Clinical efficacy of integrated Chinese-Western medicine therapy for metastatic colorectal cancer

Table 1 Emulated target trial framework for Jianpi Bushen Jiedu method in treating metastatic colorectal cancer

Study process	Real-world study protocol	Target trial emulation protocol
Inclusion criteria	(1) Age ≥ 18 years, any sex; (2) Pathologically confirmed colorectal cancer; (3) TNM stage IV; (4) Received standard Western medicine treatment; (5) First use of Jianpi Bushen Jiedu herbal medicine at baseline; (6) Expected survival ≥ 3 months at baseline; and (7) Complete baseline medical records including TCM four diagnostic methods and syndrome differentiation	Same
Exclusion criteria	(1) Patients with two or more concurrent malignancies; (2) Severe cardiac, hepatic, or renal dysfunction at baseline; (3) Patients who have undergone curative treatment and are tumor-free; and (4) Participation in any interventional clinical trial within 3 months prior to enrollment	Same
Treatment strategy	Treatment group: Oral Jianpi Bushen Jiedu herbal medicine initiated within 30 days after T0, using syndrome-specific core prescriptions with individualized modifications, duration ≥ 3 months	Observed duration-based comparison. The therapeutic principle was standardized, whereas prescriptions were individualized by syndrome. Because duration was determined after T0, this comparison may be affected by immortal time bias and is interpreted as associational
	Control group: The same therapeutic principle and individualized prescribing process, duration < 3 months. Prescription changes and self-reported use were reviewed at follow-up; a validated adherence metric was not available for all patients
Assignment procedure	Randomly assigned to one treatment strategy at baseline	Observed initiation within 30 days after T0; subsequent duration was not assigned at baseline
Treatment initiation	Randomization time	From T0 to within 30 days after T0
Blinding	Open-label	Non-blinded
Time zero	Time of intervention assignment (randomization)	Date of first oral Jianpi Bushen Jiedu prescription; duration-based classification after T0 may still introduce immortal time bias
Follow-up	From baseline until death	From T0 until death
Primary outcome	OS	Same
Causal contrast	Per-protocol effect	Adjusted associational contrast; not a definitive causal effect because treatment duration was observed during follow-up
Statistical analysis plan	Per-protocol analysis	IPW-adjusted observational analysis of measured baseline confounders; landmark and time-varying exposure analyses are needed for a complete assessment

TNM: Tumor-node-metastasis; TCM: Traditional Chinese medicine; IPW: Inverse probability weighting; OS: Overall survival.

Table 2 Baseline characteristics before and after inverse probability weighting, n (%)/mean ± SD

Covariate	Treatment (n = 490)	Control (n = 137)	P value	Treatment (n = 259)	Control (n = 111)	P value
Age	-	-	0.844	-	-	0.905
< 60 years	291 (59.39)	83 (60.58)	-	107 (41.31)	44 (39.64)	-
≥ 60 years	199 (40.61)	54 (39.42)	-	152 (58.69)	67 (60.36)	-
Sex	-	-	0.493	-	-	0.264
Male	201 (41.02)	61 (44.52)	-	156(60.23)	56 (50.45)	-
Female	289 (59.98)	76 (55.48)	-	103 (39.77)	55 (49.55)	-
Tumor location	-	-	0.105	-	-	0.305
Left colon	347 (70.82)	107 (78.10)	-	190 (73.36)	95 (85.59)	-
Right colon	143 (29.18)	30 (21.90)	-	69 (26.64)	16 (14.41)	-
Histology	-	-	0.019	-	-	0.140
Adenocarcinoma	451 (92.04)	117 (85.40)	-	238 (91.89)	92 (82.88)	-
Non-adenocarcinoma	39 (7.96)	20 (14.60)	-	21 (8.11)	19 (17.12)	-
Gene type	-	-	0.752	-	-	0.375
Wild type	146 (29.80)	43 (31.39)	-	83 (32.05)	46 (41.44)	-
Mutant	344 (70.20)	94 (68.62)	-	176 (67.95)	65 (58.56)	-
Prior treatment	-	-	0.528	-	-	0.898
Treatment-naïve	167 (34.08)	35 (25.55)	-	84 (32.43)	33 (29.73)	-
First- or second-line	265 (54.08)	78 (56.93)	-	138 (53.28)	66 (59.46)	-
Third-line or later	58 (11.84)	24 (17.52)	-	37 (14.29)	12 (10.81)	-
Palliative surgery	272 (55.51)	75 (54.74)	0.923	147 (56.76)	58 (52.25)	0.575
Prior targeted therapy	186 (37.96)	44 (32.12)	0.230	92 (35.52)	28 (25.23)	0.272
Comorbidities	148 (30.20)	75 (54.74)	< 0.001	90 (34.75)	54 (48.65)	0.155
TCM deficiency syndromes	-	-	0.187	-	-	0.755
Spleen-kidney deficiency	175 (35.72)	77 (56.20)	-	95 (36.68)	47 (42.35)	-
Liver-kidney deficiency	76 (15.51)	23 (16.79)	-	44 (16.99)	18 (16.22)	-
Liver qi stagnation with spleen deficiency	141 (28.78)	12 (8.76)	-	65 (25.10)	25 (22.52)	-
Lung-kidney deficiency	43 (8.76)	13 (9.49)	-	24 (9.27)	8 (7.20)	-
Lung–spleen deficiency	26 (5.31)	9 (6.57)	-	16 (6.18)	8 (7.20)	-
Others	29 (5.92)	3 (2.19)	-	15 (5.79)	5 (4.51)	-
TCM excess syndromes	-	-	0.001	-	-	0.687
Phlegm-stasis obstruction	236 (48.16)	60 (43.79)	-	144 (55.60)	53 (47.75)	-
Stasis-toxin obstruction	75 (15.31)	11 (8.03)	-	31 (11.97)	17 (15.32)	-
Phlegm-damp retention	156 (31.84)	48 (35.04)	-	80 (30.89)	33 (29.73)	-
Internal retention of dampness	23 (4.69)	18 (13.14)	-	4 (1.54)	9 (7.20)	-
KPS	-	-	< 0.001	-	-	0.372
< 80	295 (60.20)	40 (29.20)		139 (53.67)	67 (60.36)	-
≥ 80	195 (39.80)	97 (70.80)		120 (46.33)	44 (39.64)	-
BMI	23.49 ± 3.91	23.65 ± 3.64	0.769	23.58 ± 3.90	22.96 ± 3.75	0.427
Metastatic sites
Liver	287 (58.57)	84 (61.31)	0.694	147 (56.76)	67 (60.36)	0.383
Lung	182 (37.14)	56 (40.88)	0.488	106 (40.93)	46 (41.44)	0.947
Brain	15 (3.06)	7 (5.11)	0.296	10 (3.86)	3 (2.70)	0.409
Peritoneum	34 (6.93)	10 (7.30)	0.852	12 (4.63)	9 (8.11)	0.734

TCM: Traditional Chinese medicine; KPS: Karnofsky performance status; BMI: Body mass index.

Table 3 Multivariable Cox proportional hazards regression model

Covariate	β (coefficient)	HR	E-value	95%CI	P value
Treatment (control)	2.705	14.954	29.40	9.054-24.701	< 0.001a
Sex (male)	0.354	1.424	2.20	1.119-1.813	0.004a
Age (≥ 60 years)	-0.026	0.974	-	0.781-1.215	0.816
Tumor site (right colon)	0.149	1.161	1.59	0.905-1.491	0.241
Histology (non-adenocarcinoma)	0.455	1.576	2.53	1.058-2.347	0.025a
Gene type (mutant)	0.533	1.704	2.80	1.354-2.145	< 0.001a
Prior treatment (first- or second-line vs treatment-naive)	-0.314	0.731	-	0.559-0.955	0.023a
Prior treatment (third-line or later vs treatment-naive)	0.550	1.734	2.86	1.256-2.393	< 0.001a
Palliative surgery	-0.132	0.876	-	0.689-1.115	0.283
Prior targeted therapy	-0.069	0.933	-	0.720-1.210	0.603
Comorbidities	0.176	1.192	1.67	0.950-1.495	0.129
TCM deficiency - spleen-kidney	0.175	1.192	1.67	0.874-1.624	0.267
TCM deficiency - liver-kidney	0.452	1.572	2.52	0.959-2.576	0.073
TCM deficiency - liver qi stagnation with spleen deficiency	0.946	2.573	4.58	1.644-4.028	< 0.001a
TCM deficiency - lung-kidney	-0.038	0.963	-	0.724-1.281	0.795
TCM deficiency - lung-spleen	-0.274	0.760	-	0.477-1.210	0.247
TCM excess - phlegm-stasis obstruction	-0.167	0.846	-	0.632-1.316	0.260
TCM excess - stasis-toxin obstruction	-0.383	0.682	-	0.469-0.992	0.045a
TCM excess - phlegm-damp retention	-0.121	0.886	-	0.675-1.164	0.386
TCM excess - internal retention of dampness	0.341	1.406	2.16	0.890-2.222	0.144
KPS ≥ 80	-1.315	0.269	-	0.101-0.711	0.008a
BMI ≥ 24	-0.009	0.991	-	0.967-1.017	0.504
Liver metastasis	0.037	1.037	-	0.818-1.315	0.762
Lung metastasis	-0.102	0.903	-	0.719-1.134	0.380
Brain metastasis	0.641	1.898	3.20	1.024-3.518	0.042a
Peritoneal metastasis	0.222	1.248	1.80	0.801-1.946	0.327

^aP < 0.05.

HR: Hazard ratio; CI: Confidence interval; TCM: Traditional Chinese medicine; KPS: Karnofsky performance status; BMI: Body mass index.

Table 4 Interaction analysis

Subgroup	HR	95%CI	P value	P for interaction
Sex (male)	0.528	0.296-0.941	0.030	0.003
Sex (female)	1.676	1.014-2.770	0.044	0.003
Gene type (wild type)	0.467	0.236-0.922	0.028	0.005
Gene type (mutant)	1.463	0.989-2.163	0.057	0.005
Prior treatment (third-line or later)	2.175	1.389-3.407	0.001	0.005
TCM deficiency - liver qi stagnation with spleen deficiency	0.465	0.244-0.887	0.020	0.014
KPS < 80	2.492	1.317-4.717	0.005	0.058

HR: Hazard ratio; CI: Confidence interval; TCM: Traditional Chinese medicine; KPS: Karnofsky performance status.