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    -  Aktan M
    -  Yavuz BB
    -  Kanyilmaz G
    -  Oltulu P

 
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ORIGINAL ARTICLE
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Factors affecting pathological response and survival following neoadjuvant chemoradiotherapy in rectal cancer patients


1 Department of Radiation Oncology, Necmettin Erbakan University, Faculty of Medicine, Konya, Turkey
2 Department of Pathology, Necmettin Erbakan University, Faculty of Medicine, Konya, Turkey

Date of Submission17-May-2019
Date of Decision01-Jan-2020
Date of Acceptance16-Apr-2020
Date of Web Publication10-Dec-2020

Correspondence Address:
Meryem Aktan,
Department of Radiation Oncology, Necmettin Erbakan University, Faculty of Medicine, Konya
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_435_19

PMID: 33402599

  Abstract 


Background: Despite all advanced treatment methods for rectal cancer, not all patients can provide an adequate response, and hence, possible prognostic factors must be evaluated. The aim of this study was to evaluate the relationship between systemic inflammatory markers and pathological response, overall survival (OS) and disease-free survival (DFS) in patients treated with neoadjuvant chemoradiotherapy (nCRT).
Methods: We evaluated data of 117 patients for the period 2010 to 2017. Serum measurements of albumin, hemoglobin, C-reactive protein, modified Glasgow prognostic score (mGPS), and white cell counts were obtained. Rodel scoring system was used to determine pathologic tumor regression.
Results: Overall, 77% of the patients were in the good response group according to the radiological images. A total of 48% of patients were categorized as a good pathologic response. Pathologic response to treatment was associated with a mGPS of 0 (P = 0.001), normal platelet lymphocyte ratio (PLR) (P = 0.003), TNM stage (P = 0.03), pathologic T stage (P = 0.001), radiologic response to nCRT (P = 0.04), tumor differentiation (P = 0.001), lymphovascular invasion (LVI) (P = 0.001) and perineural invasion (P = 0.02). LVI (P = 0.04), albumin level (P = 0.05), C-reactive protein (P = 0.01), neutrophil platelet score (NPS) (P = <0.001) and mGPS (P = 0.01) had a statistically significant effect on OS. Operation type (P = 0.03), tumor differentiation (P = 0.01), depth of invasion (P = 0.03), NPS (P < 0.01), mGPS (P = 0.01), PLR (P = 0.004), neutrophil-lymphocyte ratio (P = 0.01) and LVI (P = 0.05) were statistically significant on DFS.
Conclusions: There was an association between systemic inflammatory markers and pathologic response and also, between OS and DFS. This study can be preliminary data for prospective controlled studies.


Keywords: Chemoradiotherapy, pathologic response, rectal cancer
Key Message There is a relationship between systemic inflammatory markers and treatment response in rectal cancer patients and this relationship is reflected in overall survival and disease-free survival.



How to cite this URL:
Aktan M, Yavuz BB, Kanyilmaz G, Oltulu P. Factors affecting pathological response and survival following neoadjuvant chemoradiotherapy in rectal cancer patients. Indian J Cancer [Epub ahead of print] [cited 2021 Jul 27]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=302937





  Introduction Top


Colorectal cancer is the third most common cancer and a major health problem worldwide.[1] Approximately 50% of the patients have locally advanced disease, defined as T3–4 and/or node-positive without distant metastases.[2] Also, colorectal cancer is the second most frequent cause of death in the world both in women (13%) and men (11.6%).[3] The standard treatment strategy for locally advanced rectal cancer is neoadjuvant chemoradiotherapy (nCRT) followed by surgical resection with total mesorectal excision (TME). High-resolution pelvic magnetic resonance imaging (MRI) with expert radiologist interpretation will help us to select patients who will be treated correctly with surgery. Now MRI is used to be selective in irradiating those with large volumes, involving the mesorectal fascia, with significant lymph node involvement or venous invasion findings. Due to the developments in the field of radiotherapy, the development of new treatment systems and new surgical techniques, the efficiency of treatment in rectal cancer has increased and side effects related to treatment have decreased.[4],[5] The standardization of nCRT may lead to downstaging the tumor; this strategy provides better locoregional control and potentially increases sphincter preservation.[6],[7] Also, studies suggest that nCRT is associated with improvements in both overall survival (OS) and cancer-specific survival.[8],[9] Hence, any improvement in disease-free survival (DFS) and OS rates will require better control of the systemic disease while keeping the rate of local recurrences below 5-10%.[10]

Despite all the advanced treatment methods, not all patients can provide an adequate response, and possible prognostic factors must be evaluated. Prognostic value of the systemic inflammatory response (SIR) has been studied in gastrointestinal cancers, using measurements of circulating markers including albumin, C-reactive protein (CRP), carcinoembryonic antigen (CEA), the platelet lymphocyte ratio (PLR), the neutrophil lymphocyte ratio (NLR), the modified Glasgow prognostic score (mGPS) and the neutrophil platelet score (NPS).[11],[12],[13]

The aim of this study was to evaluate the relationship between systemic inflammatory markers and pathological response in rectal cancer patients treated with nCRT. It was also aimed to evaluate the effect of systemic inflammatory markers on OS and DFS.


  Methods Top


The design of this study was approved by the Ethics Committee and Institutional Review Board of Necmettin Erbakan University Faculty of Medicine, where the study was conducted. Informed consent was obtained from all of the patients before the treatments.

Patients characteristics

Between January 2010 and January 2017, we analyzed 178 newly diagnosed rectal cancer patients, retrospectively. The patients who were enrolled in this study had the following inclusion criteria: 1) pathological diagnosis of locally advanced rectal cancer without metastasis on presentation; 2) adult patients (>18 years of age at diagnosis); 3) patients submitted to the standard protocol of neoadjuvant treatment (simultaneous chemotherapy and radiotherapy); 4) available and consistent data from the patients' charts and from the histopathological sections. Patients and/or surgical samples that did not fulfill all the listed criteria were excluded from the study and 117 patients were included in this study. Using the patients' charts and electronic medical records, the following data were obtained: demographics, Karnofsky performance status (KPS) before radiotherapy (RT), pathological diagnosis, clinical staging, nCRT schedule, dose and techniques, side effect during nCRT, surgical status after nCRT, post-nCRT radiological and pathological response, date of recurrence or metastasis, last follow-up or death and survival time.

Pre-treatment assessment

At the initial evaluation, clinical and digital rectal examination (DRE), colonoscopy, computed tomography (CT) of the thorax and abdomen was done. Tissue biopsy of the primary lesion was performed for pathological confirmation. To stage the nodal status and local transmural extension, MRI of the pelvis was performed for all patients. Patients with suspected distant metastasis, positron emission tomography - computed tomography (PET-CT) and image-guided biopsy was performed if possible. According to the AJCC Staging System, seventh edition, clinical stages were recorded.[14]

In addition, blood cell count, serum biochemistry including liver and renal function tests, serum CRP, albumin, and CEA levels were obtained. Anemia was defined as serum levels <11.5 g/dL for women and <13 g/dL for men. The CRP level was considered high if >10 mg/L, and hypoalbuminemia was defined as a level <35 g/L. The CEA was defined as normal at a value lower than 5 μg/L.

The mGPS was calculated as score 0 for CRP normal, albumin normal, score 1 for CRP high, albumin normal and score 2 for CRP high with hypoalbuminemia.[15] The PLR and NLR were calculated. Values ≤ 300 for PLR and ≤ 5 for NLR were considered normal. The NPS was calculated as Score 0 for patients with a neutrophil count <7.5 × 109/L and a platelet count <400 × 109/L, Score 1 for those with a neutrophil count >7.5 × 109/L or a platelet count >400 × 109/L, Score 2 for those with both a neutrophil count >7.5 × 109/L and a platelet count >400 × 109/L.[16]

Neo-adjuvant chemoradiotherapy

All patients who had radiological or clinical stage T2-T4 with or without lymph node positive received pelvic radiotherapy (RT) with doses 45 -54 Gy at 1.8-2 Gy per fraction in the prone position with three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) techniques. Radiotherapy was delivered for five sessions per week. During preoperative radiotherapy, all patients received concurrent chemotherapy for about 6 weeks. The chemotherapy regimens used were 5-Fluouracil (5-FU) and leucovorin or oral capecitabine. Capecitabine was given at a dose of 1650 mg/m2 per day during radiotherapy. 5-FU and leucovorin were given 1000 mg/m2 per day, as a continuous infusion on days 1–5 and 29–33.[6] Radiotherapy and capecitabine were started on the same day, and capecitabine was stopped on the last day of radiotherapy.[17] During nCRT, physical examination was done, and hematology and biochemistry were performed weekly and before each chemotherapy cycle.

Treatment response to nCRT

After nCRT for about 5-6 weeks, MRI was performed for all patients to evaluate the response. Radiologic response to therapy was recorded according to Response Evaluation Criteria in Solid Tumors (RECIST) on pre- and post-nCRT imaging.[18] Radiological response was classified as complete, partial, stable, or progressive. The complete or partial response were described as a good response, and stable or progressive response were described as a poor response.

Surgical treatment and pathological assessment

All patients were planned for surgical management by a multidisciplinary team including colorectal surgeon, radiologist, oncologist, and pathologist. The technique of resection was standardized and total mesorectal excision was applied to all patients eligible for surgery. Pathological staging was done according to the AJCC 7th edition.[14] Pathological parameters included tumor differentiation, depth of tumor penetration, the total number of lymph nodes examined, number of metastatic lymph, lymph node ratio (LNR = number of metastatic lymph/total number of the lymph node), lymphovascular (LVI) and perineural invasion (PNI) and tumor regression grade (TRG) as suggested by Rödel and Fokas.[19],[20] Each grade was defined as follows: grade 0 (no regression), grade 1 (minor regression: <25% of fibrosis in the tumor mass), grade 2 (moderate regression: 26–50% fibrosis within the tumor mass), grade 3 (good regression: >50% fibrosis vs the tumor mass), grade 4 (complete regression: no evidence of viable tumor mass).[19] Patients were dichotomized as having a good response (TRG 3 and 4) or a poor or no response (TRG 0, 1, and 2).

Follow-up

Clinical examination was performed every 3 months for two years, every 6 months for the next 3 years, and then annually. Serum CEA level, hematology and biochemistry, chest X-ray, and abdomen ultrasound performed at every control. At every 6 months, pelvic CT was obtained and colonoscopy was performed at 1 and 3 years. Lesions occurring in the pelvic or anastomosis were considered as local recurrences, while the other sites were considered as distant metastases.

Statistical analysis

Statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) (Windows software program, version 18; Chicago, USA). Grouping of the variables was performed using standard clinical thresholds. The clinical endpoints of the study were factors affecting the pathological response, OS, and DFS. The univariate effects on survival were investigated using the log-rank test. The Kaplan–Meier survival estimates were calculated. The possible factors identified with univariate analyses were entered into the Cox regression analysis. Comparisons between groups of patients were performed using the Chi-square test or Fisher's exact test (when Chi-square test assumptions don't hold due to low expected cell counts) and P value of less than 0.05 was regarded as significant.


  Results Top


Patient characteristics

A total of 117 patients were included in this study. Median Karnofsky performance status was 100 (range: 80-100) before nCRT. Tumor positive lymph nodes were suspected in 76 (65%) patients by radiological imaging. All patients underwent nCRT. Of these, 94 (80%) received RT with IMRT, 23 (20%) with 3D-CRT with a median 50 Gy dose (range: 45-54 Gy). 100 (85.5%) patients treated with oral capecitabine and 17 (14.5%) patients were with 5-FU bases chemotherapy as previously described. Patient characteristics are shown in [Table 1], complications and grades are shown in [Table 2].
Table 1: Patient characteristics

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Table 2: Complications during nCRT

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Radiological imaging after nCRT showed complete response in 12 (10.3%) patients, partial response in 78 (67%) patients, stable response in 19 (16%), and progressive response in 1 (0.9%) patient. The radiological response of 7 patients was not assessed. A total of 77% of the patients were in good response group.

Median time from the completion of nCRT to surgery was 7 weeks (range: 1-23 weeks).

In only one patient, surgery was delayed due to chronic diseases (diabetes mellitus and hypertension) and could be operated at the 23rd week. Two patients were operated one week after radiotherapy because they had a distal localized tumor and the symptoms of obstruction after radiotherapy continued. Six patients were operated on the fourth week after radiotherapy with the preference of their surgeon. The operation of all other patients was done at the earliest in the sixth week after radiotherapy. The resection technique was standardized and all patients underwent TME with preservation of the hypogastric nerves.

The majority of the patients had a normal hemoglobin (n = 79, 67.5%), normal albumin (n = 107, 91%), normal CRP (n = 76, 65%), normal CEA (n = 62, 53%), NLR ≤5 (n = 108, 92%), PLR ≤300 (n = 107, 91%), mGPS of 0 (n = 74, 63.2%) and NPS of 0 (n = 100, 85%).

Association between tumor regression grade and clinicopathologic factors

Using the Rödel classification, tumor regression grades (TRGs) were classified as grade 0 (n = 3, 2%), grade 1 (n = 22, 19%), grade 2 (n = 36, 31%), grade 3 (n = 35, 30%) or grade 4 (n = 21, 18%). TRG grade 0-1-2 (n = 61, 52%) was defined as a poor or unresponsive group. TRG grades 3 and 4 (n = 56, 48%) were defined as a group with good response.

At the time of diagnosis, 76 (65%) patients had positive lymph nodes in radiological imaging, after treatments 83 (71%) patients were lymph node negative.

Pathologic response to treatment was associated with TNM stage (P = 0.03), pathologic T stage (P = 0.001), radiologic response to CRT (P = 0.04), tumor differantiation (P = 0.001), lymphovascular invasion (P = 0.001), and perineural invasion (P = 0.02).

There was no association between nodal metastasis (P = 0.17), tumor location from anal verge (P = 0.26), depth of tumor invasion (P = 0.33), type of operation (P = 0.43), radiotherapy technique (P = 0.35) or chemotherapy type (P = 0.10).

A good pathologic response to treatment (TRG 3-4) was associated with a mGPS of 0 (P = 0.001) and a normal PLR (P = 0.003). There was no association between good pathologic response to treatment and CEA (P = 0.19), anemia (P = 0.61), CRP (P = 0.5), NPS (P = 0.44) or NLR (P = 0.1) [Table 3].
Table 3: Association between clinicopathological factors and TRG of patients undergoing nCRT and surgery for rectal cancer

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Progression and survival patterns

Median follow-up time from diagnosis was 31.6 months (range: 4.8-147.8 months). Only 1 patient in the good response group and 12 patients in the poor response group died. There was significant relation between TRG group and OS. Mean OS was 144.6 months (range 138.2- 150.9 months) for good response group, 79.5 months (range 67.8- 91.2 months) for poor response group (P = 0.003) [Figure 1]. In univariate analysis, LVI (P = 0.04), albumin level (>35 g/L) (P = 0.05), CRP (<10) (P = 0.01), NPS (P = <0.001), and mGPS (P = 0.01) had a statistically significant effect on OS. In multivariate Cox regression analyses, LVI (P = 0.009), tumor differantiation (P = 0.04), and CRP (P = 0.03) were statistically significant on OS.
Figure 1: Overall survival of patients according to pathologic response group. TRG: Tumor Regression Grade

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Median time to local recurrence or metastasis was 15.04 months (range 3.46- 66.7 months). Local recurrence developed in only 2 patients (1 patient in good response group) and distant metastasis developed in 14 patients (2 patients in good response group). Mean DFS was 134.4 months (range 116.6-152.3 months) for good response group, 74.4 months (range 62.9- 85.9 months) for poor response group (P = 0.005) [Figure 2]. In univariate analysis, operation type (LAR) (P = 0.03), postoperative tumor differantiation (P = 0.01), depth of invasion of the tumor into the rectum wall (<15 mm) (P = 0.03), NPS (P < 0.01) and mGPS (P = 0.01), PLR (<300) (P = 0.004), NLR (<5) (P = 0.01), and LVI negativity (P = 0.05) were statistically significant on DFS. Mean DFS was 117.3 months for LAR patients and 62.5 months for APR patints. Mean DFS was 124.2 months for tumor invasion depth to rectum wall <15 mm and 60 months for >15 mm. There was no statistically significant relationship between tumor location and DFS (P = 0.8), however, it was observed that the mean DFS was higher in the distal tumors (103.5 months vs 82 months). In multivariate Cox regression analyses, LVI (P = 0.04) and NPS (P = 0.04) were statistically significant on DFS.
Figure 2: Disease-free survival of patients according to pathologic response group

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  Discussion Top


The results of this study showed an association between systemic inflammation markers and pathologic response to nCRT for patients undergoing surgery for rectal cancer. In addition, there was a significant relationship between systemic inflammation markers and OS and DFS.

Tumor regression grade provides a clinically useful parameter to determine the rate of pathological response to neoadjuvant therapy. Treatment response to CRT can be an early indicator of prognosis for rectal cancer patients.[21] Several fairly similar scoring systems have been proposed depending on the rate of residual tumor cells and fibrosis.[19],[20],[22],[23],[24] These scoring systems can predict cancer-specific survival and DFS, but it is not certain which is the best. The main advantage of these scoring systems is that they do not require an additional laboratory test or time and have an interobserver concordance. Although they are based on selected areas of the tumor and semi-quantitative, they are the best method we currently have to estimate the response to neoadjuvant therapy by measuring the ratio of fibrosis to remaining tumor tissue. However, they can only be used retrospectively after nCRT and pre-operative predictive biomarkers are needed.

Several biomarkers are reported to predict response to nCRT in rectal cancer and as a marker of systemic inflammation such as serum CRP, albumin, and CEA. However, none of them have entered routine practice because of methodology and validation problems.[25],[26]

An elevated CRP expression has been associated with poor outcome after nCRT and surgery for rectal cancer.[12] We did not find any relationship between CRP and pathological response. However, the effect of serum CRP on both OS and DFS was statistically significant in our study.

The results showed that mGPS is independently associated with response to treatment and may provide more insight into the interaction between host immune response and tumor regression.[27],[28] Pretreatment mGPS score of 0 was an independent prognostic factor of a pathologic response to chemoradiotherapy for rectal cancer, even when analyzed in a model with prognostic postoperative variables such as TNM stage, PNI, and LVI, consistent with our findings.[15],[29] In our study, we observed that the response to pathologically evaluated nCRT was variable (only good response of 48%). TNM stage, radiological response after treatment, pathological T stage, tumor differentiation, presence of LVI and PNI are related to pathological response.

The prognostic value of NLR and PLR for patients undergoing nCRT in rectal cancer was demonstrated and showed that both were associated with long-term outcomes.[25],[30] We demonstrate that PLR, but not NLR, was associated with a good response to therapy. Dreyer et al. observed that NLR, but not PLR, was associated with response to therapy, as opposed to our findings.[29] And also, in our study, we find a correlation between NPS and mGPS with OS; NPS, mGPS, PLR and NLR with PFS, which recently claimed to have an impact on long-term outcomes in colorectal cancer.[13],[16]

The value of control MRI after nCRT is controversial. Some studies suggested that there was a poor correlation between post-treatment MRI appearances and clinical outcomes.[31],[32] However, prospectively controlled studies have suggested that tumor regression can be determined using MRI after nCRT, and also radiological MRI evaluation of tumor regression was correlated with both DFS and OS in patients with rectal cancer by measuring the degree of fibrosis.[33] Radiologic downstaging was correlated with a good pathologic response in our study, but we did not find any correlation with OS or DFS. In this study, only patients who completed long-course chemoradiotherapy and operated were included because previous studies have shown that long-course chemoradiotherapy has better results than short-course radiotherapy.[34] These preoperative evaluations can be help surgeons in clinical decision making before surgery because the pathological response can only be evaluated postoperatively.

There are some limitations to our study. The first limitation was that this study was based on retrospective data. The other limitation was that we did not have any data about pathological factors in biopsy material before CRT such as tumor differentiation, perineural or lymphovascular invasion. The mean follow-up time of 31.6 months seems short to analyze prognosis. However, it is thought that the data we obtained may provide information about long-term follow-up results.

In conclusion, this study demonstrated that there was an association between systemic inflammatory markers and pathologic response to CRT and also OS and DFS in rectal cancer patients. Therefore, improving the understanding of prognostic factors and response to nCRT will help to plan adjuvant therapy strategies. To improve the response to nCRT and to contribute to the survival of rectal cancer patients with anti-inflammatory and immunomodulatory treatments, more research is needed with prospective studies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Bosset JF, Calais G, Mineur L, Maingon P, Stojanovic-Rundic S, Bensadoun RJ, et al. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: Long-term results of the EORTC 22921 randomised study. Lancet Oncol 2014;15:184-90.  Back to cited text no. 34
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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