Natural history of stage I non-small cell lung cancer: implications for early detection

BACKGROUND: Concern has been raised that early detection of lung cancer may lead to the treatment of clinically indolent cancers. No population-based study has examined the natural history of patients with stage I NSCLC who receive no surgery, chemotherapy, or radiation therapy. Our hypothesis is that long-term survival in patients with untreated stage I non-small cell lung cancer (NSCLC) is uncommon. METHODS: A total of 101,844 incident cases of NSCLC in the California Cancer Center registry between 1989 and 2003 were analyzed; 19,702 patients had stage I disease, of whom 1,432 did not undergo surgical resection or receive treatment with chemotherapy or radiation. Five-year overall survival (OS) and lung cancer-specific survival were determined for this untreated group, for subsets of patients who were recommended but refused surgical resection, and for T1 tumors. RESULTS: Only 42 patients with untreated stage I NSCLC were alive 5 years after diagnosis. Five-year OS for untreated stage I NSCLC was 6% overall, 9% for T1 tumors, and 11% for patients who refused surgical resection. Five-year lung cancer-specific survival rates were 16%, 23%, and 22%, respectively. Among these untreated patients, median survival was 9 months overall, 13 months for patients with T1 disease, and 14 months for patients who refused surgical resection. CONCLUSION: Long-term survival with untreated stage I NSCLC is uncommon, and the vast majority of untreated patients die of lung cancer. Given that median survival is only 13 months in patients with T1 disease, surgical resection or other ablative therapies should not be delayed even in patients with small lung cancers.     

The impact of immunohistochemical detection of positive lymph nodes in early stage lung cancer

BACKGROUND: Detection of micrometastatic disease is an interesting area in non-small cell lung cancer (NSCLC). We conducted a study to determine whether the detection of mediastinal lymph node spread by immunohistochemical (IHC) analysis offers some prognosis with respect to patients' disease-free survival or not. METHODS: Between 1997 and 2003, twenty-one early stage lung cancer patients underwent complete resection with mediastinoscopy and systemic nodal dissection. Four hundred and twenty-six paraffin-embedded lymph node sections from 21 patients were analyzed. Epithelial specific-antigen Ab-9 and Keratin-Pan Ab-1 were used as IHC marker. RESULTS: Based on nodal spread four of the 21 patients (19.04%) were up-staged after IHC analysis. Two patients with stage IB (T2N0) up-staged to stage IIIA (T2N2); two patients staged as IIB (T2N1) up-staged to IIIA (T2N2). Statistical analysis showed that the lymphatic dissemination detected with IHC analysis was associated with reduced disease-free survival (DFS) (p = 0.002). CONCLUSIONS: Our study provides some indication that patients with lymphatic micrometastasis have a reduced DFS. Before creating a new TNM staging system, more information is needed to understand the prognostic impact of micrometastatic dissemination.     

Potential biomarkers for the early detection of lung cancer

Lung cancer remains the leading cause of cancer death among men and women in the United States. Early detection of premalignant lesions provides the possibility of treatment at earlier stages. Because malignancy develops from genetic alterations, the early detection of these genetic changes should be associated with the earliest clues to transformation. This article presents an overview of detection of molecular markers and their relevance to lung cancer. In the future, such molecular markers may play a role in guiding therapy for lung cancer.     

Sputum cytology for the detection of early lung cancer

Sputum cytology is an important step in the early diagnosis of roentgenographically occult lung cancer. It identifies primarily intraepithelial lesions, which are the most common squamous carcinomas not detected by helical CT. Patients at highest risk for lung cancer (eg, heavy smokers with airflow obstruction) should undergo sputum cytology. Patients with premalignant lesions (eg, moderate or severe dysplasia) and of course patients with carcinoma in situ or invasive carcinoma should receive fiberoptic bronchoscopy. The diagnosis and treatment of early-stage lung cancer usually has a favorable outcome. Today we have the knowledge and technology that can change the outcome of lung cancer through early identification, particularly in high-risk patients.     

ProACTH: use for early detection of lung cancer.

ProACTH was identified by radioimmunoassay and column chromatography in extracts of 38 lung carcinomas. One hundred patients were evaluated because of abnormalities on chest roentgenograms; 53 (72 per cent) of 74 with lung cancers had increased plasma ACTH immunoreactivity; all 26 with benign abnormalities had normal ACTH. Of 101 patients with obstructive lung disease, five of 20 with elevated plasma ACTH levels and two of 81 with normal plasma ACTH levels had lung cancer within two years. In three of 31 patients with granulomatous lung disease plasma ACTH levels were elevated during acute exacerbation of the disease, but they returned to normal after recovery. We conclude that plasma ACTH immunoreactivity is frequently increased early in the course of lung carcinoma.     

Therapy for stage I and stage II non-small cell lung cancer

Despite complete resection of what seems to be all evident tumor, one third to three quarters of patients with stages I and II NSCLC ultimately succumb to this neoplasm. Patients who are cured of an original NSCLC or small cell cancer remain at risk for a new primary lung cancer. Although the importance of lifelong surveillance is clear, the extent and timing of optimal follow-up remain undefined. Although clinicians refer to the development after treatment of clinically discernible sites of tumor as "recurrence," it is probably more accurate to consider these foci as "persistence"--that is, the locoregional site was not sterilized by surgery, and the distant implants were present from the outset but undetected. Although data are sparse, induction and improved adjuvant therapy for early NSCLC may be helpful. Much further experience is needed. Further study and application of biologic indicators in addition to TNM staging likely will help identify patients at high risk for surgical failure who may benefit by combination treatment.     

Hypofractionated proton beam radiotherapy for stage I lung cancer

STUDY OBJECTIVES: To determine the efficacy and toxicity of high-dose hypofractionated proton beam radiotherapy for patients with clinical stage I lung cancer. DESIGN: A prospective phase 2 clinical trial. SETTING: Loma Linda University Medical Center. PATIENTS: Subjects with clinical stage I non-small cell lung cancer who were medically inoperable or refused surgery. INTERVENTIONS: All patients were treated with proton beam radiotherapy. The target included the gross tumor volume as seen on CT scan, with additional margin to allow for respiratory motion. A multibeam treatment plan was generated. Delivered treatment was 51 cobalt Gray equivalent (CGE) in 10 fractions over 2 weeks to the initial 22 patients; the subsequent 46 patients received 60 CGE in 10 fractions over 2 weeks. RESULTS: Sixty-eight patients were analyzed for this report, with a median follow-up time of 30 months. No cases of symptomatic radiation pneumonitis or late esophageal or cardiac toxicity were seen. The 3-year local control and disease-specific survival rates were 74%, and 72%, respectively. There was significant improvement in local tumor control in T1 vs T2 tumors (87% vs 49%), with a trend toward improved survival. Cox regression analysis revealed that patients with higher performance status, female gender, and smaller tumor sizes had significantly improved survival. CONCLUSION: High-dose hypofractionated proton beam radiotherapy can be administered safely, with minimal toxicity, to patients with stage I lung cancer. Local tumor control appears to be improved when compared to historical results utilizing conventional radiotherapy, with a good expectation of disease-specific survival 3 years following treatment.     

Prediction model on disease recurrence for low risk resected stage I lung adenocarcinoma

Background and Objective

Although stage I non-small cell lung carcinoma (NSCLC) typically carries a good prognosis following complete resection, early disease recurrence can occur. An accurate survival prediction model would help refine a follow-up strategy and personalize future adjuvant therapy. We developed a post-operative prediction model based on readily available clinical information for patients with stage I adenocarcinoma.

Methods

We retrospectively studied the disease-free survival (DFS) of 408 patients with pathologically confirmed low-risk stage I adenocarcinoma of lung who underwent curative resection from 2013 to 2017. A tree-based method was employed to partition the cohort into subgroups with distinct DFS outcome and stepwise risk ratio. These covariates were included in multivariate analysis to build a scoring system to predict disease recurrence. The model was subsequently validated using a 2011–2012 cohort.

Results

Non-smoker status, stage IA disease, epidermal-growth factor receptor mutants and female gender were associated with better DFS. Multivariate analysis identified smoking status, disease stage and gender as factors necessary for the scoring system and yielded 3 distinct risk groups for DFS [99.4 (95% CI 78.3–125.3), 62.9 (95% CI 48.2–82.0), 33.7 (95% CI 24.6–46.1) months, p < 0.005]. External validation yielded an area under the curve by receiver operating characteristic analysis of 0.863 (95% CI 0.755–0.972).

Conclusion

The model could categorize post-operative patients using readily available clinical information, and may help personalize a follow-up strategy and future adjuvant therapy.     

Screening of early detection of lung cancer

Methods for detecting early lung cancers, carcinoma in situ, and dysplastic lesions of the tracheobronchial tree ultimately aim to eradicate them before they become invasive. This approach is being developed to detect early stage lung cancer, when treatment is more likely to be curative. This review describes the recent developments in lung cancer screening and the possible impact on management of lung cancer.     

Vascular endothelial growth factor and osteopontin in stage I lung adenocarcinoma.

Tumor growth and metastasis are angiogenesis-dependent processes initiated and regulated by a number of cytokines. Vascular endothelial growth factor (VEGF) is a potent angiogenic protein with a selective mitogenic effect on vascular endothelial cells. Osteopontin (OPN) induces endothelial cell migration and upregulates endothelial cell migration induced by VEGF. To clarify the cooperative role of VEGF and OPN in tumor angiogenesis, we stained VEGF, OPN, and CD34 immunohistochemically in 87 cases of stage I non-small cell lung cancer (adenocarcinoma, 55, and squamous cell carcinoma, 32). Of the 87 patients studied, 27 patients had postoperative relapse and 60 patients did not. VEGF was found in 34 of 55 cases of adenocarcinomas and 14 of 32 squamous cell carcinomas, and OPN was found in 30 of 55 adenocarcinomas and 10 of 32 squamous cell carcinomas. In adenocarcinoma, microvessel counts of VEGF-positive and OPN-positive tumors were significantly higher than VEGF-negative and OPN-negative tumors, respectively, whereas in squamous cell carcinoma they were not. More importantly, patients with VEGF- and OPN-positive stage I lung adenocarcinoma had significantly worse prognosis as compared with other groups. Cooperation of OPN is important in VEGF-mediated tumor angiogenesis in stage I lung adenocarcinoma.     

立体定向放射治疗早期非小细胞肺癌的临床研究

目的评价立体定向放射治疗早期非小细胞肺癌的疗效和放射反应。方法 54例Ⅰ期和Ⅱ期(T1,2,3N0M0)非小细胞肺癌患者接受立体定向放射治疗。90%的等剂量曲线覆盖PTV。4 Gy/f共14次或5 Gy/f共10次,每日1次,每周5次。结果 54例患者总有效率为88.89%,其中CR率为25.93%,PR率为62.96%。1年总生存率85.19%,2年总生存率75.93%,3年总生存率66.67%。1年局部无进展生存率79.63%,2年局部无进展生存率68.52%,3年局部无进展生存率53.7%。早期反应主要为一般全身反应、骨髓抑制和肺的早期放射反应,多为Ⅰ-Ⅱ级。晚期放射反应主要为照射区域局限性Ⅰ-Ⅱ级放射性肺炎。结论立体定向放射治疗早期非小细胞肺癌是安全、有效的。     

Long-term survival after videothoracoscopic lobectomy for stage I lung cancer

STUDY OBJECTIVES: The aim of this study was to evaluate our personal experience and survival curves after video-assisted thoracic surgery (VATS) lobectomies for stage I lung cancer, in comparison with the results reported in existing literature. DESIGN: Retrospective analysis of our experience and an overview of literature. SETTING: Department of Surgery, San Giuseppe Hospital, University of Milan. PATIENTS: From October 1991 to December 2001, of 257 patients with clinical stage I lung cancer, 193 patients underwent VATS lobectomy, 7 patients were declared inoperable at thoracoscopic exploration, and 57 patients were converted (18 patients for oncologic reasons and 39 patients for technical reasons). RESULTS: We observed no intraoperative mortality and no recurrence. Survival data were analyzed with the Kaplan-Meier method along with a log-rank test for statistical significance. The global survival rates at 3 years and 5 years were 77.7% and 63.64%, respectively. T1N0 patients had a better survival curve at 3 years and 5 years (83.50% and 70.21%, respectively) compared to T2N0 patients (71.13% and 56.12%). Patients < 70 years of age had better 3-year and 5-year survival rates (82.37% and 73.32%, respectively) than those > 70 years of age (57.49% and 37.09%). This difference was statistically significant (p < 0.01). CONCLUSIONS: Our results after the VATS approach match the "best" results reported in literature following conventional surgery. Minimally invasive surgery seems to imply reduced tissue damage and decreased impairment of immunologic function. VATS lobectomy permits radical oncology as accurately as lobectomy by thoracotomy, provided that long-established standards are respected. In spite of technical difficulties, it could therefore become a valid alternative in treating stage I lung cancer.     

S-adenosylmethionine as a biomarker for the early detection of lung cancer

BACKGROUND: S-Adenosylmethionine (AdoMet) is a major methyl donor for transmethylation reactions and propylamine donor for the biosynthesis of polyamines in biological systems, and therefore may play a role in lung cancer development. We hypothesized that AdoMet levels were elevated in patients with lung cancer and may prove useful as a biomarker for early lung cancer. METHODS: High-performance liquid chromatography was used to analyze plasma AdoMet levels in triplicate samples from 68 patients. This included 13 patients with lung cancer, 33 smokers with benign lung disease, and 22 healthy nonsmokers. The three groups of subjects were compared with respect to the distribution of demographic and disease characteristics and AdoMet levels. Distributions were examined using summary statistics and box plots, and nonparametric analysis of variance procedures. RESULTS: Serum AdoMet levels were elevated in patients with lung cancer as compared to smokers with benign lung disorders and healthy nonsmokers. There were no significant correlations between AdoMet levels and tumor cell types, nodule size, or other demographic variables. CONCLUSIONS: Our data demonstrate that plasma levels of AdoMet are significantly elevated in patients with lung cancer. Plasma AdoMet levels may prove to be a useful tool for the diagnosis of early lung cancer, in combination with chest CT. Registered at: clinicaltrials.gov (NCT00301119).     

Vessel invasion as a predictive factor for recurrence after surgery in stage I lung adenocarcinoma

BackgroundPatients with early-stage lung cancer who underwent R0 resection often encounter disease recurrence, especially during the early phase; thus, it is deemed vital to determine the predictive factors for recurrence after surgery. In this study, we aimed to identify the independent variables associated with recurrence after complete surgical resection of pathological stage I lung adenocarcinoma.MethodsWe retrospectively reviewed the medical records of 169 patients who underwent pulmonary resection for primary lung adenocarcinoma pathological stage I with curative intent lung cancer surgery from 2015 to December 2018 at our institution for information on the recurrence of the disease.ResultsPer the multivariate analysis, the presence of micropapillary pattern and vessel invasion were found to be independent predictors of disease recurrence after surgery (odds ratio [OR]: 9.36, 95% confidence interval [CI]: 2.42–36.2, P = 0.0012; and OR: 4.50, 95% CI: 1.52–13.4, P = 0.0068, respectively). Vessel invasion was also found to be an independent predictor of disease recurrence after surgery within a year (OR 11.4, 95% CI 3.08–42.5, P = 0.0003).ConclusionsThe presence of vessel invasion may help in distinguishing patients with the highest risk of early-phase disease recurrence after surgery. Patients with stage I adenocarcinoma with vessel invasion should undergo intensive surveillance after surgery.