Long-term oncologic outcomes of postoperative adjuvant versus salvage radiotherapy in prostate cancer: Systemic review and meta-analysis of 5-year and 10-year follow-up data

Radical prostatectomy (RP) is considered as the "gold standard" treatment of localized prostate cancer. However, when the prostate cancer cells extend beyond the prostatic fascia or invade the seminal vesicles, progression, including the biochemical or radiological recurrence after RP, is reported in 10%-50% [1, 2]. The predictors of this progression are baseline prostate-specific antigen (PSA), positive surgical margins, Gleason score, and invasion of seminal vesicle [1]. With this, the role of postoperative radiotherapy after RP in patients with these predictors remains controversial. In addition, patient selection and exact disease staging remain undiscovered, with concerns about overtreatment of patients never destined to recur in adjuvant setting, or undertreatment of patients with unrecognized metastatic or recurred lesions in salvage setting. Moreover, the accurate timing of postoperative radiotherapy, either the adjuvant or salvage setting, remains debated.

There are a few studies about the efficacy of both settings including retrospective and prospective trials. However, efficacy varies according to each study, with most of these studies carrying the limitation of being a small-sized study with short-term follow-up periods. We systemically analyzed the efficacy between both settings in patients with the above predictors with more than a 5-year follow-up period.

About one-fourths of patients who underwent RP showed biochemical or radiologic recurrence in the 10-year follow-up [4]. If the patient with high-risk factors, including high-serum PSA or pathologically local advanced (T3 or T4) or adverse pathologic factors, high Gleason score, or positive surgical margin, these patients have an increased risk of biochemical recurrence or radiologic progression in the future. There are two radiotherapeutic modalities for these high-risk patients, depending on physician belief [5]. One modality is to treat patients with high-risk factors with ART, based on pathological information of the prostatectomy specimen with an undetectable serum PSA (less than 0.2 ng/mL). The other modality is SRT, which is to closely follow up with serum PSA and perform the radiotherapy after biochemical or radiologic progression. The appropriate timing of postoperative radiotherapy, either ART or SRT, remains controversial. Although the patients can show favorable biochemical or radiologic recurrence results in the ART setting, the risk of overtreatment and toxicity of radiotherapy can pose as a problem. At the same time, although SRT may reduce the risk of overtreatment and toxicity of radiotherapy, appropriate timing of radiotherapy can be missed. This systemic review and meta-analysis included 7 studies with long-term data assessing the oncologic outcomes of both radiotherapies on 2,380 patients with high-risk prostate cancer [6, 7, 8, 9, 10, 11, 12].

Although increasing serum PSA after radiotherapy is a controversial surrogate marker for prostate cancer outcome, all the included studies showed favorable results in ART compared to SRT in 5-year and 10-year BRFS. As PSA elevation often acts as a trigger for hormone deprivation therapy, it is no surprise that a reduction in hormone deprivation therapy use of similar magnitude was also observed. Given the multiple adverse effects associated with hormone deprivation therapy, including osteoporosis, cardiovascular events, and other metabolic events, the potential hormone therapy sparing effect of ART is compelling. However, the toxicity from radiotherapy should also be considered. In current meta-analysis, ART has a reduction of risk of 39% and 31% in 5-year and 10-year BRFS, respectively, compared to SRT.

Median radiologic progression was about 6 years after radiotherapy in Southwest Oncology Group (SWOG) trial, which suggested that more than a 6-year follow-up is necessary [9]. Most of the included studies showed favorable results in ART at the 5-year follow-up. However, unlike other studies, the Arbeitsgemeinschaft Radiologische Onkologie trial did not show any difference in the 5-year PFS. In current comprehensive analysis, 5-year PFS is better in ART compared to SRT. However, this trend did not persist in 10-year PFS between ART and SRT.

Long-term OS is the most important outcome for any cancer therapy. Prostate cancer showed a relatively indolent natural course, which anticipated that long-term (more than 5 years) follow-up is necessary to assess the postprostatectomy differences in patients with prostate cancer. We included the data from more than a 5-year follow-up in this meta-analysis. OS outcome was similar among included studies except the SWOG trial, which showed more favorable results in ART [9]. This discordance among included studies may be induced from variations in quality of surgery or unrecognized selection of the patients. However, all included studies did not show any significant difference between both settings. In addition, salvage treatment may cause different outcomes after radiotherapy. In current meta-analysis, 5-year and 10-year OS also did not show any difference in both groups.

The present systemic review has the following limitations that must be taken into account. The first limitation is that we heterogeneously recruit randomized controlled studies and retrospective studies. In retrospective studies, the initiation timing of radiotherapy is somewhat different in each study, and findings were also shown in randomized controlled studies. Recent report showed men who received SRT for a slow PSA doubling time had a risk of all-cause mortality that was not significantly different from men who underwent ART [13]. Most men who had a slow PSA doubling time had a Gleason score of less than 8 and either pT2R1 or pT3R0 disease. Therefore, the number of risk factors might act as bias in outcome between ART and SRT. The second limitation is that there is a difference in dose and modality (2-dimensional, 3-dimensional, or intensity modulated radiation therapy) of radiation compared to recent practice, which may alter oncologic outcomes. Reduced dose of radiation (less than 64 Gy) was done in European Organization for the Research and Treatment of Cancer and SWOG trial [6, 9]. The third limitation is that the information about the adverse events of both RT therapies is insufficient. In OS, adverse events would be significant confounding factors for 5-year and 10-year. However, the prevalence of long-term genitourinary and gastrointestinal adverse events was uncommon [11]. Usually, the genitourinary and gastrointestinal adverse events by RT tend to late one-set. Therefore, we could estimate that the prevalence rate of adverse events of ART is higher than that of SRT. Finally, concomitant hormonal treatments were different in each studies, which also affect the result of long-term outcome between both settings.

This systemic review and meta-analysis showed ART showed significantly favorable results in 5-year PFS compared to SRT, but not in 10-year PFS and 5-year and 10-year OS. Therefore, postprostatectomy ART was not superior to SRT in long-term survival in patients with high-risk prostate cancer.