Abstract
Background:
The NALLC trial (NCT01441752) demonstrated that postoperative adjuvant chemotherapy combined with traditional Chinese medicine (TCM) improved the quality of life (QoL) and survival in resected stage Ib-IIIa non-small-cell lung cancer (NSCLC) patients. This report updates disease-free survival (DFS) and other key outcomes.
Methods:
Between December 2012 and August 2015, 334 patients were randomized to receive either adjuvant chemotherapy plus traditional Chinese herbal granules (n = 167) or adjuvant chemotherapy plus placebo (n = 167) across 7 centers. Patients continued herbal granules or placebo daily until chemotherapy completion. DFS updates data was conducted in the intention-to-treat (ITT) population.
Results:
The median follow-up was 116.87 months. Median DFS was 71.83 months for the TCM group versus 43.60 months for the control (HR: .86; 95% CI: .64-1.15; P = .31). Two-year and 5-year DFS rates were 73.60% and 50.16% for TCM, compared to 67.45% and 44.08% for the control (P = .23). Median overall survival (mOS) was not reached in either group, with 75% OS at 63.40 months for TCM and 53.67 months for the control. Five-year OS rates were 76.15% for TCM and 69.81% for the control (P = .23). Subgroup analysis showed stage Ib patients benefited from TCM in both DFS (HR: .51; P = .02) and OS (HR: .34; P = .01).
Conclusions:
Adjuvant chemotherapy combined with TCM showed a potential trend toward improved DFS in early-stage NSCLC patients.
Trial registration:
This trial was registered with Clinical.Trials.gov (Number: NCT01441752, July 14, 2011).
Keywords: non-small cell lung cancer, traditional Chinese medicine, adjuvant chemotherapy, disease-free survival, subsequent traditional Chinese medicine treatment
Introduction
Lung cancer is the second most prevalent cancer and the leading cause of cancer-related death worldwide.1,2 Non-small-cell lung cancer (NSCLC) is the most common type accounting for over 80% of cases and surgical resection remains the best treatment with curative intent for early-stage NSCLC. 3 However, even with complete resection, patients are still at a high risk of relapse and death, with the 5-year overall survival (OS) rate at 50% in stage I-IIIa NSCLC after resection. 4 Therefore, the postoperative adjuvant treatment has been of interest in an attempt to improve outcomes, resulting in 5 independent randomized clinical trials (RCTs) including ALPI, 5 IALT, 6 BLT, 7 JBR.10, 8 and ANITA. 9 Analysis of the outcomes as described in the Lung Adjuvant Cisplatin Evaluation meta-analysis study (LACE) demonstrated the survival benefit of adjuvant cisplatin-based chemotherapy. 10 Based on this evidence, cisplatin-based, 2 drugs adjuvant chemotherapy became the standard of care for postoperative stage Ib NSCLC with high-risk factors or stage II-IIIa NSCLC.11,12 In recent years, there has been great progress in adjuvant trials, with ADAURA 12 and Impower010 13 ushering in the era of adjuvant-targeted drugs and PD-1/PD-L1 inhibitors. However, EGFR mutation is found in only 47% of lung adenocarcinoma patients, 14 and more than 50% of NSCLC have no suitable targeted drugs. 15 Adjuvant immunotherapy presents several limitations. Only NSCLC patients with stage II-IIIa and PD-L1 ≥ 1% could benefit from the treatment. 16 Therefore, adjuvant chemotherapy continues to be widely used in the post-surgical treatment regimen. 17
Although adjuvant chemotherapy has improved survival in NSCLC, the percentage of disease recurrence and death remains high. LACE reported that 45% of stage Ib and 76% of stage IIIa NSCLC patients would suffer from disease recurrence or metastasis with a median follow-up of 5 years, resulting in a 5-year absolute DFS and OS benefit of only 5.8% and 5.4% respectively. 10 Meanwhile, no significant survival benefit from adjuvant chemotherapy was observed in stage Ib NSCLC patients.18,19 It is now widely accepted that potential complications and adverse events (AEs) also limit the acceptability and effectiveness of chemotherapy. Nearly 73% of patients would suffer from grade 3 to 4 hematologic toxicity and 77% would thus have at least 1 dose reduction or omission. 20
Traditional Chinese medicine (TCM) is widely used in combination with adjuvant chemotherapy in China, with more than 70% of cancer patients being treated with TCM approaches to reduce side effects and prolong survival. 21 A previous retrospective study showed that TCM users had longer DFS compared with the chemotherapy alone (P < .05). 22 In addition, a prospective cohort study has also reported that TCM therapy was a protective factor against NSCLC recurrence and metastasis in stage II-IIIa NSCLC patients (HR: .51; 95% CI: .37-.67), while also noting no TCM-related AEs. 23 While these trials demonstrated the significant advantages of TCM in the treatment of early-stage NSCLC, the median follow-up was insufficient. Since the late toxicities of chemotherapy may affect the survival time, especially in the elderly, smokers and patients with comorbidity, 18 the improvement in long-term survival with TCM therapy is still unclear.
Our previous study (NALLC) was a multicenter, randomized, double-blind and placebo-controlled clinical study of TCM based on syndrome differentiation plus adjuvant chemotherapy, which reported the improvement of the chemotherapy-related symptoms, including pain (P = .01), dry mouth (P = .007), vomiting (P = .004), diarrhea (P = .02), and fatigue (P = .019). The incidence of AEs was also significantly lower in the treatment group than in the control group (.57% vs 4.02%, P = .037). 24 In addition, stage follow-up confirmed that TCM also significantly prolonged DFS in stage Ib lung adenocarcinoma (HR: .53; 95% CI: .28-.99, P = .046). 25 Currently, there is limited data on survival in early-stage NSCLC patients receiving TCM therapy with long-term follow-up, and a previous study showed the trend of loss of survival benefit beyond 5 years of follow-up. 26 Following demonstrated benefits in the QoL and safety benefits of integrating TCM with adjuvant chemotherapy, we now present findings on its long-term outcomes, including recurrence, metastasis, and overall survival.
Materials and Methods
Study Design and Patients
Full details of the NALLC trail were described previously. 27 Briefly, patients between the ages of 18 and 75 years who were diagnosed with stage Ib-IIIa NSCLC and had undergone complete resection were enrolled in the trial. A total of 334 patients were selected from 7 centers in China.
Eligible patients were randomly assigned in a 1:1 ratio to receive adjuvant chemotherapy with TCM (n = 167) or placebo (n = 167) between December 2012 and August 2015. Randomization was performed centrally by an independent clinical research organization (CRO, Shanghai Clinical Research Center, Shanghai, China) through a secure web-based system using a computer-generated random sequence. Stratified randomization using the dynamic minimization method was performed based on clinical stage (Ib vs IIa vs IIb, and IIIa), histological subtype (adenocarcinoma vs squamous carcinoma vs glands squamous carcinoma vs large cell carcinoma, and other types), gender, QoL, and the center. This study adopted a double-blind design, in which patients, investigators, and data analysts were all blinded to treatment allocation. Randomization codes were securely maintained by the CRO and were not disclosed until the database was locked. The study was conducted in 2012 when genetic testing was not required after resection at that time. This was due to the high cost of the testing fee, which meant that not everyone was able to undergo the test.
The protocol was approved by the ethics boards of Longhua Hospital (2011LCSY014) and was registered at Clinical Trials gov (Number: NCT01441752; Date: July 14, 2011). All participants provided written informed consent prior to enrollment.
Treatment
All patients received adjuvant vinorelbine (25 mg/m2 on days 1 and 8) plus cisplatin (75 mg/m2 on day 1) or carboplatin (area under the curve [AUC] = 5 on day 1) every 4 weeks for 4 cycles. Meanwhile, the participants received TCM granules or matched placebo twice a day until the end of adjuvant chemotherapy. The details of the syndrome differentiation criteria, composition of the formulas, and pharmaceutical ingredients were described in our previous article. 24 Briefly, 3 basic syndromes, including qi syndrome deficiency, yin syndrome deficiency, and qi and yin syndrome deficiency, were determined by 2 senior physicians or deputy chief physicians according to the Chinese Medicine New Medicine Clinical Practice Guideline (Trial Implementation; published by China Medical Science Press in 2002) and Shanghai Chinese Medicine Routine Practice (written by Shanghai Municipal Commission of Health and Family Planning). Patients diagnosed with qi syndrome deficiency, yin syndrome deficiency, or qi and yin syndrome deficiency received matched TCM granules in the treatment group or placebo in the control group. Granules were used from the first day after chemotherapy, not on the day of chemotherapy. All herbal granules and placebos were produced by Jiangyin Tianjiang Pharmaceutical Co., Ltd., a pharmaceutical enterprise certified under the Good Manufacturing Practice (GMP) standards. Both preparations were produced using raw materials from the same production region and a unified batch number to ensure product consistency and quality assurance. The placebo was meticulously formulated to match the TCM granules in color, odor, taste, weight and appearance.
Assessment
The primary endpoint of this study is the QoL after adjuvant chemotherapy, which was already reached in 2017. 24 DFS was defined as the time from the date of random assignment to disease recurrence or metastasis (determined by computed tomography or magnetic resonance imaging, pathological disease on biopsy, or both) or death from any cause. OS was defined as the time from randomization to death for any reason. Patients who were still alive or lost to follow-up were censored at the date of the last confirmation of their survival. In the case of disease recurrence or metastasis, the sites of recurrence were recorded. Secondary endpoints (DFS and OS) were analyzed in the intention-to-treat (ITT) population, defined as all randomly assigned patients. The follow-up interval for all patients was 3 months in the first 2 years following the end of chemotherapy, every 6 months until 5 years, and yearly thereafter.
Statistical Analysis
The sample size calculation of this study was described previously. 27 The final OS analysis was planned to be conducted when approximately 50% of the patients had died. The survival time was the secondary endpoint which was only reported in the adenocarcinoma subgroup, and overall patient survival time was never reported. Missing values were excluded from the analysis unless otherwise specified. All of the statistical analyses were performed using R statistical packages (version 4.1.3).
The Chi-square test and t-test were employed to compare baseline and follow-up treatment characteristics. The Kaplan–Meier method was used to describe DFS and OS, and the cumulative proportion of survival at 3 and 5 years. A 2-sided log-rank test was used to compare DFS and OS between the 2 groups. The Cox proportional hazards model was used to calculate the hazard ratio (HR) for treatment, and the multivariable logistic regression model was applied to examine the characteristics of subsequent TCM treatment users. All variables with a P-value < .25 from the univariate analysis were included in the model building process. Age and sex were retained in the model regardless of their significance. After selecting the list of variables for inclusion in the final model, the functional form of each variable and multicollinearity between variables was examined. The cutoff date (July 31, 2023) was defined as the last date of follow-up for data collection and survival status confirmation.
Post hoc analyses were performed to investigate the potential long-term effects of TCM using extended follow-up data obtained nearly 10 years after completion of the original NALLC trial. Following the end of the randomized, double-blind intervention, the study entered the follow-up phase. During this period, some participants continued or initiated the use of TCM on their own initiative. This post-trial TCM use, defined as subsequent TCM treatment (STCM), was not pre-specified in the study protocol and varied in form, duration, and regimen according to individual patient needs. In contrast, during the randomized phase, all patients received standardized TCM granules or matched placebo in accordance with the protocol.
Results
Patient Characteristics and Treatment
A total of 349 patients were initially enrolled from 7 centers across China between December 2012 and August 2015. Fifteen patients were excluded from the analysis because they only had baseline randomization records but lacked treatment information and survival follow-up data, making it impossible to evaluate long-term survival outcomes. The remaining 334 patients received Chinese medicine granules or placebo in combination with NP/NC chemotherapy were included in the ITT population (Figure 1).
Figure 1.
Consort diagram showing patient disposition for the NALLC study (data cutoff: July 31, 2023).
Abbreviations: DFS, disease-free survival; TCM, traditional Chinese medicine; STCM, subsequent traditional Chinese medicine.
There was a difference in the final number of patients included in the analysis compared with our previously article. 24 This difference resulted from the objectives of the 2 studies. The previous study primarily evaluated QoL outcomes. Therefore, patients lacking complete QoL assessment data were excluded from that analysis. In contrast, the present study focused on long-term survival outcomes, and patients who had complete treatment and survival data but lacked QoL information were retained for inclusion in the current analysis. Baseline characteristics, including age, sex, smoking status, family history of tumors, comorbidities, surgical procedures, pathological diagnosis, TNM stage, chemotherapy regimen, and TCM syndrome differentiation, were balanced between the 2 groups (Table 1). And all enrolled patients had not received neoadjuvant therapy.
Table 1.
Baseline Characteristics of the Study Population.
| Parameter a | Treatment group, no. (%) | Control group, no. (%) | Total, no. (%) | χ 2 | P |
|---|---|---|---|---|---|
| Patients | 167 | 167 | 334 | ||
| Sex | .00 | 1.00 | |||
| Male | 105 (62.87) | 105 (62.87) | 210 (62.87) | ||
| Female | 62 (37.13) | 62 (37.13) | 124 (37.13) | ||
| Age, years | .15 | .70 | |||
| <65 | 126 (75.45) | 129 (77.25) | 255 (76.35) | ||
| ≥65 | 41 (24.55) | 38 (22.75) | 79 (23.65) | ||
| Smoking status | 1.45 | .23 | |||
| None or mild | 92 (55.09) | 81 (48.50) | 173 (51.8) | ||
| Serious | 75 (44.91) | 86 (51.50) | 161 (48.2) | ||
| Family tumor history | .96 | .33 | |||
| Yes | 35 (20.96) | 28 (16.77) | 63 (18.86) | ||
| No | 132 (79.04) | 139 (83.23) | 271 (81.14) | ||
| Underlying disease | .65 | .42 | |||
| Yes | 55 (32.93) | 62 (37.13) | 117 (35.03) | ||
| No | 112 (67.07) | 105 (62.87) | 217 (64.97) | ||
| Pathological diagnosis | 2.27 | .53 | |||
| Adenocarcinoma | 117 (70.06) | 117 (70.06) | 234 (70.06) | ||
| Squamous | 46 (27.54) | 41 (24.55) | 87 (26.05) | ||
| Others | 4 (2.40) | 9 (5.39) | 13 (3.89) | ||
| Pathological stage | .53 | .91 | |||
| Ib | 72 (43.11) | 76 (45.51) | 148 (44.31) | ||
| IIa-IIb | 43 (25.75) | 36 (21.56) | 79 (23.65) | ||
| IIIa | 52 (31.14) | 55 (32.93) | 107 (32.04) | ||
| Resection procedure | 2.82 | .42 | |||
| Sublobectomy | 3 (1.80) | 3 (1.80) | 6 (1.80) | ||
| Lobectomy | 155 (92.81) | 154 (92.22) | 309 (92.51) | ||
| Pneumonectomy | 2 (1.20) | 6 (3.59) | 8 (2.40) | ||
| Ohters | 7 (4.19) | 4 (2.40) | 11 (3.29) | ||
| Chemotherapy regimen | .81 | .37 | |||
| NP | 61 (36.53) | 69 (41.32) | 130 (38.92) | ||
| NC | 106 (63.47) | 98 (58.68) | 204 (61.08) | ||
| TCM syndrome | 2.04 | .36 | |||
| QD | 73 (43.71) | 79 (47.31) | 152 (45.51) | ||
| YD | 13 (7.78) | 7 (4.19) | 20 (5.99) | ||
| QYD | 81 (48.50) | 81 (48.50) | 162 (48.50) |
Abbreviations: NP, vinorelbine plus cisplatin; NC, vinorelbine plus carboplatin; TCM, traditional Chinese medicine; QD, qi syndrome deficiency; YD, yin syndrome deficiency; QYD, qi and yin syndrome deficiency.
No statistical difference was observed between the 2 groups.
Update DFS Analysis
At the point of data cutoff, the median follow-up was 116.87 months, and the longest follow-up was 135.17 months. A total of 181 (54.19%) patients suffered lung cancer recurrence or metastasis, which occurred in 52.69% (88/167) receiving TCM granules and 55.69% (93/167) receiving placebo (Figure 1). Most of patients in both groups completed the adjuvant chemotherapy and study medication. In the treatment group, 21 patients (12.57%) completed 1 to 2 cycles and 146 patients (87.43%) completed 3 to 4 cycles. In the placebo group, 14 patients (8.38%) completed 1 to 2 cycles and 153 patients (91.62%) completed 3 to 4 cycles. With regard to TCM administration, 135 patients (80.84%) in the treatment arm completed 3 to 4 cycles of herbal granules and 32 (19.16%) completed 1 to 2 cycles. Similarly, in the placebo arm, 144 patients (86.23%) and 23 (13.77%) completed 3 to 4 and 1 to 2 cycles of placebo granules, respectively. Median disease-free survival (mDFS) was 71.83 months in the treatment group and 43.60 months in the control group. Compared to the control group, the treatment group prolonged mDFS for 28.23 months, although mDFS was not statistically significantly different between the 2 arms (HR: .86; 95% CI: .64-1.15; P = .31; Figure 2a). The 2- and 5-year DFS rates were 73.60% and 50.16% with TCM granules, and 67.45% and 44.08% with placebo (P = .23). A predefined subgroup analysis of DFS, including sex, pathological diagnosis, and pathological stage, indicated that stage Ib patients could benefit from the TCM treatment (HR: .51; 95% CI: .28-.91; P = .02; Figure 2b). There was no significant difference between the 2 groups in an exploratory subgroup analysis including age and smoking history.
Figure 2.
Disease-free survival (A), and subgroup analysis (B) between the treatment group and control group. The 75% OS is expressed in months.
Abbreviations: HR, hazard ratio; CI, confidence interval; mDFS, median disease-free survival.
Analysis of Recurrence Site
The site of recurrence was similar between the 2 groups (P = .92, Table 2). Locoregional-only recurrence was the most common recurrence pattern in both groups (83/180, 46.11%), followed by distant-only recurrence (48/180, 26.67%) and distant with locoregional recurrence (44/180, 24.44%).
Table 2.
Recurrence Site.
| Recurrence pattern a | Treatment group | Control group | Total |
|---|---|---|---|
| No. (%) | No. (%) | No. (%) | |
| Patients | 87 | 93 | 180 |
| Locoregional-only | 39 (44.83) | 44 (47.31) | 83 (46.11) |
| Distant-only | 25 (28.73) | 23 (24.73) | 48 (26.67) |
| Distant with locoregional | 21 (24.13) | 23 (24.73) | 44 (24.44) |
| Unknown | 2 (2.30) | 3 (3.23) | 5 (2.78) |
No statistical difference was observed between the 2 groups.
Locoregional-only recurrence was observed in 44.83% (39/87) of patients in the treatment group and 47.31% (44/93) of patients in the control group (Table 2). In both 2 groups, the most common site of recurrence was the lung, which occurred in 53 patients (60.92%) in the treatment group and 59 patients (63.44%) in the control group. Distant-only recurrence occurred in 25 patients (28.73%) and 23 patients (24.73%) in the treatment and control groups, respectively (Table 2). Distant with locoregional recurrence was observed in 21 patients (24.13%) and 23 patients (22.58%) in the treatment and control groups, respectively. The CNS was the most frequent site of metastasis in both the treatment group (23/87, 26.44 %) and control group (17/93, 18.28%), followed by bone (24.14% and 25.81%) and liver (5.75% and 5.38%). Additionally, 5 patients had no clear documentation of the specific recurrence site, including 2 in the treatment group and 3 in the control group (Table 2).
OS Analysis
Less than half of the patients (127/334, 38.02%) died at the cut-off date, occurring in 35.33% (59/167) of the treatment group and 40.72% (68/167) of the control group (Figure 1). The median overall survival (mOS) was not reached in either group. The 75% of OS was 63.40 months in the treatment group and 53.67 months in the control group, with the average OS being 104.06 months and 98.04 months, respectively. There was no statistically significant difference in OS between the 2 arms (HR: .83; 95% CI: .58-1.17; P = .28; Figure 3a). In addition, the 5-year OS rates were 76.15% in the TCM group, and 69.81% in the placebo group, with no statistically significant differences being observed (P = .23). Among the patients who received TCM treatment, the 5-year OS rate in those with N1 and N2 disease was 81.50% and 51.54%, respectively. In the CNS metastasis cases, mOS was prolonged by 22.80 months with Chinese herbal granules (68.63 vs 45.83 months) with statistically significant differences between the 2 groups (HR: .47; 95% CI: .23-.96; P = .03). Patients with stage Ib disease could benefit from TCM treatment (HR: .34; 95% CI: .15-.76; P = .01; Figure 3b) in a predefined subgroup analysis of OS including sex, pathological diagnosis, and pathological stage. An exploratory subgroup analysis including age and smoking history showed no significant difference between the 2 groups.
Figure 3.
Overall survival (A) and subgroup analysis (B) between the treatment group and control group. The 75% OS is expressed in months.
Abbreviations: HR, hazard ratio; CI, confidence interval.
Post Hoc Analysis of Subsequent Treatment
During the follow-up period, 165 patients received the STCM therapy, including 83 patients (49.70%) from the original treatment group and 82 patients (49.10%) from the original control group. In the original treatment group, 35 patients (20.96%) did not receive any further treatment and the treatment status of 49 patients (29.34%) was unknown due to loss to follow-up or unwillingness to report. In the control group, the numbers were 34 (20.36%) and 51 (30.54%). Treatment status during the follow-up period was similar in both groups (P = .97, Figure 4). The characteristics of the patients with clear treatment status are listed in Table 3, which indicates that more stage Ib patients received STCM therapy (P < .01). A multivariate analysis, including sex, age, smoking status, family history of cancer, previous history, and pathological stage further confirmed this trend (Table 4).
Figure 4.
Treatment status during follow-up period.
Abbreviation: STCM, subsequent traditional Chinese medicine.
Table 3.
Univariate Analysis of Treatment Status During Follow-up Period.
| Parameter | STCM users (n = 165) | Non-STCM users (n = 69) | P |
|---|---|---|---|
| Sex | |||
| Male | 100 (60.61) | 50 (72.76) | .09 |
| Female | 65 (39.39) | 19 (27.54) | |
| Age, years | |||
| <65 | 128 (77.58) | 53 (76.81) | .90 |
| ≥65 | 37 (22.42) | 16 (23.19) | |
| Smoking status | |||
| None or mild | 90 (54.55) | 31 (44.93) | .18 |
| Serious | 75 (45.45) | 38 (55.07) | |
| Family tumor history | |||
| Yes | 131 (79.39) | 61 (88.41) | .10 |
| No | 34 (20.61) | 8 (11.59) | |
| Underlying disease | |||
| Yes | 97 (58.79) | 45 (65.22) | .36 |
| No | 68 (41.21) | 24 (34.78) | |
| Pathological diagnosis | |||
| LUAD | 117 (70.91) | 45 (65.22) | |
| Non-LUAD | 48 (29.09) | 24 (34.78) | |
| Pathological stage | |||
| Ib | 90 (54.55) | 23 (33.33) | |
| II-IIIa | 75 (45.45) | 46 (66.67) | |
| Resection procedure | |||
| Sublobectomy | 3 (1.82) | 1 (1.45) | .44 |
| Lobectomy | 155 (93.94) | 64 (92.75) | |
| Pneumonectomy | 2 (1.21) | 3 (4.35) | |
| Ohters | 5 (3.03) | 1 (1.45) | |
| Chemotherapy regimen | |||
| NP | 11 (6.67) | 14 (20.29) | .30 |
| NC | 154 (93.33) | 55 (79.71) | |
| TCM syndrome | |||
| QD | 67 (40.61) | 37 (53.62) | .18 |
| YD | 10 (6.06) | 4 (5.80) | |
| QYD | 88 (53.33) | 28 (40.58) | |
Abbreviations: STCM, subsequent traditional Chinese medicine treatment; OR, odds ratio; CI, confidence interval; LUAD, lung adenocarcinoma; NC, vinorelbine plus carboplatin; TCM, traditional Chinese medicine; QD, qi syndrome deficiency; YD, yin syndrome deficiency; QYD, qi and yin syndrome deficiency.
Table 4.
Multivariate Analysis of Treatment Status During Follow-up Period.
| Parameter | OR (95% CI) | P |
|---|---|---|
| Sex | ||
| Male | Reference | |
| Female | 1.37 (.54-3.48) | .51 |
| Age, years | ||
| <65 | Reference | |
| ≥65 | 1.05 (.50-2.21) | .90 |
| Smoking status | ||
| None or mild | Reference | |
| Serious | .82 (.34-1.94) | .65 |
| Family tumor history | ||
| Yes | Reference | |
| No | 2.02 (.83-4.89) | .12 |
| Underlying disease | ||
| Yes | Reference | |
| No | 1.31 (.68-2.52) | .42 |
| Pathological stage | ||
| Ib | Reference | |
| II-IIIa | .42 (.22-.78) | .01 |
| TCM syndrome | ||
| QD | Reference | |
| YD | 1.45 (.39-5.37) | .58 |
| QYD | 1.39 (.73-2.64) | .32 |
Abbreviations: OR, odds ratio; CI, confidence interval; LUAD, lung adenocarcinoma; NC, vinorelbine plus carboplatin; TCM, traditional Chinese medicine; QD, qi syndrome deficiency; YD, yin syndrome deficiency; QYD, qi and yin syndrome deficiency.
In the treatment group, the mDFS was not reached in patients who continued to receive STCM therapy. For those not receiving STCM therapy, the mDFS was 89.83 months. In the control group, the mDFS was also not achieved in STCM users. And the mDFS in non-STCM users was 18.63 months (Figure 5). Statistically, differences were observed in non-STCM users (P = .02) and were not significant in STCM users (P = .96). Univariate analysis revealed that sex, pathological diagnosis, pathological stage, intervention (granules vs placebo), and subsequent treatment status were significant predictors of DFS (Table 5). When these variables were included in the Cox proportional hazards model, we found that pathological stage and subsequent treatment status were associated with significant hazard ratios (Table 5).
Figure 5.
Disease-free survival of the 4 groups. A, treatment group and subsequent traditional Chinese medicine users; B, treatment group and non-subsequent traditional Chinese medicine users; C, control group and subsequent traditional Chinese medicine users; D, control group and non-subsequent traditional Chinese medicine users.
Table 5.
Univariate and Multivariate Analysis of DFS.
| Parameter | Univariate | Multivariate (backward) | ||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| Sex | ||||
| Male vs female | .80 (.55-1.17) | .25 | .68 (.45-1.03) | .07 |
| Age, years | ||||
| <65 vs ≥65 | .95 (.62-1.46) | .81 | ||
| Pathological diagnosis | ||||
| LUAD vs Non-LUAD | 1.33 (.87-2.04) | .19 | 1.51 (.96-2.40) | .08 |
| Pathological stage | ||||
| Ib vs II-IIIa | .29 (.19-.43) | <.01 | .29 (.19-.44) | <.01 |
| NALLC treatment grouping | ||||
| TG vs CG | .75 (.52-1.09) | .14 | .74 (.51-1.07) | .11 |
| Subsequent treatment status | ||||
| STCM vs Non-STCM | .39 (.27-.57) | <.01 | .42 (.28-.62) | <.01 |
Abbreviations: HR, hazard ratio; CI, confidence interval; STCM, subsequent traditional Chinese medicine treatment; LUAD, lung adenocarcinoma; CG, control group; TG, treatment group.
Discussion
The NALLC study was a multicenter, randomized, double-blind, placebo-controlled trial that compared QoL and survival outcomes in postoperative lung cancer patients with TCM combined with adjuvant chemotherapy versus those receiving chemotherapy alone. After almost 10 years of follow-up, we updated the mDFS to 71.83 months in the treatment group and 43.60 months in the control group. The mDFS of the placebo was similar to that of the ANITA study 9 (chemotherapy, 36.3 months). In our study, TCM treatment prolonged mDFS for 28.23 months, which showed a numerical advantage in TCM treatment. However, the difference in mDFS between the 2 groups was not statistically significant (HR: .86; 95% CI: .64-1.15; P = .31). A previous TCM study showed the same trend that Chinese herbs could prolong the DFS of patients with postoperative stage I-IIIA NSCLC, reporting a significant difference between the 2 arms (HR: .3825; 95% CI: .29-.50; P < .0001). 21 However, it was a cohort study and the TNM stage was not balanced between the 2 groups, so the outcome of the study should be viewed with caution. The 5-year DFS rate of the treatment group was 50.16%, slightly lower than that of the treatment group in the JBR.10 study (61%). 8 The JBR.10 trial differed by exclusively recruiting stage Ib-IIb patients, while the NALLC study also included stage IIIa patients. Notably, this study adopted a 4-week NP/NC regimen, which was consistent with the treatment schedules used in other major adjuvant chemotherapy trials such as JBR.10 8 and ANITA. 9 Compared with the 3-week regimen, the 4-week schedule was associated with lower toxicity, which was particularly important given that this study also evaluated patients’ QoL. 24
The mOS in the NALLC study was not reached because more than half of the patients were still alive at the time of data cutoff, indicating that the data are still immature. The 5-year OS rate was 76.15% in the treatment group and 69.81% in the placebo arm. Compared with 46% in the ANITA study, 9 the outcome from NALLC demonstrates the potential effect of TCM in improving survival rate. For patients with N1 disease in the treatment arm, the 5-year OS rate was 81.50%, which compared to 50%, 56%, and 61.4% in the IASLC database, 28 ANITA, 9 and ADJUVANT 29 studies respectively. Similarly, the 5-year OS rate for patients with N2 disease was 51.54% in NALLC, compared with 38%, 47%, and 61.4% in the 3 studies. However, it should be noted that the stage of disease was varied in these studies and the gene mutation or PD-L1 expression of the patients was unknown except in the ADJUVANT study. Improvements in OS may also have been influenced by advances in targeted and immune therapies in recent years, in addition to the potential contribution of TCM. Few TCM-related studies have reported mOS or 5-year OS rates due to limited follow-up time and small event numbers.21,22 The predefined subgroup analysis was used to further explore the factors influencing DFS and OS. No statistically significant differences were found between the 2 arms except for the pathological stage. We found that TCM therapy could prolong both DFS (HR: .51; 95% CI: .28-.91; P = .02) and OS (HR: .34; 95% CI: .15-.76; P = .01) in stage Ib patients. This observation is in contrast to that reported by others as most clinical trials, such as CALGB 9633 study 19 (HR: .83; 95% CI: .64-1.08; P = .125) and JBR.10 study 8 (P = .79) had previously concluded that stage Ib patients did not benefit from adjuvant chemotherapy. Only the ADAURA study 12 showed a benefit of osimertinib in the adjuvant setting (HR: .41; 95% CI: .23-.69). Unlike ADAURA, which enrolled only EGFR-mutant patients, NALLC demonstrated potential efficacy in a broader, unselected population.
NALLC was not the first study to demonstrate a potential advantage of adjuvant TCM therapy in postoperative NSCLC patients. Zhang et al 23 conducted a prospective cohort study of 507 patients with stage II–IIIA NSCLC who received adjuvant chemotherapy, and found that TCM users had significantly longer DFS than non-TCM users. Similarly, Zhao et al 22 retrospectively analyzed 67 patients with stage II–IIIA NSCLC and found that adjuvant TCM therapy significantly prolonged DFS compared with chemotherapy alone. More recently, Liu et al. reported in a real-world retrospective cohort of 700 patients with stage IIIA NSCLC that TCM therapy significantly improved DFS and reduced recurrence, particularly among patients with N2 disease and elderly subgroups. 30 These findings consistently indicate that TCM adjuvant therapy may help delay recurrence and improve long-term survival in postoperative NSCLC. In NALLC trial, we observed a similar trend of improved survival, and significant DFS benefits in the stage Ib subgroup. However, these results should be considered with caution. Most TCM studies are real-world or retrospective cohort analyses, which have limited evidential value. Even in NALLC, the observed benefit came from subgroup analyses.
We also reported the site of recurrence for both arms. Due to statistical power considerations, we only compared the overall pattern of recurrence between the 2 groups. Previous studies have reported that surgical factors may influence the risk of locoregional recurrence, and that higher primary tumor invasiveness, more extensive nodal involvement, and aggressive adenocarcinoma subtypes are associated with an increased likelihood of postoperative CNS metastasis.31,32 For each specific site of recurrence, we only reported the number of cases in each of the 2 groups. The pattern of recurrence was similar between the 2 groups (P = .92). About 44.83% of patients in the treatment group and 47.31% of patients in the control group suffered from locoregional-only recurrence, which was the most common recurrence pattern (46.11%), followed by distant-only recurrence (26.67%) and distant with locoregional recurrence (24.44%). The specific site of recurrence was not clear in 5 patients due to a lack of review records and missed visits. Compared with the ANITA study, 9 NALLC seemed to have more cases of locoregional-only recurrence, which was due to the different definitions of local and distant recurrence. It is reported that adjuvant TCM therapy may reduce the risk of recurrence and metastasis across multiple organs, including the lungs, liver, bone, mediastinum/pleura, and lymph nodes. 30 In NALLC trail, we observed a similar exploratory finding that TCM therapy appeared to prolong OS in patients with CNS metastasis (HR: .47; 95% CI: .23-.96; P = .03). While this trend is consistent with previous reports indicating a systemic protective effect of TCM, this result should be interpreted with caution as it is based on a subgroup analysis. We also sought to determine whether patients would continue to receive Chinese herbs during the follow-up period and whether this STCM therapy would provide a survival benefit. Post hoc analysis showed no significant difference in the distribution of the treatment during the follow-up period in the 2 groups (P > .05), and nearly half of the patients in both groups continued to receive STCM therapy. Univariate and multivariate analysis showed that more stage Ib patients tended to receive STCM therapy (P < .01), which was similar to another cross-sectional research in China. 33 This might be related to the fact that stage Ib patients usually do not need additional Western medical treatment after adjuvant chemotherapy at that time, 11 and patients usually seek TCM therapy to improve their QoL and delay disease recurrence.34,35
The necessity and value of STCM have been controversial. A previous study supported STCM therapy and revealed that a longer duration of TCM treatment could be considered a protective factor against lung cancer. 21 Meanwhile, some scholars have raised concerns about the safety and efficacy of the long-term use of herbal treatment. 31 Since the importance of continuing treatment after adjuvant chemotherapy was confirmed in ADAURA 12 and Impower010, 13 we further analyzed the mDFS of the 4 groups, including the treatment and control groups with or without STCM therapy, to explore the necessity of continuing Chinese herbal therapy during the follow-up period. Because this grouping method resulted in an unequal baseline between groups and a small sample size within each group, we only described the results in the study. We found that patients who received TCM treatment during the follow-up period did not achieve their mDFS, suggesting a trend toward the benefit of STCM therapy on DFS. The further multivariate Cox proportional hazards model further confirmed this finding (P < .01). It should be noted, however, that the granules were provided only until the end of chemotherapy, as designed in NALLC, and the herbs in STCM therapy were prescribed by the patients’ respective physicians. The composition of the herbal prescriptions varied, but the main effect was anti-tumor.
While the NALLC trial provides important evidence on the long-term effects of adjuvant TCM therapy in resected NSCLC, several limitations should be acknowledged. At the time of this study’s initiation, molecular profiling for lung cancer was not yet standardized in clinical practice. First, the lack of routine molecular testing at its outset meant that data on key biomarkers (eg, driver mutations, PD-L1) were unavailable, preventing biomarker-based prognostic analysis. Second, due to the absence of systematically recorded treatment data after recurrence or metastasis, the influence of subsequent lines of therapy on OS could not be determined. Additionally, some findings from the post-hoc analysis are preliminary and exploratory, largely because of the limited sample size, and must be confirmed in larger, dedicated cohorts.
Conclusion
This study demonstrates that TCM with adjuvant chemotherapy may improve DFS and OS in patients with resected stage Ib-IIIa NSCLC, with the benefit being primarily observed in the stage Ib subgroup. Furthermore, our findings underscore the importance of sustained TCM throughout the follow-up period.
Acknowledgments
We sincerely appreciate the contributions of all participants in this study, as well as the organizations that provided financial support for this research.
Footnotes
ORCID iDs: Di Zhou 
https://orcid.org/0009-0004-7965-6383
Ethical Considerations: This study received ethical approval from the Ethics Committee of Longhua Hospital (2011LCSY014) and was registered at Clinical Trials gov (Number: NCT01441752; Date: July 14, 2011).
Consent to Participate: All participants were fully informed about the study’s purpose and content, provided explicit informed consent, and signed consent forms before participation.
Author Contributions: Yichao Wang: Methodology, Supervision, Investigation, Writing – Original Draft. Lijing Jiao: Conceptualization, Methodology, Writing – review and editing. Zhiwei Chen, Jianfang Xu, Jiaming Che, Hai Huang, Lei Zhang, Xiaoyong Shen, Yi Yang, Jie Zhang, and Tiancheng Zhao: Supervision, Investigation, Writing – review and editing. Di Zhou, Qin Wang, and Jialin Yao: Project administration, Writing – review and editing. Wenxiao Yang: Data curation, Formal analysis, Writing – review and editing. Chenbing Sun, Jiaqi Li, and Rongzhen Ding: Investigation, Writing – review and editing. Ian Goodfellow: Writing – review and editing. Yabin Gong: Methodology, Supervision, Investigation, Writing – review and editing. Ling Xu: Conceptualization, Methodology, Supervision, Investigation, Writing – review and editing.
Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Ministry of Science and Technology of China (2023YFC3503300), Shanghai Municipality Science and Technology Commission Foundation (22ZR1462400), Shanghai Shenkang Hospital Development Center (SHDC22025209) and the Shanghai Municipal Health Commission (2025CXGZS-15, 20244Y0220), and Shanghai University of Traditional Chinese Medicine (2023LCRC13).
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data Availability Statement: The data that support the findings are available from the corresponding author upon reasonable request.
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