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ORIGINAL ARTICLE
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Predictors of pathological complete response following neoadjuvant chemoradiotherapy for rectal cancer


1 Department of General & Minimal Ïnvasive Surgery (Colorectal Division), Sher I Kashmir Institute of Medical sciences, Srinagar, India
2 Department of Biomedical and Biological Sciences, Sohail University, Karachi, Pakistan

Date of Submission03-Sep-2020
Date of Decision20-Dec-2020
Date of Acceptance23-Feb-2021
Date of Web Publication15-Oct-2021

Correspondence Address:
Asif Mehraj,
Sher I Kashmir Institute of Medical Sciences, Srinagar - 190 011, Jammu and Kashmir
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_1273_20

 > Abstract 


Background: Neoadjuvant chemoradiotherapy (NACRT) is an established treatment option for locally advanced rectal cancer (LARC). Patients achieving pathological complete response (pCR) following NACRT have better oncological outcomes and may be subjected to wait and watch policy as well. The aim of this study was to identify predictors of pCR in LARC following NACRT.
Materials and Methods: A retrospective analysis of a prospectively maintained colorectal cancer database from January 2018 to December 2019 was undertaken. A total of 129 patients of LARC who were subjected to conventional long course NACRT, followed by surgery were included in the study. Pathological response to NACRT was assessed using Mandard grading system and response was categorized as pCR or not-pCR. Correlation between various clinico pathological parameters and pCR was determined using univariate and multivariate logistic regression analysis.
Results: Mean age of patients was 53.79 ± 1.303 years. Complete pathological response (Mandard Gr 1) was achieved in 24/129 (18.6%) patients. Age of patients more than 60 years (P = 0.011; odds ratio [OR] 3.194, 95% confidence interval [CI] 1.274-8.011), interval between last dose of NACRT and surgery >8 weeks (P = 0.004; OR 4.833, 95% CI 1.874-12.467), well-differentiated tumors (P < 0.0001; OR 32.00, 95% CI 10.14–100.97) and node-negative disease (P = 0.003; OR 111.0, 95% CI 2.51–48.03) proved to be strong predictors of pCR.
Conclusion: Older age, longer interval between NACRT and surgery, node-negative disease and favorable tumor grade help in achieving better pCR rates. Awareness of these variables can be valuable in counseling patients regarding prognosis and treatment options.

Keywords: Neoadjuvant chemoradiotherapy, pathological complete response, rectal cancer, tumor regression



How to cite this URL:
Mehraj A, Baba AA, Khan B, Khan MA, Wani RA, Parray FQ, Chowdri NA. Predictors of pathological complete response following neoadjuvant chemoradiotherapy for rectal cancer. J Can Res Ther [Epub ahead of print] [cited 2021 Nov 28]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=328258




 > Introduction Top


Neoadjuvant chemoradiotherapy (NACRT) followed by total mesorectal excision is the current standard of care for locally advanced rectal cancer (LARC). It has led to a markedly reduced local recurrence rates <10% in Stage II or III rectal cancer at 5 years.[1]

Response to NACRT varies from individual to individual ranging from a pathological complete response (pCR) defined as the absence of residual tumor cells in the resected surgical specimen to no response or even disease progression. Patients with pCR have a better long-term outcomes than those without pCR.[2]

However, the tumor response to NACRT varies significantly among individuals. pCR can be achieved in 15%–27% of the patients , while as around 54%–75% show partial response and others show no response at all.[3],[4]

Hence, identifying factors that could improve the rate of pCR would be helpful for clinicians in determining prognosis and could assist with treatment decisions as well.

A complete clinical response (cCR) evaluated by clinical examination and imaging does not always correlate with a pCR, as nearly 75% of resected specimen may still harbor residual tumor cells.[5],[6] Even in patients who achieve complete pathologic resolution of their primary tumors, 15% may have residual nodal disease.[7],[8] Therefore, identifying factors that can predict pCR, may help clinicians to prognosticate patients and also help in deciding the most appropriate treatment option for them. This retrospective study was designed to identify possible predictive factors for pCR after NACRT for rectal cancer in patients at a single center.


 > Materials and Methods Top


This study was performed at a high volume colorectal surgery unit in a tertiary care teaching hospital. Between January 2018 and December 2019, all consecutive patients with LARC who were subjected to NACRT followed by surgery were included in the study. Information on demographic data, stage at presentation, and treatment administered were recorded from a prospectively maintained database for these patients. A colonoscopy/sigmoidoscopy was performed on all patients and a tissue diagnosis with biopsy was obtained before the commencement of treatment. Pre-operative staging was done using magnetic resonance imaging (MRI) of pelvis and contrast-enhanced computed tomography of the abdomen, pelvis, and chest. Patients with metastatic disease were excluded from the study. All patients were treated with long course radiotherapy at a dose of 45 Gy divided over 25 cycles. External beam radiotherapy was given over 5 days a week with daily dose of 1.8 Gy. Concurrent 5-fluorouracil-based chemotherapy via continuous infusion or orally (Capecetabine) was given to all patients. Surgery was performed after a minimum of 6 weeks following last dose of radiotherapy. Resected specimens were subjected to histopathological examination which was done by a dedicated gastrointestinal pathologist. Treatment response was reviewed and was categorized as pCR (TRG1) or not pCR (TRG 2-5) as per Mandard grading system. pCR was defined as absence of viable adeno carcinoma cells in the surgical specimen including lymph nodes. All other forms of partial response or regression were grouped into the non pCR cohort.

Statistical analysis

All the statistical analyses were carried through Statistical Package for the Social Sciences, (IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY., USA). The categorical variables have been shown in the form of frequency and percentage. The continuous variables were reported as mean and standard deviation. The associations between the categorical variables and pCR have been evaluated by the Chi-squared test. Quantitative variables were compared using Mann–Whitney rank test. Variables with P < 0.05 under the Chi-squared analyses were subjected to the logistic regression analyses. The adjusted odds ratio (AOR) with 95% confidence interval (CI) was calculated after the adjustment for the age, gender, and body mass index (BMI).


 > Results Top


Patient characteristics

A total of 129 patients were included in the study. Mean age of patients was 53.79 ± 1.303 years. 45.74% of patients were males and remaining 54.26% were female. About 18.60% of the patients were smokers. Most of the patients had an average build with a mean BMI of 22.78. The tumor histology consisted of well-differentiated adenocarcinoma in 27 (20.93%), moderately differentiated in 48 (37.21%), poorly differentiated in 30 (23.26%), and signet ring cell in 24 (18.60%) patients. The median initial CEA concentration was 3.6 ng/ml (range, 0.8 to 382.0 ng/ml). The median initial Hb concentration was 12.4 g/dL (range 9.4-16.1 g/dL). Mean platelet count was 245.9 ± 94.2. Median neutrophil/lymphocyte ratio was 3.84 ± 2.3. As far as T staging is concerned, 6 (4.65%) had T2 lesions, 72 (55.81%) had T3 lesions and remaining 51 (39.54%) patients had T4 lesions on initial radiological evaluation. Patients with T2 lesions had either concomitant lymph node-positive disease or were close to the AV, which required anal-sparing procedures. Similarly, 117 (90.70%) of patients had lymph node-positive disease.

All patients underwent surgery, comprising Low/Ultra low anterior resection in 96 (74.42%), intersphincteric resection in 9 (6.98%) and abdominoperineal resection in 24 (18.60%) patients. The mean duration of surgery following last dose of NACRT was 7.7 ± 1.22 weeks. pCR (TRG1) was achieved in 24 (18.60%) patients. 75 (58.14%) patients showed some form of regression ranging from near complete to minimal regression (TRG 2-4). 30 (23.26%) patients had no response (TRG 5) to NACRT. Baseline patient characteristics are summarized in [Table 1].
Table 1: Baseline patient characteristics

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Univariate analysis

Elderly patients more than 60 years had significantly better pCR rates as compared to those younger than 60 years (P = 0.011*; CHI = 6.505). An interval >8 weeks between the last dose of NACRT to surgery was also a significant predictive factor for pCR (P = 0.004; CHI = 8.0775). Patients with node negative disease showed a better pCR as compared to patients with node-positive disease (P = 0.003; CHI = 8.6118). Patients with well differentiated histology had higher pCR rates as compared to poorly differentiated or signet ring histology (P < 0.0001; CHI = 57.278). The differences in pCR rates among gender, smoking, BMI, hemoglobin levels, platelet count, neutrophil-to-lymphocyte ratio, initial carcino embryonic antigen levels, and T stage were not significantly associated with pCR in univariate analyses. [Table 2 summarizes univariate analysis of various predictive factors for pCR.
Table 2: Univariate analysis of predictors for pathologic complete response

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Multivariate logistic regression analysis

On logistic regression analysis, age ≥60 years (OR = 3.194, 95% CI = 1,274–8.011; AOR = 2.264, 95% CI = 0.816–6.280), interval between NACRT and surgery >8 weeks (OR = 4.833, 95% CI = 1.874–12.467; AOR = 4.764, 95% CI = 1.754–12.936), node-negative disease (OR = 111.0, 95% CI = 2.51–48.03; AOR = 24.72, 95% CI = 4.33–141.49) and well differentiated tumors (OR = 32.00, 95% CI = 10.14–100.97; AOR = 33.056, 95% CI = 9.63–113.412) were significant predictors of pCR.[Table 3]
Table 3: Logistic regression analysis for predictors of pathological complete response

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 > Discussion Top


There are several clinical, pathological and treatment variables that can help in predicting pathological response following NACRT for rectal cancer. Knowing these factors in a particular setting can help in counseling patients regarding various treatment options and ultimately regarding their prognosis as well. In the multimodal management of rectal cancer, it becomes important to identify these predictive factors in our routine practice. In recent years, the concept of wait and watch approach has been gaining lot of interest as the oncological outcomes in such patients are comparable to those receiving radical surgery, with the added advantage of avoiding surgical complications.[9],[10] Based on the clinical response which is usually assessed by clinical examination and MRI, patients who have achieved good clinical response are offered the option of wait and watch policy, where they are closely followed up to detect any early recurrence.

Neo adjuvant therapy can be administered in various forms. There is option of giving either conventional NACRT or short course radiotherapy (SCRT). There is a lot of debate in literature on the effect of type of neoadjuvant regimen on pCR rates. There are studies which conclude that the pCR rates are similar for both NACRT and SCRT[11],[12] and some suggesting that NACRT has better outcomes.[13]

Of late there is increased interest toward the concept of total neoadjuvant treatment (TNT), which involves the addition of induction chemotherapy to concomitant NACRT or SCRT and is believed to increase pCR and act on occult micrometastatic disease, leading ultimately to a better outcome. In a recent meta-analysis involving 3579 patients, 2688 were subjected to TNT and 891 to NACRT. The pooled pCR rate was 22.4% (95% CI 19.4%–25.7%) in all patients treated with TNT and it was found to increase the odds of pCR by 39% (1.40, 95% CI 1.08–1.81, P = 0.01).[14] Similar results were confirmed by Riesco-Martinez et al. in a meta-analysis involving a total of 2301 patients. TNT significantly improved pCR rate (OR = 1.99, 95% CI 1.59–2.49; P < 0.001). In addition they concluded that an improved pCR rate was achieved irrespective of the type of radiotherapy administered (long vs. short fractionation schedules).[15] We used conventional NACRT consisting of 45 Gy of radiotherapy over 25 fractions with concurrent 5-Flourouracil based treatment. Oxaliplatin may be added to the neoadjuvant regimen, which has the advantage of decreasing the distant failure rates;[16] however, our institutional protocol is to use 5 FU-based regimen only.

The pathological response to NACRT varies significantly among individuals. pCR can be achieved in 15%–27% of the patients , while as around 54%–75% show partial response and others show no response at all.[3],[4],[17] In a large study of 23,747 patients, Al Sukhni et al. showed that the pCR rate was 23.3%.[18] In our study, pCR was acheived in 18.6% of patients.

Different grading systems have been used to determine the extent of pathological response following NACRT. The most widely used TRG systems are those of Mandard et al.,[19] Dworak et al.[20] and Ryan et al.[21] We used Mandard grading system for studying various tumor regression grades. It classifies tumor regression into five sub types: TRG1 with no tumor cells; TRG 2, residual tumor cells; TRG3, predominant fibrosis and residual cells; TRG4, predominant tumor cells and fibrosis and TRG5, no tumor regression. We considered only TRG1 as pCR in our study. All other grades including TRG2/3 and TRG 4/5 were grouped together in other cohort of those patients who did not show pCR.

Various factors have been found to have a predictive value in determining pathological response.

In a recent meta-analysis involving 6725 patients, higher pCR rates were achieved in elderly patients (P = 0.0002).[22] We also found that patients >60 years had significantly better pCR rates as compared to patients younger than 60 years.

In our study, the duration of wait from the last dose of NACRT to surgery ≥8 weeks was a significant predictive factor for pCR. A systemic review and meta-analysis of 13 trials including 3584 patients evaluated whether a longer interval between the last dose of NACRT and surgery was associated with a higher pCR rate. The longer interval of more than 6-8 weeks was found to be associated with a significantly improved pCR rate.[23] Another meta-analysis of 26 publications with more than 25000 patients demonstrated that a minimum interval of 8 week between NACRT and surgery increases pCR, and improves recurrence-free survival without more surgical morbidity.[24] In 2018, Kim et al. analyzed outcomes for rectal cancer patients who received differing intervals to surgery after completion of neoadjuvant therapy. The primary outcomes measured were pCR and tumor downstaging. The authors noted a higher rate of pCR in the 9 to 11-week interval with a pCR of 8.6% (P = 0.886). Downstaging occurred most frequently in the 7 to 9-week cohort with a downstaging rate of 52.9% (P = 0.087).[25]

Many recent studies have shown that patient with lymph node positive disease had poor response to neoadjuvant treatment as compared to node negative disease. Engel, et al. analyzed 354 patients of LARC, who were subjected to neoadjuvant radiotherapy/chemoradiotherapy. They reported that patients with node negative disease had a better pCR rate as compared to node-positive patients (P = 0.031).[26] Another recent meta-analysis by Yeqian Huang et al. showed that no clinical lymph node involvement was a positive predictor of pCR (P < 0.00001) in patients with Stage II and III rectal cancer following neoadjuvant therapy.[22] In our study lymph node-negative disease was shown to be positive predictive factor for pCR.

Tumor differentiation is considered to be an important prognostic factor, with poorly differentiated and signet cell pathology having the worst outcomes in terms of recurrence and overall survival. Signet cell carcinomas are considered to be rare in the world literature with an incidence ranging from 1% to 13% in most of the studies.[27],[28],[29] However in India it is more common. In a study from Tata Memorial Hospital, Mumbai, the signet ring cell carcinomas were found in 17% of their patients.[30] In our study, a total of 24 patients (18.6%) had signet ring pathology which corresponds to the Indian data. Many studies suggest tumor differentiation to be a significant predictive factor for determining pCR.[31],[32] Similar to those studies our data also suggests that patients with well differentiated tumors had significantly better pCR rates than patients with poor histology.

The knowledge of predictive factors may help in providing more personalized treatment depending upon individual tumor response after NACRT in rectal cancer patients.


 > Conclusion Top


Elderly patients have better chances of achieving pCR as compared to young and delaying surgery beyond 8 weeks following last dose of NACRT helps in achieving better tumor regression in rectal cancer patients. Furthermore, rectal tumors with favorable grade and node negative disease have better chances of showing pCR as compared to tumors with unfavorable histology and node-positive disease respectively.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Chapman BC, Goodman K, Hosokawa P, Gleisner A, Cowan ML, Birnbaum E, et al. Improved survival in rectal cancer patients who are treated with long-course versus short-course neoadjuvant radiotherapy: A propensity-matched analysis of the NCDB. J Surg Oncol 2019;119:518-31.  Back to cited text no. 13
    
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    Tables

  [Table 1], [Table 2], [Table 3]



 

 
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