Surgical treatment of IIIb (N2), ROS1(+) non-small cell lung cancer after neoadjuvant chemotherapy combined with targeted therapy: a case report

Introduction

Non-small cell lung cancer (NSCLC) accounts for 80–85% of all lung cancer cases (1). According to the 2022 Global Cancer Report, there were 2.5 million new cases of lung cancer and 1.8 million lung cancer-related deaths worldwide. Lung cancer accounts for 12.4% and 18.7% of the total cancer incidence and deaths, respectively (2). The ROS1 fusion, has been indicated to be a valuable therapeutic target in patients with NSCLC. Importantly, ROS1 tyrosine kinase inhibitors (TKIs) have been reported to be highly efficacious in patients with NSCLC harbouring ROS1 fusion that activate the kinase domain of the ROS1 protein (3).

Crizotinib is an anaplastic lymphoma kinase (ALK)/MET/ROS1 inhibitor, and it was the first targeted drug approved by the US Food and Drug Administration (FDA) for the treatment of advanced ROS1 positive NSCLC in 2016. Since then, crizotinib has become one of the standard treatments for patients with ROS1-positive NSCLC. The EUCROSS study and several other studies have demonstrated the efficacy of crizotinib in patients with ROS1 positive NSCLC, including an objective response rate (ORR) of up to 70% and a median progression-free survival (PFS) of 19.4 months, the median overall survival (OS) of the intention-to-treat population (N=34) was 54.8 months (4). We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-151/rc).

Case presentation

A 49-year-old male who never smoked and had no family history of tumours or other risk factors visited a clinic complaining of an enlarged nodule in his right middle lung. The patient underwent a computed tomography (CT) scan in 2020, which revealed a nodule in the right middle pulmonary lobe predominantly composed of ground glass opacities (Figure 1). This finding was overlooked by the patient. A year later, a follow-up CT scan demonstrated that the nodule had increased in size and acquired a more solid appearance (Figure 2); however, owing to his hectic work schedule, the patient failed to seek further medical intervention. One month prior, another examination revealed that the nodule had continued to enlarge, with an increase in both size and solid components, and the emergence of a new nodule in the middle lobe of the right lung (Figure 3), raising suspicions of metastatic malignancy. Blood tests revealed a carcinoembryonic antigen (CEA) level of 43 ng/mL. Physical examination showed no abnormality.

Figure 1 Primary lesion in the middle lobe of the right lung (red arrow) at 2020.

Figure 2 Primary lesion in the middle lobe of the right lung (red arrow) at 2021.

Figure 3 Primary and new lesions in the lung. (A) Primary lesion in the middle lobe of the right lung (red arrow) at 2022, significantly larger than before. (B) A new lesion was found in the middle lobe of the right lung, and metastasis was considered (yellow arrow).

After admission, positron emission tomography/computed tomography (PET-CT) revealed two solid nodules in the middle lobe of the right lung, with SUVmax values of 10.13 and 9.20, both of which indicated lung cancer, and the pleura might have been invaded; several enlarged lymph nodes in the right hilar, mediastinal 2R, 4R, and 7 areas had a SUVmax value of 8.72, and the right hilar and mediastinal lymph nodes were considered to show metastasis (Figure 4). After admission, a CT-guided biopsy of the lesion was performed. Pathology revealed lung adenocarcinoma, cT3N2M0 stage IIIB, gene sequencing ROS1(+), and a programmed death ligand 1 (PD-L1) value of 70%(+). PS =0 points, then neoadjuvant therapy was given. The protocol consisted of pemetrexed combined with platinum and was repeated every three weeks. Studies have shown that neoadjuvant targeted therapy is better tolerated than chemotherapy, has a higher response rate, and fewer severe complications (5-8). Considering that the tumour was ROS1(+), whether ROS1 positive patients have the same benefit is unknown, and the patient was willing to try this combination of targeted chemotherapy after being fully informed of the associated risks and possible benefits. Afterwards, he was treated with 250 mg crizotinib orally twice a day beginning on May 26^th, 2022. He experienced grade 2 hepatic damage during neoadjuvant treatment. After 2 cycles of treatment, the chest contrast-enhanced CT image revealed that the tumour had shrunk significantly and that the mediastinal lymph nodes were not obvious (Figure 5). The CEA concentration decreased to 1.25 ng/mL. Efficacy was evaluated by partial response (PR). Subsequently, one more cycle of chemotherapy with the same regimen was performed. After three cycles of treatment, multiple disciplinary team (MDT) was performed. The tumour responded well to treatment, the patient was young and could tolerate surgery, and surgical treatment could be attempted. Then, video-assisted thoracic surgery (VATS) was performed. During the operation, obvious hyperplasia of the scars was observed in the hilus and mediastinum. After attempts, only the vein of the middle lobe of the right lung could be completely freed and severed. However, the trachea and pulmonary artery were not separated because of the dense scar tissue. No further lymph node dissection was performed after lobectomy. Pathology revealed that a few atypical irregular glands were present in one lesion in the lung. and the postoperative pathological results indicated that the primary lesion had a major pathological response (MPR) and the intrapulmonary metastases had a pathological complete response (pCR). After surgery, one more adjuvant chemotherapy treatment was given. Crizotinib has been given as targeted therapy for 29 months. The tolerability of this patient is well during treatment. No tumour recurrence has been observed thus far.

Figure 4 Hilar and mediastinal metastatic lymph nodes (green arrows) at 2022.

Figure 5 Changes of lesions and lymph nodes after treatment. (A) Primary focal shrinkage after neoadjuvant therapy (red arrow). (B) The metastases shrank after neoadjuvant therapy (yellow arrow). (C) Enlarged mediastinal lymph nodes were reduced after treatment (green arrow).

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. This study was approved by the Ethics Committee of Ningbo No. 2 Hospital (approval number: SL-NBEY-KY-2024-146-01). Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

Discussion

Lung cancer continues to be the leading cause of cancer mortality and a serious health problem despite the numerous advances made in the last decade and the rapid advance of research in this field (9). With the popularization of spiral CT in more primary hospitals, more asymptomatic lung cancers can be diagnosed and treated at early stages. However, in clinical practice, patients with locally or even advanced lung cancer are often observed. Although new targets and immune checkpoints are constantly being discovered, corresponding targeted drugs or immune checkpoint inhibitors are constantly being developed. However, for patients with stage III cancer, the long-term survival data are still lacking. Therefore, we are working hard to provide these patients with better treatment options.

Targeted therapy is an effective and safe treatment option for lung cancer patients with sensitive driver gene mutations, and it results in longer survival times and higher quality of life for patients with advanced lung cancer (10). At present, the most common gene mutation types in patients with NSCLC are EGFR, ALK, and ROS1. Currently, targeted drugs are used mainly for inoperable locally advanced disease, later disease stages or postoperative adjuvant therapy. Although studies have shown that targeted neoadjuvant therapy has good efficacy and safety in locally advanced lung cancer (8,11). There is still a lack of high-quality clinical trial data for conversion therapy or preoperative neoadjuvant therapy, and reliable evidence supporting the effectiveness of treatment is lacking. The limitation of this case is that systematic lymph node dissection was not performed during the operation. As a result, the postoperative pathological stage was not clear, and there is currently no basis for when to stop the targeted drug. ROS1 is a proto-oncogene, and ROS1 gene fusion mediates sustained kinase activation and downstream signal transmission, leading to tumour occurrence and growth. The incidence of ROS1 fusion in patients with NSCLC is 1–2% (12,13). Patients with NSCLC with ROS1 fusions tend to have clinical characteristics (younger, female, never smokers) similar to those of patients with ALK fusions (13). Unlike patients with EGFR mutations, patients with ROS1 mutations seem to have longer OS (14). Previous studies have shown that for inoperable patients with ROS1 mutations, in the phase I PROFILE 1001 study, the median PFS (mPFS) of patients with ROS1-rearranged NSCLC who received crizotinib was 19.3 months (15). The OO-1201 study revealed that among 127 East Asian patients with ROS1-positive advanced NSCLC who had received third-line or above systemic therapy, the ORR was 71.7%, and the mPFS reached 15.9 months (16).

Another study revealed that the mPFS of ROS1-positive advanced patients receiving first-line treatment with crizotinib was as long as 23 months; of these patients, 5 had an mPFS of more than 50 months, and the mOS reached 5 years (17). In inoperable patients, crizotinib has shown high disease control rates, but data on neoadjuvant therapy are lacking. This patient was diagnosed at a locally advanced stage. After preoperative chemotherapy and targeted therapy, postoperative pathological results indicated that the primary lesion had a MPR and the intrapulmonary metastases pCR. No progression of the disease was found during follow-up. In this case, due to obvious hyperplasia of hilar and mediastinal scars and incomplete development of pulmonary fissure, further lymph node sampling was difficult, which also made the postoperative pathological staging not realized. PET-CT should assist in postoperative judgment and guide the selection of postoperative adjuvant therapy in a timely manner. In our experience, preoperative neoadjuvant therapy (chemotherapy, immunotherapy, targeted therapy, etc.) does pose a challenge to the surgical process for some patients and may increase the risk of conversion. However, there is no conclusive evidence in the published literature that such treatment before surgery increases the risk of perioperative death (18). Patients with clinical stage III lung cancer have strong tumour heterogeneity and poor prognoses. Individualized treatment plans should be formulated according to the different conditions of the patients. Previous studies have suggested that for newly diagnosed lung cancer patients whose tumours are unresectable and accompanied by driver gene mutations, further local interventions [surgery, ablation, and stereotactic body radiation therapy (SBRT)] can improve survival after patients receive targeted therapy (19-21). However, these were also retrospective studies, so this patient underwent chemotherapy combined with targeted therapy and surgical resection of the lesion. postoperative pathological results showed MPR. Another case shows that a patient with ROS1 fusions at the same stage was treated with crizotinib targeted therapy alone for 10 months before surgery, the postoperative pathological results showed that 40% of the tumor cells were still alive and were surrounded by prominent fibrosis, necrosis (22). Another report showed that a stage IIIa non-small cell lung cancer, also ROS1 positive, preoperative crizotinib combined with platinum-containing double-drug chemotherapy, postoperative pathology showed pCR, the process of surgery also found significant hilar fibrosis (5).

Conclusions

In this case, targeted therapy combined with chemotherapy as the neoadjuvant treatment of choice for lung adenocarcinoma with sensitive gene mutations is safe and has proven to be effective, but this mode of treatment may also make follow-up surgery more difficult. The duration of postoperative treatment is also a matter of concern.

Acknowledgments

We thank our team for their cooperation on this report, which we hope will bring hope to those in need. We are also grateful for the patient’s trust and his families’ support.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-151/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-151/prf

Funding: This study was supported by the Ningbo Top Medical and Health Research Program (No. 2022030208).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-151/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. This study was approved by the Ethics Committee of Ningbo No. 2 Hospital (approval number: SL-NBEY-KY-2024-146-01). Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Raskova Kafkova L, Mierzwicka JM, Chakraborty P, et al. NSCLC: from tumorigenesis, immune checkpoint misuse to current and future targeted therapy. Front Immunol 2024;15:1342086. [Crossref] [PubMed]
2. Chen P, Liu Y, Wen Y, et al. Non-small cell lung cancer in China. Cancer Commun (Lond) 2022;42:937-70. [Crossref] [PubMed]
3. Lin JJ, Shaw AT. Recent Advances in Targeting ROS1 in Lung Cancer. J Thorac Oncol 2017;12:1611-25. [Crossref] [PubMed]
4. Michels S, Massutí B, Vasyliv I, et al. Overall survival and central nervous system activity of crizotinib in ROS1-rearranged lung cancer-final results of the EUCROSS trial. ESMO Open 2024;9:102237. [Crossref] [PubMed]
5. Chen R, Wang G, Zhao J, et al. Efficacy of Neoadjuvant Therapy for ROS1-Positive Locally-Advanced Lung Adenocarcinoma: A Case Report. Am J Case Rep 2024;25:e945446. [PubMed]
6. Xiong L, Li R, Sun J, et al. Erlotinib as Neoadjuvant Therapy in Stage IIIA (N2) EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Prospective, Single-Arm, Phase II Study. Oncologist 2019;24:157-e64. [Crossref] [PubMed]
7. Zhang C, Li SL, Nie Q, et al. Neoadjuvant Crizotinib in Resectable Locally Advanced Non-Small Cell Lung Cancer with ALK Rearrangement. J Thorac Oncol 2019;14:726-31. [Crossref] [PubMed]
8. Zhong WZ, Chen KN, Chen C, et al. Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment of Stage IIIA-N2 EGFR-Mutant Non-Small-Cell Lung Cancer (EMERGING-CTONG 1103): A Randomized Phase II Study. J Clin Oncol 2019;37:2235-45. [Crossref] [PubMed]
9. Mielgo-Rubio X, Martín M, Remon J, et al. Targeted therapy moves to earlier stages of non-small-cell lung cancer: emerging evidence, controversies and future challenges. Future Oncol 2021;17:4011-25. [Crossref] [PubMed]
10. Molina JR, Yang P, Cassivi SD, et al. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008;83:584-94. [Crossref] [PubMed]
11. Sun L, Guo YJ, Song J, et al. Neoadjuvant EGFR-TKI Therapy for EGFR-Mutant NSCLC: A Systematic Review and Pooled Analysis of Five Prospective Clinical Trials. Front Oncol 2021;10:586596. [Crossref] [PubMed]
12. Gainor JF, Shaw AT. Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist 2013;18:865-75. [Crossref] [PubMed]
13. Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012;30:863-70. [Crossref] [PubMed]
14. Scheffler M, Schultheis A, Teixido C, et al. ROS1 rearrangements in lung adenocarcinoma: prognostic impact, therapeutic options and genetic variability. Oncotarget 2015;6:10577-85. [Crossref] [PubMed]
15. Shaw AT, Riely GJ, Bang YJ, et al. Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001. Ann Oncol 2019;30:1121-6. [Crossref] [PubMed]
16. Wu YL, Yang JC, Kim DW, et al. Phase II Study of Crizotinib in East Asian Patients With ROS1-Positive Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 2018;36:1405-11. [Crossref] [PubMed]
17. Hoang T, Myung SK, Pham TT, et al. Comparative Efficacy of Targeted Therapies in Patients with Non-Small Cell Lung Cancer: A Network Meta-Analysis of Clinical Trials. J Clin Med 2020;9:1063. [Crossref] [PubMed]
18. Allaeys T, Berzenji L, Van Schil PE. Surgery after Induction Targeted Therapy and Immunotherapy for Lung Cancer. Cancers (Basel) 2021;13:2603. [Crossref] [PubMed]
19. Wang X, Zeng Z, Cai J, et al. Efficacy and acquired resistance for EGFR-TKI plus thoracic SBRT in patients with advanced EGFR-mutant non-small-cell lung cancer: a propensity-matched retrospective study. BMC Cancer 2021;21:482. [Crossref] [PubMed]
20. Kim F, Borgeaud M, Addeo A, et al. Management of stage III non-small-cell lung cancer: rays of hope. Explor Target Antitumor Ther 2024;5:85-95. [Crossref] [PubMed]
21. Chan OSH, Lam KC, Li JYC, et al. ATOM: A phase II study to assess efficacy of preemptive local ablative therapy to residual oligometastases of NSCLC after EGFR TKI. Lung Cancer 2020;142:41-6. [Crossref] [PubMed]
22. Zhao S, Zhu S, Lei X, et al. Use of crizotinib as neoadjuvant therapy for non-small cell lung cancers patient with ROS1 rearrangement: A case report. Thorac Cancer 2021;12:2815-8. [Crossref] [PubMed]