A Prognostic Nomogram for Stage II/III Rectal Cancer Patients Treated with Neoadjuvant Chemoradiotherapy Followed by Surgical Resection

Abstract

Background

The purpose of this study was to develop a nomogram incorporated on log odds of positive nodes (LODDS) for predicting the overall survival (OS) of stage II/III rectal cancer patients treated with neoadjuvant chemoradiotherapy (NCRT) followed by surgical resection.

Methods

The Surveillance, Epidemiology, and End Results database was used to collect information on patients diagnosed stage II/III rectal cancer between 2010 and 2015 and treated with NCRT followed by surgical resection. The Cox regression analyses were performed to determine the independent prognostic factors. In this study, LODDS was employed instead of American Joint Committee on Cancer (AJCC) 7th N stage to determine lymph node status. Then a nomogram integrating independent prognostic factors was developed to predict the 24-, 36-, and 60-month overall survival. The receiver operating characteristic (ROC) curves and calibration curves were used to validate the nomogram. Furthermore, patients were stratified into three risk groups(high-, middle-, and low-risk) based on the total points obtained from the nomogram. And Kaplan-Meier curves were plotted to compare OS of the three groups.

Results

A total of 3,829 patients were included in the study. Race, sex, age, marital status, T stage, tumor grade, tumor size, LODDS, CEA level, and postoperative chemotherapy were identified as independent prognostic factors, based on which the prognostic nomogram was developed. The ROC curves and calibration curves showed good performance of the prognostic nomogram. The Kaplan-Meier curves showed that the three risk groups had significant differences in overall survival.

Conclusion

The LODDS-incorporated prognostic nomogram was developed and showed satisfactorily discriminative and stable ability, and it is expected to be a useful tool in developing individualized treatment strategies and follow-up protocols.

1. Introduction

For patients with locally advanced rectal cancer (LARC), neoadjuvant chemoradiotherapy (NCRT) followed by surgical resection has become the standard therapy [1]. NCRT can help to downstage tumors, increase the rate of curative resection, and decrease the rate of local recurrence. According to data from the Surveillance, Epidemiology, and End Results (SEER) database, about 35.7% of patients with rectal cancer in stages II/III received NCRT༻2༽. The reason could be that the survival benefit of NCRT has so far been controversial༻3, 4༽, and radiotherapy can make surgical dissection more difficult and increase the risk of postoperative complications, such as anastomotic leakage, wound infection, and pelvic abscess ༻5༽. Patients with stage II/III rectal cancer who were treated with NCRT followed by surgical resection form a distinct cohort with specific prognosis characteristics.

Nomograms have been routinely utilized to predict cancer outcomes In recent years [6]. A nomogram integrating multiple prognostic factors can be used to estimate the probability of a particular result. Useful in individualized medicine, it has been applied to a wide range of malignancies ༻7, 8༽, For patients with rectal cancer, a number of nomograms have been developed to date. However, nomograms for stage II/III rectal cancer patients treated with NCRT followed by surgical resection have rarely been reported. The aim of this study was to utilize SEER database to develop a nomogram to predict these patients' prognosis.

The log odds of positive nodes (LODDS) was defined as the log of the ratio between the number of positive lymph nodes (PLN) and negative lymph nodes (NLN) [9]. In recent years, it has been proposed and confirmed as a reliable indicator of prognosis in a variety of cancers, such as pancreatic cancer ༻10༽, colorectal cancer ༻11༽, and gastric cancer ༻12༽, and has proven to be a superior predictive factor in patients with colorectal cancer when compared to the American Joint Committee on Cancer (AJCC) N stage ༻13, 14༽. As a result, instead of AJCC N stage, we incorporated LODDS into this nomogram and attempted to provide a practical tool for clinicians and stage II/III rectal cancer patients treated with NCRT followed by surgical resection.

2. Methods

3. Results

3.2. Prognostic Factors Associated With Os

To determine the prognostic factors, the univariate and multivariate analyses were conducted included the patients from the training cohort. As shown in Table 2. in the univariate analysis, Race, sex, age, marital status, T stage, tumor grade, tumor size, LODDS, CEA level, and postoperative chemotherapy were statistically associated with OS (P < 0.05). The effects of postoperative radiation were not statistically significant (P > 0.05). Finally, race, sex, age, marital status, T stage, tumor grade, tumor size, LODDS, CEA level, and postoperative chemotherapy were all revealed to be independent predictive variables in the multivariate analysis. Advanced age, male sex, unmarried status, higher tumor grade, elevated CEA levels, and tumor size more than 70mm was related to a higher risk of mortality. T4b and LODDS greater than − 0.4 were obviously detrimental to patient survival. Furthermore, as measured by a hazard ratio of 0.81 (95% CI: 0.693–0.947), patients who underwent postoperative chemotherapy showed a reduced mortality rate. 

3.3. Development and validation of prognostic nomogram.

A prognostic nomogram integrating independent prognositc factors for OS was developed (Fig. 2). The predicted probability of 24-, 36-, and 60-month OS could be calculated by summing the points on the nomogram for each patient's matching factors. Figure 2 displayed the survival probability of a given patients was calculated using the nomogram.

In the validation of the nomogram, the AUCs of the nomogram for the 24-, 36-, and 60-month OS In the training cohort were 0.736, 0.720, and 0.688, respectively; and 0.691, 0.696, and 0.694 in the validation cohort, respectively. The AUCs demonstrated the satisfactory discriminative power of the model (Fig. 3). In both the validation and training cohorts, the calibration curves showed a high degree of consistency between actual and nomogram-predicted survival rates (Fig. 4).

3.4. Stratification Of Risk Groups

All patients were stratified into three risk groups based on the total points obtained from the nomogram using X-tile software: high-risk (total points ≥ 368), middle-risk (339 ≤ total points < 368), and low-risk (total points < 339). As shown in Fig. 5, the Kaplan-Meier curves indicated that the three risk groups had significant differences in overall survival. The mortality rates of patients in the high-risk group were significantly higher than those in the low-risk group.

4. Discussion

In this study, the data from 3,829 patients in the SEER database were used to develop a prognostic nomogram. Although several nomograms have been established previously for patients with LARC treated with NCRT followed by surgical resection, the study by Zhifang et al. covering 785 cases [17], has certain limitations as it is a single-center study and their results lacked externally validation. The study by Valentini et al. was based on five European randomized clinical trials ༻18༽, but the variables they employed differed greatly from those in our analysis, which included tumor size, CEA level, tumor grade, marital status, and, in particular, LODDS. To the best of our knowledge, this is the first nomogram based on the SEER database that incorporates LODDS to predict the OS of stage II/III rectal cancer patients treated with NCRT followed by surgical resection.

Through multivariable Cox regression analysis, ten parameters, including race, sex, age, marital status, T stage, tumor grade, tumor size, LODDS, CEA level, and postoperative chemotherapy were determined as independent prognostic factors. It was obvious that LODDS greater than − 0.4 contributed most to the poor prognosis, followed by T4b stage.

As we all know, lymph node status plays a significant role in rectal cancer patients’ prognosis. In recent years, in addition to AJCC N stage, many scholars have proposed and analyzed other parameters to validate the status of lymph nodes, such as LODDS and the lymph node ratio (LNR). Although AJCC N stage is currently the most widely used method for lymph node classification, many researchers have pointed out its limitation since it only considers the number of positive lymph nodes and ignores the total number of lymph nodes (TLN) retrieved during surgery. In rectal cancer, TLN has been proven to be an independent prognosis-related factor [19–21]. For accurate staging of colorectal cancer, removal of at least twelve lymph nodes was recommended by AJCC. LNR involves both TLN and PLN and has been claimed to be more accurate than AJCC N stage for rectal cancer ༻22, 23༽. However, other scholars have noticed that when TLN are either all non-metastatic or all metastatic, patients with the same LNR values might be extremely varied. LODDS, as a novel lymph node classification, can overcome the drawbacks of LNR and increase the accuracy for prognostic validation, and studies have shown its superiority to LNR in rectal cancer ༻16, 24, 25༽. For LARC, LODDS was confirmed to perform better than both AJCC N stage and LNR in terms of prognostic predictive value ༻13, 14, 26༽. Therefore, the nomogram wil be more convicing and effective if LODDS is incorporated into it.

In this study, 56.9% of patients who received postoperative chemotherapy, seemed to have a better outcome. On the other hand, several large randomized controlled trials concluded that postoperative chemotherapy could not improve the OS of rectal patients receriving surgery after NCRT [27–29]. These trials, however, had significant limitations, such as poor adherence in the European Organization for Research and Treatment of Cancer trial 22921. Therefore, it remains uncertain if these patients will benefit from postoperative chemotherapy. According to current National Comprehensive Cancer Network (NCCN) recommendations, rectal patients with tumors staged as T3 or N1 and higher should consider postoperative chemotherapy after neoadjuvant chemotherapy ༻30༽. However, experts convened by the European conference on rectal cancer concluded that there is currently insufficient evidence to demonstrate the benefits of receiving adjuvant chemotherapy after preoperative chemoradiotherapy; hence, postoperative chemotherapy cannot be recommended ༻31༽. In this way, more comprehensive and conclusive researches will be conducted in the future.

To summarize, the probability of 24-, 36-, and 60-month OS of stage II/III rectal cancer patients treated with NCRT followed by surgical resection can be simply calculated by summing the points on the nomogram for each patient's matching factors. The prognostic factors included in this nomogram can be quickly accessed in clinical work, making it as a practical tool. In additional, by employing risk group stratification, patients who are at high risk can be easily tracked down and treated with a more personalized approach in early intervention. Finally, the nomogram was validated and shown to be repeatable and reliable, with satisfactory discriminative power.

There are some limitations to this study. First, as this was a retrospective analysis based on the SEER database, there was bound to be some degree of selection bias. Second, the SEER database did not offer certain information that could have affected patient outcomes, such as surgical margins, lymph/vascular or perineural invasion, and chemotherapy/radiation regimen. Future predictive models could benefit from the use of molecular tumor markers as well as genetic data.

5. Conlusion

The prognostic nomogram incorporated LODDS was established and exhibited satisfactory and stable predictive power. All factors included in the model are easily obtained in clinical practice, making it as a convenient and practical tool for predicting the prognosis of patients with stage II-III rectal cancer treated with NCRT followed by surgical resection. The nomogram is expected to be useful to make individualized treatment strategies and follow-up protocols.

Declarations

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The SEER database is an open access database, and all patient information has been de-identified, so individual consent for this retrospective analysis was waived.

Consent for publication: Not applicable.

Data Availability Statements：The datasets generated during and/or analysed during the current study are available in the SEER database repository, SEER Data & Software (cancer.gov).

Competing interests: The authors declare that they have no competing interests

Funding: None

Acknowledgments: We would like to express our gratitude to the SEER program for providing free access to the database.

 Author's contribution:Yanfei Lin was the only author of the manuscript.

References

1. Benson AB, Venook AP, Al-Hawary MM, Cederquist L, Chen YJ, Ciombor KK, et al. Rectal Cancer, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018;16(7):874–901.
2. Wang R, Zhao D, Liu YJ, Ye C, Qian JR, Dai JN, et al. Prognostic significance of preoperative radiotherapy in stage II and III rectal cancer patients: A Strobe-compliant study of SEER 18 registries database (1988–2011). Neoplasma. 2019;66(6):995–1001.
3. van Gijn W, Marijnen CA, Nagtegaal ID, Kranenbarg EM, Putter H, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. The Lancet Oncology. 2011;12(6):575–82.
4. Allegra CJ, Yothers G, O'Connell MJ, Beart RW, Wozniak TF, Pitot HC, et al. Neoadjuvant 5-FU or Capecitabine Plus Radiation With or Without Oxaliplatin in Rectal Cancer Patients: A Phase III Randomized Clinical Trial. J Natl Cancer Inst. 2015;107(11).
5. Yang J, Luo Y, Tian T, Dong P, Fu Z. Effects of Neoadjuvant Radiotherapy on Postoperative Complications in Rectal Cancer: A Meta-Analysis. J Oncol. 2022;2022:8197701.
6. Balachandran VP, Gonen M, Smith JJ, DeMatteo RP. Nomograms in oncology: more than meets the eye. The Lancet Oncology. 2015;16(4):e173-e80.
7. Yang J, Pan Z, Zhou Q, Liu Q, Zhao F, Feng X, et al. Nomogram for predicting the survival of patients with malignant melanoma: A population analysis. Oncology letters. 2019;18(4):3591–8.
8. Song K, Song J, Chen F, Lin K, Ma X, Jiang J. Prognostic nomograms for predicting overall and cancer-specific survival of high-grade osteosarcoma patients. Journal of bone oncology. 2018;13:106–13.
9. Persiani R, Cananzi FC, Biondi A, Paliani G, Tufo A, Ferrara F, et al. Log odds of positive lymph nodes in colon cancer: a meaningful ratio-based lymph node classification system. World J Surg. 2012;36(3):667–74.
10. Ramacciato G, Nigri G, Petrucciani N, Pinna AD, Ravaioli M, Jovine E, et al. Prognostic role of nodal ratio, LODDS, pN in patients with pancreatic cancer with venous involvement. BMC surgery. 2017;17(1):109.
11. Ozawa T, Ishihara S, Sunami E, Kitayama J, Watanabe T. Log odds of positive lymph nodes as a prognostic indicator in stage IV colorectal cancer patients undergoing curative resection. Journal of surgical oncology. 2015;111(4):465–71.
12. Aurello P, Petrucciani N, Nigri GR, La Torre M, Magistri P, Tierno S, et al. Log odds of positive lymph nodes (LODDS): what are their role in the prognostic assessment of gastric adenocarcinoma? Journal of gastrointestinal surgery: official journal of the Society for Surgery of the Alimentary Tract. 2014;18(7):1254–60.
13. Scarinci A, Di Cesare T, Cavaniglia D, Neri T, Colletti M, Cosenza G, et al. The impact of log odds of positive lymph nodes (LODDS) in colon and rectal cancer patient stratification: a single-center analysis of 323 patients. Updates Surg. 2018;70(1):23–31.
14. Shen F, Cui J, Cai K, Pan H, Bu H, Yu F. Prognostic accuracy of different lymph node staging systems in rectal adenocarcinoma with or without preoperative radiation therapy. Jpn J Clin Oncol. 2018;48(7):625–32.
15. Camp RL, Dolled-Filhart M, Rimm DL. X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res. 2004;10(21):7252–9.
16. Huang B, Ni M, Chen C, Cai G, Cai S. LODDS is superior to lymph node ratio for the prognosis of node-positive rectal cancer patients treated with preoperative radiotherapy. Tumori. 2017;103(1):87–92.
17. Zheng Z, Wang X, Liu Z, Lu X, Huang Y, Chi P. Individualized conditional survival nomograms for patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy and radical surgery. Eur J Surg Oncol. 2021;47(12):3175–81.
18. Valentini V, van Stiphout RG, Lammering G, Gambacorta MA, Barba MC, Bebenek M, et al. Nomograms for predicting local recurrence, distant metastases, and overall survival for patients with locally advanced rectal cancer on the basis of European randomized clinical trials. J Clin Oncol. 2011;29(23):3163–72.
19. Washington MK. Colorectal carcinoma: selected issues in pathologic examination and staging and determination of prognostic factors. Archives of pathology & laboratory medicine. 2008;132(10):1600–7.
20. Tan L, Liu ZL, Ma Z, He Z, Tang LH, Liu YL, et al. Prognostic impact of at least 12 lymph nodes after neoadjuvant therapy in rectal cancer: A meta-analysis. World journal of gastrointestinal oncology. 2020;12(12):1443–55.
21. Xu Z, Berho ME, Becerra AZ, Aquina CT, Hensley BJ, Arsalanizadeh R, et al. Lymph node yield is an independent predictor of survival in rectal cancer regardless of receipt of neoadjuvant therapy. Journal of clinical pathology. 2017;70(7):584–92.
22. Zhou D, Ye M, Bai Y, Rong L, Hou Y. Prognostic value of lymph node ratio in survival of patients with locally advanced rectal cancer. Canadian journal of surgery Journal canadien de chirurgie. 2015;58(4):237–44.
23. Kim JY, Chung SM, Choi BO, Lee IK, An CH, Won JM, et al. Prognostic significance of the lymph node ratio regarding recurrence and survival in rectal cancer patients treated with postoperative chemoradiotherapy. Gut and liver. 2012;6(2):203–9.
24. Huang B, Chen C, Ni M, Mo S, Cai G, Cai S. Log odds of positive lymph nodes is a superior prognostic indicator in stage III rectal cancer patients: A retrospective analysis of 17,632 patients in the SEER database. Int J Surg. 2016;32:24–30.
25. Lee CW, Wilkinson KH, Sheka AC, Leverson GE, Kennedy GD. The Log Odds of Positive Lymph Nodes Stratifies and Predicts Survival of High-Risk Individuals Among Stage III Rectal Cancer Patients. Oncologist. 2016;21(4):425–32.
26. Petrucciani N, Carra MC, Martinez-Perez A, Vitali GC, Landi F, Genova P, et al. Comparison of Different Nodal Staging in Patients With Locally Advanced Mid-low Rectal Cancer After Long-term Neoadjuvant Chemoradiation Therapy. Anticancer Res. 2019;39(4):2113–20.
27. Glynne-Jones R, Counsell N, Quirke P, Mortensen N, Maraveyas A, Meadows HM, et al. Chronicle: results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (XELOX) versus control. Annals of oncology: official journal of the European Society for Medical Oncology. 2014;25(7):1356–62.
28. Breugom AJ, van Gijn W, Muller EW, Berglund Å, van den Broek CBM, Fokstuen T, et al. Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial. Annals of oncology: official journal of the European Society for Medical Oncology. 2015;26(4):696–701.
29. Ahn DH, Wu C, Wei L, Williams TM, Wuthrick E, Abdel-Misih S, et al. The Efficacy of Adjuvant Chemotherapy in Patients With Stage II/III Resected Rectal Cancer Treated With Neoadjuvant Chemoradiation Therapy. Am J Clin Oncol. 2017;40(6):531–4.
30. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology. https://www.nccn.org/professionals/physician_gls (Accessed on November 09, 2021).
31. Valentini V, Aristei C, Glimelius B, Minsky BD, Beets-Tan R, Borras JM, et al. Multidisciplinary Rectal Cancer Management: 2nd European Rectal Cancer Consensus Conference (EURECA-CC2). Radiother Oncol. 2009;92(2):148 – 63.