ABSTRACT
Background and Objectives
The PROSPECT trial showed noninferiority of neoadjuvant chemotherapy (NAC) with selective chemoradiation (CRT) versus CRT alone. However, trial results are often difficult to reproduce with real‐world data. Pathologic outcomes and overall survival (OS) were evaluated by neoadjuvant strategy in locally advanced rectal adenocarcinoma patients in a national database.
Methods
The 2012–2020 National Cancer Database was queried for clinical T2N1 and T3N0‐1 rectal adenocarcinoma patients with definitive resection. Patients were categorized by neoadjuvant treatment with CRT alone, NAC alone, and NAC with CRT. Outcomes included R0 resection, pathologic complete response (PCR), and OS.
Results
Of 18 892 patients, 16 126 (85.4%) received CRT, 1018 (5.4%) NAC, and 1748 (9.3%) NAC with CRT. Patients with NAC alone or NAC with CRT were more likely to have stage‐III disease, private insurance, and academic facility treatment (all p < 0.001). NAC alone had lower adjusted odds of an R0 resection (OR 0.72; 95%CI 0.54–0.95) and PCR (OR 0.77; 95%CI 0.64–0.93). NAC with CRT demonstrated improved OS (HR 0.71; 95%CI 0.61–0.82), with no difference between NAC and CRT alone. Among patients who received adjuvant chemotherapy, no differences in OS were seen.
Conclusions
Patients who received NAC alone had worse pathologic outcomes. NAC had similar OS to CRT and NAC with CRT showed improved OS.
Keywords: chemoradiation, locally advanced rectal adenocarcinoma, neoadjuvant therapy, overall survival, pathologic complete response
Abbreviations
- CI
confidence interval
- CRT
chemoradiation
- FOLFOX
folinic acid, fluorouracil, and oxaliplatin
- LARC
locally advanced rectal adenocarcinoma
- NCDB
National Cancer Database
- PCR
pathologic complete response
- PROSPECT
Chemotherapy Alone or Chemotherapy Plus Radiation Therapy in Treating Patients with Locally Advanced Rectal Cancer Undergoing Surgery
- RAPIDO
Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation
- TME
total mesorectal excision
- TNT
total neoadjuvant treatment
1. Introduction
Neoadjuvant chemoradiation (CRT) has been the standard preoperative therapy for locally advanced rectal adenocarcinoma (LARC), with landmark studies demonstrating it reduces rates of locoregional recurrence [1, 2, 3, 4]. In this treatment approach, neoadjuvant CRT was then followed by total mesoresctal excision (TME) and adjuvant chemotherapy [5, 6]. However, CRT can decrease patients' quality of life and has been associated with significant long‐term side effects, including altered bowel control, sexual dysfunction and urinary leakage [7, 8]. Therefore, recently interest has focused on omitting CRT for a subset of patients and using neoadjuvant chemotherapy alone [9, 10].
The PROSPECT trial (Chemotherapy Alone or Chemotherapy Plus Radiation Therapy in Treating Patients with Locally Advanced Rectal Cancer Undergoing Surgery, NCT01515787) evaluated the use of neoadjuvant chemotherapy with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and selective use of chemoradiotherapy in comparison with standard CRT. This trial demonstrated noninferiority of neoadjuvant chemotherapy with selective CRT in respect to overall survival and local recurrence [9]. However, significant variation exists in the real‐world management of patients in comparison with randomized control trials due to a multitude of factors including patient‐related influences and institutional bias. The PROSPECT protocol suggested, but did not mandate, adjuvant chemotherapy with 6−8 cycles of FOLFOX. Nonetheless, rates of receipt of adjuvant chemotherapy in both study arm groups ranged from 74.9% to 77.9% [9]. This is much higher than what has been previously reported among patients with stage II and III rectal adenocarcinoma, with most reports citing rates being below 33%, and ranging from 13% to 77% by country [11, 12, 13, 14]. Real‐world analyses of complete omission of CRT have not been performed and are warranted given the significant variations in clinical practice in comparison with randomized control trials.
Recent literature suggests that the omission of CRT appears to have similar efficacy to standard neoadjuvant treatment for LARC patients, while potentially limiting side effects and improving patients' quality of life. Evaluating this concept in large, national databases may provide a more comprehensive picture of the feasibility of this treatment protocol and direct future work on the topic. The objective of this study was to evaluate the association between the neoadjuvant treatment strategy and pathologic and survival outcomes among patients with LARC. Specific pathologic outcomes assessed were an R0 resection and a pathologic complete response (PCR).
2. Materials and Methods
2.1. Study Design and Data Source
This was an observational retrospective cohort study utilizing the National Cancer Database (NCDB). The NCDB is a comprehensive database, including over 1500 hospitals and capturing data from 70% of all cancer patients treated within the United States annually [15, 16, 17]. Trained registrars abstract the data and periodic audits are performed [15, 17]. This study is considered exempt from the University Institutional Review Board review and Health Insurance Portability and Accountability Act compliant as the NCDB provides completely deidentified data [15]. The Strengthening Reporting of Observational Studies in Epidemiology guidelines were followed in reporting of methods and results [18].
2.2. Study Population
The 2012–2020 rectum participant user file was queried for patients with rectal adenocarcinoma. Rectal adenocarcinoma was identified using the International Classification of Disease for Oncology, Third Edition, codes: 8140, 8480, 8481, and 8490 [19]. Patients who were ≥ 18 years, underwent a TME and had clinical stage T2N1, T3N0, or T3N1 disease were included [20]. Patients who underwent palliative intent treatment and did not receive one of the predetermined neoadjuvant strategies outlined below were excluded. Additionally, patients missing data on key outcomes and covariates were excluded, with detailed numbers reported in Figure S1.
2.3. Primary Predictor of Interest
The primary exposure variable was neoadjuvant treatment strategy. Categories were chosen to align with the PROSPECT trial. Patients were considered as having received neoadjuvant CRT, neoadjuvant chemotherapy without CRT and neoadjuvant chemotherapy with CRT. Receipt of neoadjuvant chemotherapy with CRT after was specified to mirror the selective use of CRT after neoadjuvant FOLFOX in the PROSPECT trial among patients who had less than 20% tumor regression or any progression [9]. To be classified as having received chemotherapy patients must have received multiagent chemotherapy. Additionally, the time from the start of systemic therapy to surgery had to be at least 84 days, which served as a proxy for completion of 6 cycles of FOLFOX.
2.4. Covariates
Patient demographics included as covariates were age, sex, race, ethnicity, insurance, and comorbidities. Disease and treatment characteristics included as covariates were clinical stage and adjuvant chemotherapy. Facility characteristics included were type and the annual case volume. Age was categorized by screening eligibility as 18–44, 45–75, and > 75 years [21]. Race and ethnicity were treated as a composite variable, with categories of non‐Hispanic‐White, non‐Hispanic‐Black, Hispanic, Asian, and other. Patient comorbidities were classified according to the Charlson‐Deyo score into groups of 0, 1, 2, or > 3 [22]. Annual case volume was calculated and divided into quartiles, with the first quartile defined by fewer than 3 resections per year, the second quartile by 4–6 resections, the third quartile by 7–9 resections, and the fourth quartile by 10 or more resections.
2.5. Primary and Secondary Outcomes
The primary outcomes of interest were pathologic outcomes of an R0 resection and a PCR. An R0 resection was defined by grossly and microscopically negative margins in the NCDB. PCR was defined by a pathologic stage of T0N0 [23, 24]. PCR was only analyzed in a subset of the cohort who had pathologic staging data (Figure S1). The secondary outcome of interest was overall survival by neoadjuvant treatment strategy.
2.6. Statistical Analysis
The frequency distribution of patient, disease and hospital characteristics were calculated for the overall cohort, as well as for each neoadjuvant treatment strategy group. Univariate analyses with chi‐squared identified patient, disease and hospital factors associated with receipt of standard CRT, neoadjuvant chemotherapy without CRT and neoadjuvant chemotherapy with CRT after. Chi‐squared analyses were also used to determine the univariate frequency of an R0 resection, PCR and 5‐year mortality by neoadjuvant treatment strategy.
Covariates for multivariable models were chosen based on statistical significance in the univariate model and clinical significance. Patient clustering within hospitals was accounted for by hierarchical multivariable logistic regression models with hospital random intercepts [25]. The odds of having an R0 resection or PCR at the patient‐level were adjusted for neoadjuvant treatment strategy, age, sex, race/ethnicity, insurance, the Charlson‐Deyo comorbidity index, disease differentiation, clinical stage, facility type and annual facility case volume. Kaplan–Meier analyses with log rank tests assessed univariate associations between neoadjuvant treatment strategy and overall survival. Multilevel mixed‐effects parametric survival models with robust variance estimators and hospital‐level random effect estimated adjusted hazard ratios [25]. Multivariable survival analyses were adjusted for neoadjuvant treatment strategy, age, sex, race/ethnicity, insurance, Charlson‐Deyo comorbidity index, disease differentiation, clinical stage, receipt of an R0 resection or adjuvant chemotherapy, facility type and annual facility case volume.
A post hoc sensitivity analysis evaluated the association between neoadjuvant treatment strategy and overall survival only among patients who received adjuvant chemotherapy. This was done to account for the significant variation in the percentage of patients who received adjuvant chemotherapy in the PROSPECT trial in comparison with this real‐world analysis [26]. Statistical significance was determined using a two‐sided p < 0.05. Data analyses were performed using Stata MP version 18.0 (College Station, TX: StataCorp LLC).
3. Results
3.1. Cohort Characteristics
Overall, 18 892 patients with T2N1, T3N0, and T3N1 rectal adenocarcinoma were identified. Of these, 16 126 (85.4%) received standard CRT for neoadjuvant treatment, 1018 (5.4%) received chemotherapy without any CRT and 1748 (9.3%) received neoadjuvant chemotherapy with CRT after. Patients who received chemotherapy without and with CRT were more likely younger, had private insurance and were treated at an academic facility (p < 0.001) (Table 1). Patients who received chemotherapy with CRT were more likely to have stage III disease (75.7%) versus those who received chemotherapy without CRT (54.8%) or CRT alone (50.6%) (p < 0.001). Patients who received chemotherapy without CRT had the highest frequency of receipt of adjuvant chemotherapy at 43.9%, in comparison with chemotherapy with CRT (5.7%) and standard CRT (28.1%) (p < 0.001).
Table 1.
Patient and facility characteristics by neoadjuvant treatment strategy among those with clinical T2N1, T3N0, and T3N1 rectal adenocarcinoma.
| Characteristics | Total N = 18 892, n (%) | Standard CRT N = 16 126 (85.4), n (%) | Chemotherapy, n (%) | p‐value | |
|---|---|---|---|---|---|
| Without CRT N = 1018 (5.4) | CRT After N = 1748 (9.3) | ||||
| Age | < 0.001 | ||||
| 18–44 | 780 (4.1) | 602 (3.7) | 67 (6.6) | 111 (6.4) | |
| 45–75 | 15 261 (80.8) | 12 844 (79.9) | 825 (81.0) | 1552 (88.8) | |
| > 75 | 2851 (15.1) | 2640 (16.4) | 126 (12.4) | 85 (4.9) | |
| Sex | < 0.001 | ||||
| Male | 11 954 (63.3) | 10 124 (62.8) | 704 (69.2) | 1126 (64.4) | |
| Female | 6938 (36.7) | 6002 (37.2) | 314 (30.8) | 622 (35.6) | |
| Race/ethnicity | < 0.001 | ||||
| NH‐White | 15 137 (80.1) | 12 954 (80.3) | 782 (76.8) | 1401 (80.2) | |
| NH‐Black | 1459 (7.7) | 1276 (7.9) | 84 (8.3) | 99 (5.7) | |
| Hispanic | 1249 (6.6) | 1025 (6.4) | 89 (8.7) | 135 (7.7) | |
| Asian | 814 (4.3) | 682 (4.2) | 48 (4.7) | 84 (4.8) | |
| Other | 233 (1.2) | 189 (1.2) | 15 (1.5) | 29 (1.7) | |
| Insurance | < 0.001 | ||||
| Private | 8551 (45.3) | 6988 (43.3) | 526 (51.7) | 1037 (59.3) | |
| Medicaid | 1500 (7.9) | 1285 (8.0) | 60 (5.9) | 155 (8.9) | |
| Medicare | 7927 (42.0) | 7055 (43.8) | 387 (38.0) | 485 (27.8) | |
| Other | 325 (1.7) | 285 (1.8) | 14 (1.4) | 26 (1.5) | |
| Uninsured | 589 (3.1) | 513 (3.2) | 31 (3.1) | 45 (2.6) | |
| Charlson‐Deyo index | 0.06 | ||||
| 0 | 14 318 (75.8) | 12 160 (75.4) | 797 (78.3) | 1361 (77.9) | |
| 1 | 3180 (16.8) | 2742 (17.0) | 158 (15.5) | 280 (16.0) | |
| 2 | 849 (4.5) | 741 (4.6) | 37 (3.6) | 71 (4.1) | |
| ≥ 3 | 545 (2.9) | 483 (3.0) | 26 (2.6) | 36 (2.1) | |
| Differentiation | < 0.001 | ||||
| Well | 957 (5.1) | 896 (5.6) | 44 (4.3) | 17 (1.0) | |
| Moderate | 8674 (45.9) | 7973 (49.4) | 412 (40.5) | 289 (16.5) | |
| Poor | 1099 (5.8) | 1008 (6.3) | 58 (5.7) | 33 (1.9) | |
| Unknown | 8162 (43.2) | 6249 (38.8) | 504 (49.5) | 1409 (80.6) | |
| Clinical stage | < 0.001 | ||||
| Stage II | 8853 (46.9) | 7969 (49.4) | 460 (45.2) | 424 (24.3) | |
| Stage III | 10 039 (53.1) | 8157 (50.6) | 558 (54.8) | 1324 (75.7) | |
| Adjuvant chemotherapy | < 0.001 | ||||
| No | 13 809 (73.1) | 11 590 (71.9) | 571 (56.1) | 1648 (94.3) | |
| Yes | 5083 (26.9) | 4536 (28.1) | 447 (43.9) | 100 (5.7) | |
| Facility type | < 0.001 | ||||
| Academic | 6566 (34.8) | 5325 (33.0) | 465 (45.7) | 776 (44.4) | |
| CCP | 1147 (6.1) | 1033 (6.4) | 54 (5.3) | 60 (3.4) | |
| CCCP | 7167 (37.9) | 6398 (39.7) | 309 (30.4) | 460 (26.3) | |
| INCP | 4012 (21.2) | 3370 (20.9) | 190 (18.7) | 452 (25.9) | |
| Annual facility case volume | < 0.001 | ||||
| < 3 | 4656 (24.7) | 4129 (25.6) | 224 (22.0) | 303 (17.3) | |
| 4–6 | 5067 (26.8) | 4369 (27.1) | 242 (23.8) | 456 (26.1) | |
| 7–9 | 4597 (24.3) | 3940 (24.4) | 252 (24.8) | 405 (23.2) | |
| ≥ 10 | 4572 (24.2) | 3688 (22.9) | 300 (29.5) | 584 (33.4) | |
Note: Percentages may not add up to exactly 100% due to rounding.
Abbreviations: CCP, Community Cancer Program; CCCP, Comprehensive Community Cancer Program; CRT, chemoradiotherapy; INCP, Integrated Network Cancer Program; NH, non‐Hispanic.
3.2. Pathologic Outcomes
Patients who received chemotherapy without CRT (94.0%) had the lowest rates of R0 resection, while those who received chemotherapy with CRT after (96.5%) had the highest (p = 0.01, Table 2). On adjusted analyses, patients who received neoadjuvant chemotherapy without CRT had 0.72 lower odds of undergoing an R0 resection (95% Confidence Interval [CI] 0.54–0.95) versus those who underwent standard CRT or chemotherapy with CRT after (Table 3). Additionally, patients who had poor differentiation of their tumor (OR 0.40, 95% CI 0.27–0.59) and stage III disease (OR 0.85, 95% CI 0.73–0.98) had lower odds of an R0 resection.
Table 2.
Unadjusted rates of short‐term and long‐term outcomes of interest among patients with T2N1, T3N0, and T3N1 rectal adenocarcinoma.
| Outcomes | Total N = 18 892, n (%) | Standard CRT N = 16 126 (85.4), n (%) | Chemotherapy, n (%) | p‐value | |
|---|---|---|---|---|---|
| Without CRT N = 1018 (5.4) | CRT After N = 1748 (9.3) | ||||
| R0 resection | 0.01 | ||||
| No | 861 (4.6) | 738 (4.6) | 61 (6.0) | 62 (3.6) | |
| Yes | 18 031 (95.4) | 15 388 (95.4) | 957 (94.0) | 1686 (96.5) | |
| Follow‐up time, months | |||||
| Median (IQR) | 55 (33.3–79.6) | 48.8 (32.5–69.8) | 35.1 (25.8–47.9) | ||
| 5‐year mortality | < 0.001 | ||||
| Alive | 15 160 (80.3) | 12 691 (78.7) | 868 (85.3) | 1601 (91.6) | |
| Dead | 3730 (19.8) | 3433 (21.3) | 150 (14.7) | 147 (8.4) | |
| Outcomes | Total N = 17 575, n (%) | Standard CRT N = 14 961 (85.1), n (%) | Chemotherapy, n (%) | ||
|---|---|---|---|---|---|
| Without CRT N = 941 (5.4) | CRT After N = 1673 (9.5) | p‐value | |||
| Pathologic complete response | < 0.001 | ||||
| No | 14 431 (82.1) | 12 318 (82.3) | 799 (84.9) | 1314 (78.5) | |
| Yes | 3144 (17.9) | 2643 (17.7) | 142 (15.1) | 359 (21.5) | |
Note: Percentages may not add up to exactly 100% due to rounding.
Abbreviations: CRT, chemoradiotherapy; IQR, interquartile range.
Table 3.
Factors associated with R0 resection among patients with clinical T2N1, T3N0, and T3N1 rectal adenocarcinoma (N = 18 892).
| Variable | Adjusted odds ratio (95% confidence interval) |
|---|---|
| Neoadjuvant treatment strategy | |
| Standard CRT | Ref. |
| Chemotherapy without CRT | 0.72 (0.54–0.95) |
| Chemotherapy with CRT after | 1.12 (0.84–1.48) |
| Age | |
| 18–44 | Ref. |
| 45–75 | 0.84 (0.57–1.22) |
| > 75 | 0.69 (0.45–1.06) |
| Sex | |
| Male | Ref. |
| Female | 1.23 (1.06–1.42) |
| Race/ethnicity | |
| NH‐White | Ref. |
| NH‐Black | 0.78 (0.62–1.00) |
| Hispanic | 1.04 (0.77–1.40) |
| Asian | 0.93 (0.66–1.32) |
| Other | 0.73 (0.42–1.28) |
| Insurance | |
| Private | Ref. |
| Medicaid | 0.79 (0.61–1.02) |
| Medicare | 0.91 (0.77–1.07) |
| Other | 0.81 (0.48–1.34) |
| Uninsured | 0.55 (0.39–0.78) |
| Charlson‐Deyo index | |
| 0 | Ref. |
| 1 | 1.22 (1.00–1.48) |
| 2 | 1.20 (0.84–1.72) |
| ≥ 3 | 1.26 (0.80–1.98) |
| Differentiation | |
| Well | Ref. |
| Moderate | 0.83 (0.59–1.18) |
| Poor | 0.40 (0.27–0.59) |
| Unknown | 0.98 (0.69–1.40) |
| Clinical stage | |
| Stage II | Ref. |
| Stage III | 0.85 (0.73–0.98) |
| Facility type | |
| Academic | Ref. |
| CCP | 1.11 (0.76–1.61) |
| CCCP | 0.98 (0.80–1.21) |
| INCP | 0.89 (0.71–1.12) |
| Annual facility case volume | |
| < 3 | Ref. |
| 4–6 | 0.99 (0.80–1.23) |
| 7–9 | 1.07 (0.84–1.37) |
| ≥ 10 | 1.06 (0.82–1.38) |
Abbreviations: CCP, Community Cancer Program; CCCP, Comprehensive Community Cancer Program; CRT, chemoradiotherapy; INCP, Integrated Network Cancer Program; NH, non‐Hispanic.
Of 18 892 patients, 17 575 (93.0%) patients had data on pathologic staging. Among these, those who received neoadjuvant chemotherapy with CRT after had significantly higher rates of PCR at 21.5% in comparison with 17.7% in those who received standard CRT (p < 0.001, Table 2). Patients who received chemotherapy without CRT had the lowest PCR rate at 15.1%. On adjusted analyses, patients who received chemotherapy without CRT had 0.77 lower odds of a PCR (95% CI 0.64–0.93) (Table 4). However, no statistically significant differences in odds of a PCR were observed between those who received standard CRT and chemotherapy with CRT after (OR 1.04, 95% CI 0.90–1.19). Age older than 75 years old (OR 0.78; 95% CI 0.61–0.98), poor disease differentiation (OR 0.72; 95% CI 0.54–0.95), and higher clinical stage (OR 0.84; 95% CI 0.78–0.91) were also associated with lower odds of a PCR.
Table 4.
Factors associated with pathologic complete response among patients with T2N1, T3N0, and T3N1 rectal adenocarcinoma (N = 17 575).
| Variable | Adjusted odds ratio (95% confidence interval) |
|---|---|
| Neoadjuvant treatment strategy | |
| Standard CRT | Ref. |
| Chemotherapy without CRT | 0.77 (0.64–0.93) |
| Chemotherapy with CRT after | 1.04 (0.90–1.19) |
| Age | |
| 18–44 | Ref. |
| 45–75 | 0.95 (0.78–1.16) |
| > 75 | 0.78 (0.61–0.98) |
| Sex | |
| Male | Ref. |
| Female | 1.11 (1.02–1.20) |
| Race/ethnicity | |
| NH‐White | Ref. |
| NH‐Black | 0.82 (0.70–0.96) |
| Hispanic | 1.06 (0.90–1.25) |
| Asian | 1.05 (0.87–1.27) |
| Other | 0.92 (0.63 – 1.33) |
| Insurance | |
| Private | Ref. |
| Medicaid | 0.75 (0.64–0.89) |
| Medicare | 0.98 (0.89–1.08) |
| Other | 0.83 (0.60–1.14) |
| Uninsured | 0.76 (0.59–0.97) |
| Charlson‐Deyo index | |
| 0 | Ref. |
| 1 | 0.84 (0.75–0.94) |
| 2 | 1.15 (0.96–1.38) |
| ≥ 3 | 0.97 (0.77–1.22) |
| Differentiation | |
| Well | Ref. |
| Moderate | 1.13 (0.92–1.39) |
| Poor | 0.72 (0.54–0.95) |
| Unknown | 1.80 (1.46–2.20) |
| Clinical stage | |
| Stage II | Ref. |
| Stage III | 0.84 (0.78–0.91) |
| Facility type | |
| Academic | Ref. |
| CCP | 1.10 (0.89–1.36) |
| CCCP | 1.02 (0.91–1.14) |
| INCP | 1.10 (0.97–1.25) |
| Annual facility case volume | |
| < 3 | Ref. |
| 4–6 | 1.02 (0.90–1.15) |
| 7–9 | 1.17 (1.02–1.33) |
| ≥ 10 | 1.08 (0.93–1.25) |
Abbreviations: CCP, Community Cancer Program; CCCP, Comprehensive Community Cancer Program; CRT, chemoradiotherapy; INCP, Integrated Network Cancer Program; NH, non‐Hispanic.
3.3. Overall Survival
Patients who received neoadjuvant chemotherapy with CRT after had improved overall survival (Figure 1). Five‐year overall survival was 91.6% for patients who received chemotherapy with CRT after, 85.3% for those who received chemotherapy without CRT, and 78.7% for those who received standard CRT (p < 0.001). On adjusted analyses, patients who received neoadjuvant chemotherapy with CRT after had a 0.71 lower mortality hazard (95% CI 0.61–0.82) (Table 5). Conversely, patients with an age older than 75 years old (OR 2.38; 95% CI 1.91–2.97), increasing Charlson‐Deyo comorbidity index (OR 2.22; 95% CI 1.93–2.56), and poor disease differentiation (OR 1.43; 95% CI 1.23–1.66) were associated with an increased mortality hazard.
Figure 1.
Kaplan–Meier curve comparing overall survival by neoadjuvant treatment strategy among patients with clinical T2N1, T3N0, and T3N1 rectal adenocarcinoma.
Table 5.
Mixed‐effects cox proportional hazard regression assessing overall survival among a) all patients and b) those who received adjuvant chemotherapy for T2N1, T3N0, and T3N1 rectal adenocarcinoma.
| Variable | Adjusted hazard ratio (95% confidence interval) | |
|---|---|---|
| All patients N = 18 892 | Received adjuvant chemotherapy N = 5083 | |
| Neoadjuvant treatment strategy | ||
| Standard CRT | Ref. | Ref. |
| Chemotherapy without CRT | 0.86 (0.75–1.00) | 0.80 (0.63–1.02) |
| Chemotherapy with CRT after | 0.71 (0.61–0.82) | 1.14 (0.68–1.92) |
| Age | ||
| 18–44 | Ref. | Ref. |
| 45–75 | 1.36 (1.11–1.67) | 1.35 (0.96–1.91) |
| > 75 | 2.38 (1.91–2.97) | 2.36 (1.59–3.51) |
| Sex | ||
| Male | Ref. | Ref. |
| Female | 0.76 (0.71–0.80) | 0.77 (0.67–0.88) |
| Race/ethnicity | ||
| NH‐White | Ref. | Ref. |
| NH‐Black | 1.15 (1.03–1.29) | 1.12 (0.87–1.44) |
| Hispanic | 0.90 (0.78–1.03) | 1.02 (0.76–1.35) |
| Asian | 0.83 (0.70–0.99) | 0.73 (0.51–1.05) |
| Other | 0.90 (0.67–1.20) | 0.95 (0.54–1.67) |
| Insurance | ||
| Private | Ref. | Ref. |
| Medicaid | 1.61 (1.42–1.81) | 1.85 (1.45–2.36) |
| Medicare | 1.81 (1.68–1.95) | 1.80 (1.55–2.10) |
| Other | 1.60 (1.28–2.01) | 1.93 (1.26–2.94) |
| Uninsured | 1.48 (1.24–1.75) | 1.51 (1.07–2.13) |
| Charlson‐Deyo index | ||
| 0 | Ref. | Ref. |
| 1 | 1.36 (1.26–1.46) | 1.16 (0.98–1.38) |
| 2 | 1.36 (1.20–1.54) | 1.13 (0.82–1.56) |
| ≥ 3 | 2.22 (1.93–2.56) | 2.04 (1.43–2.91) |
| Differentiation | ||
| Well | Ref. | Ref. |
| Moderate | 0.96 (0.85–1.08) | 0.93 (0.72–1.20) |
| Poor | 1.43 (1.23–1.66) | 1.66 (1.19–2.30) |
| Unknown | 0.94 (0.84–1.07) | 0.80 (0.61–1.06) |
| Clinical stage | ||
| Stage II | Ref. | Ref. |
| Stage III | 1.07 (1.00–1.15) | 0.93 (0.81–1.07) |
| R0 resection | ||
| No | Ref. | Ref. |
| Yes | 0.38 (0.34–0.43) | 0.28 (0.22–0.36) |
| Adjuvant chemotherapy | ||
| No | Ref. | — |
| Yes | 0.76 (0.70–0.81) | — |
| Facility type | ||
| Academic | Ref. | Ref. |
| CCP | 1.12 (0.96–1.29) | 0.98 (0.69–1.38) |
| CCCP | 1.10 (1.00–1.20) | 1.28 (1.07–1.52) |
| INCP | 1.02 (0.93–1.12) | 1.04 (0.84–1.28) |
| Annual facility case volume | ||
| < 3 | Ref. | Ref. |
| 4–6 | 0.92 (0.84–1.01) | 0.80 (0.65–0.98) |
| 7–9 | 0.98 (0.88–1.08) | 0.96 (0.78–1.19) |
| ≥ 10 | 0.85 (0.76–0.95) | 0.87 (0.71–1.11) |
Abbreviations: CCP, Community Cancer Program; CCCP, Comprehensive Community Cancer Program; CRT, chemoradiotherapy; INCP, Integrated Network Cancer Program; NH, non‐Hispanic.
3.4. Sensitivity Analysis
Given that fewer than 27% of the entire cohort received adjuvant chemotherapy, sensitivity analyses were performed to assess variations in overall survival among only patients who received adjuvant chemotherapy (N = 5083). Among those who received adjuvant chemotherapy, univariate analyses demonstrated no differences in overall survival by neoadjuvant treatment strategy (p = 0.13, Figure 2). Similarly, adjusted analyses demonstrated no statistical differences in overall survival (Table 5).
Figure 2.
Kaplan–Meier curve comparing overall survival by neoadjuvant treatment strategy among patients who received adjuvant chemotherapy for clinical T2N1, T3N0, and T3N1 rectal adenocarcinoma.
4. Discussion
Recently published pilot studies and randomized controlled trials suggested the potential for omission of neoadjuvant CRT among patients with LARC who exhibit a PCR after neoadjuvant chemotherapy [9, 27, 28]. Our study evaluating a real‐world cohort from a national database demonstrated improved overall survival among patients with T2N1, T3N0, and T3N1 rectal adenocarcinoma who received neoadjuvant chemotherapy with CRT after in comparison with CRT alone. However, no differences in overall survival were seen by neoadjuvant treatment among patients who received adjuvant chemotherapy. Additionally, those who received chemotherapy without CRT after had worse pathologic outcomes, with lower odds of an R0 resection and PCR. Overall, this study supports prior work regarding overall survival, but also emphasizes the need for a better understanding regarding the effects of neoadjuvant treatment on pathologic outcomes.
Historically preoperative CRT has demonstrated reduction in local recurrence and improved disease‐free survival among patients with LARC [29]. However, the incorporation of neoadjuvant chemotherapy into the neoadjuvant treatment protocol poses an opportunity to change this paradigm. Two key trials have evaluated a total neoadjuvant treatment (TNT) approach. The UNIVANCER‐PRODIGE 23 evaluated patients who received 12 cycles of fluorouracil, leucovorin, irinotecan and oxaliplatin with CRT after versus CRT [30], and the Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation (RAPIDO) trial compared short‐course CRT with 6 or 9 cycles of neoadjuvant chemotherapy versus CRT alone [31]. Both trials demonstrated no significant differences in rates of R0 resection between experimental and control treatment groups [30, 31]. In the PROSPECT trial, while fewer than 10% of patients in the experimental arm received CRT after neoadjuvant chemotherapy, 98.9% of this group had an R0 resection versus 97.1% of the CRT group. This difference was not statistically significant though. However, in a study utilizing the National Surgical Quality Improvement Program, patients who had complete omission of neoadjuvant CRT had significantly higher rates of positive radial margins [32]. Similarly, in our study patients who received a TNT approach with 6 cycles of multiagent chemotherapy with CRT after had no differences in adjusted odds of receiving an R0 resection in comparison with those who received CRT alone (OR 1.12, 95% CI 0.84–1.48). Conversely, patients who received neoadjuvant chemotherapy without CRT after had lower adjusted odds of an R0 resection in comparison with CRT alone (OR 0.72, 95% CI 0.5–0.95). Therefore, national database studies suggest lower rates of pathologic outcomes with complete omission of CRT, with noninferior outcomes for a TNT approach.
With regard to obtaining a PCR, prior work has largely demonstrated the benefits of a TNT approach, with limited data on an only neoadjuvant chemotherapy strategy. Among patients who received TNT, both the PRODIGE 23 trial and RAPIDO trial reported a PCR rate of 28%, which was statistically higher than the CRT cohort [30, 31]. While the PROSPECT trial reported lower rates of PCR in chemotherapy group at 21.9% versus 24.3% in the CRT cohort, this difference was not statistically significant. In our study, PCR rates among patients who received a TNT approach with 6 cycles of chemotherapy and CRT were similar to those previously published around 21.5% and no differences were seen on multivariable analyses in comparison with CRT alone. However, among patients who received neoadjuvant chemotherapy without CRT, PCR rates were lower than those reported in the PROSPECT trial at 15.1%, with lower adjusted odds of PCR on multivariable analyses. Therefore, unlike the PROSPECT trial, our study suggests lower odds of a PCR among patients with complete omission of CRT. However, little information is provided in the NCDB regarding patients' initial response to neoadjuvant chemotherapy or any dose adjustments made secondary to toxicities. Future large cohort studies would benefit from an understanding of the tumor response to chemotherapy as an indicator for additional neoadjuvant therapy, and to better understand if clear patient selection criteria may limit the worse pathologic outcomes observed in our study among those with complete omission of CRT.
Furthermore, previously published literature on overall survival has demonstrated varied results for patients with a TNT approach or complete omission of CRT. A meta‐analysis of eight randomized controlled trials, including PRODIGE 23 and RAPIDO, reported improved disease‐free survival with TNT, but no statistically significant differences in overall survival [33]. Other studies have also shown a range of results, including no differences [34, 35], improved [36] and worse overall adjusted survival among patients receiving a TNT approach [23]. With regard to patients who had omission of CRT, no significant differences in 5‐year overall survival were found on adjusted analyses between the neoadjuvant chemotherapy and CRT groups in the PROSPECT trial. In a study of a multicenter, population‐based Dutch rectal adenocarcinoma cohort, despite decreasing utilization of neoadjuvant radiotherapy over time from 87% to 37%, 4‐year overall survival increased from 79.6% to 86.4% [37]. Our study adds to the growing body of literature supporting the potential for omission of CRT in patients who have a good response to neoadjuvant chemotherapy by demonstrating no differences in adjusted overall survival between patients who had chemotherapy without CRT versus CRT alone. This was true among all patients and only those patients who received adjuvant therapy. These data support the premise that there may be an opportunity to omit radiotherapy to alleviate toxicity of treatment, while maintaining survival outcomes for rectal cancer patients.
Patients in the PROSPECT trial who received neoadjuvant FOLFOX with selective CRT versus standard CRT reported improved bowel function and lower rates of diarrhea during treatment, as well as less fatigue, neuropathy and sexual dysfunction 12 months following surgical treatment [38]. Other studies have similarly shown higher rates of fecal incontinence and dissatisfaction with bowel function among patients who had CRT versus upfront surgery with TME [39, 40]. These findings highlight the potential to significantly improve the quality of life if neoadjuvant CRT can be omitted in even select patients. Our study emphasizes the importance of shared patient‐physician decision making when considering an optimal neoadjuvant approach. Overall, this report attempts to highlight the real‐world experience with omission of neoadjuvant CRT among patients with LARC. The results of our study demonstrated concerns for worse pathologic outcomes in patients with complete omission of radiation therapy. However, this did not appear to confer any differences in overall patient survival.
This study does have limitations which must be considered. First, as a retrospective, national database study, we have limited knowledge of the intent for each patient's treatment. Second, lack of certain disease‐specific variables such as tumor distance from the anal verge limit our insight into the selection of neoadjuvant therapy. Third, an incomplete understanding of physician or institutional practices, as well as patient preferences, limits our ability to completely classify patients by neoadjuvant protocol. Finally, there is limited data regarding interruptions of patients' neoadjuvant treatments. However, the large breadth of institutions included in the NCDB, and clustering of analyses by facility, aims to minimize these variations. Furthermore, our stratification of patients into three neoadjuvant cohorts, including those with omission of CRT and receipt of CRT following neoadjuvant chemotherapy, as well as specifications regarding the timeline of treatment according to expected chemotherapy cycle lengths adds to the robustness of the analyses and provides a more comprehensive representation of real‐world practices and outcomes.
5. Conclusion
This large, national database study with real‐world practices among patients with LARC supports previous findings of similar overall survival among select patients who omit CRT following neoadjuvant chemotherapy. While the adjusted odds of an R0 resection or PCR were worse in patients who omitted CRT in comparison with CRT alone, the lack of survival differences suggest selective utilization of CRT may be appropriate in the right cohort of patients. Additionally, our study emphasizes the benefits of a TNT approach. Future work should focus on a better understanding of long‐term disease‐specific outcomes by neoadjuvant strategy, optimizing risk stratification for CRT, and a better understanding of the patient experience with CRT to inform shared decision making among patients and physicians.
Conflicts of Interest
The authors declare no conflicts of interest.
Synopsis
Locally advanced rectal adenocarcinoma patients who received neoadjuvant chemotherapy without chemoradiation had lower adjusted odds of an R0 resection and pathologic complete response. Neoadjuvant chemotherapy with chemoradiation demonstrated improved overall survival, with no differences between those with neoadjuvant chemotherapy or chemoradiation alone.
Supporting information
Supporting Information.
Acknowledgments
Joanna T. Buchheit was funded by the National Institutes of Health's training grant 5R38CA245095; Surgical Multispecialty Access to Research in Residency Training (SMART) at Northwestern University. Lauren M. Janczewski is supported by a training grant from the National Cancer Institute (T32CA247801).
Presented as a poster at the Society of Surgical Oncology Annual Meeting, Atlanta, GA March 20−23, 2024.
Data Availability Statement
The data that support the findings of this study are available upon request in the American College of Surgeons National Cancer Database Rectal Participant User File.
References
- 1. Peeters K. C. M. J., Marijnen C. A. M., Nagtegaal I. D., et al., “The TME Trial After a Median Follow‐Up of 6 Years: Increased Local Control but no Survival Benefit in Irradiated Patients With Resectable Rectal Carcinoma,” Annals of Surgery 246, no. 5 (November 2007): 693–701, 10.1097/01.sla.0000257358.56863.ce. [DOI] [PubMed] [Google Scholar]
- 2. Swedish Rectal Cancer T., Cedermark B., Dahlberg M., et al., “Improved Survival With Preoperative Radiotherapy in Resectable Rectal Cancer,” New England Journal of Medicine 336, no. 14 (April 1997): 980–987, 10.1056/NEJM199704033361402. [DOI] [PubMed] [Google Scholar]
- 3. Kapiteijn E., Marijnen C. A. M., Nagtegaal I. D., et al., “Preoperative Radiotherapy Combined With Total Mesorectal Excision for Resectable Rectal Cancer,” New England Journal of Medicine 345, no. 9 (August 2001): 638–646, 10.1056/NEJMoa010580. [DOI] [PubMed] [Google Scholar]
- 4. Sauer R., Becker H., Hohenberger W., et al., “Preoperative Versus Postoperative Chemoradiotherapy for Rectal Cancer,” New England Journal of Medicine 351, no. 17 (October 2004): 1731–1740, 10.1056/NEJMoa040694. [DOI] [PubMed] [Google Scholar]
- 5. André T., Boni C., Mounedji‐Boudiaf L., et al., “Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon Cancer,” New England Journal of Medicine 350, no. 23 (June 2004): 2343–2351, 10.1056/NEJMoa032709. [DOI] [PubMed] [Google Scholar]
- 6. Smith J. J. and Garcia‐Aguilar J., “Advances and Challenges in Treatment of Locally Advanced Rectal Cancer,” Journal of Clinical Oncology 33, no. 16 (June 2015): 1797–1808, 10.1200/JCO.2014.60.1054. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Downing A., Glaser A. W., Finan P. J., et al., “Functional Outcomes and Health‐Related Quality of Life After Curative Treatment for Rectal Cancer: A Population‐Level Study in England,” International Journal of Radiation Oncology*Biology*Physics 103, no. 5 (April 2019): 1132–1142, 10.1016/j.ijrobp.2018.12.005. [DOI] [PubMed] [Google Scholar]
- 8. Knowles G., Haigh R., McLean C., Phillips H. A., Dunlop M. G., and Din F. V. N., “Long Term Effect of Surgery and Radiotherapy for Colorectal Cancer on Defecatory Function and Quality of Life,” European Journal of Oncology Nursing 17, no. 5 (October 2013): 570–577, 10.1016/j.ejon.2013.01.010. [DOI] [PubMed] [Google Scholar]
- 9. Schrag D., Shi Q., Weiser M. R., et al., “Preoperative Treatment of Locally Advanced Rectal Cancer,” New England Journal of Medicine 389, no. 4 (July 2023): 322–334, 10.1056/NEJMoa2303269. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Wo J. Y., Anker C. J., Ashman J. B., et al., “Radiation Therapy for Rectal Cancer: Executive Summary of an ASTRO Clinical Practice Guideline,” Practical Radiation Oncology 11, no. 1 (January/February 2021): 13–25, 10.1016/j.prro.2020.08.004. [DOI] [PubMed] [Google Scholar]
- 11. Khrizman P., Niland J. C., ter Veer A., et al., “Postoperative Adjuvant Chemotherapy Use in Patients With Stage II/III Rectal Cancer Treated With Neoadjuvant Therapy: A National Comprehensive Cancer Network Analysis,” Journal of Clinical Oncology 31, no. 1 (January 2013): 30–38, 10.1200/JCO.2011.40.3188. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Bregni G., Akin Telli T., Camera S., et al., “Adjuvant Chemotherapy for Rectal Cancer: Current Evidence and Recommendations for Clinical Practice,” Cancer Treatment Reviews 83 (February 2020): 101948, 10.1016/j.ctrv.2019.101948. [DOI] [PubMed] [Google Scholar]
- 13. Cheung W. Y., Neville B. A., and Earle C. C., “Etiology of Delays in the Initiation of Adjuvant Chemotherapy and Their Impact on Outcomes for Stage II and III Rectal Cancer,” Diseases of the Colon & Rectum 52, no. 6 (June 2009): 1054–1064, 10.1007/DCR.0b013e3181a51173. [DOI] [PubMed] [Google Scholar]
- 14. Tevis S. E., Kohlnhofer B. M., Stringfield S., et al., “Postoperative Complications in Patients With Rectal Cancer Are Associated With Delays in Chemotherapy That Lead to Worse Disease‐Free and Overall Survival,” Diseases of the Colon & Rectum 56, no. 12 (December 2013): 1339–1348, 10.1097/DCR.0b013e3182a857eb. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Bilimoria K. Y., Stewart A. K., Winchester D. P., and Ko C. Y., “The National Cancer Data Base: A Powerful Initiative to Improve Cancer Care in the United States,” Annals of Surgical Oncology 15, no. 3 (March 2008): 683–690, 10.1245/s10434-007-9747-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Raval M. V., Bilimoria K. Y., Stewart A. K., Bentrem D. J., and Ko C. Y., “Using the NCDB for Cancer Care Improvement: An Introduction to Available Quality Assessment Tools,” Journal of Surgical Oncology 99, no. 8 (June 2009): 488–490, 10.1002/jso.21173. [DOI] [PubMed] [Google Scholar]
- 17. Boffa D. J., Rosen J. E., Mallin K., et al., “Using the National Cancer Database for Outcomes Research: A Review,” JAMA Oncology 3, no. 12 (December 2017): 1722–1728, 10.1001/jamaoncol.2016.6905. [DOI] [PubMed] [Google Scholar]
- 18. von Elm E., Altman D. G., Egger M., Pocock S. J., Gøtzsche P. C., and Vandenbroucke J. P., “The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for Reporting Observational Studies,” International Journal of Surgery 12, no. 12 (December 2014): 1495–1499, 10.1016/j.ijsu.2014.07.013. [DOI] [PubMed] [Google Scholar]
- 19. Emile S. H., Horesh N., Freund M. R., et al., “Trends in the Characteristics, Treatment, and Outcomes of Rectal Adenocarcinoma in the US From 2004 to 2019: A National Cancer Database Analysis,” JAMA Oncology 9, no. 3 (March 2023): 355–364, 10.1001/jamaoncol.2022.6116. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Chen S. Y., Radomski S. N., Stem M., et al., “Factors Associated With Not Undergoing Surgery for Locally Advanced Rectal Cancers: An NCDB Propensity‐Matched Analysis,” Surgery 174, no. 6 (December 2023): 1323–1333, 10.1016/j.surg.2023.09.005. [DOI] [PubMed] [Google Scholar]
- 21. Davidson K. W., Barry M. J., Mangione C. M., et al., “Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement,” JAMA 325, no. 19 (2021): 1965–1977, 10.1001/jama.2021.6238. [DOI] [PubMed] [Google Scholar]
- 22. Deyo R., “Adapting a Clinical Comorbidity Index for Use With ICD‐9‐CM Administrative Databases,” Journal of Clinical Epidemiology 45, no. 6 (June 1992): 613–619, 10.1016/0895-4356(92)90133-8. [DOI] [PubMed] [Google Scholar]
- 23. Goffredo P., Khan A., Mott S. L., et al., “Total Neoadjuvant Therapy Versus Standard Neoadjuvant Chemoradiation in Patients With Locally Advanced Rectal Cancer: A Comparison of Short‐ and Long‐Term Oncologic Outcomes,” Annals of Surgery 276, no. 6 (December 2022): e819–e824, 10.1097/SLA.0000000000005141. [DOI] [PubMed] [Google Scholar]
- 24. Dossa F., Acuna S. A., Rickles A. S., et al., “Association Between Adjuvant Chemotherapy and Overall Survival in Patients With Rectal Cancer and Pathological Complete Response After Neoadjuvant Chemotherapy and Resection,” JAMA Oncology 4, no. 7 (2018): 930–937, 10.1001/jamaoncol.2017.5597. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Merkow R. P., Rademaker A. W., and Bilimoria K. Y., “Practical Guide to Surgical Data Sets: National Cancer Database (NCDB),” JAMA Surgery 153, no. 9 (September 2018): 850–851, 10.1001/jamasurg.2018.0492. [DOI] [PubMed] [Google Scholar]
- 26. Preoperative Treatment of Locally Advanced Rectal Cancer,” New England Journal of Medicine 389, no. 17 (October 2023): 1630–1632, 10.1056/NEJMc2309857. [DOI] [PubMed] [Google Scholar]
- 27. Schrag D., Weiser M. R., Goodman K. A., et al., “Neoadjuvant Chemotherapy Without Routine Use of Radiation Therapy for Patients With Locally Advanced Rectal Cancer: A Pilot Trial,” Journal of Clinical Oncology 32, no. 6 (February 2014): 513–518, 10.1200/JCO.2013.51.7904. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Ruppert R., Junginger T., Ptok H., et al., “Oncological Outcome After MRI‐Based Selection for Neoadjuvant Chemoradiotherapy in the OCUM Rectal Cancer Trial,” British Journal of Surgery 105, no. 11 (2018): 1519–1529, 10.1002/bjs.10879. [DOI] [PubMed] [Google Scholar]
- 29. Sebag‐Montefiore D., Stephens R. J., Steele R., et al., “Preoperative Radiotherapy Versus Selective Postoperative Chemoradiotherapy in Patients With Rectal Cancer (MRC CR07 and NCIC‐CTG C016): A Multicentre, Randomised Trial,” The Lancet 373, no. 9666 (March 2009): 811–820, 10.1016/S0140-6736(09)60484-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Conroy T., Bosset J. F., Etienne P. L., et al., “Neoadjuvant Chemotherapy With Folfirinox and Preoperative Chemoradiotherapy for Patients With Locally Advanced Rectal Cancer (UNICANCER‐PRODIGE 23): A Multicentre, Randomised, Open‐Label, Phase 3 Trial,” Lancet Oncology 22, no. 5 (2021): 702–715, 10.1016/S1470-2045(21)00079-6. [DOI] [PubMed] [Google Scholar]
- 31. Bahadoer R. R., Dijkstra E. A., van Etten B., et al., “Short‐Course Radiotherapy Followed by Chemotherapy Before Total Mesorectal Excision (TME) Versus Preoperative Chemoradiotherapy, TME, and Optional Adjuvant Chemotherapy in Locally Advanced Rectal Cancer (RAPIDO): A Randomised, Open‐Label, Phase 3 Trial,” The Lancet Oncology 22, no. 1 (January 2021): 29–42, 10.1016/S1470-2045(20)30555-6. [DOI] [PubMed] [Google Scholar]
- 32. Ore A. S., Dombek G. E., Cordova‐Cassia C. A., et al., “Omission of or Poor Response to Preoperative Chemoradiotherapy Impacts Radial Margin Positivity Rates in Locally Advanced Rectal Cancer,” Diseases of the Colon & Rectum 64, no. 6 (June 2021): 669–676, 10.1097/DCR.0000000000001916. [DOI] [PubMed] [Google Scholar]
- 33. Liu S., Jiang T., Xiao L., et al., “Total Neoadjuvant Therapy (TNT) Versus Standard Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: A Systematic Review and Meta‐Analysis,” Oncologist 26, no. 9 (September 2021): e1555–e1566, 10.1002/onco.13824. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Zhang X., Ma S., Guo Y., Luo Y., and Li L., “Total Neoadjuvant Therapy Versus Standard Therapy in Locally Advanced Rectal Cancer: A Systematic Review and Meta‐Analysis of 15 Trials,” PLoS One 17, no. 11 (2022): e0276599, 10.1371/journal.pone.0276599. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Yu S., Mamtani R., O'Hara M. H., et al., “Comparative Effectiveness of Total Neoadjuvant Therapy Versus Standard Adjuvant Chemotherapy for Locally Advanced Rectal Cancer,” Clinical Colorectal Cancer 20, no. 2 (June 2021): 121–129, 10.1016/j.clcc.2021.01.001. [DOI] [PubMed] [Google Scholar]
- 36. Kong J. C., Soucisse M., Michael M., et al., “Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer: A Systematic Review and Metaanalysis of Oncological and Operative Outcomes,” Annals of Surgical Oncology 28, no. 12 (November 2021): 7476–7486, 10.1245/s10434-021-09837-8. [DOI] [PubMed] [Google Scholar]
- 37. Hazen S. M. J. A., Sluckin T. C., Intven M. P. W., et al., “Abandonment of Routine Radiotherapy for Nonlocally Advanced Rectal Cancer and Oncological Outcomes,” JAMA Oncology 10, no. 2 (2023): 202–211, 10.1001/jamaoncol.2023.5444. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Basch E., Dueck A. C., Mitchell S. A., et al., “Patient‐Reported Outcomes During and After Treatment for Locally Advanced Rectal Cancer in the PROSPECT Trial (Alliance N1048),” Journal of Clinical Oncology 41, no. 21 (July 2023): 3724–3734, 10.1200/JCO.23.00903. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39. Peeters K. C. M. J., van de Velde C. J. H., Leer J. W. H., et al., “Late Side Effects of Short‐Course Preoperative Radiotherapy Combined Wwith Total Mesorectal Excision for Rectal Cancer: Increased Bowel Dysfunction in Irradiated Patients—A Dutch Colorectal Cancer Group Study,” Journal of Clinical Oncology 23, no. 25 (September 2005): 6199–6206, 10.1200/JCO.2005.14.779. [DOI] [PubMed] [Google Scholar]
- 40. Pollack J., Holm T., Cedermark B., Holmström B., and Mellgren A., “Long‐Term Effect of Preoperative Radiation Therapy on Anorectal Function,” Diseases of the Colon & Rectum 49, no. 3 (March 2006): 345–352, 10.1007/s10350-005-0296-1. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting Information.
Data Availability Statement
The data that support the findings of this study are available upon request in the American College of Surgeons National Cancer Database Rectal Participant User File.