Approximately 40% of the patients show no or only a small treatment response to nRCT [14]. In previous studies, absence of a tumor response was an independent adverse predictor of local tumor control and OS [4]. Opinions differ as to whether an nRCT has an effect on sphincter-preserving surgery rate. Reviews and metaanalyses found no significant difference in the APR rate between nRT with subsequent surgery and primary surgery, nor between nRT and nRCT [15,16]. On the other hand, individual studies have shown that a good response to nRCT in patients with distal tumor localization influenced the rate of sphincter-preserving surgeries. According to Crane et al., patients with distal tumor location within ≤ 3 cm of the anal verge were given sphincter-preserving surgery more frequently if they had a clinical complete response (cCR) following nRCT [5]. The probability of patients with cCR of having a sphincter-preserving procedure was twice as high as those without cCR (44% vs. 22%; p = 0.01). In this way the authors were able to indirectly show an effect of nRCT on the chance of sphincter preservation.
Since the tumor localization is an independent predictive parameter for the probability of a sphincter-preserving operation, we limited our evaluation to patients with low rectal cancer [5,17–21]. In this localization the available data on other predictive parameters is still very sparse. Apart from Crane et al., our analysis is the only one to date that has investigated exclusively patients with low rectal cancer treated with nRCT with a view to finding additional predictive factors for this decision.
The results of our analysis showed that the ability to perform sphincter-preserving surgery were significantly correlated with patient age, pretreatment relative lymphocyte value, and the interval between nRTC and surgery.
In our patient sample, younger patients were given sphincter-preserving surgery more often than older patients, which supports the findings of Temple et al., who also identified younger age as an independent factor for sphincter preservation [20]. In a study by Sun et al. [17] with 330 patients, the patient age only showed an effect on sphincter preservation in the univariate analysis; but younger age was a negative factor for sphincter preservation. A possible explanation is that younger patients might be diagnosed at a more advanced tumor stage. However, in our analysis there was no significant age difference between the groups with different tumor stages, so that we can rule out such an effect for our sample.
There is growing evidence that systemic immunity plays an important role in the tumor response to nRCT. The tumor-infiltrating lymphocyte density and the number of lymphocytes circulating in the peripheral blood have been shown to correlate strongly with tumor response rates [22]. High lymphocyte counts in the peripheral blood were significantly associated with better tumor response after nRCT in locally advanced rectal cancer [23,24]. Also, a higher lymphocyte count nadir during nRCT was associated with higher ypCR rates and improved survival outcomes [25]. Our study confirms that the sphincter-preserving surgery rate in distal rectal carcinoma is influenced by the pretreatment lymphocyte count in peripheral blood (23.3 vs. 21.2; p = 0.021).
The effect of the length of time between completion of nRCT and surgery remains rather unclear. Tuchinsky et al. [26] showed that increasing this interval to > 7 weeks resulted in a significantly higher rate of ypCR and near-complete pCR of 35% and 17% (p = 0.03) respectively. In the group >7 weeks, the DSF was also slightly longer (p = 0.05). Equally, Cotte et al. [27] observed an improvement of the pCR rate when the interval was extended to 6–8 weeks. However, the data on the nRCT-surgery interval are controversial in two respects. Firstly, although a longer interval increased the tumor response, and a good tumor response is assumed to be associated with a higher rate of sphincter-preserving surgery and improved OS, a longer nRCT-surgery interval did not improve these results in their cohorts [27,28]. But secondly, there are also signs that extending the interval may even reduce the OS and metastasis-free-survivals [29,30]. Our results show that the interval is an independent parameter for sphincter preservation. An interval of up to 6 weeks increases the probability of a sphincter-preserving approach (HR = 2.39, CI95%: 1.17–4.88, p = 0.016). At intervals >6 weeks, APR was performed more often (63.3% vs. 39.7%, p = 0.005). It seems that patients without a treatment response did not benefit from an interval > 6 weeks and therefore a shorter interval could be beneficial for nonresponders.
Patients in our sample who had sphincter-preserving surgery had longer DFS and OS. In the univariate comparison, they were younger, and had more often earlier clinical stages (cT4 was only 8.9%), a higher KPS (KPS 100% was 86.4%), and erythrocytes in the normal range with higher relative lymphocyte counts. We are not able to draw any conclusions about how much influence these parameters had on DSF and OS.
In interpreting our study and previous studies, it is important to remember that the endpoint TNM downstaging’ is based on the comparison between the clinical TNM stage and the histopathological TNM stage. With currently available imaging methods, it is not possible to evaluate the clinical stage reliably. 3 This applies especially to the assessment of lymph node status. A recent study by Brouwer et al. [31] yielded sensitivity, specificity, and positive and negative predictive values of 38%, 87%, 56%, 76% in 2178 rectal cancer patients without neoadjuvant short course radiotherapy (SCRT) and 56%, 67%, 47% and 75% in 3401 patients with SCRT, respectively. The known lack of accuracy in clinical lymph node staging adds uncertainty to any investigation of predictive parameters based on it. This is the reason why we decided to exclude pretherapeutic lymph node status from our analysis.
In multiple studies [7,8,13], the serum fibrinogen value proved to be a promising independent predictor of the therapeutic response and the prognosis after nRCT. Until now, we have not had any data to show whether this parameter also influences the sphincter-preserving surgery rate. In our analysis, the fibrinogen value was not associated with sphincter-preserving surgery, but the result is weakened by the fact that this information was not available for 68.9% of the patients.
A further limitation of our study may be that in 41.4% of the patients, the KPS was not recorded in the charts as a score. It was decided not to convert verbal descriptions of the patients’ general condition into scores.
The extent to which our study is comparable with other studies of predictive parameters in rectal cancer patients is limited due to different inclusion criteria and treatment regimens. However, apart from 35 of 540 patients, who were excluded due to induction chemotherapy, premature termination of radiotherapy or not undergoing surgery, all of the remaining 505 patients referred for nCRT had received a uniform regimen of concomitant chemotherapy and radiotherapy. Of these, the 280 that met the selection criteria represent, to the best of our knowledge, one of the largest single-center studies investigating parameters predictive for sphincter preservation.