Pathological Response Has Survival Benefits for Rectal Cancer following Neoadjuvant Therapy

Background Studies reporting the results of associated factors of pathological completed response (PCR) and tumor regression response in patients with rectal cancer following neoadjuvant chemoradiation therapy (nCRT) are inconsistent. The purpose of this study was to identify the prognostic factors of tumor response and outcome in rectal cancer patients.Methods The study was a retrospective analysis. Patients with locally advanced rectal cancer underwent nCRT followed by surgery from 2010 to 2014 with 5 years of follow-up. The primary outcomes were associated factors of pathological completed response and downstaging. The risk factors of survival outcome and disease recurrence were also observed.Results A total of 169 rectal cancer patients were included. The PCR rate was 17.8%, and the downstaging rate was 60.9%. Patients with a histology type of adenocarcinoma associated with PCR, and patients positive for clinical N stage were associated with downstaging. Kaplan-Meier analysis showed the PCR group performed better to a statistically significant level both in overall survival and disease recurrence free survival than the no PCR group (p= 0.033 & 0.025, respectively). Patients with a downstaging response also showed better overall survival benefits and disease recurrence free survival benefits than their counter-parts (both p<0.001). After controlling confounding variables, the risk factors of overall survival were downstaging [Hazard Ratio (HR): 0.40, 95% CI: 0.21-0.74], male, abnormal post-nCRT CEA level and abnormal Hb level. In addition, the protective factors of recurrence were downstaging and having adjuvant chemotherapy.Conclusions Among rectal cancer patients who received the neoadjuvant therapy, histology type and clinical N stage were associated with PCR and downstaging, respectively. Downstaging was an important protective factor for better overall survival and recurrence free survival. cancer type of dosage, follow-up


Background
According to the National Comprehensive Cancer Network (NCCN) guidelines, the current standardized management among locally advanced rectal cancer patients is neoadjuvant chemoradiation therapy (nCRT) followed by total mesorectal excision (TME) and adjuvant chemotherapy (1). Various studies found the association factors of better survival include tumor response regression, tumor stage, lymph-vascular invasion, cancer biomarkers, type of operation, chemotherapy regimen, radiation therapy dosage, and follow-up adherence (2)(3)(4)(5)(6).
The evidence shows presented approximately 10-38% of rectal cancer patients achieved a pathological completed response (PCR) after receiving neoadjuvant chemoradiation therapy (7). Moreover, patients who achieved PCR obtained the benefits of overall survival and disease-free survival (7). However, some studies argued PCR did not improve the survival outcomes due to the invasive treatment of resection and staging (8). Despite the inconsistent outcomes of PCR after nCRT, it is beneficial in clinical practice to identify the predictive factors of PCR and optimize the following treatments for rectal cancer patients.
Recent research has aimed to discover the predictive factors of PCR and how to achieve a better PCR rate in rectal cancer patients (9). In past studies, the biological and genetic characteristic predictive factors of PCR included carcinoembryonic antigen (CEA) levels, hemoglobin (Hb) levels, neutrophil-lymphocyte ratio (NLR), and obesity (10)(11)(12)(13)(14). In addition, the clinical predictive factors of PCR included the tumor size, nodal status, tumor histology, treatment type of chemotherapy and radiation therapy, as well as the interval from the completion of nCRT to surgery (6,(15)(16)(17).
There are discrepancies in the predictors for PCR from the previous research and disparities of the risk factors as well as survival outcome among rectal cancer patients who underwent nCRT and TME. Therefore, this comprehensive research was conducted to identify the factors influencing PCR and downstaging after receiving nCRT and to explore the risk factors of survival and recurrence among rectal patients from a single institution's experience.

Methods
We retrospectively reviewed the medical records of patients with newly diagnosed rectal cancer who underwent neoadjuvant chemo-radiation therapy followed by surgery at Taipei Medical University Hospital in Taiwan from January 2010 to July 2014. Patients were followed up until July 2019 with five years follow-up duration. Patients who received the short course of neoadjuvant radiation therapy were excluded from the study. The degree of tumor response following neoadjuvant CRT was observed, including pathological completed response (PCR) with no viable cancer cells and downstaging. Downstaging was defined as any occurrence of decreasing pathological stage status from the initial stage status. Additionally, the College of American Pathologists (CAP) tumor regression grade (18) was abstracted from the medical record as follows: grade 0 (complete response), no viable cancer cells; grade 1 (moderate response), single or small groups of cancer cells; grade 2 (minimal response), residual cancer outgrown by fibrosis; and grade 3 (poor response), minimal or no tumor kill, extensive residual cancer. The follow-up status and duration of disease recurrence and survival status after the primary operation date were recorded.
The patient characteristics included age at diagnosis, sex, body mass index (BMI), initial clinical stage, clinical primary tumor (T) stage, clinical regional lymph node (N) stage, tumor histology type from the colonoscopy report prior to the surgery, histology differentiation grade after the surgery, American Society of Anesthesiologists (ASA) physical Statius Classification (18), lymph vascular invasion, number of lymph nodes involved, tumor size, circumferential resection margin (CRM), pre-nCRT hemoglobin (Hb) level, and pre-nCRT CEA level. The post-nCRT CEA concentration level was recorded following the nCRT and prior to surgery. The surgery type was categorized in to three types as open laparotomy, robotic surgery using the Da Vinci surgical system, and laparoscopy surgery. The neoadjuvant chemotherapy regimen was classified as the regimen containing (1) Oxaliplatin or Capecitabine, (2) fluorouracil (5FU) and leucovorin, (3) 5FU alone. If the patient received adjuvant chemotherapy, it was logged into a binary variable. We further classified the BMI value into a non-obese group and obese group at a cutoff point of 30 kg/m 2 ; also, we divided the Hb value into normal and abnormal at a cutoff point of 12 g/dL. The CEA concentration level was analyzed for normal and abnormal levels at a cut-off point of 5 ng/mL.

Results
A total of 169 newly diagnosed rectal cancer patients who underwent neoadjuvant chemoradiation therapy and surgery were included in the study. Overall, 30 (17.8%) patients achieved PCR and 103 (60.9%) patients displayed downstaging. In addition, the average age at diagnosis was 58.4±13.2 years old, and 67.2% (117/174) were male. The majority of patients in the analysis were diagnosed with clinical stage II (29%) and clinical stage III (71%) cancer. Among those patients, the rate of PCR and downstaging were 18% and 65%, respectively. Additionally, of the four patients showing no PCR but (y) p stage 0, the (y)pT stage was found carcinoma in situ (Tis).
As a result, there was a statistically significant difference between the PCR and no PCR group among the histology type of adenocarcinoma (p=0.034) and lymph-vascular invasion (p<0.001). However, there were no statistically significant difference in age at diagnosis, sex, BMI, tumor staging, distance from anal verge, surgery type, ASA classification, the type of neoadjuvant chemotherapy regimen, pre and post nCRT CEA status, and pre-nCRT Hb level between patients with PCR or no PCR (all p> 0.05) (table 1).
Moreover, there was a significant difference between the downstaging group and nonresponse group in clinical stage, clinic N stage, CRM, and lymph-vascular invasion.

PCR and downstaging for survival and disease recurrence outcome
The mean duration of survival among the PCR group was 12 months longer than the no PCR group, which is statistically significant (p= 0.010); also, the mean time of disease recurrence following surgery was 17 months longer in the PCR group than the no PCR group (p= 0.001). According to the results of Kaplan-Meier analysis, the PCR group had better survival benefits, to a level of statistical significance, both in overall survival and disease recurrence free survival than the no PCR group with p values of 0.033 and 0.025, respectively ( Figure 1A and 1B). Moreover, the group displaying downstaging also demonstrated significantly better overall survival benefits and disease recurrence free survival benefits than the group without a downstaging response (both p values were <0.001) ( Figure 1C and 1D).
Further, between the mortality and survivor groups, there were significant differences in age, sex, clinical stage, pre-nCRT Hb level, pre-nCRT and post-nCRT CEA level, lymph vascular invasion, time to survival and disease recurrence, surgery type, ASA classification, CAP regression grade, received adjuvant chemotherapy (all p< 0.05) ( Table   2). Distance from the anal verge was marginally but still significantly lower in the recurrence population (5.67 ± 2.77 cm) than the non-recurrence patients (4.68 ± 2.35 cm). Among the recurrence group, there were significantly more patients who received adjuvant chemotherapy than the non-recurrence group (62.16%).

Associated factors of tumor response
According to the results of multivariate logistic regression, the histology type of  (Table 3).

Discussion
This single institution, retrospective, cohort study proved the promising survival benefits of rectal cancer patient who had PCR treated with neoadjuvant therapy and surgery.
Despite PCR not being proven to be a significant predictor of better survival rate or recurrence-free survival rate by univariate logistic regression, PCR was still proven to be a significant predictor of a longer survival length and remaining recurrence-free. Moreover, patients showing pathological downstaging had a significantly better survival rate and recurrence-free survival rate in the survival analysis. Our results are consistent with previous findings (6,15). Therefore, the implication is patients with either a pathological completed response or downstaging exhibit the benefits of better survival and recurrence free outcome.
We found rectal cancer patients with a histology type of adenocarcinoma tumor had a significant association with achieving PCR. However, the AUC value from the analysis showed a weak predictive power of PCR. This relevant study (17) suggested adenocarcinoma in rectal cancer was more resistant to both chemotherapy and radiotherapy than non-adenocarcinoma. Further, previous studies advised mucinous adenocarcinoma has a higher mortality risk and warrants more aggressive treatment regimens (19,20). Hence, awareness of the rectal cancer histology type before administering an effective treatment regimen might improve the PCR rate and survival outcome in clinical practice.
Various studies have shown clinical factors such as type of nodal positive, neoadjuvant chemotherapy, obesity, CEA concentration level, Hb level are associated with an improved PCR rate in rectal cancer patients who received neoadjuvant CRT (7, 9-12, 14, 17, 21).
However, none of the predictive factors in our study demonstrated an improved PCR rate.
In addition to PCR, the positive clinical N stage was the only predictive factor of downstaging. The finding could be explained by patients with clinical stage III being the highest proportion in this cohort. Thus, the response of patients with early stage to nCRT was marginal, which was not enough to achieve minimal downstaging. Second, the false positive imaging diagnosis of the node metastatic could also influence the clinical staging.
We also examined both pre and post nCRT CEA levels using the cut-off point of 5 ng/ml.
The results showed no difference between normal and abnormal CEA levels in predicting PCR and downstaging.
We further explored other risk factors of survival outcome and disease recurrence. Our multivariate logistic regression demonstrated a best fit prediction model of survival including tumor downstaging, sex, pre-nCRT Hb level, and post-nCRT CEA level. The outcome of our experience was consistent with previous studies (3,4,22). However, contrary to our survival outcome predictor of tumor downstaging, a study in Singapore did not show a survival benefit from tumor downstaging (8). In addition, regardless of whether PCR was achieved, patients who received adjuvant chemotherapy were more likely to have better survival outcome and less likely to relapse following surgery. (Table 5 We found an abnormal post-nCRT CEA level was also a risk factor in survival (aOR: 1.91, 95%CI: 1.05-3.48) according to the multivariate logistic regression. Similarly, the evidence (11) proved a low post-nCRT CEA level was a strong predictor of PCR, which also pointed to a better survival outcome. In addition to predicting survival and PCR, regular follow-up surveillance of the CEA level among rectal cancer patients is recommended by the guidelines (27). The study also points to the importance of proactive follow-up surveillance of CEA level monitoring, which benefits rectal cancer survivorship.

Limitations
Although this study had a larger sample size to evaluate the associated factors of PCR and outcome than past single institution studies, the current sample size is still inadequate to perform further analysis. In addition, some clinical data such as genetic biomarkers could not be obtained due to the retrospective study design and the data not being in the routine clinical practice at that time. Therefore, future study is recommended to obtain more recently diagnosed patients for increasing the sample size and obtaining more comprehensive parameters for identifying the potential associated factors.

Conclusions
In conclusion, our findings suggest histology and clinical N stage are associated with PCR and downstaging among rectal cancer patients after nCRT followed by surgery. Patients  Values are presented as mean ± standard deviation or number (%) by t-test or chi-square test. Values are presented as mean ± standard deviation or number (%) by t-test or chi-square test.