A prospective study assessing the pattern of response of local disease at DCE-MRI after salvage radiotherapy for prostate cancer

doi:10.21203/rs.3.rs-1350793/v1

Background: To assess the pattern of response of presumed local lesions at dynamic contrast enhancement magnetic resonance imaging (DCE-MRI) after salvage radiotherapy (sRT).

Methods: This is a prospective study conducted at a single Institution accruing patients with one or more local failures at DCE-MRI after radical prostatectomy between August 2017 and June 2020. Patients underwent exclusive sRT delivering 66-69 Gy and 73.5 Gy in 30 fractions to the whole prostatic fossa and to the local failure(s) seen at DCE-MRI, respectively.

Patients were offered DCE-MRI at 3 month-intervals after sRT until complete dis-appearance (CR) of the lesion(s) or up to a maximum of 4 re-evaluations.

Results: 62 patients with 72 nodules were enrolled. All patients underwent the 1^st re-evaluation, and 33 patients (53.2%) showed a CR. The median time to CR was 4.7 months. Four patients did not undergo further testing before achieving a CR and even considering these patients as no responses, the vast majority (87.1%, 95%CI: 78.5-94.4%) of lesions would have completely disappeared by 12 months from the end of sRT.

The volume of the lesion at pre-sRT DCE-MRI was an independent predictor of CR at the 1^st re-evaluation (OR: 0.076, 95%CI: 0.009-0.667; p=0.020) along with time elapsed from sRT (OR: 3.399, 95% CI: 1.156-9.993, p=0.026).

Conclusions: The present study documents the complete dis-appearance of the vast majority of local lesions after dose-escalated sRT though this requires several months after sRT; timing of CR is at least in part predictable based on the volume of the lesion.

Trial registration: Clinicaltrials.gov NCT04703543, registered July 15 2020, retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04703543.

prostate cancer

salvage radiotherapy

dynamic contrast enhancement magnetic resonance imaging

local failure

The proper evaluation of response to therapy is crucial in cancer treatment evolution and amelioration. Acknowledging the presence of residual disease after a local therapy helps to tailor treatment intent and its aggressiveness.

After exclusive salvage radiotherapy (sRT) for a presumed local failure following radical prostatectomy, about 30-40% of patients show further biochemical progression at 5 years (1-3). However, serum prostate specific antigen (PSA) measurement lacks spatial information and the pattern of failure of patients in this clinical scenario remains unclear for the majority of them (2-5). The paucity of data on the local response rate to sRT is partly due to the fact that none of the above studies requested a detailed imaging study of the prostatic fossa before sRT consistently with the recommendations (6) and the limitations of the imaging modalities (7) at the time these studies were undertaken. An exception is the SAKK trial, though MRI of the prostatic fossa was done in only about a third of the patients and multiparametric sequences were not required per protocol (1). If the prostatic fossa is not properly staged before sRT, response cannot be obviously assessed.

At our Institution multiparametric magnetic resonance is part of the restaging process for patients with a biochemical failure after radical prostatectomy (RP) and it is systematically performed in patients who are candidates for sRT (8). As part of a prospective study enrolling patients with a presumed local failure at restaging MRI and undergoing exclusive sRT (9), local response was assessed at regular intervals with dynamic contrast enhancement magnetic resonance imaging (DCE-MRI) during follow up, providing unique data on local response of prostate cancer to sRT.

The present prospective study was conducted at a single Institution between August 2017 and June 2020 (Clinicaltrials.gov NCT04703543). The study was approved by the Institutional Review Board (RS 946/17) and specific written informed consent was obtained by each patient before enrollment. Selection criteria as well as other methodological aspects of the study have been reported previously in details (9). In order to be eligible, patients had to have an history of localized prostate cancer treated with RP, followed by an undetectable (<0.1 ng/ml) PSA and a subsequent biochemical recurrence (2 consecutive PSA rises up to 0.2 ng/ml or higher). At restaging with DCE-MRI, all patients had to harbor a presumed local failure defined as an early/fast enhancing discrete lesion on DCE-MRI possibly with a T2w hyperintense lesion (8, 9). The location of each detected lesion was classified as per Connolly et al in perianastomotic, bladder neck and retrovesical (10).

All scans were obtained at our Institution and details can be found elsewhere (9).

All patients then underwent sRT, consisting in an intensity modulated approach to the whole prostatic bed to 66-69 Gy in 30 fractions. Presumed local failures at DCE-MRI were prescribed 73.5 Gy with a simultaneous integrated boost technique. The presumed site of local failure at DCE-MRI was outlined as clinical target volume (CTV) after co-registration to the planning computed tomography (11). The CTV was enlarged by an 8 mm isotropic margin to the planning target volume (PTV). When treated (9), the pelvic nodes (bilateral internal, external and common iliac lymph nodes as well as pre-sacral lymph nodes) were prescribed 54 Gy in 30 fractions. Details on treatment planning and delivery have been reported previously (8).

All patients were offered repeated DCE-MRI (rDCE-MRI) at our Institution as described above and interpreted by the same single observer (L.B.). Response was assessed exclusively on DCE sequences and defined with a qualitative method as it follows: complete response (CR) as the complete disappearance of the target lesion at DCE-MRI, partial response (PR) as any reduction of the size of the area/volume of early/fast enhancement, no response (NR) as no change in size/volume of the target lesion at DCE-MRI.

The first rDCE-MRI was planned at 3 months after sRT completion. In patients without a complete response, imaging was repeated at 3-month intervals until complete dis-appearance or a maximum of 4 repeated scans. In case of complete response, no further scans were offered.

The endpoint of the study is the achievement of a CR at rDCE-MRI during the follow up. Therefore, responses were further dichotomized in CR and noCR, that includes both PR and NR. For patients with multiple local lesions, CR implied the complete disappearance of all lesions seen before sRT. The analysis was initially set for a complete database (no missing observations during the follow up). Unfortunately, some patients did not undergo all planned examinations. Therefore, the analysis has been carried in terms of both actual cumulative incidence (the number of new CRs divided by the total number of individuals at risk) and actuarial cumulative incidence using the Kaplan Meier estimate censoring for patients who did not undergo further testing at the date of last examination. Groups were compared with the chi-squared test, the Mann–Whitney rank test or the log-rank test when appropriate. For proportions, confidence intervals (CI) were computed with the Wilson score method without continuity correction.

Univariable/multivariable binary logistic regression analyses on CR were performed considering the Gleason Grade Grouping at RP (1-2 vs 3 vs 4-5), the PSA value at failure (continuum), the PSA doubling time at failure (continuum), the nodule volume at pre-sRT MRI (continuum), the number of failures at pre-sRT MRI (1 vs multiple), the time interval between RP and sRT (continuum), the time interval between the end of sRT and rDCE-MRI (continuum), the percent decrease of PSA at the 5^th week of sRT (continuum) and the location of the failure, anastomotic (yes vs no), in the bladder neck (yes vs no) and retrovesical (yes vs no). For patients with multiple lesions, the total volume was computed by adding up each nodule volume.

PSA recurrence after sRT was defined as a 0.2 ng/ml PSA rise above the nadir (12). Statistical significance was claimed for p values <0.05. All statistical tests were performed using GraphPad (version 8.0.1, GraphPad Software Inc., San Diego, CA) and SPSS (version 25, IBM, Armonk, USA).

Patients and scans

Sixty-two patients with 72 lesions were enrolled. Selected patient characteristics have been reported before in details (9) and are summarized in Supplementary Table 1. Briefly, 9 patients were found to harbor multiple local failures: 8 patients had 2 lesions, 1 patient, 3 lesions. All patients underwent sRT and no one received androgen deprivation until biochemical failure after sRT. At the time of analysis, median follow up is 27.1 months (IQR: 19.5-33.3 months).

As shown in Table 1, all patients underwent the 1^st repeated DCE-MRI at a median time of 3.3 (IQR: 3.1-4.1) months after treatment completion. Of the patients without a complete response at the 1^st re-evaluation, 1 was implanted a cardiac device and was unable to undergo further MRI scans. Three more patients declined additional testing after the 1^st (N=2) or the 2^nd (N=1) re-evaluation due to issues related to the COVID-19 pandemia.

Regarding the 4 patients lost to re-evaluation before achieving a CR, 3 are biochemically controlled at the last follow up (27.0, 24.5 and 14.1 months after sRT, respectively). The 4^th patient had a PSA progression while showing a local PR: the biochemical failure was recorded at 4.23 months after sRT and both re-evaluation #1 (3.67 mths) and #2 (7.63 mths) revealed a partial response. After the second re-evaluation he was started on androgen deprivation and declined further MRI testing.

Responses

Responses at each re-evaluation are summarized in Table 1 and illustrated for each patient in Supplementary Figure 1.

Figure 1 shows both the actual and the actuarial cumulative rates of CR. The difference between the two approaches is negligible and for both approaches the median time to CR was identical at 4.7 months (95%CI: 3.4-6.0 mths and 3.8-5.6 mths for the actual and the actuarial methods, respectively). Even in the more conservative scenario (actual method), the vast majority (87.1%, 95%CI: 78.5-94.4%) of lesions would have completely disappeared by 12 months from the end of sRT.

Predictors of response

At the first re-evaluation, 33 patients (53.2%, 95%CI: 41.0-65.1%) were found to be without evidence of local disease. Results of logistic regression on CR at the 1^st re-evaluation are summarized in Table 2. Independent predictors were the volume of the presumed local lesion at pre-sRT MRI and the time elapsed between sRT and the re-evaluation. Due to both missing observations and the limited (<10) number of events at the subsequent re-evaluation time points, no further logistic regression testing was performed.

We categorized baseline lesion volumes at DCE-MRI according to tertiles and the cumulative

incidences of CR in each subgroup are illustrated in Figure 2. All 4 incompletely evaluated lesions belong to the sub-set of lesions larger than 4.5 cc at baseline. Nevertheless, both the actuarial and the actual methods provide identical median times to CR for all sub-groups: 3.6 months (95%CI: 3.3-3.8 mths), 4.7 months (95%CI: 4.0-5.4 mths) and 6.6 months (95%CI: 5.5-7.7 mths) for lesions less than 2cc, between 2 and 4.5cc and larger than 4.5 cc at diagnosis, respectively. The difference among subgroups is highly significant (p=0.009 and p=0.003 according the actuarial and the actual approaches, respectively).

For lesions up to 4.5 cc before sRT we were able to document their complete disappearance by 13 months from the end of treatment (Figure 2). Conversely, out of lesions larger than 4.5cc only slightly more than 2/3 would have completely disappeared by 12 months (66.7%, 95%CI: 45.4%-82.8% and 69.6%, 95%CI: 49.4%-89.8% according to the actual and the actuarial methods, respectively).

About 50% of patients undergoing RP for localized prostate cancer develop a biochemical failure despite a window of PSA undetectability. While there is some discussion on which PSA threshold best predicts further metastases, both the American and the European Urology as well as Radiation Oncology associations agree to offer ‘early’ salvage radiotherapy in case of 2 consecutive PSA rises above 0.2 ng/ml (13, 14). The optimal dose of sRT remains controversial, with 64-66 Gy at 2 Gy per fraction considered the minimum prescribed dose to the whole prostatic fossa (14, 15). However, even if sRT is started at PSA levels below 0.5 ng/ml, up to 50% of patients harbor one or more visible lesions in the prostatic bed at high resolution DCE-MRI (9, 16, 17). Though a minority of the detected lesions may be falsely positives (8, 18, 19) and the detection of a local lesion per se is a favorable prognostic factor (12, 16, 20), there are concerns on the appropriateness of such limited dosages of radiation. Indeed, in a recent randomized trial comparing two dose levels of sRT, local recurrence alone or in combination with other sites represented 21.6% of all first events of clinical progression after 64 Gy (1). Moreover, a systematic review showed that each Gy improves the biochemical-free survival after sRT by 2.6% suggesting that a total dose above 70 Gy should be administered (21). It has been prospectively shown that local treatment may in turn impact distant metastasis rates in the postoperative setting (22). In order to limit the risk of toxicity associated with dose escalation (14), it seems reasonable to limit the highest prescribed dose level to the site of presumed local disease. We have systematically pursued this strategy in patients undergoing sRT at our institution and here we confirm that the vast majority of local lesions disappears completely after 73.5 Gy in 30 fractions (8).

Prostate cancer response to radiotherapy is monitored usually throughout serum PSA values (23) and little is known on both the clinical/instrumental response rate of prostate cancer along with its timing after radiotherapy (8, 24). Pilepich and Hederman in the post-radiation evaluation of 262 patients in the pre-PSA era showed CR rates at 12 months similar to those reported in Figure 1 with smaller primary tumors regressing somewhat faster than larger ones at digital rectal exam (25).

While DCE-MRI, and in particular changes in apparent diffusion coefficient, have been used to assess the response of prostate cancer to primary radiotherapy (26, 27), the post-RP/pre-sRT setting is different due to the lack of normal prostate tissue surrounding the lesion and the presence of anatomical changes due to surgery (28). Though in previously untreated prostate cancer the diagnostic role of DCE-MRI is marginal (29), it represents the most important sequence in the detection of recurrent disease after RP (30) since recurrent tumor neo-angiogenesis is composed by disorganized and permeable blood vessels that result in an early hyper-intense focal lesion (28). Even if early radiation-induced changes may actually increase vessel permeability and thus potentially increase tumor flare (28), successful radiotherapy leads to fibrosis and decreased blood flow/permeability that has been associated with pathologically complete responses in various cancer sub-sites (31-34).

We have found that sRT is highly effective in obtaining the complete resolution of local lesions. Interestingly, response was found to be a time-dependent process even within the same re-evaluation window (Table 2) and, as shown in Figure 1, assessment of response at DCE-MRI should be deferred several months after sRT end. Moreover, despite DCE is a functional test, we found the lesion volume to be the only additional independent predictor of response at multivariable analysis. Surprisingly, none of the factors potentially correlated with tumor aggressiveness (i.e. Gleason score) were found to predict the timing of response. On the other hand, microvessel density, that is a surrogate of angiogenesis, has been inconsistently correlated to pathologic tumor stage and Gleason score in prostate cancer (35). Limitations of the present study include the fact that the time interval of re-evaluation was delayed by a few months due to issues related to the COVID-19 pandemia (Table 1). In particular, the 3^rd re-evaluation took place on average at 10.7 months instead of 9 months, even if this has minimal impact on the interpretation of the results (Figure 1). More importantly, 4 (6.4%) patients were lost before achieving a CR and this prevents us to draw firm conclusions on the long term response of larger lesions. However, the cumulative incidence for lesions larger than 4.5 cc are quite similar up to 12 months regardless the method used for computation of rates, suggesting that until this time point results are not impacted by censoring. Moreover, as discussed elsewhere (9), we assumed all detected local lesions to be prostate cancer-related at baseline despite an estimated rate of false positives for multiparametric MR up to 10% (18, 36). Therefore, the goal of 100% for the cumulative incidence of CR might be unrealistic in absence of a baseline positive biopsy though false positive lesions usually remain unchanged after sRT as discussed elsewhere (8).

The present prospective study documents the complete dis-appearance of the vast majority of presumed local lesions after dose-escalated sRT though this requires several months after treatment completion. The timing of CR is at least in part predictable based on the volume of the lesion with smaller lesions responding quicker and within ≈1 year from treatment end.

Ethics approval and consent to participate: The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of the ‘Regina Elena’ National Cancer Institute (protocol code 946/17) and approved 13 June 2017.

Consent for publication: Informed consent was obtained from all subjects involved in the study.

Data availability: https://gbox.garr.it/garrbox/index.php/s/aJGRXorIc8ItRFy.

Competing interests: The authors declare that they have no competing interests.

Funding: The author(s) received no specific funding for this work.

Authors’ contribution: conceptualization G.S., methodology G.S. and D.G., software, V.L., D.G. and G.S., validation, A.F. (Adriana Faiella), A.F. (Alessia Farneti), P.D. and L.B., formal analysis, D.G., investigation, G.S., P.V., resources, A.F. (Adriana Faiella), data curation, A.F. (Adriana Faiella) and M.B., writing—original draft preparation, G.S. and M.B., writing—review and editing, L.B. and M.B., supervision, G.S. All authors have read and agreed to the published version of the manuscript.

Acknowledgments: Not applicable.

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Table 1. Summary of findings at rDCE-MRI.

	A	B	A-B
Re-ev #	Patients due for scanning	noCR not further evaluated	# patients actually scanned	Median time (mths) of scan after sRT (IQR)	Complete Response	No Response	Partial Response
	(#)	(#)	(#)	(months)	(#)	(#)	(#)
1^st	62	0	62	3.3 (3.1-4.1)	33	2	27
2^nd	29	1	28	6.8 (6.5-7.6)	20	0	8
3^rd	9	3	6	10.7 (10.6-12.6)	4	0	2
4^th	5	4	1	16.7	1	0	0

Abbreviations: Re-ev: re-evaluation

Table 2. Logistic Regression on CR at 1^st re-evaluation

			Univariable			Multivariable
Covariate	Strata	# patients	OR	95%CI	p value	OR	95%CI	p value
Volume @ baseline MRI (cc)	Continuum	62	0.207	0.045-0.958	0.044	0.076	0.009-0.667	0.020
PSADT (mths)	Continuum	62	0.977	0.948-1.006	0.120
PSA @ fail (ng/ml)	Continuum	62	0.843	0.558-1.274	0.418
Site failure Anastomosis	No	25	1
	Yes	37	1.422	0.513-3.940	0.498
Site failure Bladder Neck	No	45	1
	Yes	17	0.512	0.165-1.588	0.246
Site failure Retrovesical	No	47	1
	Yes	15	1.437	0.441-4.682	0.547
Time RP/sRT (mths)	Continuum	62	0.991	0.980-1.002	0.117
GGG	1-2	29	1
	3	25	0.880	0.301-2.574	0.816
	4-5	8	0.813	0.169-3.895	0.795
Time from sRT (mths)	Continuum	62	2.472	1.050-5.818	0.038	3.399	1.156-9.993	0.026
PSA decrease @ wk 5 (%)	Continuum	62	1.026	1.003-1.049	0.024	1.025	0.999-1.050	0.058
PSA decrease @ 1^st ev (%)	Continuum	62	1.025	0.998-1.052	0.067
# Failures	1	53	1
	2-3	9	1.116	0.269-4.622	0.880
Pelvic node coverage	No	33	1
	Yes	29	0.893	0.328-2.427	0.824

No competing interests reported.

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A prospective study assessing the pattern of response of local disease at DCE-MRI after salvage radiotherapy for prostate cancer

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