Year : 2022 | Volume
: 18 | Issue : 2 | Page : 323--328
Recent advances in nonsurgical treatment of pulmonary ground-glass nodules
Yongmei Kong1, Hui Xu1, Yahan Huang1, Xinyuan Lv2, Xin Ye3,
1 Shandong First Medical University & Shandong Academy of Medical Sciences., Taian; Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, Shandong, China
2 Kweichow Moutai Hospital, Zunyi, Guizhou, China
3 Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, Shandong, China
Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, No. 16766, Jingshi Road, Jinan, Shandong Province 250014
Since the 1990s, low-dose computed tomography technology has been used in lung cancer screening. With the increase of computed tomography screening, the detection rate of ground-glass nodules (GGN) has increased dramatically. At present, the main treatment strategy for GGN is surgical resection. However, for patients with poor cardiopulmonary functions, a history of lung resection, multiple pulmonary nodules, or the age of >75 years, surgical resection is very difficult and not medically encouraged. This article reviews the applications and outcomes evaluation of nonsurgical treatments, such as chemotherapy, radiotherapy, moleculartargeted drug therapy, immunity therapy, and image-guided thermal ablation in patients with GGN.
|How to cite this article:|
Kong Y, Xu H, Huang Y, Lv X, Ye X. Recent advances in nonsurgical treatment of pulmonary ground-glass nodules.J Can Res Ther 2022;18:323-328
|How to cite this URL:|
Kong Y, Xu H, Huang Y, Lv X, Ye X. Recent advances in nonsurgical treatment of pulmonary ground-glass nodules. J Can Res Ther [serial online] 2022 [cited 2022 Jul 4 ];18:323-328
Available from: https://www.cancerjournal.net/text.asp?2022/18/2/323/345536
In 2011, the National Lung Screening Trial reported, for the first time, that lung cancer mortality in high-risk populations could be reduced by 20% using low-dose computed tomography (LDCT) screening instead of the standard chest X-ray. As LDCT screening programs have been widely performed in recent years, asymptomatic pulmonary nodules have been detected in increasing numbers. The detection rate of the nodules in China is 20%–80%.,,, However, >97% of the nodules screened with LDCT are benign. Lung cancer has a detection rate of only 0.7%–2.3%.,,,,, A detection rate that is too high may lead to overdiagnosis, overtreatment, a waste of medical resources, and higher levels of anxiety in patients.,,,, Current guidelines for the screening and treatment of pulmonary nodules are mainly medical follow-up and surgical resection. With the recent advancements in surgery, particularly that of the universal use of video-assisted thoracoscopic surgery (VATS), outcomes have generally improved and postoperative complications have remarkably reduced,,,, but there are still many unsolved problems.
A pulmonary nodule is often considered an early-stage predictor of lung cancer. However, lung cancer with ground-glass nodules (GGNs) is characterized by “indolent” development, with distant metastases in very few patients. It has a favorable prognosis and the 5-year overall survival (OS) after surgery is 100%.,,,,,,, It is a special subtype of lung cancer as it differs from “traditional” early-stage lung cancer. The following problems exist in the premature use of VATS to remove this type of lesion: (1) Premature surgical intervention for pulmonary nodules, particularly for precancerous lesions, will lead to premature organ damage and lung function loss. Moreover, early surgery cannot significantly improve the OS of patients compared with follow-up and elective surgery. (2) There are no clear selection criteria for surgical methods for multiple pulmonary nodules and no principle for the follow-up management of residual nodules.(3) Preoperative diagnosis of pulmonary nodules is made by imaging, without pathological evidence, so surgical resection of pulmonary nodules judged to be at risk preoperatively may turn out to be unnecessary when lesions are found to be benign, risking postoperative complications.,, (4) As the population ages, increasing numbers of patients with early-stage lung cancer have been diagnosed at the age of >75 years, for which surgery is almost impossible. Therefore, for patients with insufficient lung function reserve or patients whose surgical technique is not feasible, a nonsurgical treatment modality is needed. Commonly used nonsurgical treatments mainly include systemic treatment, stereotactic body radiation therapy (SBRT), and image-guided thermal ablation (IGTA).
In 2017, Lu et al. retrospectively evaluated the outcomes of persistent pulmonary GGNs in patients with lung adenocarcinoma who underwent chemotherapy. Fifty-one patients with 91 GGNs satisfied the inclusion criteria (male 25, female 26, with the average age being: 63.8 years). All patients underwent either cisplatin or carboplatin chemotherapy for at least 2 cycles. Out of the 91 GGNs, 60 nodules were ≥1 cm, 87 were pure ground-glass, and 19 were multiple. The mean follow-up duration was 24.1 ± 17.9 months. During the follow-up period, on a per-nodule basis, 86 of GGNs remained unchanged in size while five of GGNs increased in size. There were no significant differences in the average diameter, attenuation value, volume, and mass of GGNs before and after chemotherapy. Lu et al. suggested that chemotherapy may have no effect on persistent pulmonary GGNs.
In 2020, Zhang et al. conducted a related retrospective analysis, which included 44 patients with nodules (3 males, and 41 females, with a median age of 54.5 years), and a total of 55 GGNs (including 35 pure GGNs, 20 mixed GGNs, with an average size of 12 mm). All patients had malignant tumors (30 breast cancers, 8 lung cancers, 3 cervical cancers, 2 ovarian cancers, and 1 rectal cancer) other than lung nodules. Although the chemotherapy regimen was not specifically designed for GGN lesions, the eight patients with concurrent lung cancer all received four cycles of platinum-based chemotherapy, and the other 34 patients received platinum, pemetrexed, paclitaxel, and docetaxel or gemcitabine. After chemotherapy, all GGNs were surgically removed. Postoperative pathology revealed adenocarcinoma. The comparison of computed tomography (CT) images before chemotherapy and CT before surgery (the median interval was 10 months) showed that 30 GGNs remained unchanged both in tumor size and consolidation size, while 19 GGNs increased in tumor size, one increased in consolidation size, and five increased in both tumor and consolidation sizes. At the same time, immunohistochemical staining was performed for Ki-67, caspase-3, and beta-galactosidase (β-gal), and the results showed that the expression levels of Ki-67, caspase-3, or β-gal in lung adenocarcinoma with or without chemotherapy was not statistically significant. Therefore, they believed that a lung adenocarcinoma with GGNs does not respond to chemotherapy. For these patients, chemotherapy should not be a treatment option.
Molecular-Targeted Drug Treatment (Tyrosine Kinase Inhibitors, TKIs)
In 2016, Liu et al. performed genetic testings on 159 lung nodules (the largest lesions had an average diameter of 2.23 ± 0.91 cm) in 78 patients out of which 75 patients had two lesions and three patients had three lesions, and the study found that the epidermal growth factor receptor (EGFR) mutation rate of these patients was 48.7% (38 of 78 cases). Considering the fact that in multiple primary lung adenocarcinomas, with most of the lesions being manifested as multiple GGNs on imaging examinations, many of them have EGFR mutations, therefore, EGFR-TKIs have been recommended as an adjuvant treatment after surgery of early nonsmall-cell lung cancer (NSCLC) with EGFR mutations. In order to confirm whether postoperative EGFR-TKIs were effective for unresected persistent GGNs in EGFR-mutated synchronous multiple primary lung cancers (sMPLC) patients, Cheng et al. conducted a related study, which retrieved 143 GGNs with EGFR mutations who had undergone surgical removal of part of the main lesions from 2014 to 2018. Sixty-six patients, with 134 lesions in total, received postoperative TKIs (the drugs include: Gefitinib, erlotinib, icatinib, afatinib, and ositinib). In terms of lesions, 32 of them became smaller, while seven increased, and the remaining 95 showed no significant change. The response rate of the lesions was 23.9% (32/134). The study was the first to observe the effect of postoperative EGFR-TKIs treatment on unresected GGNs in sMPLC patients with EGFR mutations. In Cheng's study, postoperative EGFR-TKIs treatment showed the activity of residual persistent GGNs after surgery. For the Malignant Tumors III stage, there are more than two residual lesions, mixed component lesions, or with a diameter of residual lesions ≥8 mm as an auxiliary target after surgery. The benefits associated with treatment are more significant. However, whether EGFR-TKIs are effective in the treatment of pulmonary nodules requires more multicenter prospective randomized controlled trials.
In 2020, Wu et al. carried out a related case report that a male patient with MPNs confirmed that the expression of PD-L1 was positive by immunohistochemical staining. Initially, the patient refused surgery for his reasons and received three cycles of pembrolizumab immunotherapy combined with pemetrexed chemotherapy. Thereafter, the immunotherapy treatment was suspended because of immune-related pneumonia, and anti-inflammatory treatment for pneumonia was given for 2 weeks. After the patient recovered, the main GGNs were surgically removed, and no other anti-tumor treatment was received after the operation. After 12 months of follow-up, the imaging results showed that almost all the remaining GGNs gradually achieved complete remission, and the tumor markers gradually returned to the normal range. This phenomenon is called the tailing effect of immunotherapy, and it proves that immunotherapy is effective for patients with GGNs. This was only a case report, and more multicenter prospective randomized controlled trials are needed to determine whether immunotherapy is effective in the treatment of pulmonary nodules.
Stereotactic Body Radiation Therapy
For patients with early stages of NSCLC who are unable or unwilling to undergo surgical resection, SBRT is an alternative therapy for patients with inoperable early-stage NSCLC. In 2019, Eriguchi et al. analyzed the prognosis of SBRT in patients with early-stage NSCLC, and retrospectively analyzed 88 operable NSCLC patients (having a median age of 79 years) with CT1-2N0M0 who received SBRT, out of which 59 patients were pathologically diagnosed with NSCLC, and the remaining 29 patients were clinically diagnosed with NSCLC. All patients received SBRT due to refusal of surgery (radiotherapy dose of 50 Gy for peripheral lesions and 40 Gy for central lesions). An average follow-up of 40 months was carried out after SBRT. The results showed that the 5-year cause-specific survival rate (CSS) and OS rate of GGNs (24 cases) were 100% and 100%, respectively, while those of solid tumor patients were 83% and 59%, respectively. Eriguchi et al. believed that SBRT has a good prognosis for early-stage operable NSCLC with GGNs. For high-risk operable patients, further research is necessary to select good SBRT candidates.
The following year, Onishi et al. conducted a similar retrospective analysis. The study included 84 cases (42 males, 42 females, with an average age of 75 years old) of stage I lung cancer with GGNs (median tumor size of 20 mm, solid component <50%, no metastasis). All patients received SBRT. After a median follow-up of 33 months, two patients developed distant metastases (one brain metastasis, and the other was bone metastasis), and both the patients had a history of surgical treatment of lung cancer before SBRT. The results showed that the OS of the total, for operable and inoperable patients at 3 years were 98.7%, 97.1%, and 100.0%, respectively. There was no statistical difference in OS and RFS between operable and inoperable subgroups. The 3-year CSS and OS rates were 98.2 and 94.6%, respectively. They believe that although more cases and longer follow-up are needed, SBRT may be one of the radical treatment options for GGNs.
In the same year, Tomita et al. conducted a meta-analysis. The study included 756 NSCLC patients (574 received surgery, 182 received SBRT). All patients received propensity score-matching (PSM) and compared the results of surgery and radiotherapy in patients with stage cI NSCLC through PSM to avoid bias. PSM identified 120 patients with similar characteristics from each group. After PSM, the ratio of GGNs between the surgery group and the SBRT group remained balanced. The median follow-up time of the surgery and SBRT groups were 58 months and 75 months, respectively. The results showed that the OS and PFS of the surgery group were slightly better than those of the SBRT group, but there was no significant difference in survival rates between them. Tomita et al. believed that although the 3-year OS and CSS rates of SBRT groups are slightly lower than those of the surgical group. Therefore, SBRT provides an alternative method for patients with GGNs who cannot tolerate surgery. The most commonly used nonsurgical treatment method for GGNs.
However, there were very few clinical studies on SBRT for treating GGN, especially on multifocal GGNs. The possible reasons are as follows (1) it is very difficult to obtain the pathologic results of GGN (2) adenocarcinoma in situ and minimally invasive adenocarcinoma have lepidic growth, and target volume can hardly be determined; (3) multitarget radiation may be too toxic; and (4) due to the influence of radiation pneumonia, sometimes it is difficult to evaluate the local efficacy of GGN after SBRT.
Proton Beam Therapy
SBRT is an alternative method to surgery for patients with pulmonary nodules. However, the use of X-rays still involves the risk of radiation-induced complications, such as radiation pneumonitis. In order to reduce the occurrence of radiological complications, experts have turned their research directions to proton beams. Unlike photon beams, such as X-rays, proton beams have a very rapid energy loss before stopping in the body, resulting in a sharp local dose peak (Bragg Peak). In order to explore the efficacy of proton beam therapy (PBT) in GGN patients, Nagata et al. analyzed 48 GGN-type lung cancer (median age being 70.9 ± 9.2 years, 54.2% male) who received PBT, with 53 lesions in total. Of these, 44 were stage IA1‒3, while 9 were stage IB. The 3-year OS, definitive feasibility study, and luxury car tax rates of 53 tumors after PBT were 91.7%, 85.4%, and 92.5%, respectively. Therefore, Ichiro believed that PBT may be a promising alternative when GGN-type lung cancer cannot be surgically removed.
Image-Guided Thermal Ablation
As a precise minimally invasive technique, IGTA has been increasingly used to treat early-stage lung cancer.,,, IGTA is a treatment technique that uses the biological effects of heat to directly cause irreversible damage or coagulative necrosis of tumor cells in the lesion tissue for one or more specific tumor lesions in a certain organ. IGTA approaches that are currently used for GGNs treatment mainly include radiofrequency ablation (RFA), cryoablation, and microwave ablation (MWA).
In 2014, Kodama et al. counted 33 patients with primary lung cancer (14 men and 19 women) who received RFA treatment from August 2004 to May 2012. The average age was 71.1 ± 10.4 years), with a total of 42 GGNs (the average maximum tumor diameter was 1.6 ± 0.9 cm), out of which 20 lesions were pure GGNs, and the other 22 were mixed GGNs. All GGNs were subjected to RFA. During an average follow-up of 42 ± 23 months, 10 patients found tumor recurrence, four patients found local tumor progression, two patients found both local tumor progression and distant metastasis, while two patients found local tumor progression and distant metastasis at the same time. The local tumor progression rate was 0% at 1 year, 15.1% at 3 years, and 24.5% at 5 years. Overall, the 1-year, 3-year, and 5-year OS rates of all patients were 100%, 96.4%, and 96.4%, respectively. In addition, the 3-year OS and CSS rates were 96.4% and 100%, respectively. Therefore, they believed that RFA is a feasible, safe, and useful treatment option for the control of GGNs-dominant lung adenocarcinoma. This was the first time that RFA was ever reported to treat GGN in the whole wide world.
In 2014, Iguchi et al. also retrospectively assessed the prognosis of patients with GGNs receiving RFA, 16 patients (5 males and 11 females, of an average age of 72.6 years) with 17 lung cancer lesions showed GGNs (with an average long-axis diameter being 1.6 cm) and received 20 RFA. Among them, three cases underwent the second RFA due to local progression after the first RFA. The median follow-up period for tumors was 61.5 months (the range being 6.1–96.6 months). One patient died due to the recurrence of other cancers, the remaining 15 patients were still alive. The 1-year OS and DSS rates were 93.3 and 100%, respectively, while the 5-year survival rate was 93.3% and 100%, respectively. Iguchi et al. believed that RFA is safe and effective in the treatment of lung cancer complicated by GGNs, and has a good survival rate.
Kim et al., in 2015, were the first to report the application of cryoablation in patients with GGNs. The patient in this case report (a 59-year-old woman) had multiple GGNs (a 12 mm partial solid nodule in the right middle lobe, a 7 mm pure GGN in the upper right lobe, and each lower lobe has two 5 mm pure GGNs), and had undergone multiple surgical resections. The patient did not have sufficient pulmonary functional reserve to tolerate any additional surgery. Therefore, the pure GGNs of the left lower lobe of the patient were cryoablated. The results proved that in the 6-month follow-up after cryoablation, CT scan showed that the left lower lobe nodule was completely ablated, and no recurrence occurred. Therefore, Kim et al. believed that cryoablation may be a suitable adjuvant treatment option for pure GGNs. It only requires further prospective investigation and long-term follow-up.
In 2019, Liu et al. followed up 14 patients with GGNs undergoing cryoablation, eight men and six women, with an average age of 63.00 ± 10.61 years, and a total of 19 lung nodules (the average size of GGNs was 1.08 cm). All patients successfully completed the ablation. 1 week after cryoablation, the lung function of the patients was lower than before the operation. However, 1 month after cryoablation, most patients' lung function returned to normal. After an average of 24 months, the GGNs of the lung lobes of all patients had been successfully ablated without any recurrence. Liu believed that cryoablation may be a suitable option for patients with lung nodules who refused to undergo surgery or biopsy.
In 2018, Yang's et al. conducted a retrospective study on 51 patients with pulmonary nodules (22 males and 29 females, with an average age of 69.4 ± 10.1 years) who underwent MWA from 2013 to 2017. A total of 51 cases of lung adenocarcinoma lesions showed GGNs (mean long axis diameter 18.7 ± 6.05 mm), and all lesions underwent MWA. One patient underwent the second MWA due to the progression of the disease. During the median follow-up period of 27.02 months (range: 7–45 months), the 3-year local progression-free survival (LPFS), CSS, and OS rates were 98%, 100%, and 96%, respectively. Therefore, Yang et al. believed that CT-guided percutaneous MWA is a feasible, safe and useful treatment method for GGN-pulmonary adenocarcinoma. It will become an alternative method for the treatment of patients with peripheral GGN-lung adenocarcinoma who are medically inoperable. This was the first time that MWA was reported to treat GGN in the world.
Furthermore, in 2019, Huang et al. retrospectively evaluated the feasibility, safety, and short-term efficacy of MWA in the treatment of multiple simultaneous GGNs of the lung. The study included 33 patients consisting of nine males and 24 females, with an average age of 59.6 ± 10.0 years. In all, there were 103 cases, 84 cases of which were pure GGN, while19 cases were mixed GGNs, with an average size of 12.3 ± 6.3 mm). Patients underwent 66 MWA. The median follow-up period was 18.1 months (range: 6.8–37.7 months). The 3-year LPF and OS rates were both 100%. The technical success rate was 100%, and there were no deaths related to the MWA procedure. Therefore, they believed that CT-guided percutaneous MWA treatment of multiple synchronized lung GGNs is feasible, safe, and effective.
In 2020, Xue et al. reported a case of multiple GGNs treated with CT-guided MW in a 44-year-old male with no family history of tumors. Blood tests and tumor markers were negative. CT scans showed both lungs had multiple GGNs and partial lower lobe lesions. The patient refused surgical treatment, but rather received MWA simultaneous biopsy of the right lower lobe GGNs and the left lower lobe GGNs. Pathology of both nodules was diagnosed as invasive adenocarcinoma. After ablation at 18 months, the previous GGNs gradually disappeared and were replaced by reactive fibrous scars. Therefore, Xue et al. believed that MWA is a successful and safe alternative for patients with multiple GGNs who cannot or refuse to undergo surgery.
Most recently, in 2021, Chi et al. retrospectively evaluated the safety and technical efficacy of a customized blunt-tip microwave ablation antenna for CT-guided ablation of GGN. All consented patients with GGNs who underwent MWA treatment using a conventional sharp-tip antenna (group A) or new blunt-tip antenna. Sixteen (7 males, 9 females, with the mean age being 64.9 ± 12.3 years) and 26 (11 males, 15 females with a mean age of 66.5 ± 10.7 years) patients were enrolled in groups A and B, respectively. The technique was successfully performed in all patients and a follow-up CT scan at 24 h after MWA showed that the technical efficacy rate was 100% in both groups. Twelve (75.0%) Grade I complications were noted in group A, whereas 11 (42.3%) were noted in group B (P = 0.039, Chi-square test). No bleeding occurred within the lesions in group B. Chi et al. believed that the blunt-tip MWA antenna is a safe and technically effective tool for ablating GGN lesions.
To sum up, no study has proved that chemotherapy is beneficial to the patient after GGN resection. For GGNs with EGFR mutations, TKIs may be beneficial to patients. At the same time, immunotherapy may also be beneficial to patients with GGNs. However, the long-term follow-up results from prospective randomized controlled trials are needed. SBRT and PBT have certain limitations in the treatment of pulmonary GGNs, and there are a few relevant clinical studies. IGTA, a new weapon in the treatment of GGNs has shown its advantages but there are still many problems, such as: (1) There is a lack of long-term (>10 years) follow-up on clinical outcomes. (2) There are a few clinical trials on the use of IGTA for GGNs. It is necessary to perform a prospective, randomized controlled, multicenter clinical trial of IGTA for GGNs. (3) How to accurately locate and improve the positive rate of biopsy and complete local ablation is one of the directions of future work;,,,,, (5) People still entertain some doubts about the thermal ablation technology for the treatment of pulmonary nodules, and further work is needed to change the traditional thinking about the technology so that the technology can be popularized and applied.
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Conflicts of interest
There are no conflicts of interest.
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