Primary lung cancer (lung cancer) is the malignant tumor that poses the greatest threat to human health and life, and ranks first among malignant tumor deaths in China. Currently, surgery is still the preferred treatment method for early-stage lung cancer, and the 5-year survival rate of patients can reach over 70% after surgery, but the 5-year survival rate of surgical treatment for localized mid- to late-stage lung cancer is only about 20%. Therefore, “early detection, early diagnosis and early treatment” is still the most effective measure to improve the cure rate and reduce the mortality rate of lung cancer. In recent years, with the advancement of medical imaging technology, endoscopic technology and minimally invasive surgical technology, the diagnosis and treatment strategy of lung cancer, especially early stage lung cancer, has undergone profound changes.
I. Early lung cancer diagnosis
A number of clinical studies using sputum cytology and X-ray chest radiographs to screen for early-stage lung cancer were conducted in the 1970s. The results showed that although more lung cancer patients were detected and more surgical treatments were performed, the overall mortality rate of lung cancer patients was not significantly reduced. In recent years, with the development of medical imaging technology, especially spiral CT scanning, more small volume peripheral type lung nodules can be detected. Countries such as the United States, Japan and Europe have begun to use low-dose CT (LDCT) for early lung cancer screening studies.
In 2006, the New England Journal of Medicine reported the results of the I-ELCAP study, which found that the positive rate of LDCT for detecting small lung nodules was significantly higher than that of conventional X-ray chest radiographs, and that more than 80% of screened lung cancer patients had stage I lung cancer, with a 10-year survival rate of more than 90% of patients after surgical resection. The authors concluded that participation in LDCT screening reduced the risk of death from lung cancer and hypothesized that LDCT screening could reduce lung cancer mortality by 80%.
The NLST study is the first large prospective study comparing LDCT and X-ray chest radiographs for lung cancer screening. Since its inception in 2002, the NLST study has enrolled 53,000 heavy smokers. 1060 lung cancer patients [645 per 100,000 (person/year)] were diagnosed in the LDCT group and 941 lung cancer patients [572 per 100,000 (person/year)] were diagnosed in the X-ray chest radiograph group.
Lung cancer-specific mortality analysis showed 247 deaths/100,000 (person/year) in the low-dose CT group and 309 deaths/100,000 (person/year) in the X-ray chest radiograph group.LDCT screening resulted in a relative reduction in lung cancer mortality by 20% and a significant reduction in all-cause mortality by 6.7%.
II. Preoperative staging of early lung cancer
1. T-staging CT can accurately assess the size of the primary lung tumor and its invasion of the chest wall, diaphragm, mediastinum and other important organs, and conventional fiberoptic bronchoscopy can visually observe the specific location of the tumor and the distance from the ramus and main bronchi. For some patients whose primary tumors are close to the periphery of the lung, conventional fiberoptic bronchoscopy cannot obtain positive results, and their locations are not suitable for percutaneous lung puncture biopsy, the advent of electromagnetic navigation bronchoscopy (ENB) has made this difficult problem easy.
2. Regional lymph node N-staging For lung cancer without distant metastasis, the presence or absence of mediastinal lymph node metastasis is a key factor in deciding the treatment modality.
(1) Non-invasive lymph node staging methods for lung cancer include chest CT and PET-CT. the sensitivity and specificity of chest enhanced CT for determining mediastinal lymph node metastasis are 51% (95% CI: 47%-54%) and 86% (95% CI: 84%-88%), respectively. Although its accuracy is not high, it is the best clinical study method for non-invasive mediastinal anatomy, which allows further invasive examination of suspected mediastinal lymph nodes and improves accurate anatomical localization and pathological diagnosis.PET-CT technology had high expectations when it first appeared, but its aura has gradually faded after more than 10 years of clinical application.44 well-documented clinical studies from 1994 to 2006 found that The sensitivity and specificity of PET-CT in evaluating N-stage of lung cancer were 74% (95% CI: 69%-79%) and 85% (95% CI: 82%-88%), respectively.
(2) Invasive staging methods for lymph nodes of lung cancer. Mediastinoscopy is currently the gold standard for N-staging of mediastinal lymph nodes in lung cancer. With the maturation and popularization of new technologies such as transbronchial needle aspiration biopsy (TBNA), ultrasound endoscopy-guided fine-needle aspiration biopsy (EUS-FNA) and EBUS-TBNA, the means of mediastinal lymph node staging for lung cancer have begun to diversify.
The mediastinal lymph nodes that can be biopsied by EBUS-TBNA include groups l, 2, 4, and 7, but the para-aortic and inferior mediastinal lymph nodes (groups 5, 6, 8, and 9) are more difficult to reach. Because the outside diameter of the ultrasound endoscopic probe is only 6.9 mm, it is possible to reach deeper into the main bronchi and even into the lobar bronchi to explore groups 10 and 11 and some of the group 12 lymph nodes.
EBUS-TBNA was first used in clinical practice in 2004 and has since rapidly spread to major medical centers. Literature reports and clinical studies have shown that EBUS-TBNA has a high sensitivity (89% to 99%) and 100% specificity in staging mediastinal lymph nodes in lung cancer. At the same time, the safety of this technique is fully guaranteed by the use of a special puncture needle, as the puncture biopsy is performed under real-time ultrasound image surveillance. To date, no relevant serious complications have been reported in the literature.
With the increased clinical application of EBUS-TBNA, the use of mediastinoscopy in lung cancer staging has gradually decreased. In 2007, clinical practice guidelines for lung cancer such as the National Comprehensive Cancer Network (NCCN) and the American College of Chest Physicians (ACCP) recommended EBUS as one of the standard methods for determining mediastinal lymph node staging in lung cancer. However, EBUS is not yet a complete substitute for mediastinoscopy, and patients with negative EBUS-TBNA results sometimes need to undergo further surgical examinations such as mediastinoscopy for confirmation, in order to minimize unnecessary open-heart surgery.
In a group of non-small cell lung cancer (NSCLC) with 42% mediastinal lymph node metastasis, the sensitivity and false-negative rate of the combination of EUS-FNA and EBUS-TBNA were 97% and 2%, respectively.
Early lung cancer surgical treatment
In the early 1990s, Kirby et al. first reported TV-assisted thoracoscopic surgery (VATS), after which the technique gradually became popular worldwide. early on, some thoracic surgeons could not accept VATS lobectomy for lung cancer, mainly worrying about two aspects: whether it complied with the principles of surgical oncology and whether it had sufficient safety. 2006 McKenna et al. reported the clinical results of 1100 VATS Lobectomy cases. 84.7% of patients had no postoperative complications, 2.5% of patients had intermediate open chest, 4.1% of patients required blood transfusion, the median hospital stay was 3 days, and the incisional recurrence rate was 0.57%. This result showed a better surgical safety.
It is now believed that peripheral NSCLC in clinical stage I is the best indication for VATS, and the safety and efficacy of its surgery are not significantly different compared with traditional open-heart surgery, and the postoperative complication rate is significantly lower than that of traditional open-heart surgery. The results of a multi-center clinical study led by the Lung Cancer Center of Capital Medical University in China and the United States on adjuvant chemotherapy after lung cancer surgery showed that the number of days of hospitalization after VATS was shorter than that of traditional open-heart surgery, and the time to start adjuvant chemotherapy was significantly earlier than that of traditional open-heart surgery.
VATS has been widely carried out in major medical centers in China, and the unique thoracoscopic lobectomy surgical approaches have been developed according to the specific conditions of thoracoscopic instruments and equipment in each region, the experience of the operator in technical training and the proficiency of mastering the technique, as well as the affordability of patients in different regions, such as “one-way” The “one-way” surgery, “single-operating hole” surgery, “Wang’s technique” and so on. With continuous technical proficiency, experienced thoracic surgeons have been able to perform more complex lung cancer surgeries with VATS lobectomy, such as bronchial sleeve lobectomy, pulmonary artery and other large vessel resection and reconstruction, etc. Scholars in China have begun to try to expand the indications for VATS to clinical stage II and III lung cancer.
2. Sublobar resection The classic study of the North American Lung Cancer Study Group found that sublobar resection (including segmental lung resection and wedge resection) did not reduce the incidence of perioperative complications and mortality, while the postoperative local recurrence rate was significantly higher than that of lobectomy, establishing the status of lobectomy in the surgical treatment of early-stage lung cancer with a diameter of <3 cm.
With the advent of multi-row spiral CT technology, lung cancer has the opportunity to be clinically detected at an earlier stage, and the clinical application of PET has made the diagnosis and staging of lung cancer more accurate than before. Some scholars selected some early peripheral type NSCLC with diameter <2 cm for lung segmental resection or wedge resection plus regional lymph node removal, and obtained the same clinical results as lobectomy. Japanese scholars reported that sublobar resection plus regional lymph node sampling for peripheral type lung cancer of <2 cm in diameter had a 5-year survival rate of 93%.
Compared to lung wedge resection, lung segmental resection obtained better local control and had more accurate pathological staging. There are still many uncertainties regarding lung segmental resection for lung cancer, mainly in the following aspects.
(1) Tumor size and location: Several studies have shown no significant difference in 5-year disease-free survival (DFS) between segmental lung resection and lobectomy in tumors ≤2 cm in diameter, 84.6% and 87.4%, respectively. In addition, to ensure adequate margins, the tumor should be selected to be located in the peripheral 1/3 of the lung and in the anatomical center of the lung segment to be resected, with margins of 15 mm or more on both sides. Otherwise, it is advisable to choose a lung segment resection or lobectomy that conforms to the lung segment.
(2) Special pathological type: ground glass shadow (GGO) is a special pathological type, and GGO detected by CT is more likely to be carcinoma in situ or early NSCLC, so this group of patients may benefit more from lung segment resection. It was found that patients with non-mucinous bronchoalveolar carcinoma (BAC) had up to 100% DFS with lung segmental resection.
(3) Lung segments suitable for anatomical segmental resection: At present, the commonly used lung segmental resections in clinical practice include left intrinsic upper lobe resection, lingual segmental resection, bilateral lower lobe dorsal segmental resection and basal segmental resection. Lung cancer located in the S1-S3 segments of the upper lobe has a local recurrence rate of 23%, so segmental lung resection is not recommended. It is important to emphasize that samples of hilar and segmental lymph nodes should be taken and rapid frozen pathological examination should be performed before performing segmental lung resection, and if the result is positive, lung resection should be changed to lobectomy, and if the result is negative, lung segmental resection should be continued.
Currently, the main evidence for lung segmental resection for early-stage lung cancer comes from retrospective studies, and there is a lack of results from large prospective multicenter randomized controlled clinical studies, therefore, it is controversial whether lung segmental resection can become the standard procedure for early-stage lung cancer. Four large-sample multicenter prospective randomized clinical trial programs [American College of Surgeons Oncology Collaborative Group (ACOSOG) Z4032, Cancer and Leukemia Group B (CALGB) 140503, and Japan Clinical Oncology Group (JCOG) 0804] are currently evaluating the efficacy of sublobar resection for early-stage lung cancer. The major lung cancer research project (D14110000214002) of the Municipal Science Committee undertaken by Xuanwu Hospital of Capital Medical University – Early Lung Cancer Resection Scope Clinical Study Program enrolled 630 cases of T≤2cm N0M0 NSCLC, assigned to lobectomy and sub lobectomy in a 2:1 ratio, and compared the two groups of patients differences in local recurrence rates, long-term survival and lung function between the two groups. These large sample clinical trials are expected to answer the controversy of sublobar resection for early-stage NSCLC.
IV. Non-surgical treatment of early-stage lung cancer
Although lung cancer surgical treatment has been minimally invasive, there are still some lung cancer patients who cannot or do not want to receive surgical treatment because of their physical condition or religious beliefs. The emergence of tumor radiofrequency ablation, argon helium knife and stereotactic radiotherapy technology has brought hope to cure lung cancer for these patients.
1. Image guided radiofrequency ablation (RFA) RFA has a primary complete remission rate of 38%-70% and a secondary complete remission rate of 19%-25% for lung cancer with a diameter of 0.3-8.0 cm and an average diameter of <5.0 cm, with an overall efficiency of more than 70%. Several large studies have reported recurrence rates of 35% to 50% after RFA treatment. In contrast, a single-center prospective study reported a local control rate of 93% at 1.5 years after RFA treatment in lung cancer patients. As long as the lesions do not invade important organs such as the hilum and trachea, most of them can completely inactivate the tumor tissue after multiple treatments.
Most of the current studies are retrospective studies of a small number of cases reporting 1-year survival rates of 63% to 85%, 2-year survival rates of 55% to 65%, and 3-year survival rates of 15% to 46% for stage I NSCLC. In a multicenter prospective clinical study, percutaneous RFA was performed on a total of 183 tumors in 106 lung cancer patients, of which 33 were NSCLC patients who were not suitable for surgical resection. 99% of the patients were able to complete the operation successfully without treatment-related deaths. 1-year and 2-year survival rates after RFA for NSCLC patients were 92% and 73%, respectively, with stage I NSCLC patients had a 2-year survival rate of 92%.
Ambrogi et al. recently reported the long-term follow-up results of RFA for stage I lung cancer. RFA combined with radiotherapy and chemotherapy significantly prolonged the survival of patients, effectively reduced the local recurrence rate of lung cancer and improved the functional status of patients. In a study comparing radiotherapy alone with radiotherapy combined with RFA in 24 patients with inoperable stage I NSCLC, the cumulative survival rates at 2 and 5 years were 50% and 39%, respectively. The investigators concluded that the two have complementary effects and can improve the treatment effect.
2. Stereotactic body radiation therapy (SBRT) SBRT is an improvement of cranial stereotactic radiosurgery technique, and the single dose can be as high as 10-20 Gy, which is much higher than the 2-3 Gy of conventional radiotherapy. 6 years, exciting preliminary results have been achieved. In 14 studies using SBRT equivalent biological doses of more than 100 Gy, patients had local tumor control rates of 74% to 100% and survival rates of 42% to 91%. While patients tolerated SBRT well, complications were mild, and treatment-related death occurred in only 1 of nearly 30 recent clinical studies.
Because of the excellent results of SBRT for early-stage NSCLC, some scholars have asked whether SBRT could replace surgery as the standard treatment for early-stage NSCLC. However, large prospective randomized subgroup studies are needed to determine this due to concerns about the late adverse effects of radiation therapy. The International Association for the Study of Lung Cancer (IASLC) initiated an international multicenter phase III clinical study in 2007 in which patients with stage I NSCLC were randomized to receive either radical surgery or SBRT, and the study will compare the treatment outcomes, complications, and quality of survival between the two, and the results have the potential to lead to a major paradigm shift in the treatment of early-stage NSCLC.
It should be noted that although RFA and SBRT have achieved similar local control rates to surgery for early peripheral lung cancer, there is no evidence to support the use of such non-surgical local control techniques as an appropriate choice of treatment for operable early peripheral lung cancer. Previous studies have shown that even for peripheral lung cancer <2 cm in diameter with a clinical diagnosis of T1N0M0, tumor resection plus lymph node dissection reveals lymph node metastases in up to 40% of patients, 50% of which are mediastinal lymph node metastases, and performing RFA or SBRT alone will undoubtedly deprive this group of patients of radical treatment.
In conclusion, with the development of screening methods and examination techniques, “early detection, early diagnosis and early treatment” of lung cancer is possible, and new technologies such as ENB, EBUS-TBNA, minimally invasive thoracic surgery and RFA have provided new means for the diagnosis and treatment of early lung cancer. The future diagnosis and treatment of early stage lung cancer is a multidisciplinary treatment model combining surgery, medical oncology, radiotherapy and imaging, and an individualized treatment model combining clinical and molecular biology technologies. With the clinical application of these new treatment strategies, a solid foundation has been laid for improving the efficacy of early stage lung cancer and improving the survival quality of patients.