Abstract
Background:
Colorectal cancer is the most common malignancy in Saudi males and third most common in females. Patients with locally advanced colon cancer may eventually develop metastatic disease if not treated promptly and according to guidelines. The recent National Comprehensive Cancer Network guideline recommends tumor resection followed by adjuvant chemotherapy for stage III and high-risk stage II tumors. Therefore, the objective of this study was to characterize patients with locally advanced colon cancer and identify factors associated with the use of adjuvant chemotherapy and the addition of oxaliplatin in locally advanced colon cancer patients.
Methods:
All patients diagnosed with locally advanced colon cancer at National Guard Health Affairs (NGHA) during 2016-2021 were investigated. Patients’ characteristics were compared using Chi-square and Fisher exact test, whereas predictors of adjuvant chemotherapy/Oxaliplatin use were identified using univariate and multivariate logistic regression.
Results:
Out of 222 patients diagnosed with locally advanced colon cancer, 133 received adjuvant chemotherapy. Factors associated with adjuvant chemotherapy administration were age and smoking status. In the multivariable analysis, older patients were less likely to receive oxaliplatin than younger patients. Stage III patients diagnosed during 2019-2021 had 5.61 times higher odds of receiving oxaliplatin.
Conclusion:
The findings of this study show that older patients and smokers are less likely to be treated with adjuvant chemotherapy. Moreover, age as well as diagnosis year were important determinants of oxaliplatin administration in stage III locally advanced colon cancer patients.
Keywords: Adjuvant treatment, chemotherapy, colon cancer, registry, Saudi Arabia
INTRODUCTION
Colorectal cancer (CRC) is a common malignancy with a global incidence of 1.9 million cases in 2020, that is projected to increase to 3.2 million cases in 2040.[1] Local and regional stage CRC accounts for more than half of the incidence of the disease.[2,3] Locally advanced colon cancer (LACC) consists of stage IIb/c and stage III, representing advanced tumors that have not yet metastasized to distant organs. Although LACC is curable with a radical resection (R0 resection with negative margins), it is an aggressive form of CRC with a recurrence rate of 20%-56% depending on the extent of the resected tumor margin, the depth of invasion (T stage), and the number of involved lymph nodes (N stage), with a corresponding survival rate of 25%-60%.[4] Despite being curable with radical resection, LACC is often diagnosed at an advanced stage, making timely treatment crucial for better patient outcomes.
The National Comprehensive Cancer Network (NCCN) Clinical Practice Guideline in Oncology is broadly recognized by healthcare providers as the standard of care for many tumor sites including CRC. The current NCCN guidelines recommend surgical resection followed by adjuvant chemotherapy for all stage III tumors and stage II tumors with high-risk features including perivascular/perineural invasion, tumors with poor histology/differentiation, with positive resected margin, especially in patients who underwent emergency surgery.[5,6,7] Several studies have shown that adherence to NCCN guidelines tends to reduce recurrence rates and increase survival of LACC patients (55% to 67%).[6] Nonetheless, there is a lack of research about the utilization of healthcare services, including adjuvant chemotherapy (ACT), in oncology patients, particularly in Saudi Arabia, where population-based screening is lacking. In Saudi Arabia, CRC is the most commonly diagnosed tumor in males and third in females, with more than two-thirds diagnosed at advanced stages.[8] In the latest report available in 2018, the age-adjusted incidence rates per 10[5] people in males and females were 13.9 and 11.3, respectively.[9] Recently, we have also reported increasing trends in CRC incidences in both early and late-onset CRC.[10] About one-third of LACC will eventually develop metastatic disease if not treated timely and according to guidelines. Accordingly, measuring treatment utilization level is the first step in determining whether the clinical practice is consistent with the NCCN guidelines. Understanding current utilization is also useful for research aiming to elucidate factors contributing to under-utilization such as lack of referral to medical oncologists (MO), MO not offering ACT to given patients, or patients refusing recommended ACT. Currently, no study has assessed ACT utilization among LACC patients in Saudi Arabia or elucidated factors associated with utilization.
Therefore, the objective of the present study, which is the first of subsequent studies that focus on LACC patients, was to characterize patients with LACC, describe the type of chemotherapy used, investigate factors associated with ACT use, and among the recipients of ACT, measure the patterns and determinants of oxaliplatin addition. We hypothesize that older patients, patients with higher Charlson Comorbidity Index (CCI) scores, and patients with less advanced Tumor, Nodes, and Metastasis (TNM) stage are less likely to receive ACT compared to their counterparts. By understanding current utilization and factors associated with utilization, this study can improve adherence to NCCN guidelines and ultimately improve patient outcomes.
PATIENTS AND METHODS
Data sources
This retrospective cohort study used data from the National Guard Health Affairs (NGHA) electronic medical record system as well as tumor registry. Demographics and clinical variables were collected for all colon cancer patients who were treated at the NGHA healthcare facility in Riyadh. The study was approved by the Institutional Review Board at King Abdullah International Medical Research Centre (NRC21R/458/11) on 13th November 2021.
Study population
The study population comprised all colon cancer patients aged 18 years or older who fulfilled the American Joint Cancer Committee (AJCC) 8th edition criteria for high-risk stage II and stage III colon cancer, during the period 2016-2021, at NGHA.[11] All LACC patients with at least 6 months of membership in the NGHA system before cancer diagnosis, who underwent surgery, were included in the current analysis [Figure S1 (78.4KB, tif) ].
Study variables
Patient and tumor characteristics
Variables obtained from the cancer registry included patients’ demographics, which are age at diagnosis, sex, marital status (unmarried, married, and unknown), body mass index (BMI) (grouped into three categories: under or normal weight, overweight, and obese), CCI, and smoking status. In addition, clinical data on tumor characteristics were extracted. The examined variables included tumor stage, which was categorized based on the AJCC staging system as T and N stages. T variable denotes the extent of the tumor and was subclassified into T1 or T2, T3, and T4. N refers to the number of lymph nodes involved and was subclassified into N0, N1, or N2.
In addition, other variables were collected including tumor grade (well or moderately differentiated, poorly or undifferentiated), histological type (adenocarcinoma and others), and the diagnosis year. Surgical approach (open or laparoscopic) and surgery type (elective or urgent) were retrieved as well. The time lapse between the diagnosis date and surgery was also calculated and presented in days.
Outcome variables
The outcome of the study was the receipt of ACT and the addition of oxaliplatin.
Statistical analysis
Descriptive statistics were computed using mean (standard deviation, SD), median (interquartile, IQR) for continuous variables, and frequencies for categorical variables. Chi-square and Fisher’s exact tests were used to compare the characteristics of different treatment groups. Continuous variables, including age and survival time, were compared using student’s t-test and Wilcoxon tests. Moreover, univariate and multivariate logistic regressions were used to estimate the univariate and multivariable association between the outcome variables and covariates. A multivariate backward elimination regression was used with an entry criterion of P ≤ 0.20. All tests were 2-sided, and a P of ≤0.05 was considered statistically significant. Statistical analysis was performed using SAS Statistical Software Version 9.4 (SAS Institute Inc. Cary, NC).
RESULTS
Figure 1 displays the prevalence of ACT use between 2016 and 2021, stratified by tumor stage. Overall, ACT utilization was higher in stage III patients compared with stage II patients. Oxaliplatin administration was also higher for stage III patients compared with stage II LACC patients [Figure 2].
Figure 1.
Prevalence of Adjuvant Chemotherapy use by stage of tumor 2016-2021. The blue line indicates the prevalence of ACT use in stage II colon cancer patients, while the orange line indicates the prevalence among stage III colon cancer patients
Figure 2.
Prevalence of Oxaliplatin use by stage of tumor 2016-2021. The blue line represents the prevalence of Oxaliplatin use in stage II colon cancer patients, while the orange line represents the prevalence among stage III colon cancer patients
The characteristics of LACC patients are presented in Table 1. About 50% of stage II colon cancer patients (n = 50) received ACT, whereas 72% of stage III patients received ACT. The study showed a significant difference in the administration of ACT based on age group (<70 and ≥70 years of age), with a higher percentage of patients <70 years old in both stages receiving ACT compared to older patients.
Table 1.
Characteristics of locally advanced colon cancer patients by stage and adjuvant chemotherapy (ACT) status, MNGHA, 2016-2022
| Characteristics | Stage II | Stage III | ||||||
|---|---|---|---|---|---|---|---|---|
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| Total (%) | Received ACT | No ACT | P | Total (%) | Received ACT | No ACT | P | |
| n | 102 | 50 (49.02) | 52 (50.98) | 115 | 83 (72.17) | 32 (27.83) | ||
| Age, in years | ||||||||
| Mean (SD) | 62.20 (13.15) | 58.62 (11.38) | 65.65 (13.91) | <0.01 | 61.33 (14.05) | 58.98 (12.94) | 67.43 (15.15) | <0.01 |
| Median (IQR) | 62.0 (18) | 59.0 (15) | 69.0 (18.50) | 62.0 (20) | 60.0 (18) | 69.0 (22) | ||
| Age in years | ||||||||
| <70 | 70 (68.63) | 41 (82.0) | 29 (55.77) | <0.01 | 83 (72.17) | 65 (78.31) | 18 (56.25) | 0.02 |
| ≥70 | 32 (31.37) | 9 (18.0) | 23 (44.23) | 32 (27.83) | 18 (21.69) | 14 (43.75) | ||
| Sex | ||||||||
| Male | 63 (61.76) | 29 (58.0) | 34 (65.38) | 0.44 | 69 (60.0) | 49 (59.04) | 20 (62.50) | 0.73 |
| Female | 39 (38.24) | 21 (42.0) | 18 (34.62) | 46 (40.0) | 34 (40.96) | 12 (37.50) | ||
| Marital status | ||||||||
| Married | 82 (80.39) | 39 (78.0) | 43 (82.69) | 0.36 | 89 (77.39) | 67 (80.72) | 22 (68.75) | 0.32 |
| Unmarried | 10 (9.80) | 7 (14.0) | 3 (5.77) | 15 (13.04) | 9 (10.84) | 6 (18.75) | ||
| Unknown | 10 (9.80) | 4 (8.0) | 6 (11.54) | 11 (9.57) | 7 (8.43) | 4 (12.50) | ||
| BMI | ||||||||
| Under/normal weight | 33 (32.35) | 19 (38.0) | 14 (26.92) | 0.19 | 30 (26.09) | 20 (24.10) | 10 (31.25) | 0.07 |
| Overweight | 33 (32.35) | 12 (24.0) | 21 (40.38) | 40 (34.78) | 34 (40.96) | 6 (18.75) | ||
| Obese | 36 (36.70) | 19 (38.0) | 17 (32.69) | 45 (39.13) | 29 (34.94) | 16 (50.00) | ||
| CCI | ||||||||
| 0 | 13 (12.75) | 8 (16.0) | 5 (9.62) | 0.63 | 26 (22.61) | 18 (21.69) | 8 (25.00) | 0.60 |
| 1 | 21 (20.59) | 10 (20.0) | 11 (21.15) | 21 (18.26) | 17 (20.48) | 4 (12.50) | ||
| ≥2 | 68 (66.67) | 32 (64.0) | 36 (69.23) | 68 (59.13) | 48 (57.83) | 20 (62.50) | ||
| Diagnosis year | ||||||||
| 2016-2018 | 25 (24.51) | 11 (22.0) | 14 (26.92) | 0.56 | 49 (42.61) | 40 (48.19) | 9 (28.13) | 0.05 |
| 2019-2021 | 77 (75.49) | 39 (78.0) | 38 (73.08) | 66 (57.39) | 43 (51.81) | 23 (71.88) | ||
| Histological type | ||||||||
| Adenocarcinoma (AC), NOS | 94 (92.16) | 48 (96.0) | 46 (88.46) | 0.26 | 106 (92.17) | 76 (91.57) | 30 (93.75) | 1.00 |
| Others | 8 (7.84) | 2 (7.52) | 6 (11.54) | 9 (7.83) | 7 (8.43) | 2 (6.25) | ||
| Tumor grade | ||||||||
| Well/moderately differentiated | 95 (93.14) | 46 (92.0) | 49 (94.23) | 0.84 | 104 (90.43) | 75 (90.36) | 29 (90.63) | 0.71 |
| Poorly/undifferentiated | 6 (5.88) | 3 (6.0) | 3 (5.77) | 9 (7.83) | 7 (8.43) | 2 (6.25) | ||
| Unknown | 1 (0.98) | 1 (2.0) | 0 (0.0) | 2 (1.74) | 1 (1.20) | 1 (3.13) | ||
| TNM (T) | ||||||||
| T1 or T2 | 6 (5.83) | 1 (1.96) | 5 (9.62) | 0.13 | 9 (7.83) | 8 (9.64) | 1 (3.13) | 0.11 |
| T3 | 76 (73.79) | 37 (72.55) | 39 (75.0) | 73 (63.48) | 48 (57.83) | 25 (78.13) | ||
| T4 | 21 (20.39) | 13 (25.49) | 8 (15.38) | 33 (28.70) | 27 (32.53) | 6 (18.75) | ||
| TNM (N) | ||||||||
| N0 | 102 (100.0) | 50 (100.0) | 52 (100.0) | - | - | - | 0.74 | |
| N1 | - | - | - | 80 (69.57) | 57 (68.67) | 23 (71.88) | ||
| N2 or N3 | - | - | - | 35 (30.43) | 26 (31.33) | 9 (28.13) | ||
| Surgery type | ||||||||
| Elective | 84 (83.17) | 39 (78.0) | 45 88.24) | 0.17 | 103 (91.15) | 74 (90.24) | 29 (93.55) | 0.72 |
| Emergency | 17 (16.83) | 11 (22.0) | 6 (11.76) | 10 (8.85) | 8 (9.76) | 2 (6.45) | ||
| Surgical approach | ||||||||
| Open | 68 (66.67) | 37 (74.0) | 31 (59.62) | 0.12 | 75 (65.22) | 54 (65.06) | 21 (65.63) | 0.95 |
| Laparoscopic | 34 (33.33) | 13 (26.0) | 21 (40.38) | 40 (34.78) | 29 (34.94) | 11 (34.38) | ||
| Smoking status | ||||||||
| Smoker | 9 (8.82) | 1 (2.0) | 8 (15.38) | 0.02 | 8 (6.96) | 6 (7.23) | 2 (6.25) | 0.83 |
| Non-smoker | 89 (87.25) | 48 (96.0) | 41 (78.85) | 105 (91.30) | 76 (91.57) | 29 (90.63) | ||
| Unknown | 4 (3.92) | 1 (2.0) | 3 (5.77) | 2 (1.74) | 1 (1.20) | 1 (3.13) | ||
| Time between diagnosis and surgery | ||||||||
| Median, days (IQR) | 15 (37.5) | 12.5 (25.5) | 21 (45.25) | 0.07 | 13 (32) | 9 (32) | 16.5 (37.75) | 0.63 |
Compared to patients who had received ACT, those with no ACT presented with more comorbidities (CCI ≥2, stage II: 69.23% vs 64.0%, stage III: 62.50% vs 57.83%), were more likely to be smokers (stage II: 15.38% vs 2.0%; P = 0.02) and had a longer duration between diagnosis and surgery (stage II: 21vs 12.5 days, stage III: 16.5 vs 9 days).
Table 2 shows the characteristics of LACC patients who received ACT stratified by tumor stage and oxaliplatin status. Compared to patients who received oxaliplatin, those with no oxaliplatin were older, ≥70 years (stage II: 77.78% vs 5.41%, stage III: 55.0% vs 11.11%; P = <0.01), males (stage II: 76.92%, stage III: 70.0%), with well or moderately differentiated tumors (stage II: 92.85%, stage III: 90.0%), and had ≥2 CCI (stage II: 64.29%, stage III: 80.0%). A significant association between the year of diagnosis and the receipt of oxaliplatin in stage III patients was found. Patients diagnosed between 2019 and 2021 were more likely to receive oxaliplatin (60.32%) than those diagnosed between 2016 and 2018 (39.68%).
Table 2.
Characteristics of locally advanced colon cancer patients by stage and oxaliplatin status, MNGHA, 2016-2022
| Characteristics | Stage II | Stage III | ||||||
|---|---|---|---|---|---|---|---|---|
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| Total (%) | Oxaliplatin | No Oxaliplatin | P | Total (%) | Oxaliplatin | No Oxaliplatin | P | |
| n | 50 | 37 (74.0) | 13 (26.0) | 83 | 63 (75.90) | 20 (24.10) | ||
| Age, in years | ||||||||
| Mean (SD) | 58.62 (11.38) | 55.67 (10.61) | 67.0 (9.36) | <0.01 | 58.98 (12.94) | 55.09 (11.12) | 71.25 (10.56) | <0.01 |
| Median (IQR) | 59.0 (15) | 57.0 (13) | 70.0 (18) | 60.0 (18) | 54.0 (15) | 74.0 (17) | ||
| Age in years | ||||||||
| <70 | 41 (82.0) | 35 (94.59) | 6 (46.15) | <0.01 | 65 (78.31) | 56 (88.89) | 9 (45.0) | <0.01 |
| ≥70 | 9 (18.0) | 2 (5.41) | 7 (77.78) | 18 (21.69) | 7 (11.11) | 11 (55.0) | ||
| Sex | ||||||||
| Male | 29 (58.0) | 19 (51.35) | 10 (76.92) | 0.19 | 49 (59.04) | 35 (55.56) | 14 (70.0) | 0.25 |
| Female | 21 (42.0) | 18 (48.65) | 3 (23.08) | 34 (40.96) | 28 (44.44) | 6 (30.0) | ||
| Marital status | ||||||||
| Married | 39 (78.0) | 28 (75.68) | 11 (84.62) | 0.71 | 67 (80.72) | 49 (73.13) | 18 (26.87) | 0.22 |
| Unmarried | 11 (22.0) | 9 (24.32) | 2 (15.38) | 16 (19.28) | 14 (87.50) | 2 (12.50) | ||
| BMI | ||||||||
| Under/normal weight | 19 (38.0) | 13 (35.14) | 6 (46.15) | 0.76 | 20 (24.10) | 18 (28.57) | 2 (10.0) | 0.10 |
| Overweight | 12 (24.0) | 10 (27.03) | 2 (15.38) | 34 (40.96) | 22 (34.92) | 12 (60.0) | ||
| Obese | 19 (38.0) | 14 (37.84) | 5 (38.46) | 29 (34.94) | 23 (36.51) | 6 (30.0) | ||
| CCI | ||||||||
| 0 | 9 (17.65) | 8 (21.62) | 1 (7.14) | 0.33 | 18 (21.69) | 16 (25.40) | 2 (10.0) | 0.08 |
| 1 | 10 (19.61) | 6 (16.22) | 4 (28.57) | 17 (20.48) | 15 (23.81) | 2 (10.0) | ||
| ≥2 | 32 (62.75) | 23 (62.16) | 9 (64.29) | 48 (57.83) | 32 (50.79) | 16 (80.0) | ||
| Diagnosis year | ||||||||
| 2016-2018 | 11 (22.0) | 8 (21.62) | 3 (23.08) | 1.00 | 40 (48.19) | 25 (39.68) | 15 (75.0) | <0.01 |
| 2019-2021 | 39 (78.0) | 29 (78.38) | 10 (76.92) | 43 (51.81) | 38 (60.32) | 5 (25.0) | ||
| Histological type | ||||||||
| Adenocarcinoma (AC), NOS | 48 (96.0) | 91 (92.86) | 32 (91.43) | 0.45 | 76 (91.57) | 57 (90.48) | 19 (95.0) | 1.00 |
| Others | 2 (4.0) | 1 (2.70) | 1 (7.69) | 7 (8.43) | 6 (9.52) | 1 (5.0) | ||
| Tumor grade | ||||||||
| Well/moderately differentiated | 46 (90.20) | 33 (89.19) | 13 (100.0) | 0.71 | 75 (90.36) | 57 (90.48) | 18 (90.0) | 1.00 |
| Poorly/undifferentiated | 4 (7.84) | 3 (8.11) | 1 (7.14) | 7 (8.43) | 5 (7.94) | 2 (10.0) | ||
| Unknown | 1 (2.0) | 1 (2.70) | 0 (0.0) | 1 (1.20) | 1 (1.59) | 0 (0.0) | ||
| TNM (T) | ||||||||
| T1 or T2 | - | - | - | 0.47 | 8 (9.64) | 6 (9.52) | 2 (10.0) | 0.37 |
| T3 | 37 (74.0) | 26 (70.27) | 11 (84.62) | 48 (57.83) | 39 (61.90) | 9 (45.0) | ||
| T4 | 13 (26.0) | 11 (29.73) | 2 (15.38) | 27 (32.53) | 18 (28.57) | 9 (45.0) | ||
| TNM (N) | ||||||||
| N0 | 50 (100.0) | 37 (74.0) | 13 (26.0) | - | - | - | - | |
| N1 | - | - | - | - | 57 (68.67) | 42 (66.67) | 15 (75.0) | 0.48 |
| N2 or N3 | - | - | - | 26 (31.33) | 21 (33.33) | 5 (25.0) | ||
| Surgery type | ||||||||
| Elective | 39 (78.0) | 30 (81.08) | 9 (69.23) | 0.44 | 74 (90.24) | 55 (88.71) | 19 (95.0) | 0.67 |
| Emergency | 11 (22.0) | 7 (18.92) | 4 (30.77) | 8 (9.76) | 7 (11.29) | 1 (5.0) | ||
| Surgical approach | ||||||||
| Open | 37 (74.0) | 29 (78.38) | 8 (61.54) | 0.28 | 54 (65.06) | 41 (65.08) | 13 (65.0) | 0.99 |
| Laparoscopic | 13 (26.0) | 8 (21.62) | 5 (38.46) | 29 (34.94) | 22 (34.92) | 7 (35.0) | ||
| Smoking status | ||||||||
| Smoker | 2 (3.92) | 1 (2.70) | 1 (7.14) | 0.57 | 6 (7.23) | 4 (6.35) | 2 (10.0) | 0.17 |
| Non-smoker | 48 (96.0) | 35 (94.59) | 13 (92.86) | 76 (91.57) | 59 (93.65) | 17 (85.0) | ||
| Unknown | 1 (2.0) | 1 (2.70) | 0 (0.0) | 1 (1.20) | 0 (0.0) | 1 (5.0) | ||
Table 3 depicts different regimens of ACT treatment for LACC patients by tumor stage. All patients treated with chemotherapy received ACT. The majority of stage III patients received capecitabine or 5-FU (72%), while only 8.27% of patients in both groups received FOLFOX. Table 4 shows the univariate and multivariate analysis for the predictors of receiving ACT as well as oxaliplatin stratified by tumor stage. Age was independently associated with ACT administration. Patients aged 70 years or older were significantly less likely to receive ACT than those under the age of 70 (stage II: OR = 0.25, 95% CI = 0.10-0.64, stage III: OR = 0.04, 95% CI = 0.008-0.295). Moreover, smokers were significantly less likely to receive ACT than non-smokers (stage II: OR = 0.09, 95% CI = 0.01-0.81, stage III: OR = 0.09, 95% CI = 0.01-0.81). Regarding predictors of receiving oxaliplatin, older patients have lower odds of receiving oxaliplatin (stage II: OR = 0.04, 95% CI = 0.008-0.29, stage III: OR = 0.08, 95% CI = 0.02-0.32). In stage III patients, those who were diagnosed between 2019 and 2021 had 5.61 times higher odds of receiving oxaliplatin (OR = 5.61, 95% CI = 1.50-20.90).
Table 3.
Management plan for patients with LACC, MNGHA, 2016-2022
| Site | Line of treatment | Chemotherapy regimen | n (%) | Stage II | Stage III |
|---|---|---|---|---|---|
| LACC* | Adjuvant chemotherapy (n=133) | ||||
| Capecitabine/5-FU | 133 (100.0) | 50 (49.02) | 83 (72.17) | ||
| CAPOX | 96 (72.18) | 36 (35.29) | 60 (52.17) | ||
| FOLFOX | 11 (8.27) | 3 (2.94) | 8 (6.95) |
*LACC: Locally advanced colon cancer
Table 4.
Predictors of ACT use and oxaliplatin use among colon cancer patients, NGHA 2016–2022
| Predictors of ACT | Predictors of oxaliplatin | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
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| Stage II | Stage III | Stage II | Stage III | |||||||||||||
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| Univariate | Multivariate | Univariate | Multivariate | Univariate | Multivariate | Univariate | Multivariate | |||||||||
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| OR | 95% CI | OR | 95% CI | OR | 95% CI | OR | 95% CI | OR | 95% CI | OR | 95% CI | OR | 95% CI | OR | 95% CI | |
| Age in years | ||||||||||||||||
| <70 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 |
| ≥70 | 0.68 | (0.27-0.11) | 0.25 | (0.10-0.64) | 0.35 | (0.15-0.85) | 0.25 | (0.10-0.64) | 0.05 | (0.008-0.29) | 0.049 | (0.008-0.29) | 0.10 | (0.03-0.33) | 0.08 | (0.02-0.32) |
| Sex | ||||||||||||||||
| Male | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | ||||||||
| Female | 1.36 | (0.61-3.04) | 1.15 | (0.50-2.68) | 3.15 | (0.74-13.35) | 1.87 | (0.64-5.48) | ||||||||
| Marital status | ||||||||||||||||
| Unmarried | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | ||||||||
| Married | 1.36 | (0.35-5.18) | 2.03 | (0.65-6.35) | 0.84 | (0.08-9.06) | 0.34 | (0.04-2.92) | ||||||||
| Unknown | 3.49 | (0.54-22.29) | 1.16 | (0.23-5.81) | 2.00 | (0.09-44.34) | 0.75 | (0.04-14.57) | ||||||||
| BMI | ||||||||||||||||
| Normal weight | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | ||||||||
| Overweight | 0.42 | (0.15-1.13) | 2.83 | (0.89-8.98) | 2.30 | (0.38-13.96) | 0.20 | (0.04-1.03) | ||||||||
| Obese | 0.82 | (0.31-2.13) | 0.90 | (0.34-2.40) | 1.29 | (0.31-5.27) | 0.43 | (0.08-2.37) | ||||||||
| CCI | ||||||||||||||||
| 0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | ||||||||
| 1 | 0.56 | (0.13-2.32) | 1.88 | (0.48-7.44) | 0.18 | (0.02-2.13) | 0.94 | (0.11-7.52) | ||||||||
| ≥2 | 0.556 | (0.16-1.87) | 1.06 | (0.39-2.85) | 0.32 | (0.04-2.93) | 0.25 | (0.05-1.22) | ||||||||
| Diagnosis year | ||||||||||||||||
| 2016-2018 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | ||||||
| 2019-2021 | 1.30 | (0.52-3.23) | 0.42 | (0.17-1.01) | 1.08 | (0.24-4.92) | 4.56 | (1.47-14.13) | 5.61 | (1.50-20.90) | ||||||
| Histological type | ||||||||||||||||
| Adenocarcinoma (AC), NOS | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | ||||||||
| Others | 0.31 | (0.06-1.66) | 1.38 | (0.27-7.03) | 0.33 | (0.02-5.75) | 2.0 | (0.14-4.42) | ||||||||
| Tumor grade | ||||||||||||||||
| Well/moderately differentiated | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | ||||||||
| Poorly/undifferentiated | 1.07 | (0.20-5.54) | 1.35 | (0.26-6.89) | 1.18 | (0.11-12.42) | 0.78 | (0.23-17.68) | ||||||||
| Unknown | - | - | 0.38 | (0.02-6.39) | - | - | - | - | ||||||||
| TNM (T) | ||||||||||||||||
| T1 or T2 | 1.0 | 1.0 | 1.0 | 1.0 | - | - | 1.0 | 1.0 | ||||||||
| T3 | 4.74 | (0.52-42.52) | 0.24 | (0.02-2.02) | 1.0 | 1.0 | 1.44 | (0.25-8.36) | ||||||||
| T4 | 8.12 | (0.79-82.70) | 0.56 | (0.05-5.38) | 2.32 | (0.44-12.28) | 0.67 | (0.11-3.99) | ||||||||
| TNM (N) | ||||||||||||||||
| N0 | - | - | - | - | - | - | - | |||||||||
| N1 | - | - | - | 1.0 | 1.0 | - | - | 1.0 | 1.0 | |||||||
| N2 or N3 | - | - | - | 1.16 | (0.47-2.86) | - | - | 1.50 | (0.48-4.68) | |||||||
| Surgical approach | ||||||||||||||||
| Open | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | ||||||||
| Laparoscopic | 0.52 | (0.22-1.20) | 1.02 | (0.43-2.41) | 0.44 | (0.11-1.73) | 0.99 | (0.34-2.86) | ||||||||
| Smoking status | ||||||||||||||||
| Non-smoker | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | ||||
| Smoker | 0.11 | (0.01-0.89) | 0.09 | (0.01-0.81) | 1.14 | (0.21-5.99) | 0.09 | (0.01-0.81) | 0.37 | (0.02-6.38) | 0.58 | (0.09-3.42) | ||||
| Unknown | 0.27 | (0.02-2.84) | 0.23 | (0.02-2.52) | 0.38 | (0.02-6.30) | 0.23 | (0.02-2.52) | - | - | - | - | ||||
DISCUSSION
This study aimed to characterize Saudi patients diagnosed with LACC, assess the utilization of ACT and oxaliplatin among these patients, and elucidate factors associated with ACT and oxaliplatin use in a contemporary cohort of the Saudi population (2016-2021). Overall, we found that less than two-thirds of the studied population received ACT as recommended by NCCN. Compared to patients who had received ACT, those with no ACT were older and had a higher frequency of smoking. Specifically, our investigations show that patients diagnosed with LACC who underwent curative surgery or who were smokers, were less likely to receive adjuvant chemotherapy as recommended when they are older (≥70 years old). After adjusting for covariates, we found that older patients and smokers were less likely to receive adjuvant chemotherapy. These findings are consistent with previous studies.[12,13,14,15]
The fact that only 49.02% of stage II and 72.17% of stage III LACC patients had received ACT after curative surgery might suggest unindicated treatment or underutilization of a recommended treatment due to patients’ factors, such as refusal of treatment.[16] Nonetheless, this figure is lesser than what is reported in some prior studies but is similar to others.[17,18,19,20,21] ACT has been recommended as a standard of care and has been used since the 1990s.[22] In 2015, a meta-analysis of RCTs and observational studies showed that the 5-year OS has increased from half of the patients who did not receive ACT to 63% in those who had been administered ACT.[23] Given the improved OS among recipients of ACT, not receiving ACT, if indicated, should be elucidated in future studies. Potential reasons for not receiving ACT could be attributed to older age, the presence of multiple comorbidities or patients’ frailty, patients’ wishes/refusal of ACT, as well as the type of surgical procedure, and if the postoperative recovery time was prolonged or complicated.[24,25,26] Among those who received ACT, the most prescribed ACT regimens were capecitabine plus oxaliplatin (CAPOX) followed by 5-FU plus oxaliplatin (FOLFOX). Both CAPOX and FOLFOX have been recommended by NCCN guidelines in LACC patients, based on several RCTs and observational studies.[27,28] Based on two trials (IDEA and TOSCA), the choice between CAPOX and FOLFOX depended on the duration of treatment and risk. That is, treatment with CAPOX for three months in low-risk stage III (T3N1) patients was almost as effective and perhaps safer (less likely to develop peripheral neuropathy) than those with six months treatment. Counterintuitively, high-risk stage II patients would benefit more from six months of treatment. Although the overall FOLFOX use is low in our population, almost 30% of recipients are stage II compared to almost 40% of CAPOX. Both IDEA and TOSCA reported the efficacy of CAPOX and FOLFOX with differing recurrence risks and duration of therapy.
Older age continued to be a significant predictive factor for not receiving ACT.[6] Specifically, patients older than 70 years in our population were less likely to receive ACT, possibly due to intolerance to ACT or a high likelihood of toxicity, despite prior findings of increased benefits of ACT in older patients with stage III colon cancer.[6] Determining barriers to initiating and continuing ACT adherence, especially among old patients, is paramount. For instance, frequent hospital visits to administer ACT could become infrequent if safe home/remote infusion unit administration of ACT were possible.[29,30,31]
Likewise, we found that younger patients were more likely to receive oxaliplatin with 5-FU or capecitabine. While randomized controlled trials showed increased overall survival and less recurrence with oxaliplatin use, as previously mentioned, its use in our study was limited to patients <70 years old and those with higher T/N stages. These findings might reflect the neurotoxicity associated with oxaliplatin use which may be worrisome in older patients and those with major comorbidities.
Several factors have been investigated to elucidate reasons for not receiving ACT when indicated,[14] including the provider specialty, the healthcare facility, and the patient. For instance, 25% of the referrals to MO were attributed to the operating surgeons, and once the patients were referred, only 11% of ACT utilization was attributed to MO.[14] Multidisciplinary team involvement before surgery is associated with 3-year colon-cancer-specific survival of 80% compared to 68% in non-multidisciplinary teams.[7] The patient’s refusal to receive chemotherapy is another reason for the under-utilization of indicated therapy.[24] While the present study was not designed to answer these questions, our results support the notion that patients not offered chemotherapy were more likely to be frail and/or have severe comorbidities.[32]
The findings presented in this study should be read, given the following limitations. First, while the data used is based on a cancer registry with rigorously registered demographic and clinical data, the data is retrospective. Second, although we might have attempted to identify predictors of ACT and oxaliplatin use and the type of ACT use, we did not investigate reasons behind not initiating ACT when indicated, which would have been informative for MOs and policymakers. However, the results of this study equip healthcare professionals with the knowledge they need to make informed decisions about the care of LACC patients. This can lead to utilizing effective treatment approaches that can eventually improve patient outcomes and optimize overall care. Future studies should illuminate the reasons for not initiating the ACT and completing ACT courses at the population level. Third, while hospital referral might influence our findings, we attempted to minimize its effect by ensuring continuous membership in the NGHA system for at least 6 months before cancer diagnosis. Lastly, the Mismatch Repair (MMR) status, which is more predictive in stage II patients, was unavailable. To sum up, our investigations suggest that patient age and smoking status are key factors that shape the administration of ACT and oxaliplatin use in LACC patients.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Eligibility criteria of the study population
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Eligibility criteria of the study population