Determinants and effects of positive surgical margins after prostatectomy on prostate cancer mortality: a population-based study

Prostate cancer is the second most frequently diagnosed cancer and the fifth most common fatal cancer among men worldwide, the fourth for developed countries[1]. A high percentage of men are diagnosed with early stage disease due to the spontaneous generalization of prostate specific antigen (PSA) screening[2]. Radical prostatectomy is the main treatment option for clinically localized prostate cancer, as shown by the randomized Scandinavian prostate Cancer Group Study Number 4 (SPCG-4)[3]. However, as shown recently by Wilt et al., the difference between radical prostatectomy and watchful waiting was not significant[4]. Positive surgical margins (PSMs), identified as the presence of cancer at the inked resection margin of the prostatectomy specimen, are a relatively frequent finding after prostatectomy and reported in many articles with proportions ranging from 10 to 40%[5]. Although there are many reports and studies available, questions remain regarding determinants and effects of PSM. Furthermore, in relation to survival, surgical margins are the only factor which could be influenced by the surgeon, contrary to tumour characteristics.

Some investigations have correlated patient, clinical and histo-pathological findings with surgical margin status after prostatectomy[6‐8]. Coelho et al., investigated several determinants of surgical margins, such as type of surgery, location of PSM, prostate weight and tumour volume[6]; Williams et al., investigated determinants such as period of surgery, geographical region, type of surgery and surgeon caseload[7]; and finally Vesey et al., studied surgeon caseload and prostate weight[8]. They all found that the tumour characteristics such as clinical stage, pathological stage, Gleason score and the percentage of tumour in the prostate were more often significantly associated with surgical margin status.

Furthermore, several studies have investigated the association between surgical margins and outcome after radical prostatectomy[9‐17]. Two types of outcomes are usually described in this context; either PSA biochemical recurrence (BCR) through routine serum PSA monitoring every six months after treatment, and/or prostate cancer-specific survival (PCSS). PSM after radical prostatectomy is known to be an independent risk factor for BCR; however, there is no wide consensus on its impact on survival[14‐16]. Although most studies reporting on BCR show significant association with PSM[9‐12], studies reporting on PCSS show mostly non-significant association with PSM[13‐17].

The aim of the present study was twofold; 1) to assess patient, physician and tumour characteristics associated with PSM after prostatectomy, and 2) to assess if PSM is an independent prognostic factor for prostate cancer-specific mortality (PCSS).

In the current study, we found that more aggressive tumour characteristics are responsible for both PSM after prostatectomy and worse prostate cancer-specific survival. Although, surgical margin status was associated with prostate cancer-specific survival in univariate analysis with PSM patients showing a doubled risk of dying as compared to NSM patients, this increased risk disappeared after adjusting for variables related to the gravity of the disease in the multivariate analysis. Yossepowitch et al., have recently published a systematic review of the literature covering the last ten years, on positive surgical margins after radical prostatectomy evaluating also their oncologic impacts[22]. The authors concluded that the long term impact of positive margins on cancer progression and specific survival is highly variable and largely dependent on additional risk modifiers. In fact, they noted that while all the revised studies showed a significant association between positive margins and biochemical recurrence, the data pertaining to metastatic progression and death were less consistent with only two studies indicating that PSMs were significantly associated with an increased risk of prostate cancer-specific mortality[15, 23]. In the Surveillance, Epidemiology and End Results (SEER) data analysis, Wright et al., found a 2.6-fold increased unadjusted risk of prostate cancer-specific mortality that remained significant also after adjusting for grade, stage, additional radiotherapy, age, race, registry and year of diagnosis. However, when stratified by adverse pathological features of the tumour these findings held only for those with higher grade or pT3 tumours[15]. In a more recent study on a single surgeon cohort, Chalfin et al., showed that PSM had a statistically significant, but modest, adverse effect on prostate cancer-specific mortality in a model including Gleason score, year of surgery and pathological stage[23]. Similarly to these studies, in our study we found a strong association of prostate cancer-specific mortality with PSM in univariate analysis, however, this association disappeared in the multivariate analysis. Unlike these studies in our multivariate model we simultaneously adjusted for all the pathological adverse tumour features, including Gleason, stage, PSA level, percent of the tumour in the prostate, which emerged as the strongest predictors of mortality. Consistently with the results of another recent study, our results suggest that PSM alone does not increase the risk of dying from prostate cancer[24].

In the literature, surgical margins after prostatectomy are evaluated in different ways through different study designs. Population based studies are valuable designs mostly because of the large cohorts involved, however the accuracy is often not very high. After a systematic audit of the SEER registry, Shah et al., showed that 30% of radical prostatectomies performed in 2007 were inaccurately coded, and concluded that clinicians and investigators should recognize the limitations of tumour registry data on PSM[25]. For the current study, we opened all the files and re-checked all parameters and information, improving the accuracy of our compared to the available literature based on cancer registries. This could explain why the overall proportion of 38.2% PSM is higher, compared to the range found in other studies[5]. The proportion of PSM decreased during the study period, from 50% in 1990–1994, to 31% in 2005–2008. Stage shift and surgeons at the end of the learning curve of prostatectomy, may explain the finding of significantly lower PSM rates in the later prostatectomies. In fact, we found that the ratio of cancer with pathological T0-T2/T3-T4 went from 0.7 in 1990–1994, to 3.4 in 2005–2008 (test for trend = 54.58, p < 0.001). On the other hand, we also observed in the univariate analysis that "closed" surgeries such as laparoscopic and robot-assisted surgeries yielded significantly less PSM, confirming the findings of Touijer et al.[26] However, for the cases treated in the private sector, the surgical procedure was not always reported. Also, most robot-assisted surgeries reported in our study were performed in the public hospital by a selected group of surgeons. The number of deaths from prostate cancer in the groups of surgery procedures was too low to allow showing an association with survival.

The present study was a retrospective analysis with a relative short follow-up, which is the main limitation of the study. This could be the main reason for the absence of impact of PSM on PCSS. If we accept that BCR is a surrogate of PCSS, since the influence of PSM on BCR is well established, we could foresee that only a study with a median time of follow-up > 10 years would be able to highlight PSM as a significant predictor of PCSS on a multivariate basis. However, we could not provide data regarding biochemical recurrences, as the Geneva Cancer Registry does not collect this information. Furthermore, the number of prostate cancer deaths was very low (n = 33 at 10 year and n = 51 at the end of follow-up), another possible reason for underpowered results. However, we observed similar survival rates in other studies[14, 15]. Another limitation is the use of different pathology laboratories (private and public) in the area. This could have caused inter-observer variability, which was evident in the classification of close surgical margins: 72% were reported from the private pathology laboratory and 28% from the public laboratory. Because of the limited number of patients with close surgical margins, those patients were regrouped together with the negative surgical margins in further analyses, as already suggested in the literature[21]. Another limitation of the study is the relatively high percentage of patients lost to follow-up (12.2%). This is peculiar to the Geneva canton, related to the fact that Geneva is an international city, with 43% of the population consisting of foreigners and a strong work-related migration rate. We compared the patients lost to follow-up to the rest of the study population and found no significant differences in terms of patient, tumour and treatment characteristics. Therefore, we find it unlikely that this selection could have strongly biased our results in terms of the impact of PSM on mortality. On the other hand, because 12% of the cohort was not at risk of prostate cancer mortality, the substantial number of patients who were lost to follow-up could be one of the reasons for the high specific survival rate that we observed. As we had only partial information on the presence of comorbidities, this variable was not included in our analysis. However, in this population comorbidities are expected to have had only a limited impact on survival as the population is younger and therefore healthier; among the 231 study patients for whom information on comorbidities was available, only 32% reported at least one comorbidity, as opposed to 51% of all prostate cancer patients aged >65 years in our registry. Another variable we did not include in the analyses, as available only since 2008, was the information about nerve-sparing approach, however, previous studies have shown that nerve-sparing procedures are safe and not associated with an increased positive margin rate nor on disease progression[27]. The strength of our study is that the population-based approach permits both to generalize the results to the whole population and to examine the effect of PSM in routine care. In addition, the re-opening of all the patients’ files gave further strength to this study, since we were able to double-check and validate all the data. If we consider the context of data collection in a cancer registry, one could generally recommend, as recently stated by Raldow et al., that the extension of the treatment registration period from six to nine months or even one year, especially in the case of prostate cancer treatment, could be an advantage for future studies like this one[28]. Finally, in our analyses we could take into account of a large number of important prognostic factors for prostate cancer mortality.

Although the association between PSM and survival is not clear, the link with biochemical recurrence is well established[9‐12]. Indeed, in the 2011 European Association of Urology guidelines, as well as the National Comprehensive Cancer Network (NCCN) guidelines, it has been recommended to take into account surgical margin status in the adjuvant treatment decision, as an independent risk factor for BCR[29, 30]. In a recent publication, Lu et al., found that close surgical margins as well were independently associated with a twofold risk of postoperative biochemical recurrence and suggest that close margins might be an indicator of local recurrence, and therefore also be of relevance when considering salvage therapy[31]. To date only the SWOG 8794 trial with its long median follow-up could demonstrate improved overall survival with adjuvant radiation therapy in men with pT3a and/or positive margin disease in exploratory analysis. However, the differential effect of adjuvant radiotherapy vs early salvage radiotherapy was not evaluated in this trial, as salvage at PSA recurrence was not mandated by protocol in the observation arm ([32]). In a situation where the scientific evidence in favour of early vs. delayed use of radiotherapy to control local recurrence is still lacking, it seems reasonable to add the information on PSM to the other clinical prognostic variables in order to obtain a more comprehensive assessment of the individual risk[22].

To conclude, our data showed that surgical margins after prostatectomy are predominantly predicted by tumour characteristics, but are not independently associated with prostate cancer-specific survival. Aggressive tumour characteristics are correlated with both positive surgical margins after prostatectomy and worse prostate cancer-specific survival. These results should be considered for future research and when evaluating patients with a PSM for adjuvant and/or salvage therapy.