Dosimetric Predictors of Toxicity after Prostate Stereotactic Body Radiotherapy: A Single-Institutional Experience of 145 Patients

Round 1

Reviewer 1 Report

This is a single institutional 4-fraction prostate SBRT experience, correlating the dosimetric parameters and toxicity outcomes. There is sufficient data of interest, and will useful addition to the literature, however, there are several points that need clarification, and I would recommend some of the following changes.

 

General comment:

-       Apart from stating specific dosimetry parameters are correlated with specific toxicities, it will be useful to specify what cut off is useful to mitigate the risk of toxicities. E.g. rectal D10cc and V30Gy are associated with acute GI toxicities, so, what constraints should be recommended based on the data in this paper? This is especially that there are more limited data on 4-fraction prostate SBRT (apart from Seymour et al and Wang et al)

 

Methods:

-        Table 1 should be under Results. Also recommend going with ISUP Grade grouping rather than the long-list of Gleason 3+3, 3+4, 3+5 etc… Also, the number doesn’t match up that there are 48 patients with ISUP Grade group 4 and above, but only 10 who were classified as ‘high risk’. Please double check and correct. For BED, please specify what alpha-beta used e.g., 1.5? Also, readers will want to know your target volume coverage e.g. CTV and PTV D90, D95, D99 etc.

-        Fiducial markers “were inserted into the apex and base of the prostate” – are there 2 or 3 fiducials inserted?

-        “80mL saline was injected into bladder via urethral catheter for CT simulation” – were the catheters left in situ for CT simulation? And is urethra contoured as an OAR? Will be of interest to correlate the urethral dosimetry with toxicities

-        Target volume same for all risk groups (low/ intermediate/ high risk) – e.g., only proximal 1cm SV in the CTV including for high-risk? What about pelvic nodes RT?

-        Given that spacers will impact on your dosimetry (and likely toxicity), and there are only 3 patients in the cohort, I would recommend excluding these 3 patients for a ‘cleaner’ cohort for analyses.

-        Line 70-75 re: ADT use – it is a bit difficult to read this section. What readers want to know is e.g., men who had intermediate risk prostate cancer had total of X months of ADT, and started X months before prostate SBRT. just stating an average of 7.8 months is not informative.  

Results

-        Please specify range of follow-up: median follow-up was 42.9 months (range: X- X months)

-        There was mention of BFS and OS in the results (line 97-98), but no mention of that in the methods e.g., for statistical analyses, time-to-event for BFS and OS (e.g., from start date of SBRT or end date of SBRT?). Also, not meaningful to have the overall BFS and OS, combining low/ intermediate/ high risk prostate cancer – especially having almost one-third of patients with high risk (please check your number who had high risk as per comments in Methods above). One option is to not mention oncological outcomes in this paper given that the focus is toxicity i.e., to drop the one sentence in the manuscript that mentioned BFS and OS (line 97-98).

-        Recommend being more specific in the Results section of the manuscript (as well as in the Results in Abstract) e.g., instead of “One-tenth of patients suffered from Grade ≥2 toxicities. The GU toxicity rate was double that of GI toxicity”, should state “X% had Grade ≥2 GU toxicities and X% had grade ≥2 GI toxicities”. Also, avoid phrases e.g., “a few patents suffered from late…” a few can be a big range.

-        Table 3: recommend having 95%CI for HR

-        Also, double check the definition for D10cc (in abstract) – it should be dose to the hottest 10cc volume, rather than ‘minimum dose received by 10cc’

Author Response

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Reviewer 2 Report

The study's strengths include the use of a competing risk analysis to evaluate both radiotherapy-related and patient-related risk factors, as well as the identification of specific dose-volume histogram parameters associated with acute and late toxicities. The fact that acute GU and GI events correlated with prostate volume and rectal dose, respectively, while late GI toxicity, frequency, and rectal hemorrhage correlated with bladder and rectal doses, respectively, may be particularly useful for clinicians in managing potential toxicities.

However, the study also has limitations. For example, the lack of a control group makes it difficult to determine whether the observed toxicities are specifically associated with SBRT or would occur with other treatments as well. Additionally, the study only included patients treated with a specific dose and fractionation schedule, so it is unclear whether the results would apply to other treatment regimens. Finally, the study did not evaluate quality of life outcomes, which are important for assessing the overall impact of treatment on patients.

In conclusion, the study provides valuable information about the relationships between dose index and adverse events in prostate SBRT. While there are limitations to the study, the findings suggest that SBRT may be an acceptable treatment option for certain patients with prostate cancer, particularly when specific dose-volume histogram parameters are considered.

Author Response

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Reviewer 3 Report

The author of the study aims to evaluate the associations between dosimetric parameters and patient-reported outcomes.  In the prostate cancer diagnosis, there are several treatment options Stereotactic body radiation therapy (SBRT) is one of them. A disadvantage of SRS/SBRT/SABR is that this technique is suitable only for small, well-defined tumors that can be seen on imaging such as CT or MR scans, thus this approach is not suitable for all situations.

The author concluded in the manuscript that “Toxicities after SBRT for localized prostate cancer using 32–36 Gy/4 fractions were acceptable”. Dose escalation has been shown in many trials, as well as registry data, to improve biochemical outcomes.

The author should also mention the clinical guidelines for e.g. NCCN and others. The NCCN guidelines emphasize that SBRT and IMRT likely have similar toxicity profiles.

It is interesting to know the influence of long -time treatment (ADT)  among high-risk patients in combination with SBRT and the toxicity level.

 

Does the author observe the poor quality of life; in terms of cognitive impairment, in patients going through ADT and later treated with SBRT? 

Author Response

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Reviewer 4 Report

The manuscript by Fujii et al., "Dosimetric predictors of toxicity after prostate stereotactic body radiotherapy: A single-institutional experience of 145 patients", systematically investigates the relationships between adverse events and dose index for prostate SBRT. The study includes 145 patients, irradiated with 32–36 Gy in 4 fractions. The median follow-up duration was 42.9 months, and one-tenth of patients suffered from Grade ≥2 toxicities. The risk factors, such as dose-volume histogram parameters (Radiotherapy-related) and T stage and Gleason score (patient-related) were evaluated in a competing risk analysis. The analysis showed that acute toxicities correlated with volume receiving a medium dose level and that late toxicities correlated with the highest point dose of organs at risk. While this study used a retrospective design with a short follow-up duration and limited access to collected items, the findings are useful and timely.

Author Response

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