This article reports on results of a study that examined overall survival differences according to chemotherapy intensity (doublet vs. monotherapy) in patients with clinical stage II or III rectal adenocarcinoma who were treated with neoadjuvant chemoradiotherapy followed by surgery and adjuvant chemotherapy.
Keywords: Rectal cancer, Stage II, Stage III, Adjuvant, Oxaliplatin
Abstract
Background.
Current guidelines include the use of adjuvant oxaliplatin in clinical stage II or III rectal adenocarcinoma. However, its efficacy is supported by a single phase II trial. We aimed to examine whether oxaliplatin confers survival benefit in this patient population.
Methods.
Using the National Cancer Database (2006–2013) we identified 6,868 individuals with clinical stage II or III rectal adenocarcinoma treated with neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy. We used multivariate Cox regression to evaluate survival differences according to treatment intensity and change from clinical to pathological stage.
Results.
We demonstrated an association with improved overall survival with the use of doublet adjuvant chemotherapy in pathological stage III rectal adenocarcinoma (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.67–0.92). This association was confirmed in patients with clinical stage III and subsequent pathological stage III disease (HR, 0.69; 95% CI, 0.57–0.83) and was not observed in patients who progressed from clinical stage II to pathological stage III disease. Doublet adjuvant chemotherapy was not associated with improved overall survival in patients with pathological stage 0 or I disease, regardless of their clinical stage.
Conclusion.
Adjuvant oxaliplatin following neoadjuvant chemoradiotherapy in rectal adenocarcinoma was confirmed in patients with clinical stage III and subsequent pathological stage III disease. Omission of oxaliplatin can be considered in pathological complete response or pathological stage I disease.
Implications for Practice.
Current guidelines include the use of oxaliplatin as part of adjuvant chemotherapy (AC) in patients with clinical stage II or III rectal adenocarcinoma (RAC). However, its efficacy is supported only by a single phase II trial. This study found an association with improved overall survival with the use of doublet AC in patients diagnosed with clinical stage III and subsequent pathological stage III, and not in patients with pathological stage 0 or I, regardless of their clinical stage. Therefore, omission of oxaliplatin can be considered in patients with either pathological complete response or pathological stage I RAC, thereby avoiding oxaliplatin‐induced neuropathy.
摘要
背景。目前的指南包括在临床 II 或 III 期直肠腺癌中使用奥沙利铂辅助化疗。然而，他的疗效仅由单臂 II 期试验支持。我们的目的是检验奥沙利铂是否对该患者群体的生存有益。
方法。通过国家癌症数据库(2006 ‐ 2013 年)，我们确定了 6 868 名经过新辅助放化疗、手术和辅助化疗治疗的临床 II 期或 III 期直肠腺癌患者。我们使用多变量 Cox 回归分析根据治疗强度和从临床到病理分期的改变来评估的生存期差异。
结果。我们证实了在病理 III 期直肠腺癌中使用双联辅助化疗与总生存率得到改善之间存在关联 [风险比 (HR)，0.78；95% 置信区间 (CI)，0.67‐0.92]。这种关联在临床 III 期和随后的病理 III 期疾病(HR，0.69；95% CI，0.57‐0.83)的患者中得到证实，且并未在从临床 II 期进展至病理 III 期疾病的患者中观察到。无论临床分期如何，双联辅助化疗与病理 0 期或 I 期患者的总体生存率改善均无关。
结论。在临床 III 期和随后的病理 III 期疾病患者中确认了直肠腺癌新辅助放化疗后进行奥沙利铂辅助化疗。在病理性完全缓解或病理性 I 期疾病中可考虑省掉奥沙利铂辅助化疗。
实践意义:目前的指南包括在临床 II 期或 III 期直肠腺癌 (RAC) 患者中使用奥沙利铂作为辅助化疗 (AC) 的一部分。然而，其功效仅由单臂 II 期试验支持。本研究发现，无论其临床分期如何，在被诊断为临床 III 期和随后的病理 III 期的患者中，而不是在病理 0 期或 I 期的患者中，使用双联 AC 与总生存率得到改善存在关联。因此，在病理性完全缓解或病理 I 期 RAC 的患者中可以考虑省掉奥沙利铂，从而避免奥沙利铂诱发的神经病变。
Introduction
Colorectal cancer is the third most common cancer and the second‐leading cause of cancer‐related deaths in men and women combined in the U.S. [1]. Rectal cancer represents around 30% of colorectal cases (www.cancer.org). Current treatment guidelines for locally advanced rectal cancer include neoadjuvant chemoradiotherapy (NACRT), followed by total mesorectal excision and postoperative adjuvant chemotherapy. National Comprehensive Cancer Network (NCCN) guidelines recommend doublet adjuvant chemotherapy, that is, oxalipatin added to 5‐fluorouracil (5FU)‐based regimens, for both clinical stage II and III disease. However, no clear evidence exists for the efficacy of adding oxaliplatin in this setting, with only one positive randomized phase II trial addressing this issue specifically [2]. Furthermore, there is a lack of data regarding the predictive value of the various possible combinations of clinical and pathological stages (before NACRT and after surgery, respectively) in determining the efficacy of adding oxaliplatin in the adjuvant setting.
In this study we used a U.S.‐based nationwide oncology data set to examine the magnitude of overall survival differences according to chemotherapy intensity (doublet vs. monotherapy) in clinical stage II or III rectal adenocarcinoma patients treated with NACRT followed by surgery and adjuvant chemotherapy.
Materials and Methods
Data Source and Patient Population
Our cohort was derived from the National Cancer Database (NCDB), a hospital‐based cancer registry, from 2006 to 2013. The NCDB captures data on 70% of cancer diagnoses in the U.S. from more than 1,400 hospitals with cancer programs accredited by the American College of Surgeons’ Commission on Cancer and the American Cancer Society [3]. The cohort included all individuals with clinical stage II (T3–4N0M0) or III (TanyN1–2M0) rectal adenocarcinoma who received NACRT followed by surgery and adjuvant chemotherapy. Patients who progressed following NACRT and were found to have metastatic disease after surgery were excluded (supplemental online Fig. 1).
Definition of Variables
The primary exposure of interest was adjuvant chemotherapy regimen, defined as either monotherapy or doublet chemotherapy. Covariates included treatment intensity, age, sex, race, patient comorbidities score (Charlson‐Deyo comorbidity condition [CDCC]) [4], [5], and tumor grade. Adjuvant chemotherapy was defined as either monotherapy or doublet chemotherapy under the chemotherapy variable in the NCDB. Race and ethnicity were used to create a composite variable categorized as white, black, or other/unknown. Tumor grade was defined as well differentiated, moderately differentiated, poorly differentiated, or undifferentiated.
Definition of Outcomes
The primary outcome was overall survival, measured from the time of cancer diagnosis until death of any cause or last follow‐up.
Statistical Analysis
Patients were grouped according to adjuvant chemotherapy regimen, defined as either monotherapy or doublet chemotherapy. Baseline characteristics in each risk group were compared using the chi‐square test for categorical variables and Student's t test for continuous variables. Overall survival was measured from date of diagnosis. Difference in overall survival was compared between the groups according to clinical and postoperative pathological stage. Cox proportional hazards were used to assess this effect. The proportional hazards assumption was evaluated using Schoenfeld residuals. The Cox model was adjusted for age, sex, and CDCC variables. In a secondary analysis, we further analyzed the effect of neoadjuvant chemotherapy, that is, change from clinical to pathological stage, on overall survival.
All statistical analyses were performed using Stata/IC software version 13.0 (StataCorp, College Station, TX). A two‐sided p value <.05 was used to define significance.
Results
We identified 6,868 individuals with clinical stage II or III rectal adenocarcinoma who received NACRT, followed by surgical resection and adjuvant chemotherapy (supplemental online Fig. 1), with a median follow‐up time of 41.8 months (interquartile range, 27.2–61.5 months). Patients were stratified according to adjuvant chemotherapy intensity, that is, monotherapy versus doublet chemotherapy. Both groups had similar baseline sex, race, and histological grade. As expected, patients who received adjuvant doublet chemotherapy were younger and had a lower Charlson‐Deyo comorbidity score (Table 1).
Table 1. Patient characteristics.
Abbreviations: CDCC, Charlson‐Deyo comorbidity condition; IQR, interquartile range.
Patients diagnosed with clinical stage II or III disease benefited from adjuvant doublet chemotherapy compared with monotherapy, with a hazard ratio (HR) of 0.87 (95% confidence interval [CI], 0.77–0.98). The benefit was statistically significant only for clinical stage III patients, with an HR of 0.83 (95% CI, 0.71–0.97; Table 2 and Fig. 1). Patients with pathological stage III benefited from adjuvant doublet chemotherapy (HR, 0.78; 95% CI, 0.67–0.92; Table 2 and Fig. 2), whereas patients with pathological stage II had a trend toward benefit that was not statistically significant (HR, 0.82; 95% CI, 0.66–1.02; Table 2 and Fig. 2).
Table 2. The effect of adjuvant treatment intensity on overall survival according to clinical and pathological staging.
Adjusted for age at diagnosis, sex, and Charlson‐Deyo comorbidity condition.
Abbreviations: CI, confidence interval; HR, hazard ratio.
Figure 1.
Overall survival among patients with clinical stage III rectal adenocarcinoma who received neoadjuvant chemoradiotherapy followed by surgery, according to adjuvant chemotherapy regimen.
Figure 2.
Overall survival among patients with pathological stage II and III rectal adenocarcinoma who received neoadjuvant chemoradiotherapy followed by surgery, according to adjuvant chemotherapy regimen.
We next analyzed the data according to response to NACRT. Patients with pathological stage III who were originally clinical stage III benefited from adjuvant doublet chemotherapy with an HR of 0.69 (95% CI, 0.57–0.83; Table 3 and Fig. 3B), whereas those who progressed from clinical stage II during NACRT did not benefit from adjuvant doublet chemotherapy (Table 3). Patients with clinical stage II and subsequent pathological stage II had a trend toward benefit which was not statistically significant (HR, 0.78; 95% CI, 0.58–1.03; Table 3 and Fig. 3A). Patients with pathological stage 0 to I did not benefit from adjuvant doublet chemotherapy, regardless of their clinical stage (Table 3).
Table 3. The effect of adjuvant treatment intensity on overall survival according to staging before and after neoadjuvant chemoradiotherapy.
Adjusted for age at diagnosis, sex, and Charlson‐Deyo comorbidity condition.
Abbreviations: CI, confidence interval; HR, hazard ratio.
Figure 3.
Overall survival among patients who received neoadjuvant chemoradiotherapy followed by surgery, according to adjuvant chemotherapy regimen. (A): Patients with clinical stage II and subsequent pathological stage II disease. (B): Patients with clinical stage III and subsequent pathological stage III disease.
Discussion
In this study we demonstrated that the use of doublet adjuvant chemotherapy was associated with improved overall survival in patients with pathological stage III rectal adenocarcinoma, who received NACRT followed by surgical resection. This association of a benefit for doublet adjuvant chemotherapy in pathological stage III was confirmed in patients with clinical stage III and was not observed in patients who progressed from clinical stage II. Doublet adjuvant chemotherapy was not associated with improved overall survival in patients with pathological stage 0 (i.e., pathological complete response) or stage I after surgery, regardless of their clinical stage. Notably, a trend toward statistical significance was noted in patients with clinical stage II and subsequent pathological stage II.
Oxaliplatin use is associated with several side effects, the most debilitating of which is cumulative neurotoxicity, which can profoundly impact the quality of life of cancer survivors [6], [7]. Our data suggest that patients with clinical stage II or III rectal adenocarcinoma, who have pathologic staging of stage 0 or I, could potentially be spared from using oxaliplatin as part of adjuvant therapy, thereby avoiding oxaliplatin‐induced neuropathy.
Current NCCN guidelines suggest that all patients with clinical stage II or III rectal adenocarcinoma should receive doublet adjuvant chemotherapy (www.nccn.org, version 3.2018). Our results support the value of adding oxaliplatin to the adjuvant setting in patients with clinical stage III but also suggest a lack of benefit in patients with clinical stage II disease.
Two previous studies addressed the possible benefit of adding oxaliplatin in the adjuvant setting of rectal adenocarcinoma. The first trial, and the only one evaluating the addition of oxaliplatin to the adjuvant treatment alone, was the randomized phase II ADORE trial, which compared adjuvant 5FU and leucovorin with FOLFOX in patients with pathological stage II or III rectal adenocarcinoma. Results from this trial suggest that the addition of oxaliplatin to 5FU and leucovorin improved the 3‐year disease‐free survival (DFS) from 71.6% to 62.9% (HR, 0.66; 95% CI, 0.43–0.99). However, 3‐year DFS was improved only for patients with pathological stage III disease, and not for patients with stage II [2]. The second trial, the phase III CAO/ARO/AIO‐04 trial, evaluated the possible benefit of adding oxaliplatin to 5FU‐based NACRT and adjuvant chemotherapy. In this trial, 3‐year DFS was improved from 71.2% to 75.9% in patients receiving oxaliplatin, regardless of the pathological stage [8]. Therefore, our results support the findings of the ADORE trial, suggesting that pathological staging is of value in decision‐making regarding the addition of oxaliplatin to 5FU‐based adjuvant therapy. In the same vein, NCCN guidelines may be refined to include not only clinical stage but also pathological stage in decision‐making about whether or not to add oxaliplatin to the adjuvant treatment.
Strengths of our study include the large size of the cohort used for analysis, the detailed available information for both clinical and pathological staging, the ability to clearly define patients who received NACRT and adjuvant chemotherapy, and the adjustments performed for the common confounders (i.e., age, sex, and comorbidities).
The main limitation of using the NCDB was lack of information regarding duration and type of chemotherapy. The NCDB does not include a field specifically for oxaliplatin use. However, it is the only agent used as an addition to 5FU‐based adjuvant chemotherapy for rectal adenocarcinoma. In addition, we could not distinguish between capecitabine and 5‐FU as the backbone of adjuvant therapy. Of note, previous studies suggested no difference in efficacy between capecitabine and 5‐FU in the adjuvant setting [9], [10]. Furthermore, pathologic stage distribution in our data set included a lower than previously reported pathologic complete response rate [11], [12], [13]. These previous studies varied in their pathologic stage distribution, presumably in part because of a different chemotherapy used during NACRT. The low rate of pathologic complete response we report, which was regardless of adjuvant therapy administration, may be a result of our data set being a large hospital‐based cancer registry, better reflecting real‐world data, and the different agents used during NACRT. Our data set also lacks disease‐free survival, cancer recurrence rate, and cancer‐specific survival data, which may all better reflect the effect of doublet adjuvant chemotherapy. The NCDB includes data for overall survival, which is a more clinically relevant parameter, although it might be biased by baseline patient characteristics, such as age and performance status. Finally, the NCDB does not contain information on the modalities used for clinical staging, mainly either computed tomography or magnetic resonance imaging (MRI). However, a comparative effectiveness review by the Agency for Healthcare Research and Quality for 2014 came to the conclusion that computed tomography and MRI are equally accurate assessing clinical T and N stage in rectal cancer [14]. MRI was favored for avoiding overstaging of clinical N stage [14].
Conclusion
Our findings suggest that the use of oxaliplatin in the adjuvant setting of clinical stage II or III rectal adenocarcinoma may be limited to patients with clinical stage III and subsequent pathological stage III disease. Furthermore, oxaliplatin might be omitted in patients with pathological stage 0 or I disease. For pathological stage II, our results are inconclusive. These results will enable clinicians to define patients that may be spared from adjuvant oxaliplatin thereby reducing oxaliplatin‐induced neuropathy, and on the other hand supporting the need for aggressive therapy.
See http://www.TheOncologist.com for supplemental material available online.
Author Contributions
Conception/design: Ofer Margalit, Ronac Mamtani, Scott Kopetz, Yu‐Xiao Yang, Bruce Giantonio, Ben Boursi
Provision of study material or patients: Ofer Margalit, Ronac Mamtani, Yu‐Xiao Yang, Bruce Giantonio, Ben Boursi
Collection and/or assembly of data: Ofer Margalit, Ronac Mamtani, Yu‐Xiao Yang, Bruce Giantonio, Ben Boursi
Data analysis and interpretation: Ofer Margalit, Ronac Mamtani, Scott Kopetz, Yu‐Xiao Yang, Bruce Giantonio, Ben Boursi
Manuscript writing: Ofer Margalit, Ronac Mamtani, Scott Kopetz, Yu‐Xiao Yang, Kim A. Reiss, Talia Golan, Naama Halpern, Dan Aderka, Bruce Giantonio, Einat Shacham‐Shmueli, Ben Boursi
Final approval of manuscript: Ofer Margalit, Ronac Mamtani, Scott Kopetz, Yu‐Xiao Yang, Kim A. Reiss, Talia Golan, Naama Halpern, Dan Aderka, Bruce Giantonio, Einat Shacham‐Shmueli, Ben Boursi
Disclosures
Kim A. Reiss: Clovis Oncology, Bristol‐Myers Squibb, TesaroBio, Lilly Oncology (RF). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
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