Dynamic Changes in Prostate-Specific Antigen After Androgen Deprivation Therapy for Prostate Cancer are Strongly Associated with Biochemical Progression-Free Survival: A Multicenter Retrospective Analysis

doi:10.21203/rs.3.rs-820937/v1

Objectives: The risk factors for prostate cancer to progress to castration-resistant prostate cancer after androgen deprivation treatment (ADT) are still not to be well defined. We conducted this investigation in an attempt to determine factors that predicted the prognosis in a series of patients with prostate cancer after ADT.

Methods: We retrospectively analyzed the database of patients treated with androgen deprivation prostate cancer who were hospitalized in the Second Affiliated Hospital of Bengbu Medical College and Maoming People's Hospital from 2015.1.1 to 2020.12.30. PSA dynamic changes, including nadir PSA (nPSA), time to nadir PSA (TTN), were examined regularly. Cox risk proportional regression model was used for univariate and multivariate analysis; Kaplan-Meier survival curve and Log-rank test were used to compare and analyze differences in biochemical progression-free survival (bPFS) between groups.

Results: During the follow-up with a median time of 43.5 months, a total of 163 men were included in the study. The median bPFS of the two groups with nPSA lower than 0.2ng/ml and ≥0.2ng/ml were 27.6 months and 13.5, respectively, with significant differences between the groups (Log-rank p<0.001); The median bPFS of the two groups with TTN ≥9 months and less than 9 were 27.8 months and 13.5 months, respectively, with significant differences between the groups (Log rank p<0.001).

Conclusions: PSA dynamic changes after androgen deprivation treatment of prostate cancer can be used as prognostic indicators for bPFS. The lower the nadir PSA value and the longer the time to nadir, the longer the bPFS of patients with prostatic cancer after androgen deprivation treatment.

Cancer Biology

Oncology

Prostatic cancer

PSA changes

androgen deprivation treatment

biochemical progress-free survival

The incidence of prostate cancer in China increased at an average annual rate of approximately 12.6% between 2000 and 2005. As of 2015, the latest data from a large epidemiological survey showed that the incidence of prostate cancer in mainland China has approached approximately 10 per 100,000, vaulting to the highest incidence of urological tumors.^[1] Compared with developed countries in Europe and the United States, approximately 68% of prostate cancer patients in mainland China exhibit metastatic tumors at the time of diagnosis. ^[2] Androgen deprivation is the standard treatment modality for this type of prostate cancer. However, after a median of 18–24 months of good initial response in prostate cancer patients, ^[3] treatment will inevitably become more problematic as prostate-specific antigen (PSA) levels rise again, disease will progress, and tumors become castration-resistant.

The search for effective and accurate predictive markers of disease progression after androgen deprivation therapy for prostate cancer has been one of several “hot topics” of clinical exploration. PSA has played an important role in the screening, diagnosis, detection, and prognosis of prostate cancer since its introduction to clinical practice 30 years ago. ^[3] After androgen deprivation therapy for prostate cancer, a series of dynamic changes in serum PSA levels occur, and various factors affected by these changes may provide important prognostic information. However, considerable controversy persists regarding the utility of PSA nadir (nPSA) values, time to nadir PSA (TTN), and halving time after androgen deprivation therapy for prostate cancer in the prognostic determination of prostate cancer, ^[4–6] and need to be analyzed in more clinical studies.

We retrospectively analyzed data housed in prostate cancer databases in two medical centers, collected basic information on prostate cancer patients, performed standardized follow-up, and documented dynamic changes in PSA levels after androgen deprivation therapy up to the appearance of disease to elucidate the prognostic role of PSA nadir values as well as time to nadir in patients who underwent androgen deprivation therapy for prostate cancer.

Study subjects

Data from prostate cancer patients admitted to the ward for androgen deprivation therapy between January 1, 2015 and December 30, 2020, were extracted from the database of treatment and follow-up of prostate cancer patients in the Department of Urology, Second Affiliated Hospital of Bengbu Medical College, and the Department of Urology, People’s Hospital of Maoming, Guangdong Province, China. Patients who also met the following criteria and had available long-term post-treatment PSA follow-up data were included in this study. Specific inclusion criteria were as follows.

Eligible patients had to be diagnosed with prostate cancer based on pathological findings from prostate puncture biopsy.
Age ≥ 50 years at the time of onset.
Diagnosis of metastatic prostate cancer or locally progressive prostate cancer based on clinical or pathological examination, or unsuitable for curative treatment due to life expectancy or general condition.
No previous androgen deprivation therapy of any type for prostate cancer.
Good general condition with no serious abnormalities in liver or kidney function.
Did not receive any form of curative treatment for prostate cancer before treatment.
No other concomitant malignancies.
Complete information regarding pre-treatment clinical assessment, including basic information, chief complaint(s), physical examination, imaging, laboratory tests, and pathological findings.
Treated with androgen deprivation in the form of total androgen blockade (i.e., surgical/pharmacological castration + anti-androgen drugs).
Patients have not undergone other treatment modalities, including radical surgery, radiotherapy, and/or chemotherapy while receiving androgen deprivation therapy or until the onset of castration resistance after treatment. More specifically, androgen deprivation therapy could not be used as a component of neoadjuvant or adjuvant therapy.

Follow-up

Follow-up began after the patients were discharged from hospital, and serum PSA level was tested every 1 to 3 months for the first 2 years and every 3 to 6 months, on average, from the third year onward. Data regarding basic patient information, PSA level at initiation of androgen deprivation therapy, PSA nadir, time to nadir, and PSA halving time were collected and analyzed.

PSA nadir was defined as the lowest PSA level during androgen deprivation therapy, while time to nadir was defined as the time from initiation of androgen deprivation therapy to nPSA. PSA halving time reflected the rate of PSA decline after the start of androgen deprivation therapy. nPSA as well as TTN were used to calculate halving time in this study.

Biochemical progression was defined as 3 consecutive elevated PSA tests results, one week apart, and greater than the nadir of 50% two times. Biochemical progression-free survival (bPFS) was defined as the time from initial treatment to the first PSA elevation at the time of first biochemical progression.

Tumor load was defined using criteria from the Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) study of at least four bone metastases and at least one metastasis outside the median bone or in the pelvis, or the presence of visceral metastases.^[7]

Statistical analysis

Continuous variables are expressed as mean ± standard deviation, and non-continuous variables are expressed as median, including Gleason score. Appropriate comparative tests, such as analysis of variance and Fisher's exact test, were used to compare continuous and categorical variables. Cox risk proportional regression models were constructed for univariate and multivariate analyses of bPFS, including age, body mass index, staging, Gleason score, and metastatic load, as well as post-treatment PSA halving time, nadir value, and time to nadir. Receiver operating characteristic (ROC) curve analysis was used to determine cut-off values, and Kaplan-Meier survival curves to assess bPFS time in each group. The log-rank test was used to detect differences between groups, differences with P < 0.05 were considered to be statistically significant. All analyses were performed using SPSS version 27.0.1.0 (IBM Corporation, Armonk, NY, USA) software.

Overall analysis

A total of 163 patients fulfilled the inclusion criteria for this study and had long-term PSA monitoring follow-up records available. The age range of patients was 53–89 years, with a median age of 72 years. There were 12 patients at the T1-2N0M0 stage (limited early stage with PSA > 50 ng/mL), 32 at T3-4M0 (focal progressive), and 119 at M1 (metastatic). All patients had prostate cancer confirmed by prostate puncture biopsy. Nine (5.5%) patients underwent surgical castration and the remaining 94.5% were treated with subcutaneous goserelin acetate (3.6 mg once/28 days) as androgen deprivation therapy. All patients received oral bicalutamide (50 mg every day) concomitantly with castration treatment. The median follow-up was 43.5 months. Thirteen (8.0%) patients were lost to follow-up. Basic characteristics of the patients are summarized in Table 1.

Screening for prognostic risk factors

Risk factors associated with biochemical progression of PSA were analyzed using univariate and multivariate Cox regression. As shown in Table 2, in terms of PSA biochemical progression, only whether PSA declined to ≤ 2 ng/mL (hazard ratio [HR] 0.462, P = 0.001), and PSA time to nadir less than 9 months (HR 1.736, P = 0.021) were independent risk factors for disease progression. PSA half time more than 3 months tended to increase the risk of disease progress (HR 1.346), however, it was not statistically significant (P = 0.338). PSA falling to < 0.2 ng/ml were associated with a good prognosis, while the risk for disease progression was lower when the time to PSA nadir was longer.

Dynamic changes in PSA levels and survival with biochemical progression-free

Absolute levels of PSA after treatment: As shown in Table 3, the lower the PSA nadir value, the lower the risk for bPFS. After controlling for other variables (Gleason score, stage, initial PSA level, age, body mass index, and tumor load), lower PSA nadir value still predicted lower bPFS.

Rate of PSA change after treatment: As shown in Table 4, for patients in whom PSA level decreased to < 4 ng/ml (“normalization”) after treatment, the risk for PFS was lower when the PSA “normalization time” was shorter, but a statistical correlation with castration resistance could not be demonstrated. In this case, when grouped of 8 ~12, 12~24, and >24 weeks for intergroup comparison, shorter time to nadir was associated with better patient prognosis, and PSA “normalization time” more than 24 weeks could be used as an independent predictor (HR 0.695, P = 0.001). This suggests that prognosis is better when PSA level falls into the reference ranges faster after androgen deprivation therapy.

Analysis of PSA time to nadir—in contrast to PSA “normalization time”—revealed that longer PSA time to nadir was associated with a decreased risk for bPFS and remained a statistically significant predictor after controlling for other risk factors. In this study, the same conclusions were obtained by choosing 6, 10, and 12 months as the cut-off values.

Finally, in terms of PSA halving time, group comparisons using 0.5, 1, 1.5, and 3 months as cut-off values revealed that the shorter the PSA halving time, the worse the prognosis. The faster the PSA decreased to the lowest value, the worse the prognosis was, regardless of the adjustment for PSA nadir value. However, none of the group comparisons demonstrated statistically significant.

Optimization of PSA nadir values and time cut-offs for reaching the nadir: Results showed (Figure 1) that the area under the curve (AUC) for PSA nadir and PSA time to nadir were 0.804 and 0.833, respectively, which were > 0.7 but both were < 0.9, indicating that both had a certain degree of accuracy for prognostic judgments. In particular, the sensitivity of PSA nadir value was 65.7% and the specificity was 73.6% when 0.2 ng/ml was used as the best cut-off value. Moreover, PSA nadir > 0.2 ng/ml suggested a poor prognosis, while PSA nadir ≤ 0.2 ng/ml suggested a good prognosis. Similarly, for PSA time to nadir, 9 months was the most appropriate threshold, with a sensitivity of 71.6% and a specificity of 73.9%. Patients with a time to nadir > 9 months had a better prognosis.

In addition, the AUC for PSA halving time was 0.563, which was < 0.7, thus indicating a lack of accuracy of this indicator as a prognostic criterion for bPFS.

As shown in Figure 2, the median bPFS was 27.6 months and 13.5 for cases in two groups with PSA nadir < 0.2 ng/ml and ≥ 0.2 ng/ml, respectively, and there was significant difference between groups (P < 0.001 [log-rank]). The median bPFS was 27.8 months and 13.5 months for cases in two groups with TTN ≥ 9 months and < 9 months, respectively, and there was significant difference between the two groups (P < 0.001 [log rank]).

Due to the current characteristics of prostate cancer incidence in China, androgen deprivation therapy for this disease remains an important topic to be explored. ^[6] PSA not only plays an important role in prostate cancer screening, but also in follow-up after androgen deprivation therapy. Dynamic changes in PSA levels after androgen deprivation therapy are of important prognostic value, and observations have been derived from curves reflecting these changes, such as PSA nadir, time to PSA nadir, and PSA halving time. ^[8] However, controversy remains in previous clinical studies investigating the predictive significance of these indicators when applied to the progression of prostate cancer to castration resistance. ^[9]

In this study, multicenter case-review analysis revealed that patients with PSA nadir values < 0.2 ng/ml had significantly (p < 0.001) better disease-free survival (median survival time up to 27.6 months) than those with nadir values > 0.2 ng/ml (median PFS, 13.5 months) and a 67.7% lower risk for progression (hazard ratio, 0.323). Similar findings have been confirmed in previous studies, ^{[6, 10]} in which the lower the PSA nadir, the better the prognosis; however, the nadir cut-off values reported in different studies vary slightly. ^{[5,6,10−13]} Most studies concluded a cut-off value of 0.2 ng/ml, ^{[5, 10, 11, 13]} and some suggest that PSA nadir should be as low as unmeasurable so that patients have a better prognosis, ^[14] or somewhat higher, 4.0 ng/ml. ^[12] These differences may be explained by different study populations and follow-up methods.

The present study found that time to nadir was also closely related to prognosis, with longer time to PSA nadir (TTN) being associated with longer bPFS. The median time to bPFS in the group of prostate cancer patients with TTN > 9 months was 27.8 months, while that in the group of cases with TTN < 9 months was only 14.5 months, and there was a statistically significant difference (P = 0.004); which were consistent with the findings reported in previous studies. ^{[11, 13, 15–17]} The TTN cut-off values set by different studies vary, ranging from 6 to 12 months, with most studies setting a cut-off value of 9 months. ^{[11, 15]}

In our study, we also found that the lower the nPSA, the lower the risk for bPFS (P < 0.001). This is consistent with findings reported in previous studies.^[18] This study used nPSA and TTN as continuous variables to analyze and compare several subgroups. The results showed that the risk for bPFS increased 1.794-fold in the subgroup with nPSA between 0.2 and 4 and 5.332-fold in the subgroup with nPSA > 4 compared to the subgroup with TTN > 12 months, and that the risk increased by 1.245-fold at TTN < 12 months and 3.408-fold at TTN < 6 months compared to the subgroup with TTN > 12 months.^[18]

In this study, ROC curve analysis revealed that PSA halving time did not predict prognosis after androgen deprivation therapy in prostate cancer patients compared to the nPSA and TTN index. The AUC was only 0.553, which did not reach 0.7, suggesting that this indicator has no prognostic significance for prognosis determination. This may be related to the fact that the rate of PSA decay after androgen deprivation therapy for prostate cancer is not constant. It has been suggested that androgen deprivation therapy for prostate cancer progresses through three phases ^[19]: androgen-PSA response, tumor atrophy, and proliferation quiescence. Due to the heterogeneity of prostate cancer, the tumor contains different proportions of hormone-non-dependent cancer cells within the tumor, the rate of PSA decline and the time of tumor cell adaptation naturally differ, and the currently defined PSA halving time is difficult to accurately reflect the proportion of androgen-non-dependent cancer cells and, thus, cannot predict the prognosis of prostate cancer.^[8]

In addition to the above observations, early PSA response to androgen deprivation therapy for prostate cancer (PSA decline > 30% at the first 4 weeks or > 30% at 12 weeks) is commonly used as a prognostic indicator.^{[20, 21]} Kinetic changes in serum PSA levels have been applied not only for the prognosis of hormone-sensitive prostate cancer, but also for second-line androgen deprivation therapy in castration-resistant prostate cancer,^{[22, 23]} or as a prognostic monitoring indicator for chemotherapy in castration-resistant prostate cancer.^[24]

Limitations of this study include its retrospective design, the small number of patients, and possible differences in criteria between the two centers during follow-up observations, all of which may have had an impact on the conclusions. The study’s metrics failed to include more currently used common metrics such as overall survival or disease-specific survival.

This study further confirmed that nPSA and TTN can be used as predictors after androgen deprivation therapy for prostate cancer, and that patients with nPSA values < 0.2 ng/ml and TTN > 9 months had a better prognosis.

ADT, androgen deprivation treatment, bPFS, biochemical progression-free survival, PSA, prostate specific antigen, TTN, time to nadir, HR, hazard ratio, CI, confidence interval

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Our study was granted an exemption from requiring ethics approval from the Ethics Committee of The Second Affiliated Hospital of Bengbu Medical College and the Ethics Committee of Maoming People`s Hospital, as it was retrospectively analysis. All the experiment protocol for involving human data was in accordance with the guidelines of our institutional or Declaration of Helsinki in the manuscript, and the written informed consent from study participants were obtained.

COSENT FOR PUBLICATION

Not applicable.

AVAILABILITY OF DATA AND MATERIALS

The analyzed data sets generated during the study are available from the corresponding author on reasonable request.

COMPETING INTERESTS

All authors declare no competing interests.

FUNDING

This work was supported by grants from the Key Projects of Provincial Educational Department, Anhui Province, China Mainland (No. KJ2019A0373), and Bengbu Medical College, Anhui Province, China mainland (No. BYKC201912), High-level Hospital Construction Research Project of Maoming People`s Hospital and Maoming Municipal Science and Technology Bureau Special Plan (No. 201116164553097).

AUTHOR CONTRIBUTIONS

MQH conceived of and carried out the retrospective studies, participated in the statistical analysis and drafted the manuscript. YFM participated in the data acquisition and performed the statistical analysis. KZZ, CG and AMW participated in its design and coordination. All authors read and approved the final manuscript.

ACKNOWLEDGMENTS

None.

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Table 1. Baseline characteristic of patients with prostatic cancer

Variables		No. of patients
Age (y)	53~90
Mean ± SD	74.36 ± 6.75
Median	72
BMI (kg/m²)
Mean ± SD	23.52 ± 3.26
Median	24.4
Subgroups of BMI	%
< 20	18.40	30
20 ~ 25	56.45	92
> 25	25.15	41
Clinic stage
T1/T2 M0	7.36	12
T3/T4/N1 M0	19.63	32
M1	73.01	119
Pathologic diagnosis (%)
adenocarcinoma	99.4	162
non-adenocarcinoma	0.6	1
Gleason score
≤ 6	3.07	5
3 + 4 = 7	15.95	26
4 + 3 = 7	25.77	42
8 ~ 10	55.21	90
Methods of ADT
Surgical castration	5.52	9
Medical castration	94.48	154
Prostatic volume (mL)
Mean ± SD	55.32 ± 23.54
Median	47.86
PSA at diagnosis (ng/ml)
Mean ± SD	126.47 ± 12.36
Median	98.59
Nadir PSA (ng/ml)
Mean ± SD	2.36 ± 7.36
subgroups
< 0.2	44.79	73
0.2 ~ 4	33.74	55
> 4	21.47	35
Time to nadir (month)	9.26
Bone scan
Positive	73.00 %	119
Negative	27.00 %	44
Metastasis tumor burden ^a
low	26.05 %	31
high	73.95 %	88

Abbreviations: BMI, body mass index, ADT, androgen deprivation treatment, PSA, prostate specific antigen.

^a only including 119 metastasis cases.

Table 2. Univariate and multivariate analysis of potential risk factors for biochemic progress-free survival

Variable	Univariate		Multivariate
Variable	HR (95% CI)	p	HR (95% CI)	p
Age ^a	0.965 (0.953~0.992)	0.010	0.993 (0.963~1.023)	0.568
BMI	1.025 (0.967~1.078)	0.259
Gleason score	1.146 (0.980~1.354)	0.059
Stage ^a	1.452 (1.142~1.698)	0.024	0.986 (0.968~1.028)	0.924
Metastasis tumor burden ^{a, b}	1.534 (1.283~1.845)	0.000	1.152 (0.946~1.521)	0.178
PSA level at diagnosis ^a	1.023 (1.001~1.030)	0.002	1.002 (0.989~1.021)	0.910
PSA nadir (ng/mL)
> 2	1.000 (reference)		1.000 (reference)
≤ 2	0.462 (0.374 ~ 0.523)	0.001	0.492 (0.348 ~ 0.583)	0.003
TTN (months)
> 9	1.000 (reference)		1.000 (reference)
≤ 9	1.736 (1.422 ~ 2.033)	0.021	1.713 (1.583~ 2.198)	0.012
PSA half time (months)
≤ 3	1.000 (reference)		1.000 (reference)
> 3	1.346 (1.135 ~ 1.864)	0.338

Abbreviations: CI, confidence interval, BMI, body mass index, ADT, androgen deprivation treatment, PSA, prostate specific antigen, TTN, time to nadir.

^asignificant at univariate analysis and carried onward to multivariate analysis,

^b only including 119 metastasis cases.

Table 3. Cox analysis the relationship between PSA nadir and bPFS

PSA nadir (ng/mL)	HR (95% CI)	p-value
Univariate analysis
≤ 0.2	1.000 (reference)
0.2~1.0	1.329 (1.131 ~ 1.344)	0.014
1.0~2.0	1.921 (1.244 ~ 2.336)	0.016
>2.0	2.538 (1.964 ~ 3.756)	0.000
	p for trend < 0.01
Multivariate analysis
≤ 0.2	1.000 (reference)
0.2~1.0	1.237 (1.190 ~ 1.463)	0.000
1.0~2.0	2.327 (2.153 ~ 3.161)	0.000
>2.0	3.489 (2.268 ~ 3.997)	0.000
	p for trend < 0.01

Abbreviations: PSA, prostate specific antigen, bPFS, biochemic progression-free survival, HR, hazard ratio, CI, confidence interval.

Table 4. Cox analysis the relationship between PSA changing velocity and bPFS

	Univariate analysis		Multivariate analysis
	HR (95 % CI)	p-value	HR (95 % CI)	p-value
Time to PSA ≤ 4 ng/mL (weeks)
≤ 4	1.000 (reference)		1.000 (reference)
4~8	0.845 (0.803 ~ 0.948)	0.927
8~12	0.748 (0.526 ~ 1.048)	0.086
12~24	0.756 (0.532 ~ 1.067)	0.114
>24	0.656 (0.476 ~ 0.927)	0.021	0.695 (0.623 ~ 0.821)	0.001
Time to PSA nadir (months)
≤ 6	1.000 (reference)		1.000 (reference)
6~9^a	0.936 (0.824 ~ 1.002)	0.026	0.902 (0.824 ~ 0.968)	0.001
> 9^a	0.532 (0.282 ~ 0.713)	0.000	0.503 (0.213 ~ 0.698)	0.000
	p for trend < 0.01		p for trend < 0.01
PSA halving time (months)
≤ 0.5	1.000 (reference)		1.000 (reference)
0.5~1	1.136 (0.995 ~ 1.226)	0.132
1~1.5	0.910 (0.736 ~ 1.623)	0.364
1.5~3	0.653 (0.497~ 0.936)	0.098
> 3	0.536 (0.485 ~ 0.663)	0.063

^asignificant at univariate analysis and carried onward to multivariate analysis,

Abbreviations: PSA, prostate specific antigen, bPFS, biochemic progression-free survival, HR, hazard ratio, CI, confidence interval.

No competing interests reported.

Dynamic Changes in Prostate-Specific Antigen After Androgen Deprivation Therapy for Prostate Cancer are Strongly Associated with Biochemical Progression-Free Survival: A Multicenter Retrospective Analysis

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