Influence of Active Surveillance on Gleason Score Upgrade and Prognosis in Low- and Favorable Intermediate-Risk Prostate Cancer

Round 1

Reviewer 1 Report

Authors say that " Zhang et al. proposed that higher clinical T stage and positive cores < 3 increased the risk of GSU" (line 59, bibliographic reference number 10).

But this paper says that "positive cores ≥ 3 increased the risk of GSU).

Please, check it.

 

I suggest improving the quality of figures

 

Author Response

1. Authors say that " Zhang et al. proposed that higher clinical T stage and positive cores < 3 increased the risk of GSU" (line 59, bibliographic reference number 10).But this paper says that "positive cores ≥ 3 increased the risk of GSU).Please, check it.

Response: The reviewer’s comment is well appreciated. We are grateful to the appreciations and constructive suggestions on our manuscript from you.

First, according to existing studies, we can find two opposite conclusions. One believed that a small number of positive cores may lead to the occurrence of GSU [1], while the other believed that a large number of positive cores is more likely to lead to tumor progression [2]. In the case of more accurate puncture, the number of positive cores is often related to the degree of tumor invasion in the prostate cancer. Therefore, it is not accurate to focus only on the number of positive cores, and the percentage of positive cores in the puncture specimens may be a more effective indicator, which has been reported in other studies [3].

Second, zhang et al. pointed out that clinical stage≥T2c, the number of positive cores <3, and lower positive rate of biopsy were the risk factors of GSU, which indicated that selection error played a major role in GSU. We considered that it was not accurate to only look at the number of positive cores, and even the opposite results can be obtained when the puncture was relatively accurate. Therefore, it may be more rigorous to add the index of positive puncture cores rate.

Third, at present, ultrasound guided prostate biopsy is the mainstream of clinical application, which may lead to selection bias in diagnosis, that is, some prostate cancer specimens with high gleason score may not be collected. This is the main cause of GSU in low-risk prostate cancer.

Fourth, our study suggested that the proportion of positive cores >25% in low-risk prostate cancer may contribute to the development of GSU, which made more sense than the number of positive cores. In order to make the article more rigorous, we have replaced "Zhang et al. proposed that higher clinical T stage and positive cores < 3 increased the risk of GSU" with “Zhang et al. proposed that higher clinical T stage increased the risk of GSU in the cohort with GS = 6”.

Thanks for your comment.

 

 

1. Thomas C, Pfirrmann K, Pieles F, et al. Predictors for clinically relevant Gleason score upgrade in patients undergoing radical prostatectomy. BJU Int. 2012;109(2):214-219. doi:10.1111/j.1464-410X.2011.10187.x
2. Athanazio D, Gotto G, Shea-Budgell M, Yilmaz A, Trpkov K. Global Gleason grade groups in prostate cancer: concordance of biopsy and radical prostatectomy grades and predictors of upgrade and downgrade. Histopathology. 2017;70(7):1098-1106. doi:10.1111/his.13179
3. Park HJ, Ha YS, Park SY, et al. Incidence of upgrading and upstaging in patients with low-volume Gleason score 3+4 prostate cancers at biopsy: finding a new group eligible for active surveillance. Urol Int. 2013;90(3):301-305. doi:10.1159/000345292

 

Reviewer 2 Report

It is an interesting study, but some concerns and revision should be done before to be accepted.

1. In introduction:    line 40   : for 26% "\", It is a typo ??

2. In introduction :   line 49-50  :......," the Gleason score upgrade (GSU) 

occasionally occurred when samples were compared from radical prostatectomy and biopsy ".      "when samples were compared from radical prosattectomy  and biopsy "  is a pleonasm . 

3. In introduction :Line 59-60  "However, most of them are small sample studies and addressed factors such as "AS duration and stratification of risks."

The later sentence seems to be incomplete.

4.  You have to explain what is the reason for  using AS duration  as a variable. 

5. In the results: Most of the enrolled patients were followed-up for less than 6 months.  only 0.8 % over 2 years. This will    

 made AS duration analyses deviation.

6. No repeated biopsy  Gleason score data available  during AS duration ?

7. In line 120-121   : total cancer specific mortality : 407/2820= 14.4 %  , AS : 389/2327= 16.7 %    , Can you explain  why ?

8. The Figures are fuzzy and difficult to identify. Please revised your figures.

9.Please address more and  elucidate the possible theoretical explanation between AS duration and GSU.    

Author Response

1. In introduction:  line 40  : for 26% "\", It is a typo ??

Response: Thank you very much for your correction.

We have deleted the symbol of the typo in line 40.

Thank you for straightening this out for us, which is very important to improve the quality of the article

 

2. In introduction :   line 49-50  :......," the Gleason score upgrade (GSU) occasionally occurred when samples were compared from radical prostatectomy and biopsy ".      "when samples were compared from radical prostatectomy and biopsy "  is a pleonasm . 

Response: Thank you very much for your comment

We have deleted " when samples were compared from radical prostatectomy and biopsy " in the manuscript, changed it to "However, once some patients stopped AS and underwent surgery, the Gleason score upgrade (GSU) occasionally occurred during subsequent radical surgery."

Your suggestion is essential to improve the quality of our manuscript.

 

3. In introduction: Line 59-60 "However, most of them are small sample studies and addressed factors such as "AS duration and stratification of risks."The later sentence seems to be incomplete.

Response: The reviewer’s comment is well appreciated.

We have replaced "However, most of them are small sample studies and addressed factors such as AS duration and stratification of risks." with "However, most of them are small sample studies and don’t addressed factors such as AS duration and stratification of risks, which are critical for patients choosing AS." in the revised manuscript.

Thank you very much for your great comment.

 

4. You have to explain what is the reason for using AS duration as a variable. 

Response: The reviewer’s comment is well appreciated. 

First, in recent years, AS has emerged as one of the preferred treatment for prostate cancer, especially for low - and favorable - intermediate - risk prostate cancer. Through AS, we can preserve urination and sexual function as much as possible until the cancer requires further intervention. This trend was also confirmed by Walker et al.’s study [1]. Therefore, AS is also a key indicator that needs much attention in clinical practice, but there are few relevant studies at present.

Second, although most current studies suggested that AS did not affect the prognosis of patients, they didn’t stratify the AS duration and risk of prostate. In fact, during the long-term monitoring, some patients have pathological upgrading, which may affect the recurrence of prostate cancer and the prognosis of these patients. By stratifying the AS duration, we can provide theoretical basis for prostate cancer monitoring with different risks, especially for unfavorite medium-risk prostate cancer, which is only suitable for short-term monitoring.

Third, according to your suggestion, we have added" By stratifying the AS duration and the risk of prostate cancer, we can develop individualized AS programs to prevent patients from pathological upgrading or poor prognosis due to long-term monitoring." into "introduction" section.

Thank you for your great comment.

 

1.Walker CH, Marchetti KA, Singhal U, Morgan TM. Active surveillance for prostate cancer: selection criteria, guidelines, and outcomes. World J Urol. 2022;40(1):35-42. doi:10.1007/s00345-021-03622-8

 

5. In the results: Most of the enrolled patients were followed-up for less than 6 months.  only 0.8 % over 2 years. This will  made AS duration analyses deviation.

Response: Thank you very much for your comment. We are grateful to the appreciations and constructive suggestions on our manuscript from you.

First, when analyzing the data, we also noticed that most patients preferred short-term monitoring, while fewer patients chose long-term monitoring, which might affect the accuracy of the results. However, we considered that in short-term monitoring, the progression of tumor was not obvious and there was no significant difference in prognosis. We needed to clarify whether long-term monitoring had an impact on the GSU and the prognosis, so we still considered taking AS duartion > 2 years into the analysis.

Second, due to the deviation of the variables of the patients included in this study, there may be some bias. We have added "Besides, only 0.8% of the patients chose long-term monitoring in this study, which might have biased the statistical results." into "limitation" section in the revised manuscript. This bias can be compensated by a larger sample size from the SEER database.

Third, after receiving your comments, we re-analyzed the data and combined AS duration > 2 years with AS duration > 1 year. We found that the conclusions obtained in logistic regression and competitive risk model were still consistent with the previous results (The above analysis results have been uploaded to the supplementary materials). The only difference between the two conclusions was that it was impossible to distinguish whether being monitored for more than two years in unfavorable moderate risk prostate cancer would have an impact on prognosis. Taking into account the existing conclusions, we are still considering including data from more than two years of monitoring. 

Thank you for your great comment.

 

 

6. No repeated biopsy Gleason score data available during AS duration ?

Response: The reviewer’s comment is well appreciated. 

First, prostate puncture is the gold standard for the diagnosis of prostate cancer. After diagnosis of prostate cancer, we prefer to monitor patients by reviewing PSA and pelvic MRI results. Repeated prostate puncture as an invasive procedure may cause the risk of prostate cancer spreading. At present, there are few patients who undergo repeated prostate puncture after diagnosis.

Second, since our data are from the SEER database, there is no record of whether the patient underwent prostate puncture again after diagnosis. SEER*stat 8.4.0 software was used to extract the data of gleason score by available code, as shown in supplementary material 3. We checked the data again according to the code in the coding manual, and did not find the data of repeated prostate biopsy included.

Third, we highly agree with your suggestion that the pathological escalation of some prostate cancer may not be accompanied by elevated PSA or other imaging manifestations, but can be detected by prostate biopsy. This can also be one of our research directions.

Thank you for your great comment.

 

7. In line 120-121: total cancer specific mortality : 407/2820= 14.4 %  , AS : 389/2327= 16.7%, Can you explain why ?

Response: Thank you very much for your comment.

First, We checked the data again and found that there was an error caused by the data retention of the previous version. In fact, a total of 2327 patients who chose to AS died, of which 339 were cancer-specific deaths. Based on the above data, cancer-specific deaths accounted for 14.5% of the total deaths, and there was no significant statistical difference between both, which is consistent with the conclusion of the competitive risk model

Second, we have replaced "Among those who chose AS, 2327 died, of which 389 were cancer-specific." with "Among those who chose AS, 2327 died, of which 339 were cancer-specific." in the revised manuscript.

Thank you very much for your correction.

 

8. The Figures are fuzzy and difficult to identify. Please revised your figures.

Response: Thank you very much for your comment.

We have increased the picture resolution to 300 as required.

Your suggestion is very important to improve the quality of our manuscript.

 

9. Please address more and elucidate the possible theoretical explanation between AS duration and GSU.    

Response: The reviewer’s comment is well appreciated. 

First, AS is the recommended initial management strategy for some patients with low-grade prostate cancer and an option for selected patients with favorable intermediate-risk disease. In Org’s study, they pointed out that the number of patients choosing AS increased from 33% in 2009 to 67% in 2016 in Australia [1]. This trend is not only in Australia, but in some other countries, which provides the demographic basis for GSU.

Second, prostate cancer is a low-grade malignant tumor. Only a small number of patients develop pathological upgrade in a short period of time. The pathological upgrade process of most patients is lengthy, and may not progress even after 3 or 5 years of follow-up. Moreover, many patients are not regularly monitored, and these patients are more likely to have further tumor progression or metastasis [2]. In conclusion, long-term AS provides a time basis for the occurrence of GSU.

Third, reasons for GSU may include i) biological progression or cancer dedifferentiation [3]; ii) sampling error at diagnosis(Although sampling error, where the tumour present in the needle core does not adequately reflect the tumour present in the prostate, is commonly cited as the most important cause of tumour undergrading, a systematic analysis of its contribution to error has not been performed, particularly in the era of routine 10 – 12 core biopsies [4]); iii) changes in pathological classification with time(Pathological grading of prostate cancer changed with the implementation of the International Society of Urological Pathology (ISUP) modified Gleason grading system[5] ); and/or iv) inter observer variability.

Fourth, the main categories i and ii were discussed in this study. Sampling bias is more common in low-risk prostate cancer, while tumor cell dedifferentiation or pathological variation are more common in patients with medium-risk prostate cancer over time. Therefore, we tried to target a safe AS duration by identifying the likelihood of GSU over time in different risk prostate cancer.

We are grateful to the constructive suggestions on our manuscript from you.

1. Ong WL, Evans SM, Evans M, et al. Trends in Conservative Management for Low-risk Prostate Cancer in a Population-based Cohort of Australian Men Diagnosed Between 2009 and 2016. Eur Urol Oncol. 2021;4(2):319-322. doi:10.1016/j.euo.2019.04.006
2. Soeterik TFW, van Melick HHE, Dijksman LM, Biesma DH, Witjes JA, van Basten JA. Follow-up in Active Surveillance for Prostate Cancer: Strict Protocol Adherence Remains Important for PRIAS-ineligible Patients. Eur Urol Oncol. 2019;2(5):483-489. doi:10.1016/j.euo.2019.01.010.
3. Press BH, Jones T, Olawoyin O, et al. Association Between a 22-feature Genomic Classifier and Biopsy Gleason Upgrade During Active Surveillance for Prostate Cancer. Eur Urol Open Sci. 2022;37:113-119. Published 2022 Feb 11. doi:10.1016/j.euros.2022.01.008
4. Corcoran NM, Hovens CM, Hong MK, et al. Underestimation of Gleason score at prostate biopsy reflects sampling error in lower volume tumours. BJU Int. 2012;109(5):660-664. doi:10.1111/j.1464-410X.2011.10543.x
5. Dong F, Wang C, Farris AB, et al. Impact on the clinical outcome of prostate cancer by the 2005 international society of urological pathology modified Gleason grading system. Am J Surg Pathol. 2012;36(6):838-843. doi:10.1097/PAS.0b013e3182486faf

Author Response File: Author Response.docx