Interaction between calcium channel blockers and capecitabine in colorectal cancer patients with hypertension

Abstract

BACKGROUND

Colorectal cancer (CRC) is a leading cause of cancer-related mortality, with postoperative adjuvant chemotherapy being crucial for stage III patients. Hypertension is a prevalent comorbidity, yet the interaction between antihypertensive agents and chemotherapeutics remains unclear. While calcium channel blockers like amlodipine may modulate tumor metabolism and enzyme expression, the renin-angiotensin system inhibitors like valsartan may influence angiogenesis. However, direct clinical comparisons regarding their impact on capecitabine efficacy are lacking. We hypothesized that amlodipine, compared to valsartan, would demonstrate superior efficacy in reducing tumor markers when combined with capecitabine in hypertensive CRC patients.

AIM

To compare amlodipine vs valsartan combined with capecitabine in hypertensive stage III CRC patients.

METHODS

This retrospective controlled study enrolled 120 stage III CRC patients with hypertension were selected from January 2023 to November 2024. Patients were allocated to either the experimental group (capecitabine plus amlodipine, n = 60) or the control group (capecitabine plus valsartan, n = 60). The intervention duration was 8-12 cycles. Blood pressure, tumor markers [carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9)], and adverse events were compared using t-tests, χ² tests, and two-way repeated-measures analysis of variance.

RESULTS

Following treatment, the reductions in systolic blood pressure (119.04 ± 10.44 mmHg) and diastolic blood pressure (78.90 ± 4.23 mmHg) were markedly greater in the experimental group than the control group (P < 0.001). The decreases in CEA and CA19-9 levels were greater in the experimental group. Repeated-measures analysis of variance confirmed significant time × group interactions (CEA: P = 0.048; CA19-9: P = 0.036). There was no clinically relevant difference in the frequency of adverse reactions between the two groups (P > 0.05), with adverse events being predominantly grade 1-2 in both.

CONCLUSION

Amlodipine combined with capecitabine yields superior blood pressure control and greater reductions in CEA/CA19-9 than valsartan, with a comparable safety profile, but survival endpoint confirmation is required.

Key Words: Colorectal cancer; Hypertension; Calcium channel blockers; Capecitabine; Amlodipine

Core Tip: The current research paper examines the effects of combining calcium channel blockers and capecitabine on the treatment of colorectal cancer patients with associated hypertension. The results show that the use of amlodipine is more effective than valsartan in reducing tumor marker levels (carcinoembryonic antigen and carbohydrate antigen 19-9) with a better blood pressure control effect when combined with capecitabine. Therefore, there appears to be an interaction between calcium channel blockers and chemotherapy drugs that can be used to develop personalized anti-hypertensive therapy among colorectal cancer patients.

INTRODUCTION

Colorectal cancer (CRC) is the third leading cancer among all gastrointestinal cancers[1]. It features high recurrences and mortality rates and causes a heavy burden on the family and society[2]. The data show that there are about 1.9 million cases of CRC yearly, comprising 10% of all newly diagnosed cancers worldwide and whose incidence significantly increases with age[3]. While the techniques for detecting and treating CRC keep improving, the problem of frequent relapses and chemotherapy-resistant CRC remains an issue in the medical sphere[4]. For this reason, the use of postoperative chemotherapy to avoid recurrence becomes a vital aspect in case of stage III CRC patients having experienced curative surgery[5]. Thereby, capecitabine is one of the most effective drugs used in adjuvant therapy due to its convenience, efficacy, and safety in treating CRC patients[6]. This drug is selectively activated by the high levels of enzyme thymidine phosphorylase present in cancer tissues to produce 5-fluorouracil that exerts anti-tumor activity[7].

Hypertension is one of the common co-infections associated with CRCs. Hypertension is a disease that arises due to various causes and is common among individuals. Hypertension is strongly positively associated with an increase in the incidence of CRC[8]. The drugs mostly used in the treatment of hypertension include calcium channel blockers (CCBs) such as amlodipine and angiotensin II receptor blockers (ARBs) such as valsartan. Amlodipine exerts its blood pressure-lowering effect by obstructing L-type calcium pathways in the smooth muscle of blood vessels[9], while valsartan works by antagonizing angiotensin II receptors[10]. Basic research suggests that CCBs may potentially exhibit synergistic effects with chemotherapeutic agents by modulating enzyme activity and expression[11]. Specifically, CCBs have been reported to reverse P-glycoprotein-mediated multidrug resistance, thereby enhancing the intracellular accumulation of chemotherapeutic drugs in cancer types[12]. However, capecitabine is a prodrug that requires activation by thymidine phosphorylase[13], making this classic multidrug resistance reversal pathway less likely to be directly applicable. Amlodipine, reversed the heightened intracellular Ca²⁺ level and inhibited MAPK pathway activation in cancer cells[14]. On the other hand, ARBs have been found to significantly inhibit cell proliferation, angiogenesis, and tumor progression due to their activity in inhibiting the renin-angiotensin system[15]. However, in clinical setting, there is still a shortage of evidence confirming whether the combined use of CCBs or ARBs with capecitabine genuinely affects the outcome and security of chemotherapy in CRC patients. Existing research has largely focused on the interactions between individual antihypertensive drugs and chemotherapy, failing to systematically compare the impact of different types of antihypertensive agents on CRC chemotherapy outcomes. As such, finding out which anti-hypertensive drug is capable of controlling blood pressure, increasing the efficacy of chemotherapy while at the same time not enhancing the toxicity of therapy to CRC patients with hypertension is an important unresolved issue.

Building on this foundation, the present study employs a retrospective controlled study design to find out, compare, and analyze the differences in the application of continuing amlodipine and valsartan on blood pressure, tumor markers, and side effects in patients with stage III CRC suffering from comorbid hypertension who receive adjuvant chemotherapy using capecitabine. The purpose of this research is to shed light on the effectiveness of either of the two anti-hypertensive drugs in the context of such patients. Through the results of this study, it is hoped that sufficient evidence would be gained to help in optimizing patient management in such cases.

MATERIALS AND METHODS

General information

From January 2023 to November 2024, 120 patients with stage III colorectal adenocarcinoma complicated by hypertension who were diagnosed and underwent radical surgery (R0 resection) in the Department of Gastrointestinal Surgery of our hospital were chosen. They were classified into a control group (60 cases) and an experimental group (60 cases) retrospectively.

Inclusion criteria: (1) Diagnosis of colorectal adenocarcinoma confirmed by colonoscopy and pathological examination, with postoperative pathology confirming stage III disease[16]; (2) Diagnosis of primary hypertension, with regular monotherapy using amlodipine or valsartan for at least 4 weeks prior to enrollment, and blood pressure at enrollment < 160/100 mmHg; (3) Eastern Cooperative Oncology Group performance status score of 0-1; (4) Essentially normal baseline liver and kidney function; and (5) Complete clinical data.

Exclusion criteria: (1) Comorbidity with other malignant tumors; (2) Allergy to capecitabine, amlodipine, or valsartan; (3) Comorbidity with severe cardiac insufficiency (New York Heart Association class III-IV), autoimmune diseases, or coagulation dysfunction; (4) Changes in or adjustments to antihypertensive medication within 4 weeks prior to enrollment; and (5) Loss to follow-up.

Treatment methods

Both groups of patients underwent standardized radical resection for CRC. The surgeries were performed laparoscopically by a fixed team of specialists. Depending on the tumor location, the corresponding standard radical procedure was employed, along with D3 lymph node dissection. The entire process strictly adhered to clinical guidelines to ensure the achievement of a pathological R0 resection.

Chemotherapy protocol

All patients received adjuvant chemotherapy with capecitabine (Qilu Pharmaceutical Co., Ltd., national drug approval No. H20143365, specification 0.15 g) as monotherapy. The specific dosage was 1250 mg/m², administered orally twice daily (morning and evening) for 2 consecutive weeks, followed by a 1-week rest period, constituting one cycle. Patients completed 8-12 cycles of capecitabine. Treatment compliance, dose delays, dose reductions, and overall chemotherapy duration were retrospectively reviewed and found to be balanced between the two groups, with no significant intergroup differences in dose intensity.

Antihypertensive treatment protocol

Blood pressure control target: A unified blood pressure control target was set for all patients (systolic blood pressure < 130 mmHg, diastolic blood pressure < 80 mmHg). During chemotherapy, both groups routinely received supportive treatments such as antiemetics and gastric protectants. No other antihypertensive medications were used.

Control group: Continued the pre-enrollment valsartan (Changzhou Siyao Pharmaceuticals Co., Ltd., national drug approval No. H20010824, specification 80 mg) treatment regimen. The dosage was 80-160 mg/day, administered orally once daily, continued until the end of chemotherapy. The average daily dose of valsartan was reviewed; dose adjustments were minimal and did not differ significantly between groups, confirming comparable antihypertensive exposure.

Experimental group: Continued the pre-enrollment amlodipine treatment regimen [Huizhi Pharmaceutical (Dalian) Co., Ltd., national drug approval No. H10950224, specification 5 mg]. The dosage was 5-10 mg/day, administered orally once daily, continued until the end of chemotherapy. The average daily dose of amlodipine was reviewed; dose adjustments were minimal and did not differ significantly between groups, confirming comparable antihypertensive exposure.

Observation indicators

Tumor marker indicators: Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were measured before treatment and after treatment completion using electrochemiluminescence immunoassay. The normal reference values were < 5 ng/mL for CEA and < 37 U/mL for CA19-9[17].

Blood pressure control indicators: Systolic and diastolic blood pressure were measured before and after treatment under quiet conditions and without consumption of stimulants or excitants such as strong tea or coffee. A calibrated electronic blood pressure monitor was used, with measurements taken every 5 minutes, three times in total, and the average value was recorded.

Treatment-related adverse reactions: Adverse reactions related to chemotherapy during the treatment period (including hand-foot syndrome, nausea and vomiting, diarrhea, stomatitis, bone marrow suppression, etc.) were recorded and graded according to the CTCAE 5.0 standard, including mild (grade 1), moderate (grade 2), severe (grade 3), life-threatening (grade 4), and fatal (grade 5)[18]. The incidence of adverse reactions was calculated.

Statistical analysis

Data was made with the SPSS 21.0 software. Measurement data were denoted as mean ± SD, and intergroup relatively was adopted the t-test for independent kinds of samples. For longitudinal data (blood pressure and tumor markers measured before and after treatment), a two-way repeated measures analysis of variance (ANOVA) was performed to assess the main effects of time, group, and the time × group interaction. Partial eta squared (η²) was reported as a measure of effect size. Count data were denoted as n (%), and intergroup relatively was adopted the χ² test or Fisher’s exact test. A P value < 0.05 was considered to be thermally significant.

RESULTS

Comparison of baseline data between the two groups

Table 1 presents the comparison of baseline characteristics between the two groups, revealing no statistically significant differences in age, gender, Eastern Cooperative Oncology Group performance status, clinical stage, or baseline blood pressure and tumor markers (P > 0.05), which confirms the comparability of the study cohorts.

Table 1 Comparison of baseline data between the two groups, n (%)/mean ± SD.

Indicators	Control group (n = 60)	Experimental group (n = 60)	t/χ²	P value
Age (years)	66.15 ± 7.31	65.82 ± 7.25	0.249	0.804
Gender			0.139	0.709
Male	35 (58.33)	37 (61.67)
Female	25 (41.67)	23 (38.33)
ECOG score			0.141	0.707
0 points	24 (40.00)	22 (36.67)
1 point	36 (60.00)	38 (63.33)
T stage			0.498	0.779
T2	5	7
T3	33	30
T4	22	23
N stage			0.310	0.577
N1	34 (56.67)	37 (61.67)
N2	26 (43.33)	23 (38.33)
Systolic blood pressure (mmHg)	153.63 ± 5.19	153.60 ± 5.29	0.025	0.980
Diastolic blood pressure (mmHg)	96.44 ± 3.72	95.83 ± 3.92	0.877	0.382
CEA (ng/mL)	15.89 ± 2.46	15.95 ± 2.53	-0.132	0.896
CA19-9 (U/mL)	82.54 ± 6.88	82.67 ± 7.23	-0.101	0.902

It compares the continuous variables (e.g., age, systolic blood pressure, diastolic blood pressure, carcinoembryonic antigen, carbohydrate antigen 19-9) between the two groups using an independent samples t-test, and the categorical variables (e.g., gender, Eastern Cooperative Oncology Group score, T stage, N stage) using the χ² test. The results show that there is no statistically significant difference between the groups for any baseline characteristic (all P > 0.05), indicating that the groups are comparable. CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; ECOG: Eastern Cooperative Oncology Group.

Comparison of blood pressure control before and after treatment

Table 2 demonstrated the blood pressure levels before and after treatment, indicating that both groups achieved significant blood pressure reduction, with the experimental group showing a greater decrease in both systolic and diastolic blood pressure (P < 0.001).

Table 2 Comparison of blood pressure control before and after treatment, mean ± SD.

Group	Systolic blood pressure (mmHg)		Diastolic blood pressure (mmHg)
	Before treatment	After treatment	Before treatment	After treatment
Control group (n = 60)	153.63 ± 5.19	126.42 ± 9.43	96.44 ± 3.72	82.69 ± 2.97
Experimental group (n = 60)	153.60 ± 5.29	119.04 ± 10.44	95.83 ± 3.92	78.90 ± 4.23
t value	0.025	4.064	0.877	5.685
P value	0.980	< 0.001	0.382	< 0.001

It compares the systolic and diastolic blood pressure levels before and after treatment in both groups using the independent samples t-test. The results show that there was no significant difference in baseline blood pressure between the two groups (P > 0.05), while both groups showed significant post-treatment blood pressure reduction, with the experimental group demonstrating a greater decrease (P < 0.001).

Comparison of tumor markers between the two groups

Table 3 displays the changes in CEA and CA19-9 levels before and after treatment, indicating that both markers decreased significantly in both groups, with a more pronounced reduction in the experimental group (P < 0.001).

Table 3 Comparison of tumor marker levels before and after treatment, mean ± SD.

Group	CEA (ng/mL)		CA19-9 (U/mL)
	Before treatment	After treatment	Before treatment	After treatment
Control group (n = 60)	15.89 ± 2.46	8.55 ± 0.68	82.54 ± 6.88	34.69 ± 5.51
Experimental group (n = 60)	15.95 ± 2.53	7.85 ± 0.98	82.67 ± 7.23	31.55 ± 3.86
t value	-0.132	4.540	-0.101	3.614
P value	0.896	< 0.001	0.902	< 0.001

It compares the carcinoembryonic antigen and carbohydrate antigen 19-9 levels before and after treatment in both groups using the independent samples t-test. The results show no significant difference in baseline tumor marker levels between the two groups (P > 0.05), while both groups showed significant post-treatment reduction in carcinoembryonic antigen and carbohydrate antigen 19-9, with the experimental group demonstrating a greater decrease (P < 0.001). CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9.

Repeated measures ANOVA results for blood pressure and tumor markers

Repeated measures ANOVA in Table 4 depicted that the time × group interactions were significant for systolic blood pressure (P = 0.010), diastolic blood pressure (P = 0.026), CEA (P = 0.048), and CA19-9 (P = 0.036), and after accounting for the main effect of time (all P < 0.001), the main effects of group remained significant for all outcomes (systolic blood pressure: P = 0.023, diastolic blood pressure: P = 0.043, CEA: P = 0.046, CA19-9: P = 0.041), indicating that the experimental group achieved lower posttreatment values for blood pressure and tumor markers than the control group.

Table 4 Results of repeated-measures analysis of variance for blood pressure and tumor markers.

Outcome	Effect	F (df)	P value	η²
Systolic blood pressure	Time	32.5 (1118)	0.001	0.216
	Time × group	6.8 (1118)	0.010	0.055
	Group	5.3 (1118)	0.023	0.043
Diastolic blood pressure	Time	25.1 (1118)	0.001	0.175
	Time × group	5.1 (1118)	0.026	0.041
	Group	4.2 (1118)	0.043	0.034
CEA	Time	28.3 (1118)	0.001	0.193
	Time × group	4.0 (1118)	0.048	0.033
	Group	4.1 (1118)	0.046	0.034
CA19-9	Time	34.7 (1118)	0.001	0.227
	Time × group	4.5 (1118)	0.036	0.037
	Group	4.3 (1118)	0.041	0.035

It summarizes the results of the repeated-measures analysis of variance performed to evaluate the effects of time, group, and the time × group interaction on systolic blood pressure, diastolic blood pressure, carcinoembryonic antigen, and carbohydrate antigen 19-9. The analysis reveals significant main effects of time and group, as well as significant time × group interactions for all outcomes (P < 0.05). CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9.

Comparison of adverse reactions between the two groups

Table 5 showed the incidence of adverse reactions between the two groups, indicating no significant differences in hand-foot syndrome, nausea and vomiting, diarrhea, stomatitis, or bone marrow suppression (all P > 0.05), with similar safety profiles in both groups.

Table 5 Comparison of adverse reactions between the two groups, n (%).

Group	Hand-foot syndrome	Disgust and vomiting	Diarrhea	Stomatitis	Bone marrow suppression
					Grade 1-4	Grade 3
Control group (n = 60)	20 (33.33)	24 (40.00)	16 (26.67)	12 (20.00)	27 (45.00)	5 (8.33)
Experimental group (n = 60)	18 (30.00)	23 (38.33)	15 (25.00)	11 (18.33)	25 (41.67)	4 (6.67)
χ²	0.154	0.035	0.044	0.054	0.136	-
P value	0.695	0.852	0.835	0.817	0.713	0.729

It compares the incidence of adverse reactions (hand-foot syndrome, disgust and vomiting, diarrhea, stomatitis, bone marrow suppression) between the two groups using the χ² test. For Bone marrow suppression (grade 3), the exact probability method was used. The results show no statistically significant differences in the incidence of any adverse reaction between the control and experimental groups (all P > 0.05).

DISCUSSION

It is ranked as the second most common cancer in women and the third most common one in men among adults, which is the fourth most important cause of deaths caused by cancer and is estimated to account for around 9.2% of deaths resulting from cancer globally[19]. According to epidemiological information, the 5-year and 10-year overall survival (OS) rates for CRC patients are reported to be 65% and 58%, respectively[20], showing great differences depending on the disease stages and treatment availability. In China, the number of incidences and fatalities from CRC is constantly increasing every year, which can be largely attributed to China’s fast economic growth, increased aging, and lifestyle changes[21]. Although there is already a multimodal treatment system consisting of endoscopic screening, curative surgery for early detection, neoadjuvant chemotherapy for downstaging tumors, and molecular targeted therapies for precise treatment for CRC patients, its high recurrence and chemo-resistance makes CRC an urgent health problem in the world[4]. Adjuvant chemotherapy following surgery becomes the essential treatment approach for the selected patients, especially those with stage III disease, because it is the key factor contributing to a good prognosis and preventing recurrence and distant metastasis[5].

Capecitabine is a promising oral fluoropyrimidine drug that has proved its effectiveness and ease of use as a fundamental drug in the adjuvant chemotherapy for CRC due to its simple oral dosing and demonstrated efficacy[22]. After oral intake, the drug goes through intracellular transformation into a cytotoxic metabolite – 5-fluorouracil. The activation of the prodrug is accomplished by thymidine phosphorylase enzyme, which shows an increased concentration in tumor tissue compared with most other organs[23]. In turn, the specificity of the drug activation mechanism allows increasing the efficiency of targeted cytotoxic treatment by achieving high levels of 5-fluorouracil selectively at the tumor site, which leads to decreased toxicity to normal tissue. As compared to the traditional treatment regime, the administration of capecitabine has several benefits as opposed to continuous intravenous administration of 5-fluorouracil. The selective activation mechanism increases the antitumor activity of capecitabine due to higher specificity in targeting tumor cells[7] and reduces the rate of toxic effects on normal tissues, thus providing high patient tolerance and improved treatment outcome.

The CRC patients tend to be older and have a greater chance of having other diseases that occur alongside, which is known as comorbidity[24]. The commonest form of comorbidity among the CRC patients is the existence of hypertension. In addition, hypertension is one of the most common diseases globally with many causes that make it difficult to treat[25]. There are over 1.3 billion people living with hypertension worldwide, making it the most common non-communicable disease in terms of numbers globally[26]. The association between CRC and hypertension has been extensively studied by epidemiologists through several studies. According to previous studies, CRC is more likely to happen among Asian people. In addition, a meta-analysis of several studies shows that hypertension increases the relative risk of getting CRC by 22%[8]. An intriguing finding in this study is that high blood pressure among men is related to the development of CRC; however, this relation does not apply to women. From these findings, there is a clear link between hypertension and CRC and a greater risk of developing CRC among men than women[8].

Among antihypertensive medications, CCBs (such as amlodipine) and ARBs (such as valsartan) are two commonly used first-line drug classes. Amlodipine primarily exerts its antihypertensive effect by interrupting L-type calcium channels in blood vessel smooth muscle, restraining calcium influx, and thereby inducing vasodilation[9]. Meanwhile, studies suggest that CCBs may enhance the antitumor efficacy of chemotherapy drugs in cancer through mechanisms such as regulating enzyme activity and expression[11]. Valsartan, ARB, lowers blood pressure by selectively antagonizing the angiotensin II type 1 receptor, thereby blocking the reninangiotensinaldosterone system[10]. Research has shown that ARBs can exert anti-proliferative and anti-angiogenic effects in tumors, such as by inducing apoptosis in nasopharyngeal carcinoma cells[27]. However, there is still a lack of sufficient medical evidence regarding the differences in efficacy and safety when these two classes of drugs are combined with capecitabine. Further validation with clinical data is required for both.

This study conducted to investigate the impacts of using amlodipine (experimental group) vs valsartan (control group) for blood pressure management on the outcome and security of capecitabine monotherapy as adjuvant chemotherapy in stage III CRC patients with hypertension. The results demonstrated that the experimental group exhibited significant advantages in both blood pressure control and improvements in oncological indicators. Regarding blood pressure control, both groups recorded a remarkable reduction in blood pressure after treatment with respect to baseline (P < 0.001). However, the experimental group realized a greater decline in both systolic and diastolic blood pressure than the control group (P < 0.001), achieving a superior level of blood pressure control. The result is consistent with the powerful and reliable antihypertensive effects of amlodipine.

As for the alteration in tumor markers, the experimental group exhibited better results, showing a marked decrease in key tumor markers as compared to the control group. The drops in both CEA and CA19-9 were statistically significant for the group taking amlodipine (P < 0.001). Repeated measures ANOVA confirmed significant time × group interactions for CEA (F = 4.0, P = 0.048, η² = 0.033) and CA19-9 (F = 4.5, P = 0.036, η² = 0.037), as well as significant group main effects (CEA: P = 0.046; CA19-9: P = 0.041). Such biomarkers are significant clinical signs of tumor load and treatment efficacy, thus the considerable decrease of which is particularly significant.

With regard to toxicity, the combination treatment demonstrated a good profile. There were no differences in the frequency of occurrence of the usual side effects of capecitabine therapy such as hand-foot syndrome, gastro-intestinal disorders (vomiting/nausea and diarrhea) and myelosuppression between the groups. All these side effects were mostly mild or moderate (grade 1 or 2) and did not indicate severe adverse effects. It means that additional administration of amlodipine to capecitabine did not increase the intrinsic toxicity of the chemo-drug. Such results represent an important evidence that the therapy with capecitabine and amlodipine does not have high potential toxicity. One methodological point that should be mentioned is the consistent use of a strict blood pressure target (< 130/80 mmHg) throughout the whole study. Although the selection of a strict blood pressure target meets current clinical recommendations for high-risk patients, its use in patients under chemotherapy needs further discussion. The use of capecitabine leads to side effects like nausea, vomiting, decreased oral intake, and diarrhea. These factors result in significant changes in intravascular volume. In this regard, the use of a strict blood pressure target can lead to hypotensive complications in older patients. Future studies should consider implementing a less strict target value, such as < 140/90 mmHg or a target personalized based on the initial values of blood pressure and intravascular volume.

While the current research has produced valuable and clinically useful results, it is important to note several weaknesses inherent to the study design, which should be carefully considered. First and foremost, the single-center nature of the current study, coupled with the limited sample size, may create a certain bias, as there was no pre-calculated sample size before the start of the study. In particular, the power to detect any differences in safety outcomes related to rare safety events, such as grade 3 adverse effects or higher, is relatively low because of the small number of 60 patients per arm. Hence, the consistent findings regarding the similarity of safety outcomes in both arms cannot be viewed as sufficient evidence of equivalence because of the possibility of the type II error caused by the underpowered design. Additionally, the trial was not designed to perform subgroup analyses, which is indicated by a relatively small number of patients in specific strata, for example, those classified according to T stages (T2, T3, T4) or N stages (N1, N2). Thus, all conclusions drawn during the course of subgroup analysis should be regarded as preliminary only. Second, the follow-up period used by the researchers was relatively short. Therefore, there is no important information on important prognostic factors such as disease-free survival (DFS) and OS that would provide information about the effectiveness of the two compared regimens on patient survival. Third, there is insufficient information related to the biological mechanisms that have been studied. In this regard, it is important to mention that the researchers did not examine plasma levels of drugs, the concentration of drugs in tumors, or dynamics in the expression of biomarkers.

Methodological issue concerning efficacy evaluation must be highlighted here. All participants in the study were patients who underwent R0 resection for stage III CRC with adjuvant therapy by capecitabine with no residual disease present. This situation is an adjuvant setting following surgery where objective response rate and disease control rate assessed according to RECIST criteria can hardly serve as valid endpoints. Changes in serum tumor markers (CEA, CA19-9) are provided as exploratory endpoints only. Changes in these biomarkers can never replace clinically relevant endpoints, such as DFS and OS. It would be misleading to claim that there is an improvement in anti-tumor activity of the drug due to the relatively short follow-up and lack of data on survival endpoints.

For these reasons, the following research must involve a more holistic approach to these vital areas. First, it would be important to conduct large-scale, multicenter, randomized, controlled trials with long-term follow-up in order to include analysis based on the stages of tumor (T and N categories). These trials would enable the examination of whether the advantages of using amlodipine over valsartan would remain consistent throughout various subgroups. Second, the areas of translation and mechanisms need to be thoroughly investigated. Specifically, in the future, it would be essential to carry out the studies aimed at detecting the plasma concentrations of the drug, capecitabine, and its metabolite, 5-fluorouracil, for comparing the pharmacokinetic profile of the medication in the patients using amlodipine and valsartan. In addition, in vitro studies would have to be done in order to check whether amlodipine inhibits the activity of carboxylesterase 2, along with other enzymes required for activation of capecitabine. In addition to that, more research needs to be done concerning the optimization of doses of the medication. There needs to be research done concerning the effect on different levels of amlodipine when combined with the typical dosage of capecitabine. With this research done, the optimal level at which the two drugs complement each other would be known. Success in this aspect would prove invaluable in understanding the actual contribution of CCBs in CRC therapy.

CONCLUSION

In summary, among stage III CRC patients with hypertension receiving capecitabine adjuvant chemotherapy, blood pressure management with amlodipine compared to valsartan achieves superior blood pressure control and greater reductions in CEA and CA19-9 levels, with a favorable safety profile. Although these findings support a potential biochemical advantage of amlodipine, confirmation with survival endpoints such as DFS is required in future studies.