Innovative Approaches in Prostate Cancer Treatment – An Interview with Dr. Jörg Zimmermann

The combination of normofractionated external beam radiotherapy and low-dose-rate (LDR) brachytherapy has been considered a highly effective treatment for intermediate- and high-risk prostate cancer since the early days of TRUS-guided LDR. It results in almost no local recurrences, is generally well tolerated and does not cause urinary incontinence, which is of utmost importance to patients. In recent decades, a combination of LDR iodine-125 seeds with a reference dose of 108 Gy has been used together with standard external fractionation of 46 to 50 Gy at 2 Gy per day.

The first publication in which this traditional combination of LDR and EBRT was modified appeared in 2020 by Kollmeier et al. ⁽¹⁾ from MSKCC New York. They combined Pd-103 seeds with 100 Gy, followed by 25 Gy (5 fractions of 5 Gy each) 4 weeks later. This concept showed excellent tumour control and very few side effects in terms of GU, GI and sexual toxicity.

At the ESTRO 2024 conference, Dr. Jörg Zimmermann presented the groundbreaking early results of this clinical study: Low-Dose-Rate (LDR) brachytherapy with 5*5Gy Stereotactic Body Radiation Therapy (SBRT) for the treatment of prostate cancer. Read the abstract here.

This innovative approach offers new hope for improving patient outcomes while minimizing treatment duration and resource intensity. In this interview, Dr. Zimmermann provides insights into the rationale behind combining these two therapies, the study’s promising results, and what this could mean for the future of prostate cancer treatment.

Eckert & Ziegler (E&Z): Dr. Zimmermann, thank you so much for your time. Regarding your study, can you share the motivation behind combining LDR brachytherapy with ultrahypofractionated SBRT in your study? What clinical or scientific evidence led you to explore this combination as a treatment option for prostate cancer?

Dr. Jörg Zimmermann (JZ): The decisive factor for us was primarily the above-mentioned 2020 publication by Kollmeier et al. The standard combination, which we have used before, requires a high level of medical effort despite its proven advantages. Especially at the beginning of the COVID-19 pandemic, it was extremely difficult to guarantee the exact timing for LDR and the five-week course radiation treatment. So ultimately, COVID-19 contributed to the adoption of the MSKCC approach, which combines LDR with five days of external stereotactic radiation instead of a five-week treatment.

E&Z: How did you determine the inclusion criteria for patients in this study? Were there specific characteristics that made some patients more suitable for this treatment than others?

JZ: We began to include all patients with intermediate- or high-risk prostate cancer who were eligible for brachytherapy but also required radiation therapy to the seminal vesicles and primary lymph nodes. The risk calculation tables developed by Partin et al. were used to estimate lymph node metastasis. If the risk of lymph node metastasis was < 10% or the patients refused ADT, ADT was not performed. ADT was mandatory only in patients with very high risk and a risk of lymph node metastasis > 20%. However, most of our patients had moderate to favorable high risk with a low risk of lymph node metastasis.

E&Z: Could you give us an overview of the study design and the treatment protocols used for the patients involved? What was unique about the methods applied in this combination therapy?

JZ: The study design was simple. There were two arms, for which we expected very similar results.

The first arm began with LDR 108 Gy iodine-125 strands and was completed after three months with stereotactic radiation 25 Gy/5f.

The other arm was treated in exactly the opposite manner, starting with 25 Gy/5 f and completing treatment 4 weeks later with LDR 108 Gy using iodine-125 strands.

SBRT was administered in 5 fractions of 5 Gy every 2 days at the beginning, later in 5 fractions of 5 Gy each day in only one week. Cone beam CT images were taken daily, and later on adaptive planning was performed as needed. The target volume included the prostate with a margin of 3 mm, the seminal vesicles and also the first lymphatic channels around the seminal vesicles. The deep pelvic lymph nodes were not included.

Functional parameters were assessed at baseline after 6 months and 12 months using the EPIC-26 questionnaire, which is used by the ICHOM (International Consortium for Health Outcomes Measurement, www.ichom.org), and acute toxicities were recorded using the CTCAE. In addition, we assessed biochemical control and local control, defined as PSA increase > nadir + 2 ng/ml or the use of salvage therapy or ADT. All patients provided their written informed consent.

E&Z: What are the key early results from your study in terms of oncological outcomes and treatment-related toxicities? How do these results compare with more conventional treatments like EBRT?

JZ: In our abstract, we presented the initial results of this new combination treatment. First, during the entire period, only one patient with a high-risk disease showed distant oncological progression within 4 months after treatment, resulting in biochemical control rates of 100% for medium-risk diseases and 98% for high-risk diseases. Local control was 100% across the entire cohort. The median PSA value after 12 months was 0.93 ng/ml (0.1–1.82 ng/ml).

E&Z: In terms of patient-reported outcomes, what have you observed regarding urinary symptoms, bowel function, and sexual health post-treatment? How do these compare to the outcomes from traditional prostate cancer treatments?

JZ.: This was the second aspect relating to patient-related outcome parameters. Functional data were available for 85 patients at the start of the study and 6 and 12 months after treatment. All patients (100%) reported grade I or II urinary toxicity within the first few months after treatment, but no higher-grade toxicity was observed, and no patient required urinary catheterization. Rectal toxicity was also low, with grade 1 toxicity reported in 43 patients (50.5%).

The reported sexual activity was already low at the start of the study. After 6 and 12 months, ADT had a significant impact on sexual activity. Functional impairments were less severe after 12 months than after 6 months.

E&Z: Based on the data you’ve collected so far, what conclusions can be drawn about the overall safety and efficacy of this combined approach?

JZ: Based on our findings over the past now five years, the combination of LDR and SBRT 25/5 is an excellent strategy. Why?

1. It has really very moderate toxicity.
2. It is a very effective treatment. To date, we have not observed any local tumor progression. A few patients experienced PSA relapse, which was identified as lymphatic progression outside the SBRT radiation volume. We are currently conducting further studies to identify these patients and slightly increase the SBRT volume.
3. It is a very comfortable treatment. It allows the patient to complete external radiation therapy in just one week instead of five weeks.
4. It also reduces costs, as fewer fractions are required. However, this aspect naturally depends on reimbursement regulations.

E&Z: What radiobiological or procedural advantages may favor your new concept?

JZ: In recent years, the Radonc community has recognised that not all prostate tumors have a very low alpha/beta value of 1 or 1.5. More aggressive tumors, such as those found in unfavorable medium- and high-risk diseases, are estimated to have alpha/beta values of 2, 3.5 or even 5.
Ultra-hypofractionated (UHF) treatment alone therefore will lead to a very high local recurrence rate in these groups, as the EQD 2 decreases rapidly with increasing alpha/beta values. This is also the reason for the need for parallel antihormonal treatment.
On the other hand, in LDR brachytherapy regimens, EQD 2 INCREASES in prostate tumors with higher alpha/beta values, as has been known since Dale’s calculations in 1985.⁽²⁾
The combination of UHF-SBRT with LDR brachytherapy still results in a higher EQD 2 for more aggressive tumors with a higher alpha/beta value due to the LDR component but overall shows a more balanced ratio of physical and biological dose. This supports our two observations of both very good local tumor control and very good tolerability.

E&Z: What additional factors should clinicians consider when selecting patients for this treatment? How might this combined therapy approach evolve in the future as more data becomes available?

JZ: The combined therapy of LDR and SBRT will, of course, first have to establish itself in our rather conservative radonc community environment. Randomized studies would naturally be desirable but are once again difficult due to the completely different approaches of EBRT vs. SBRT. A very big advantage is that the LDR/SBRT combination obviously does not require hormone therapy for effective local tumor control. We believe that ADT can be limited to the advanced high-risk group to improve the effect of EBRT/SBRT on lymphatic drainage. We do not need ADT for local curation inside the prostate organ. The well-known side effects of ADT when used with radiation treatment of prostate cancer can therefore be omitted.

E&Z: Dr. Zimmermann, thank you very much for your insights!

¹ Low dose rate brachytherapy combined with ultra hypofractionated radiation therapy for clinically localized, intermediate-risk prostate cancer: Results from a prospective trial, Marisa A. Kollmeier et al. 2020, Int J Radiat Oncol Biol Phys. 2020 November 15; 108(4): 905–913

² The application of the linear-quadratic dose-effect equation to fractionated and protracted radiotherapy. R.G. Dale 1985, The British Journal of Radiology, 58, 515-528