Research Article | | Peer-Reviewed

Predictive and Prognostic Factors Related to Chemoradioresistance in Neoadjuvant Treatment of Locally Advanced Rectal Cancer at Panama

Received: 5 March 2024     Accepted: 26 March 2024     Published: 12 April 2024
Views:       Downloads:
Abstract

Background: In Panama, and the rest of Latin America, there are few publications on chemoradioresistance, it leads to poor prognosis and represents the main reason for failure of therapy, ultimately it can lead to tumor recurrence and metastasis. Objective: Identify factors associated with chemoradioresistance in the neoadjuvant treatment of locally advanced rectal cancer at the Instituto Oncológico Nacional de Panamá, period 2016-2020. Methodology: This retrospective study included 71 patients with LARC who received neoadjuvant chemoradiotherapy and surgery. Chemoradioresistant patients were those who did not reach a higher pathological stage of ypT2NO and the results were compared. Results: Of the 71 patients, pathological complete response (pCR) was achieved in 34 patients (48%). 49% of patients met chemoradioresistance criteria. In this group, the median CEA was 136 ng/ml, the median hemoglobin was 12 g/dl, and the median BMI was 26 kg/m2. The median radiation dose was 5000Gy. The time between completion of chemoradiotherapy and surgery was 110 days (16 weeks). Depending on the type of surgery, 65% who underwent low anterior resection were chemoradioresistant. The variables with statistical significance were the CEA value >5 ng/mL (OR=1.81, p=0.026) prior to the start of neoadjuvant treatment, with a lower pCR rate. Likewise, the ECOG scale (OR=2.51, p=0.015) was a risk factor related to chemoradioresistance, the lower the ECOG, the lower the risk of chemoradioresistance. The median overall survival and median recurrence-free survival was not reached in both groups and there was no statistically significant difference. Conclusions: Significant interactions were identified between CEA levels prior to the start of neoadjuvant treatment with the pathological complete response rate and the ECOG score with chemoradioresistance. Therefore, these factors can be used to predict patient outcomes, will help optimize personalized treatment strategies and improve patient outcomes.

Published in Cancer Research Journal (Volume 12, Issue 2)
DOI 10.11648/j.crj.20241202.11
Page(s) 21-26
Creative Commons

This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.

Copyright

Copyright © The Author(s), 2024. Published by Science Publishing Group

Keywords

Locally Advanced Rectal Cancer, Chemoradiotherapy, Pathological Complete Response, Chemoradioresistance

1. Introduction
The Colorectal cancer is the fourth most frequently diagnosed cancer and second leading cause of cancer death in the US . Recent data show increased incidence in patients less than 65 years of age. The authors estimate that the incidence rates for rectal cancers will increase by 124.2%, for patients 20 to 34 . The database at the Instituto Oncológico Nacional de Panamá for the year 2021 estimated that Rectal Cancer ranked ninth in frequency distribution for both sexes, representing 3.4% of all cancers diagnosed in that year , where the main management of Locally Advanced Rectal Cancer (LARC) of neoadjuvant chemotherapy and radiotherapy (nCRT). In Panama, and the rest of Latin America, there are few publications on chemoradioresistance, it leads to a poor prognosis and represents the main reason for therapy failure, which can lead to local recurrence and metastasis.
Identification of factors that influence histological response can help predict prognosis and propose organ preservation for good responders. Multiple studies have correlated pathological complete response with disease-free survival and overall survival . It is essential to increase complete pathological responses, but it is unclear what clinical factors are involved.
The objective of the study is to evaluate the predictive and prognostic factors, as well as the incidence of chemoradioresistance, defined as patients who do not downstage to ypT2N0, after neoadjuvant treatment. These data would propose changes in the institutional practice if necessary and the departments that interfere in this management will benefit.
2. Materials and Methods
Retrospective, cross-sectional observational study who, data were obtained from electronic records of patients with Locally Advanced Rectal Cancer who received neoadjuvant treatment at the Instituto Oncológico Nacional de Panamá, between January 2016 and December 2020. The primary point of the study was to identify the predictive and prognostic factors related to chemoradioresistance in the neoadjuvant treatment of locally advanced rectal cancer of patients treated in the institution.

2.1. Patient Selection

The following inclusion criteria were used in this study:
1. Patients older than 18 years.
2. Diagnosis of locally advanced rectal cancer with histological type adenocarcinomas and treated with Neoadjuvant chemoradiotherapy therapy.
The following exclusion criteria were used in this study:
1. Patients who received total neoadjuvant chemotherapy.
2. Patients who received induction chemotherapy.
3. Patients who received chemotherapy other than fluoropyrimidines.
4. Patients with palliative colostomy prior to the start of treatment.
5. Patients with double primaries.

2.2. Statistical Analysis

The information were collected and analyzed using IBM SPSS Statistics version 23 and Stata 17. Patient characteristics were reported using frequency and descriptive statistics. The Kaplan-Meier method was used to analyze recurrence-free survival and overall survival.
3. Results

3.1. Patients’ Characteristics

71 patients with LARC who were treated with nCRT and surgery were enrolled; 44 patients were male (62%), and 27 patients were female (38%), with a median age of 63 years (range 34 to 87). About 43% of all patients had a tumor located at middle rectum, 42% at lower rectum and 15% at upper rectum. Baseline characteristics are detailed in Table 1. There were 35 patients (49.3%) who were considered to have chemoradioresistance (patients who did not reduce their stage to ypT2N0 or lower after receiving neoadjuvant treatment). Regarding the ECOG scale, 27 patients were recorded with ECOG 1 in the first evaluation equivalent to 77%, 7 patients with ECOG 0 (20%) and only 1 patient was recorded with ECOG 2. In this study 34 patients (97%) presented with a locally advanced clinical stage compared to 1 patient (3%) who presented with a localized clinical stage. The most frequent grade of histological differentiation was moderately differentiated in 94% of patients, followed by well differentiated in the remaining 6%. Regarding the 36 patients (50.7%) considered responders, the ECOG scale were 0 in 20 patients, the remaining 16 patients had an ECOG of 1. In this group, 35 patients (97%) presented with a locally advanced clinical stage compared to 1 patient (3%) who is recorded with a localized clinical stage. The most frequent grade of histological differentiation was moderately differentiated in 94% of patients, followed by well differentiated in the remaining 6%.
Table 1. Patient characteristics.

Characteristics

No. of patients (%)

Chemoradioresistance

Chemoradiosensitive

Total, n (%)

35 (49)

36 (51)

Age (years), median [range]

63 [34-85]

62 [36-87]

Sex, n (%)

Male

25 (71)

19 (53)

Female

10 (29)

17 (47)

Pretreatment ECOG performance status, n (%)

0

7 (20)

20 (56)

1

27 (77)

16 (44)

2

1 (3)

0

Pretreatment CEA (ng/mL, median [range])

136 [122-396]

27 [4-51]

Pretreatment Hb (g/dL, median [range])

12 [11-12.8]

13 [12-14]

Pretreatment BMI (kg/m2, median [range])

26 [24-29]

25 [24-27]

Stage, n (%)

Localized

1 (3)

1 (3)

Locally Advanced

34 (97)

35 (97)

Histological Grade, n (%)

Well differentiated

2 (6)

2 (6)

Moderately differentiated

33 (94)

34 (94)

*ECOG, the Eastern Cooperative Oncology Group; CEA, carcinoembryonic antigen; Hb, Hemoglobin; BMI, body mass index.

3.2. Treatment and Postoperative Pathological Features

All patients received 5-fluorouracil-based chemotherapy, CapeOx (capecitabine + oxaliplatin), orally or via intravenous infusion with concurrent radiotherapy to pelvis, followed by surgery and posterior adjuvant chemotherapy. The median dose of RT was 50 Gy. Of the 71 patients in the study, we obtained a total of 34 complete pathological responses (pCR) (48%) and 37 partial pathological responses (52%). In the Chemoradiosensitive patients, 34 patients obtained a complete pathological response (95%), and 2 patients had partial pathological response. As for the 35 chemoradioresistant patients, they only achieved a partial pathological response (Table 2).
Table 2. Treatment and Postoperative pathological features.

Characteristics

No. of patients (%)

Chemoradioresistance

Chemoradiosensitive

Radiotherapy dose, n (%)

50 Gy

23 (68)

20 (56)

45 Gy

6 (18)

6 (16)

50.4 Gy

4 (12)

10 (28)

54 Gy

1 (2)

0

The neoadjuvant–surgery interval (day, median)

110

105

Types of surgical procedures, n (%)

Low anterior resection

26 (74)

20 (56)

Abdominoperineal resection

9 (26)

16 (44)

Pathological response, n (%)

Complete response

0

34 (95)

Partial response

35 (100)

2 (5)

3.3. Characteristic Parameters with Tumor Response

Univariate analysis showed significant associations between good tumor response and the preoperative pretreatment levels of CEA >5 ng/mL (OR=1.81, p=0.026) and the ECOG scale (OR=2.51, p=0.015). After a follow-up of 52 months, the median overall and recurrence-free survival was not reached in both groups and a statistically significant difference was not observed.
4. Discussion
To the best of our knowledge, this is the largest study to date on predictive and prognostic factors of response to preoperative chemoradiation in patients with rectal cancer in the region. Results show that the CEA value >5 ng/mL prior to the neoadjuvant treatment was significantly correlated with a lower rate of pCR. Likewise, the ECOG scale was a risk factor related to chemoradioresistance, the lower the ECOG, the lower the risk of chemoradioresistance.
The CEA marker is the most widely available and the most used in the management of colorectal cancer. Probst et al examined 18,113 patients with locally advanced rectal cancer (LARC) selected from the National Cancer Database from 2006-2011, 47% had elevated CEA before treatment, which was significantly associated with a decrease in pCR (OR=0.65, p < 0.001), pathological regression of the tumor (OR=0.74, p < 0.001) and downstaging (OR=0.77, p < 0.001). A CEA level ≤5 ng/mL was a significant predictor of size reduction (OR=16.0, p=0.014) and was significantly associated with size reduction (>60%, p=0.012) in the study results by Yeo .
A recently published study on the prognostic importance of preoperative hematological parameters in patients with non-metastatic rectal cancer undergoing neoadjuvant chemoradiotherapy and radical surgery included 96 patients. Univariate analysis showed significant associations between poor overall survival and preoperative Hb level (≤11.2 g/dL vs. > 11.2 g/dL, P=0.030) . In our study we found a trend towards significance between the Hb level < 9 g/dL and the development of chemoradioresistance (p=0.06).
Research on the best interval between the end of radiation and surgery began to appear as early as the 1990s, the most famous of which was the Lyon R90-01 randomized trial . It was generally accepted that the interval should be extended to 6-8 weeks because the long interval group showed a better pathological response. Another phase II clinical trial to investigate interval extension and administration of additional mFOLFOX-6 during the waiting period found that the 11-week group showed a modest increase in pCR rate without increased complications . When the median time interval reached 19.3 weeks, the pCR rate reached 38% . However, the tumor response did not seem to obviously improve as the time interval increased in blinded fashion. Rombouts et al. retrieved 1073 LARC patients from the population-based Netherlands Cancer Registry between 2006 and 2011, and the highest proportion of patients with stage ypT0-1N0 was 26.6% when the treatment interval ranged from 11 and 12 weeks. Slothaak et al. also observed that the proportion of stage ypT0-1N0 reached a maximum of 23.2% with intervals of 10 to 11 weeks, followed by a decreasing trend, similar to this study cohort.
Previously, a multicenter study conducted in Italy indicated that radiation dose intensification (range 52.5–57.5 Gy) appeared feasible, safe, and effective in terms of pathological response . Of which the people who underwent local excision, one month later, reported no postoperative complications. More recently, a prospective observational study mentioned that radiation dose intensification, administered 60 Gy in 30 fractions, showed a better pathological response with acceptable toxicity related to neoadjuvant chemoradiotherapy in T3 tumors . A longer follow-up period is warranted. Some potential factors may provide a higher probability for the choice of local excision in LARC and deserve further investigation.
In rectal cancer in stages II and III, management is based on chemoradiotherapy, currently knowing the importance and understanding the predictive factors involved in follow-up and treatment has great implications in predicting the results.
Among the limitations of the study, the data were derived from a single institution, with a low number of patients. It is necessary to perform prospective studies with a larger volume of patients to corroborate our findings.
5. Conclusions
Significant interaction were identified between CEA levels prior to the start of neoadjuvant treatment with the pathological complete response rate and the ECOG score with chemoradioresistance. Therefore, these factors can be used to predict patient outcomes, will help optimize personalized treatment strategies and improve patient outcomes.
Abbreviations
LARC: Locally Advanced Rectal Cancer
pCR: pathological Complete Response
CEA, carcinoembryonic antigen
BMI: Body Mass Index
ECOG: Eastern Cooperative Oncology Group
nCRT: neoadjuvant chemotherapy and radiotherapy
Hb: Hemoglobin
Conflicts of Interest
The authors declare no conflicts of interest.
References
[1] Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022.
[2] Weinberg BA, Marshall JL, Salem ME. The Growing Challenge of Young Adults With Colorectal Cancer. Oncology (Williston Park) 2017; 31: 381-389.
[3] Instituto Oncológico Nacional Registro Hospitalario de Cáncer (RHC-ION) 2021.
[4] Carolina De la Pinta, Margarita Martín, Asunción Hervás, Luis Cristian Perna, Eva Fernández-Lizarbe, Fernando López, Víctor Jose Duque, Sonsoles Sancho. Predictive factors for tumour response after the neoadjuvant-treatment of rectal adenocarcinoma. Journal of Coloproctology. Volume 40, Issue 2, 2020, Pages 112-119, ISSN 2237-9363.
[5] Gosavi R, Chia C, Michael M, Heriot AG, Warrier SK, Kong JC. Neoadjuvant chemotherapy in locally advanced colon cancer: a systematic review and meta-analysis. Int J Colorectal Dis. 2021.
[6] Teppei Kono, Hiroyuki Maeda, Yutaka Miyano, Kunihiro Oyama, Taro Koike, Shunichi Shiozawa, Hideaki Oda, Kazuhiko Yoshimatsu. A case of cT4b recto-sigmoidal cancer obtained pathological complete response by preoperative chemotherapy with 4 cycles of mFOLFOX6 plus panitumumab. J-STAGE. 2020 Volume 28 Issue 2 Pages 133-136.
[7] Probst CP, Becerra AZ, Aquina CT, Tejani MA, Hensley BJ, González MG, Noyes K, Monson JRT, Fleming FJ. Watch and wait? Elevated pretreatment CEA is associated with decreased pathological complete response in rectal cancer. J Gastrointest Surg. 2016; 20: 43–52.
[8] Yeo S-G. Association of pretreatment serum carcinoembryonic antigen levels with chemoradiation-induced downstaging and downsizing of rectal cancer. Mol Clin Oncol. 2016; 4: 631–5.
[9] Lin YE, Huang SY, Chang TH, Chou TW, Hung LC, Huang CC, Lin JB, Lin JC. Prognostic significance of the preoperative hematological parameters in non-metastatic rectal cancer patients undergoing neoadjuvant chemoradiotherapy and radical surgery. Ther Radiol Oncol 2022; 6: 5.
[10] Cotte E, Passot G, Decullier E, Maurice C, Glehen O, François Y, Lorchel F, Chapet O, Gerard J-P. Pathologic response, when increased by longer interval, is a marker but not the cause of good prognosis in rectal cancer: 17-year follow-up of the lyon R90–01 randomized trial. Int J Radiat Oncol Biol Phys. 2016; 94: 544–53.
[11] Garcia-Aguilar J, Smith DD, Avila K, Bergsland EK, Chu P, Krieg RM. Timing of Rectal Cancer Response to Chemoradiation C: Optimal timing of surgery after chemoradiation for advanced rectal cancer: preliminary results of a multicenter, nonrandomized phase II prospective trial. Ann Surg. 2011; 254: 97–102.
[12] Garcia-Aguilar J, Chow OS, Smith DD, Marcet JE, Cataldo PA, Varma MG, Kumar AS, Oommen S, Coutsoftides T, Hunt SR, et al. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial. Lancet Oncol. 2015; 16: 957–66.
[13] Rombouts, A. J. M., Hugen, N., Elferink, M. A. G., Nagtegaal, I. D., & de Wilt, J. H. W. (2016). Treatment Interval between Neoadjuvant Chemoradiotherapy and Surgery in Rectal Cancer Patients: A Population-Based Study. Annals of surgical oncology, 23(11), 3593–3601.
[14] Sloothaak, D. A., Geijsen, D. E., van Leersum, N. J., Punt, C. J., Buskens, C. J., Bemelman, W. A., Tanis, P. J., & Dutch Surgical Colorectal Audit (2013). Optimal time interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer. The British journal of surgery, 100(7), 933–939.
[15] Lupattelli M, Matrone F, Gambacorta MA, Osti M, Macchia G, Palazzari E, Nicosia L, Navarria F, Chiloiro G, Valentini V, Aristei C, De Paoli A. Preoperative intensity-modulated radiotherapy with a simultaneous integrated boost combined with Capecitabine in locally advanced rectal cancer: short-term results of a multicentric study. Radiat Oncol. 2017 Aug 22; 12(1): 139. PMID: 28830475; PMCID: PMC5568311.
[16] Bertocchi E, Barugola G, Nicosia L, et al. A comparative analysis between radiation dose intensification and conventional fractionation in neoadjuvant locally advanced rectal cancer: a monocentric prospective observational study. La Radiologia Medica. 2020 Oct; 125(10): 990-998. PMID: 32277332.
Cite This Article
  • APA Style

    Jerez, D. A., Luz, C. E. L., Llerena, J. P., Arauz, R. (2024). Predictive and Prognostic Factors Related to Chemoradioresistance in Neoadjuvant Treatment of Locally Advanced Rectal Cancer at Panama. Cancer Research Journal, 12(2), 21-26. https://doi.org/10.11648/j.crj.20241202.11

    Copy | Download

    ACS Style

    Jerez, D. A.; Luz, C. E. L.; Llerena, J. P.; Arauz, R. Predictive and Prognostic Factors Related to Chemoradioresistance in Neoadjuvant Treatment of Locally Advanced Rectal Cancer at Panama. Cancer Res. J. 2024, 12(2), 21-26. doi: 10.11648/j.crj.20241202.11

    Copy | Download

    AMA Style

    Jerez DA, Luz CEL, Llerena JP, Arauz R. Predictive and Prognostic Factors Related to Chemoradioresistance in Neoadjuvant Treatment of Locally Advanced Rectal Cancer at Panama. Cancer Res J. 2024;12(2):21-26. doi: 10.11648/j.crj.20241202.11

    Copy | Download

  • @article{10.11648/j.crj.20241202.11,
      author = {Daliana Alcantara Jerez and Carla Eloy La Luz and Jose Pinto Llerena and Rafael Arauz},
      title = {Predictive and Prognostic Factors Related to Chemoradioresistance in Neoadjuvant Treatment of Locally Advanced Rectal Cancer at Panama 
    },
      journal = {Cancer Research Journal},
      volume = {12},
      number = {2},
      pages = {21-26},
      doi = {10.11648/j.crj.20241202.11},
      url = {https://doi.org/10.11648/j.crj.20241202.11},
      eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.crj.20241202.11},
      abstract = {Background: In Panama, and the rest of Latin America, there are few publications on chemoradioresistance, it leads to poor prognosis and represents the main reason for failure of therapy, ultimately it can lead to tumor recurrence and metastasis. Objective: Identify factors associated with chemoradioresistance in the neoadjuvant treatment of locally advanced rectal cancer at the Instituto Oncológico Nacional de Panamá, period 2016-2020. Methodology: This retrospective study included 71 patients with LARC who received neoadjuvant chemoradiotherapy and surgery. Chemoradioresistant patients were those who did not reach a higher pathological stage of ypT2NO and the results were compared. Results: Of the 71 patients, pathological complete response (pCR) was achieved in 34 patients (48%). 49% of patients met chemoradioresistance criteria. In this group, the median CEA was 136 ng/ml, the median hemoglobin was 12 g/dl, and the median BMI was 26 kg/m2. The median radiation dose was 5000Gy. The time between completion of chemoradiotherapy and surgery was 110 days (16 weeks). Depending on the type of surgery, 65% who underwent low anterior resection were chemoradioresistant. The variables with statistical significance were the CEA value >5 ng/mL (OR=1.81, p=0.026) prior to the start of neoadjuvant treatment, with a lower pCR rate. Likewise, the ECOG scale (OR=2.51, p=0.015) was a risk factor related to chemoradioresistance, the lower the ECOG, the lower the risk of chemoradioresistance. The median overall survival and median recurrence-free survival was not reached in both groups and there was no statistically significant difference. Conclusions: Significant interactions were identified between CEA levels prior to the start of neoadjuvant treatment with the pathological complete response rate and the ECOG score with chemoradioresistance. Therefore, these factors can be used to predict patient outcomes, will help optimize personalized treatment strategies and improve patient outcomes.
    },
     year = {2024}
    }
    

    Copy | Download

  • TY  - JOUR
    T1  - Predictive and Prognostic Factors Related to Chemoradioresistance in Neoadjuvant Treatment of Locally Advanced Rectal Cancer at Panama 
    
    AU  - Daliana Alcantara Jerez
    AU  - Carla Eloy La Luz
    AU  - Jose Pinto Llerena
    AU  - Rafael Arauz
    Y1  - 2024/04/12
    PY  - 2024
    N1  - https://doi.org/10.11648/j.crj.20241202.11
    DO  - 10.11648/j.crj.20241202.11
    T2  - Cancer Research Journal
    JF  - Cancer Research Journal
    JO  - Cancer Research Journal
    SP  - 21
    EP  - 26
    PB  - Science Publishing Group
    SN  - 2330-8214
    UR  - https://doi.org/10.11648/j.crj.20241202.11
    AB  - Background: In Panama, and the rest of Latin America, there are few publications on chemoradioresistance, it leads to poor prognosis and represents the main reason for failure of therapy, ultimately it can lead to tumor recurrence and metastasis. Objective: Identify factors associated with chemoradioresistance in the neoadjuvant treatment of locally advanced rectal cancer at the Instituto Oncológico Nacional de Panamá, period 2016-2020. Methodology: This retrospective study included 71 patients with LARC who received neoadjuvant chemoradiotherapy and surgery. Chemoradioresistant patients were those who did not reach a higher pathological stage of ypT2NO and the results were compared. Results: Of the 71 patients, pathological complete response (pCR) was achieved in 34 patients (48%). 49% of patients met chemoradioresistance criteria. In this group, the median CEA was 136 ng/ml, the median hemoglobin was 12 g/dl, and the median BMI was 26 kg/m2. The median radiation dose was 5000Gy. The time between completion of chemoradiotherapy and surgery was 110 days (16 weeks). Depending on the type of surgery, 65% who underwent low anterior resection were chemoradioresistant. The variables with statistical significance were the CEA value >5 ng/mL (OR=1.81, p=0.026) prior to the start of neoadjuvant treatment, with a lower pCR rate. Likewise, the ECOG scale (OR=2.51, p=0.015) was a risk factor related to chemoradioresistance, the lower the ECOG, the lower the risk of chemoradioresistance. The median overall survival and median recurrence-free survival was not reached in both groups and there was no statistically significant difference. Conclusions: Significant interactions were identified between CEA levels prior to the start of neoadjuvant treatment with the pathological complete response rate and the ECOG score with chemoradioresistance. Therefore, these factors can be used to predict patient outcomes, will help optimize personalized treatment strategies and improve patient outcomes.
    
    VL  - 12
    IS  - 2
    ER  - 

    Copy | Download

Author Information