Lung cancer is the most common malignancy and the leading cause of cancer-related deaths worldwide (18.4% of total cancer deaths, GLOBOCAN 2018) (1). The burden of lung cancer is extremely diverse in Asian countries. The highest incidence was observed in Japan followed by countries closer to Europe such as Armenia, Turkey and Kazakhstan as well as South-East Asia and Korea, whereas the lowest incidence was reported in Western Asian countries including Yemen and Saudi Arabia (2). South-East Asia reported 160,068 new cases and 146,990 deaths in 2018 with 23,667 new cases and 20,710 deaths reported from Vietnam (3). Although the incidence of lung cancer in Vietnam is higher than the global incidence (14.4% versus 11.6%), the mortality rate is similar to the rest of the world (18.4%) (4, 5). In the Association of South-East Asian Nations countries, the age-standardised mortality rates (per 100,000) for males and females were highest in Armenia (58.5 and 8.5), Vietnam (35.4 and 11.1) and Singapore (41.5 and 17.2) and lowest in Cambodia (21.6 and 8.7) and Indonesia (19.4 and 6) (6). The age-adjusted death rate was estimated at 24.73 per 100,000 for both genders together, putting Vietnam at the 37^th position in the world for lung cancer (7).

Non-small-cell lung cancer (NSCLC) accounts for about 85% of all new lung cancer cases (8). Approximately 25% to 30% of patients with NSCLC are diagnosed at stage III, described as a heterogeneous disease with either locally advanced tumour spread and/or mediastinal lymph node involvement, without clinical evidence of distant spread (9–12). Long-term survival is generally poor in stage III disease, with a 5-year median overall survival (mOS) of 36%, 26% and 13% for stage IIIA, IIIB and IIIC, respectively (13). In Vietnam, more than 80% of cases of lung cancer were NSCLC and the majority of cases (about 89%) were found in the advanced stages (IIIB or IV) (14). A study from 2014 estimated the economic burden of NSCLC in Vietnam to be >3,517 billion Vietnamese Dong, equivalent to $150 million (15). In Asia, epidermal growth factor receptor (EGFR) mutation rates in patients with NSCLC are high with approximately 47.0% in Eastern and South-Eastern Asia. Vietnam has the highest rate of EGFR mutations at 64.0% (8).

Due to heterogeneity, optimum management of stage III NSCLC remains a challenge. Surgical resection, though the preferred treatment, might not be plausible in all patients with stage III disease (16). Hence, a multi-modal management approach involving surgery, radiation and systemic agents is frequently practised. Concurrent platinum-based chemotherapy (CT) and radiotherapy (RT) are the standard of care for unresectable stage III disease with mOS ranging from 15 to 29 months (12, 17–24). Recent studies have combined immune therapy with concurrent CT and RT (cCRT), resulting in the emergence of new multi-modal combination approaches for stage III NSCLC (25, 26). Durvalumab consolidation therapy for patients with unresectable/inoperable stage III NSCLC who have not progressed on ≥2 cycles of cCRT is the new standard of care (12).

Given the significant burden of NSCLC leading to increased economic impact in Vietnam, cost-effective strategies and wide coverage are needed to manage NSCLC cases (15). A systematic and evidence-based approach to cancer care, particularly lung cancer, is a priority for Vietnam’s healthcare system (5). The data about prevalent treatment patterns and their associated survival outcomes for stage III NSCLC in the Vietnamese population is limited (27).

Vietnam was a part of the real-world evidence study KINDLE, conducted at 100 centres from 19 countries across Asia, Africa, the Middle East and Latin America (28). The primary objective of the global KINDLE study was to determine the treatment patterns and clinical outcomes of patients with stage III NSCLC, as specified by the American Joint Committee on Cancer (AJCC) criteria (7^th edition) in the pre-immuno-oncology era. Here we present data for stage III NSCLC in the Vietnamese population to determine the treatment patterns and clinical outcomes in patients.

To our knowledge, this is the first real-world study reporting the treatment patterns and their associated clinical outcomes in a group of Vietnamese patients with stage III NSCLC. This research offers an overview of treatment and survival trends of unresectable/inoperable stage III NSCLC. MDT discussion in lung cancer is known to be associated with better treatment decisions, which potentially improves outcomes and quality of life for patients with lung cancer (29, 30). In our study, a majority (97.3%) of the cases were not discussed at MDT meetings. Although both the participating centres are multi-speciality cancer care (including medical oncologists, radiologists, pathologists and thoracic surgeons), MDT management of lung cancer was not established as part of routine clinical practice in Vietnam during the period of this study.

A recent study assessing real-world clinical outcomes in Medicare patients reported a higher (61.0%) proportion of patients being treated with CRT in stage IIIA and 39.0% in stage IIIB (22, 31). With almost 14 treatment modalities being used as initial therapy, our study observed a wide difference in the treatment trends. More than half of the patients (61.7%) underwent palliative therapy as initial treatment. The American Society of Clinical Oncology guidelines recommend early palliative care to improve symptoms, quality of life and increase survival. Palliative care for NSCLC is categorised into 2 major groups, namely, supportive care and tumour-directed treatment (includes palliative CT and RT) (32). As initial therapy, CT alone was the dominant therapy (43.3%), showing that patients had limited access to RT, given to only 17.0% of the patients. In 2017, intensity-modulated radiation therapy was sparingly used and only 36 linear machines were available in Vietnam for external radiation therapy with 3D-conformal radiation therapy techniques in the country resulting in a low rate of RT and CRT (33). As second- or third-line therapies upon relapse, palliative therapy was the most preferred option in Vietnamese patients and rather the only option administered in the third-line therapy in stage IIIA NSCLC, whereas in KINDLE-global, CT alone was the most favoured second- or third-line therapy after recurrence, followed by RT alone in >20% of patients (28).

Our Vietnam data reports statistically significant longer mPFS (11.9 versus 7.8 months; HR 0.53 [95% CI, 0.36 to 0.78]; p = 0.001) and mOS (28.2 versus 20.0 months; HR 0.53 [95% CI, 0.31 to 0.90]; p = 0.016) in stage IIIA as compared with stage IIIB disease. Similar results were also observed in the KINDLE-global cohort, where longer mPFS (14.3 versus 10.2 months; HR 0.86 [95% CI, 0.77 to 0.96]; p < 0.01) and mOS (43.8 versus 27.7 months; HR 0.78 [95% CI, 0.68 to 0.90]; p = 0.0005) were observed in stage IIIA than stage IIIB [28]. In a Vietnamese study, 51 patients with advanced NSCLC underwent first-line combination CT with pemetrexed and cisplatin followed by pemetrexed maintenance; mPFS and mOS were reported to be 7.8 months and 16.1 months, respectively (34). In our study, CRT-based therapy prolonged mPFS (13.7 and 8.6 months) and mOS (28.1 and 23.1 months) irrespective of stage IIIA or IIIB. Similar results were seen in a retrospective Korean study where unresectable stage III patients treated with CRT had better mOS (30.3 months) (95% CI, 26.6 to 34.0) compared with palliative therapy (14.7 months) (95% CI, 13.0 to 16.4) (35).

Real-world data about the adherence to guideline-directed therapies and patient outcomes especially from low-and-middle-income countries are limited. Several randomised clinical studies have also shown a beneficial effect of cCRT compared with sCRT or RT alone in unresectable patients (20–22). In a retrospective study from Vietnam, 5,220 patients with stage III lung cancer were analysed over 3 years of which 70 stage III lung cancer patients having valid survival information were identified (11.7%). The 3-year survival probability of patients with surgery and/or CRT was 34.3% (16.2% to 72.4%), which was higher (10.6%) than CT or RT alone (4.9% to 23.2%; p = 0.055) (15). Another study showed a survival benefit with cCRT having better survival benefits than systemic therapy (14.7 versus 10.9 months) and RT (7.8 months) (36). The preliminary findings of PERTAIN study suggest that implementation of fluorodeoxyglucose-positron emission tomography/CT-guided cCRT results in a substantial improvement in mPFS and mOS for patients with stage III NSCLC in low-and-middle-income countries (37). As a multi-modal treatment, cCRT remains the standard of care for stage III NSCLC with proven benefits over single treatment approaches (38). However, in our study, the use of the cCRT regimen was quite low (12.7%) as initial therapy in comparison to CT alone (43.3%). The most probable reason for this practice was that the MDT meeting approach was employed for discussing <5% of the cases. The MDT (lung cancer tumour boards) requires close collaboration between medical oncologists, radiologists and thoracic surgeons to make an informed decision based on the resectability of the tumour on considering cCRT as an initial treatment modality. Improving the capacity of the radiation approach for stage III NSCLC patients is an important solution for Vietnam. Though the role of MDT is to identify eligible patients who can tolerate cCRT over other approaches, the survival gain of aggressive cCRT may be negated by its severe toxicities (39).

In univariate analysis, adenocarcinoma was a significant positive predictive factor for mOS in both stage IIIA and IIIB disease. The mOS was found to be better in patients with adenocarcinoma (p < 0.046) than in patients with other carcinomas. The female gender was associated with a significantly lower risk of death in both stage IIIA and IIIB. Several studies have shown the female gender as a good prognostic factor (40, 41). However, in one of the studies, no significant difference was found between genders in terms of survival (3-year survival, 29% versus 24%). This was attributed to a smaller proportion of patients being females and which may have influenced the statistical power (42). Adenocarcinoma has a higher association with smoking in females. The DNA adduct levels are higher among females with adenocarcinoma than their male counterparts after adjustment for smoking dose, and thus females are at higher risk as they are exposed to higher levels of tobacco carcinogens than males (43). Only a small number of patients were available with EGFR test results (n = 25) and the prevalence was found to be 20% (n = 5). Adenocarcinoma is the most frequently encountered histological type of NSCLC, accounting for about half of the cases of NSCLC (44, 45). Adenocarcinoma is also reported to have a better prognosis as compared with other histology subtypes of NSCLC.

With a 1-year survival rate of 42% and a 5-year survival rate of 16%, the survival rate of patients with lung cancer remains low in Vietnam (6). The poor prognosis reflects existing treatment gaps in the management of lung cancer in Vietnam. This KINDLE-Vietnam data provides a benchmark for understanding the treatment patterns, which will be important for evaluating the effectiveness of newer therapies in this population as they become part of clinical practice guidelines. This evidence will also support patient access in Vietnam as a majority (almost 80%) of cancer care (examination and treatment) is covered by health insurance (46).

The limitations of our study include the small sample size and the known challenges of a retrospective study design in real-world settings. Additionally, data collection was limited to the availability of existing health records, resulting in missing data, as many patients could have been lost to routine clinical follow-up. In the initial therapy setting, the study duration covers the era before immunotherapy approval. Thus, the data on the effectiveness of targeted and immunotherapy agents have not been captured in the study.

KINDLE-Vietnam study describes the treatment patterns in stage III NSCLC and offers real-world insights into the therapy landscape in the Vietnamese population. Although the study notes adherence to the treatment protocols for CRT-based therapy as the initial therapy in most patients with unresectable disease, there is a definite gap in the optimal selection and sequencing of different treatment approaches. The findings also highlight the need for newer treatment options like immunotherapy in patients with unresectable disease post CRT. Concurrent CRT has been shown to produce better outcomes than sequential CRT. In addition, the PACIFIC trial established CRT followed by 1 year of durvalumab as the standard of care in patients with unresectable stage III NSCLC. Nevertheless, there remains to be a high unmet need for identifying patients in the early stages of NSCLC. Strategies for improving patient outcomes, including guideline adoption, physician education and multidisciplinary management, and catering to increased access to novel agents like immunotherapy and targeted therapy are needed. The data obtained from this study will also contribute to a consolidated framework to help understand the unmet clinical needs in Vietnam in line with their current focus of strengthening the National Cancer Control Programme initiative, in addition to providing baseline data to determine the potential effect of new therapies on the treatment of stage III NSCLC in this region.

KINDLE Global Data Poster Presented at ASCO: Jazieh AR, et al. Contemporary Management and Associated Outcomes of 3,151 Patients With Stage III Non-small Cell Lung Cancer (NSCLC) in a Real-world Setting: Results of KINDLE, a Multicountry Observational Study. J Clin Oncol (2020) 38:15_suppl, 9043-9043. KINDLE Global Data Manuscript Published: Jazieh AR, et al. Real-World Treatment Patterns and Clinical Outcomes in Patients With Stage III NSCLC: Results of KINDLE, a Multicountry Observational Study. J Thorac Oncol (2021) 16(10):1733-1744. DOI:10.1016/j.jtho.2021.05.003.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the Ethic Committee in Biomedical Research - National Cancer Hospital, the Ethic Committee in Biomedical Research - HCM Oncology Hospital, and the National Ethic Committee in Biomedical research - Vietnam Ministry of Health. The patients/participants provided their written informed consent to participate in this study.

TVD, TBD: Conceptualization, Methodology, Writing, Investigation, Editing. TP: Conceptualization, Writing, Methodology, Visualization, Editing. RH, AK: Conceptualization, Methodology, Editing. All authors contributed to the article and approved the submitted version.

Authors RH, AK and TP are employed by the company AstraZeneca.

The authors declare that the KINDLE study and this manuscript writing were funded by AstraZeneca. The funder had the following involvement with the study: study design, analysis, interpretation of data, and the writing of this article.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.