Cryoablation versus radiation therapy for low and intermediate risk localized prostate cancer: a propensity score-adjusted cohort analysis of oncologic outcomes CURRENT STATUS:

Background: We are aiming to compare the oncologic outcomes between cryoablation and radiation therapy for low or intermediate risk localized prostate cancer. Methods : Among patients diagnosed between 2004 and 2016 in SEER databases, we identified cases confirmed low or intermediate risk prostate adenocarcinoma treated with radiation treatment (n = 93041) or cryoablation (n = 2350). Propensity score matching (PSM) was performed. Kaplan-Meier method, Cox proportional hazards model were used to calculate cancer specific mortality (CSM) and overall survival (OS) in the unmatched and matched cohort, and in subgroups based on clinical characteristics. Results: A total of 95391 patients who were diagnosed with first prostate adenocarcinoma and treated with radiation treatment (97.54%) or cryoablation (2.46%) were identified. In the matched cohort, cryoablation group has similar CSM (HR 1.13, 95%CI 0.72-1.77, P=0.6) and worse OS (HR 1.20, 95%CI 1.04-1.39, P=0.01) than radiation treatment group in the non-adjusted model as well as those in the adjusted model (HR 1.06, 95%CI 0.68-1.65, P=0.8; HR 1.18, 95%CI 1.02-1.36, P=0.02, respectively). For low risk disease, CSM and OS outcomes were similar between cryoablation and radiation treatment group. Last but not least, for intermediate risk patients, compared with radiation treatment group, cryoablation group has similar CSM (HR 1.26, 95%CI 0.90-1.77, P=0.2) and inferior OS (HR 1.17, 95%CI 1.04-1.32, P=0.01). Conclusion: In summary, for low risk disease, CSM and OS outcomes were similar between cryoablation and radiation treatment group. For intermediate risk disease, we found that radiation treatment group showed superior OS than cryoablation group. versus RT with outcomes. HR1 indicates an increased risk of outcome in patients receiving cryoablation.


Introduction
In the current era, prostate cancer is a commonly diagnosed malignancy in elderly men 1 . With increasing use of prostate specific antigen (PSA) for detection of prostate cancer, the amount of cases of prostate cancer continue to rise 2, 3 . Furthermore, the majority of individuals are diagnosed in the local, early disease stage. Therefore, the treatment strategy of early prostate cancer is great of importance. Currently, either radical prostatectomy or radiation treatment is the gold standard of therapy of patients with localized prostate cancer 4 . Although both interventions have favorable longterm oncologic outcomes, due to targeting the entire prostate gland cause significant complications including incontinence, erectile dysfunction, and rectal injury et al 5, 6 . Taking the above negative effects of radical prostatectomy or radiotherapy into consideration, therefore, minimally invasive treatment such as cryoablation maybe the valid alternative to overtreatment and observation for localized prostate cancer with acceptable oncologic outcomes. At present, which therapy is better for localized prostate cancer is of growing interest and is worthy of further study. Furthermore, favorable oncologic and functional outcomes have been reported from minimal invasive therapies targeting areas of lesion rather than the entire prostate 7-9 .
To the best of our knowledge, multiple consensus groups have highlighted that low risk patients should not routinely be offered focal therapy and that the ideal patients are those with localized intermediate risk disease 8

Covariates
Baseline clinical characteristics were adjusted for analyses, including age, PSA, T stage, Gleason Score, marital status, race and risk stratification.

Outcomes
The outcomes consisted of cancer specific mortality (CSM) and overall survival (OS) estimated by Kaplan Meier method.

Statistical analysis
For baseline clinical characteristics, categorical variables are presented in terms of frequency with its proportion. Statistical difference between proportions of the two groups (cryoablation vs. radiation treatment) was determined by Chi-square test. CSM and OS were compared of two groups by using the unadjusted Kaplan Meier curves with the log-rank test followed by Cox regression models adjusting for several demographic and tumor characteristics.
Subgroup analyses were performed by stratifying patients by age, T stage, PSA, Gleason Score and risk stratification. To confirm the results, we performed a secondary analysis using propensity score matching (PSM) since two groups differed significantly in some of the baseline characteristics.
Propensity scores were estimated in multivariable logistic regression models, where the dependent variables was the treatment (cryoablation vs. radiation treatment). The independent variables (age, PSA, T stage, Gleason Score, race and risk stratification) were performed in the PSM analysis. The greedy matching method within specified caliper distances was applied to match patients in two groups with the matching ratio of 1:6 using a caliper equal to 0.05 13 . Inverse probability of treatment weighing (IPTW) and standardized mortality ratio weighting (SMRW) calculated with the propensity score to estimate the relationship between treatment types and outcomes among the entire cohort.

Baseline clinical characteristics
The baseline clinical characteristics were summarized in Table 1. A total of 95391 patients who were diagnosed with first prostate adenocarcinoma and treated with radiation treatment (97.54%) or cryoablation (2.46%) were identified. In the unmatched cohort, compared with patients underwent radiation treatment, those underwent cryoablation were older (P < 0.001), more likely to be white (P = 0.004), with low PSA (P < 0.001), high T stage (P < 0.001), high Gleason score (GS) (P < 0.001) and intermediate risk (P < 0.001).  Fig. 1. Results showed that CSM was similar between radiation treatment and cryoablation group (P = 0.17) (Fig. 1a). Furthermore, the radiation treatment group has a better OS than cryoablation group (P < 0.0001) (Fig. 1b) (Table S1).

Discussion
Previously studies had demonstrated that cryoablation is an effective treatment and minimally invasive, with low surgical risk, low morbidity, with good results in the long follow-up in terms of

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