Salvage radiotherapy following radical prostatectomy: Long term oncological and functional outcomes (median 96 months) in 108 patients

ORIGINAL PAPER

Pietro Pepe 1, Marinella Tamburo 2, Michele Pennisi 1, Dario Marletta 2, Francesco Marletta 2 .

1 Azienda Ospedaliera Cannizzaro, Urology Unit; 2 Azienda Ospedaliera Cannizzaro, Radiotherapy Unit.

SUMMARY Introduction. To evaluate oncological and functional outcomes in men submitted to salvage radio therapy (sRT) following radical retropubic prostatectomy (RRP). Materials and Methods. In the years 2003-2020, 108 patients received sRT because biochemical recurrence (BCR) defined as 2 consecutive prostate specific antigen (PSA) values than 0.2 ng/ml and rising after RRP (median 49 months). All patients have been treated up to 66.0-70.4 Gy with single dose of 1.8-2.0 Gy fractions. Predictive factors were analyzed to evaluate prostate specific antigen (PSA) and clinical response to radiotherapy. Results. Median follow-up after sRT was 96 months (12-204 months); 54/108 (54.7%) men had PSA response (PSA value < 0.2 ng/ml), conversely 49/108 (45.3%) demonstrated BCR during follow up. Clinical stage (pT2 vs > pT3), pathological ISUP Grading Group (GG < 3 vs GG > 4), pre-radiotherapy median PSA value (0.55 vs 1.83 ng/ml) and pathological node-involvement were highly predictive for BCR (p < 0.05). Clinical complications following sRT were characterized by late gastrointestinal (GI) and genitourinary toxicity (GU) in 9 (9.5%) and 12 cases (11.8%), respectively. Conclusions. Salvage RT following RP constitutes a curative therapy in about 50% of the cases with a low rate of GI (9.5%) and GU (11.8%) late complications. The oncological outcome is correlated with pathological stage, ISUP Grade Group, node-involvement and pre-sRT PSA value.

KEY WORDS: Prostate cancer; salvage radiotherapy and prostate cancer; oncological outcome and radical prostatectomy.

INTRODUCTION

Salvage radiation therapy (sRT) is considered the most common treatment option employed in case of biochemical recurrence (BCR) after radical prostatectomy (RP) and its effectiveness dependent on the PSA level at the time of treatment (1, 2). Many studies have shown that early sRT at a PSA level < 0.5 ng/ml (2) has been associated with improved BCR, metastasis-free survival, and cancer-specific survival (3). The potential benefit of sRT must be weighed against the potential deleterious effect on functional outcomes, particularly, erectile function, urinary continence (4), and bowel disease; in fact sRT affect long term continence and toxicity irrespective of time of initiation for RT (5, 6). Additionally, a considerable proportion of patients treated with post-surgery radiotherapy may experience early and late high-grade toxicity (7). The impact of sRT on the biochemical control varies according to the clinical and pathological features of patients; moreover, in the presence of unfavorable risk factors multimodal treatment is highly recommended (8). In this study, we report long term functional and oncological outocomes in men submitted to sRT following radical retropubic prostatectomy (RRP).

MATERIALS AND METHODS

In the years 2003-2020, 108 patients received sRT following RRP (9-11) because BCR defined as 2 consecutive PSA values than 0.2 ng/ml and rising (1). Nobody had suspicious rectal examination, in addition median number of nodes removed by surgery was equal to 12 (range: 3-27 nodes). Overall, median PSA value before starting sRT was 0.68 ng/ml (range: 0.17-4.2 ng/ml). All the patients with PSA value > 1 ng/ml underwent diagnostic imaging (lungabdominal CT or, in the last five years, choline PET-CT scan); none of the patients showed any clinical evidence of distant metastases before they received sRT. On the contrary, in the presence of PSA value below 1 ng/ml the patients underwent sRT without any imaging evaluation.

Clinical parameters of men submitted to sRT are listed in Table 1. Image-guidate radiotherapy tecniques (IGRT) with daily CBCT were performed for all patients, 20/108 (18.5%) patients have been treated with 3-dimensional conformal RT (3D-CRT), 49/108 (45.4%) with intensity modulated RT (IMRT) and 39/108 (36.1%) volumetric modulated arc therapy (VMAT). These techniques allow improved dose homogeneity and reduction in radiation dose to normal structures, such as the bladder and rectal wall; 43/108 (39.8%) patients subjected to whole-pelvic radiation therapy and 65/108 (60.2%) received bed prostate treatment. For all patients a median total dose of 68 Gy (range: 66-70.4 Gy) was delivered with single dose of 1.8-2 Gy. Clinical and pathological findings predictive of PSA response to sRT were evaluated. The long-term oncological and functional outcomes after sRT has been retrospectively evaluated. A probability (p) level of less than 0.05 was considered statistically significant.

RESULTS

DISCUSSION

Salvage RT started about 4 years (median 49 months) from RRP: 59/108 (54.7%) patients had a complete and stable PSA response (< 0.2 ng/ml) during follow up, conversely 49 (45.3%) demonstrated BCR over the time. Overall, median follow-up was 96 months (range: 12-204 months) resulting equal to 64 vs 50 months in men RT responders vs RT non responders. In men with complete PSA response median PSA before RT was 0.55 ng/ml (range 0.17-2 ng/ml) and 24/59 (40.7%) vs 35/59 (50.7%) had a PCa ISUP GG1 vs GG2-3, respectively. In the 49/108 (45.3%) patients who developed BCR following sRT median PSA was 1.83 ng/ml (range: 0.18-4.3), 4/49 (8.1%) had positive nodes and 39/49 (80%) of them needed androgen deprivation therapy (ADT). Pathological stage (pT2 vs > pT3) (Figure 1), pathological Grade Group (GG < 3 vs GG > 4), pre-radiotherapy PSA value (0.55 vs 1.83 ng/ml) and nodes involvement (Figure 2) were highly predictive of BCR (p < 0.05). Stereotassic radioterapy was administered in 6 men and only in 2 (33.3%) cases a temporary PSA response was recorded. Functional outcomes of men submitted to sRT are listed in Table 2; in detail 11.8% (12 cases) and 9.5% (9 cases) of the patients reported late G2/G3 genitourinary (GU) and gastrointestinal (GI) complications (Table 2).

BCR alone is not a surrogate of overall survival and/or PCa specific survival; therefore, a lot of Table 1. Clinical and pathological parameters in 108 patients submitted to salvage radiotherapy. prognostic indicators are used in clinical practice to assess the patient level risk to initiate early treatment or to adopt a pTNM (number of patients) GG 1 GG 2 GG 3 GG 4 GG 5 Median PSA (ng/ml) strategy of surveillance; the decision making should be performed by multidisciplinary team to adopt an informed pT2 (70) 21 26 - - - 0.40 individualised approach (12). BCR pT3 (37) 3 14 27 10 6 1.2 occurs in 27-53% of patients after definitive therapy (13); in detail 24-35% pT4 (1) - - - - 1 4.3 of men who develop BCR will experiN+ (4) - - - 3 1 4.3 ence clinical recurrence within 15 years from surgery and 2-6% of them will dieADT (40) - - 23 10 7 2.6 from PCa (14). Pathological stage, preISUP GG: International Society of Urologic Pathology Grade Group; PSA: prostate specific antigen; N+: positive nodes; ADT: antiandrogen deprivation therapy. operative PSA value, Gleason score < 8, presence of positive surgical margins, pre sRT PSA value and PSA nadir < 0.1 ng/ml correlate with lower risk of recurrence (15). Kashihara et al. (16) in 120 Table 2. Functional outcome in 108 patients submitted to salvage radiotherapy (sRT) for PSA recurrence. men submitted to sRT demonstrated in multivariate analysis that biochemical response was significantly favourable in sRT complications Early complications within 6 months number of patients (%) Late complications after 6 months number of patients (%) men with PSA value < 0.5 ng/ml and pathological Gleason score < 7. Mishra et al. (17) in 186 men submitted to adjuvant RT vs sRT demonstrated that the GU (dysuria, urinary urgency, 54 cases (50%) 10 cases (10%) G2 long-term outcomes (88-103 months) hematuria) 2 cases (1.8%) % G3 freedom from metastatic failure was GI (diarrhea, bowel disease, rectal bleedind) 4 cases (4.3%) 8 cases (8.6%) G2 1 case (0.9%) G3 superimposable; at the same time, Fossati et al. (18) in 510 men pT3N0 demonstrated at long term follow up no GU: genitourinary; GI: gastrointestinal. significant defferences in term of overall RTOG/EORTC: Late Radiation Morbidity Scoring (Grade 1-Grade 4) Scheme. survival between immediate postoperaAvailable at: www.rtog.org/ResearchAssociates/AdverseEventReporting/RTO- tive adjuvant radiation therapy and early GEORTCLLateRadiationMorbidityScoringSchema.aspx sRT (PSA < 0.5 ng/ml). Galla et al. (19)

Figure 1. pT stages, antiandrogen deprivation theraphy (ADT), timing of salvage radiotherapy from retropubic radical prostatectomy (RRP) and follow up in 108 patients: correlation with PSA response.

Figure 2. ISUP Grade Groups correlated to PSA response in the 108 patients submitted to salvage radiotherapy.

ISUP GG: Grade Group International Society of Urologic Pathology

in 234 men with BCR who underwent sRT at a median follow of 117 months reported a PSA response and PCa specific survival equal to 54 and 94%; in detail, in multivariate analysis pathological stage, Gleason score and the last PSA value before RT were the best predictors of survival. Buscariollo et al. (20) in 718 men submitted to adjuvant RT vs sRT at a median follow up of about 8 years showed an improved PSA response performing adjuvant RT but a superimposable overall survival. Fossati et al. (21) reported in 728 patients submitted to sRT that men who had increased number of lymph nodes resected at RP had improved outcomes. Ying et al. (22) in 61 patients who underwent sRT at a median follow up of ten years reported a PSA failure and an overall survival equal to 56 vs 67%, respectively showing a worse prognosis in men with early PSA failure (< 1 year from radiotherapy). Gandaglia et al. (23) in 525 men submitted to salvage RT reported a reduction in the rate of metastasis in men with more aggressive clinical characteristics (pT3b/4 and grade group > 4) when concomitant androgen deprivation therapy was added; Carrie et al. (24) in 743 men enrolled in a open-label multicentre randomised controlled trial demonstrated that adding short-term androgen suppression to sRT improved benefits in men who PSA rises after a postsurgical period when it is undetectable. In our series, at median follow-up of 96 months (range: 12204), 59/108 (54.7%) patients had a complete and stable PSA response (< 0.2 ng/ml) during follow up, conversely 49 (45.3%) demonstrated over the time BCR. Pathological stage, PCa ISUP Grade Group, pre-radiotherapy PSA value and nodes involvement resulted highly predictive of BCR (p < 0.05). Finally, long term functional outcomes demonstrated late GU and GI complications only in 11.8% (12 cases) vs 9.5% (9 cases), respectively. Regarding our results some considerations should be made. First, the study is retrospective. Second, although our results are in agreement with the literature data the long time of follow up (median 96 months) allows to better evaluate oncological and functional outcomes following sRT. Third, no conclusions could be made about stereotassic sRT because the very limited number of cases evaluated (25). Finally, the introduction in clinical practice of new diagnostic imaging (i.e., PSMA PET scan), probably, will improve targeted sRT treatment (26).

CONCLUSIONS

sRT following RP constitutes a curative therapy in about 50% of the cases with a low rate of GI (9.5%) and GU (11.8%) late complications; the oncological outcomes are directly correlate with pathological stage, ISUP Grade Group, nodes involvement and pre-sRT PSA value.

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CORRESPONDENCE

Pietro Pepe, MD Urology Unit - Cannizzaro Hospital, Via Messina 829, Catania (Italy) E-mail: piepepe@hotmail.com Phone. + 39 95 7263285 Fax. + 39 95 7263259