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. At present, surgery is still the preferred treatment method for early-stage lung cancer, and the 5-year survival rate of patients after surgery can reach over 70%, 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, and 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 lung cancer death 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-years)] were diagnosed in the LDCT group and 941 lung cancer patients [572 per 100,000 (person-years)] were diagnosed in the X-ray chest radiograph group.
Lung cancer-specific mortality analysis showed 247 deaths/100,000 (person-years) in the low-dose CT group and 309 deaths/100,000 (person-years) 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-stage lung cancer
2.1 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. Conventional fiberoptic bronchoscopy can visually observe the specific location of the tumor and the distance from the ramus and main bronchus. For some patients whose primary tumors are close to the periphery of the lung, where positive results cannot be obtained by conventional fiberoptic bronchoscopy, and whose location is not suitable for percutaneous lung puncture biopsy, the advent of electromagnetic navigation bronchoscopy (ENB) has made this difficult problem easy.
2.2 Regional lymph node N-staging
For lung cancer without distant metastasis, the clear 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 noninvasive dissection of the mediastinum, allowing further invasive examination of suspected mediastinal lymph nodes and improving accurate anatomical localization and pathological diagnosis.
The sensitivity and specificity of PET-CT in evaluating the N-stage of lung cancer were found to be 74% (95% CI: 69%-79%) and 85% (95% CI: 82%-88%), respectively, in 44 clinical studies with complete data from 1994 to 2006.
(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 of 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 deep into the main bronchus and even the lobar bronchus 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 using a special puncture needle, as the puncture biopsy is performed under real-time surveillance of ultrasound images. To date, no 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, the National Comprehensive Cancer Network (NCCN) and the American College of Chest Physicians (ACCP) and other clinical practice guidelines for lung cancer 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.
III. Surgical treatment of early-stage lung cancer
3.1 Minimally invasive thoracic surgery technique Kirby et al. first reported television-assisted thoracoscopic surgery (VATS) in the early 1990s, 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. in 2006 McKenna et al. reported 1100 cases of VATS
Lobectomy clinical results, 84.7% of patients had no postoperative complications, 2.5% had an intermediate open chest, 4.1% required blood transfusion, the median length of 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, with no significant difference in safety and efficacy compared with traditional open-heart surgery, and a significantly lower postoperative complication rate than 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 and proficiency of the operator in technical training and 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 increasing 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.
3.2 Sublobar lobectomy
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 <3 cm in diameter.
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 have 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 <2 cm in diameter had a 5-year survival rate of 93% in patients.
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, which are mainly reflected 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, with 84.6% and
87.4%. 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 in accordance with the lung segment.
(2) Special pathological type: ground glass like shadow (GGO) is a special pathological type, and GGO found 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 has been found that patients with non-mucinous bronchoalveolar carcinoma (BAC) have 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 results are positive, lung resection should be changed to lobectomy, and if the results are 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) undertaken by Xuanwu Hospital of Capital Medical University, a major lung cancer research project of the Municipal Science Committee – early lung cancer resection scope clinical research program enrolled 630 cases with T≤2cm
N0M0
NSCLC, allocated to lobectomy and sublobar resection in a 2:1 ratio, to compare the differences in local recurrence rate, 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 radiofrequency ablation of tumors, argon helium knife and stereotactic radiotherapy techniques have brought hope for curing lung cancer for this group of patients.
4.1
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 cancers with a diameter of 0.3-8.0 cm and an average diameter of <5.0 cm, with an overall effective rate mostly exceeding 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. A multicenter prospective clinical study showed that percutaneous RFA was performed in 106 lung cancer patients with a total of 183 tumors, of which 33 were NSCLC patients who were not suitable for surgical resection. 99% of the patients were able to complete the operation successfully, and no treatment-related deaths occurred.
The 1- and 2-year survival rates of NSCLC patients after RFA treatment were 92% and 73%, respectively, with a high 2-year survival rate of 92% in stage I NSCLC patients.
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 may improve treatment outcomes.
4.2
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 conventional radiotherapy of 2-3 Gy. Since SBRT was first used for the treatment of body tumors in 1991, research groups from countries and organizations in Europe, the United States and Japan have applied it in the radiotherapy of lung cancer, especially in the past 5-6 years , exciting preliminary results have been achieved.
In 14 studies using SBRT at 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 of care 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 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 with 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.