment for localised prostate cancer. Likewise, several studies have shown the effectiveness of the treatment modality in combination with EBRT for intermediate- and high-risk patients. ^{Reference Chao, Joon and Khoo28,Reference Lee, Barocas and Zhao29} Additionally, there have been investigations in combination with anti-hormonal therapy as a systemic treatment. ^{Reference Morris, Tyldesley and Rodda30} Interesting future study areas relating to LDR brachytherapy are high precision-focussed therapies for patients with low- and favourable intermediate-risk prostate cancer based on highly specialised MRI and/or PET/CT scans. ^{Reference Mason, Adiotomre and Bownes31–Reference Maenhout, Peters and Moerland33} LDR brachytherapy may also serve as a part of dose escalation concepts. ^{Reference Zelefsky, Pei and Chou34}