Detection and Treatment of Lung Adenocarcinoma at Pre-/minimally Invasive Stage: Is It Lead-time Bias?

doi:10.21203/rs.3.rs-1501338/v1

Download PDF

Research Article

Detection and Treatment of Lung Adenocarcinoma at Pre-/minimally Invasive Stage: Is It Lead-time Bias?

https://doi.org/10.21203/rs.3.rs-1501338/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Objectives: This study investigates whether lead-time bias contributes to the excellent survival of AIS and MIA.

Methods: We enrolled patients with resected adenocarcinoma from 2008-2012. Age, sex, smoke history, surgical approach, radiological features, invasive stage and postoperative follow-up data were documented. 1:1 PSM was performed to balance the influence of sex and smoking status on survival. After matching, the average age of two groups was compared to calculate the lead time of diagnosis. The gain in life years for adenocarcinoma diagnosed at pre-/minimally invasive stage was estimated by subtracting the “lead time” and “median survival year of IAC” from “the life expectancy of AIS/MIA patients” referring to Centre for Health and Information.

Results: There were 124 AIS/MIA patients and 1148 IAC patients. The frequency of female and never-smoking patients in AIS/MIA group was much higher than that in IAC group. PSM analysis identified 124 patient pairs. No cancer-related death and recurrence were observed among AIS/MIA patients in 5 years after surgery. For IAC patients, 5-year disease-specific survival rate was 73.5% and median survival is 13.5 years. The average age of AIS/MIA group and IAC group are 53.6 years and 58.2 years, respectively. The lead time between diagnosis of AIS/MIA and IAC is 4.6 years. Referring to Centre for Health and Information, the life expectancy of patients with AIS/MIA diagnosed at 53.6 years old is 28.9 years. With adjustment for the lead time, the gain in life years for adenocarcinoma diagnosed at pre-/minimally invasive stage is 10.8 years.

Conclusions: With adjustment for the lead time between diagnosis of AIS/MIA and IAC, resecting lung adenocarcinoma at pre-/minimally invasive stage can improve life expectancy. The excellent survival of AIS/MIA is not lead time bias.

Lung cancer screening

lead-time bias

adenocarcinoma in situ

minimally invasive adenocarcinoma

Lung cancer by far remains the leading cause of cancer death in the worldwide, representing estimated 18% of all cancer deaths¹. In recent years, several independent, international, randomized controlled clinical trials have demonstrated that low-dose computed tomography (CT) screening reduces lung cancer mortality^2–5. The earlier detection of lung cancer made by low-dose CT screening can explain the reduction of mortality as the diagnosis at early-stage can lead earlier surgical intervention. However, the concerns about lead-time bias in low-dose CT screening have been raised^6,7.

Detection of the disease at an earlier time point by screening causes a false prolonged survival time. This is called lead-time bias^8–10. In low-dose CT screening trials, lung adenocarcinoma was the most often detected subtype of lung cancer^5,11,12. In 2011, adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) were newly defined as two special subtypes of lung adenocarcinoma¹³. 5 or 10-year recurrence free survival of AIS/MIA has been reported 100%¹⁴. In this study, we aim to find out whether the lead-time bias contributes to the excellent survival of AIS/MIA.

We enrolled patients with resected adenocarcinoma from 2008–2012. Patients with previous cancer history were excluded. Age, sex, smoke history, surgical approach, radiological features and postoperative follow-up data were documented. Patients were followed with routinely chest CT every 4 months for the first 3 years after the operation, every 6 months for the next 2 years, and every 12 months thereafter. Telephone follow-up was also used as a complement. Disease-specific survival rate is defined as the percentage of patients who have not died from cancer recurrence or metastasis.

All the identified patients underwent a complete surgical resection and signed informed consent to allow their biological samples to be pathologically analyzed. AIS/MIA and invasive adenocarcinoma (IAC) were confirmed by paraffin section and based on the classification of lung adenocarcinoma released by International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS)¹⁵. Stage IV lung adenocarcinoma were excluded. Each histologic sample was reviewed by two pathologists.

The stepwise progression of lung adenocarcinoma proposed by Noguchi revealed that AIS/MIA would develop into IAC¹⁶. 1:1 propensity score matching (PSM) was performed to the influence of sex and smoking status on survival, with a caliper value set at 0.01. We compared the average age of AIS/MIA patients and IAC patients to calculate the lead time of diagnosis, following the method in the work of Yang et al¹⁷. The gain in life years for adenocarcinoma diagnosed at pre-/minimally invasive stage was estimated by subtracting the “lead time” and “median survival year of IAC” from “the life expectancy of AIS/MIA patients” referring to Centre for Health and Information¹⁸ (Fig. 1). SPSS (version 22.0; IBM Corp, Armonk, NY) was used to analyze the baseline data of AIS/MIA and IAC patients with Pearson’s chi-squared test.

Totally 124 AIS/MIA patients and 1148 IAC patients were reviewed. There were 68.5% female patients and 87.1% never-smoking patients among AIS/MIA group, while 55.4% female patients and 64.0% never-smoking patients among IAC group. 63.7% AIS/MIA patients underwent wedge resection and 88.4% IAC patients underwent lobectomy (Table 1).

Table 1

Baseline of patients with resected pre-/minimally invasive adenocarcinomas and invasive adenocarcinomas
Variables (n, %)	AIS/MIA (n = 124)	IAC (n = 1148)
Age (year, mean ± SD)	53.6 ± 9.5	58.9 ± 10.1
Sex			P < 0.001
Male	39 (31.5)	512 (44.6)
Female	85 (68.5)	636 (55.4)
Smoke status			P < 0.001
Ever	16 (12.9)	413 (36.0)
Never	108 (87.1)	735 (64.0)
Surgery			P < 0.001
Pneumonectomy	0 (0)	19 (1.7)
Lobectomy	43 (34.7)	1015 (88.4)
Segmentectomy	2 (1.6)	18 (1.5)
Wedge	79 (63.7)	96 (8.4)
AIS: Adenocarcinoma in situ MIA: Minimally invasive adenocarcinoma IAC: Invasive adenocarcinoma

As the frequency of female and never-smoking patients in AIS/MIA group was much higher than that in IAC group, we performed 1:1 PSM to the influence of sex and smoking status on survival. PSM analysis identified 124 patient pairs from two patient groups. No cancer-related death and recurrence were observed among AIS/MIA patients in 5 years after surgery. For IAC patients, 5-year disease-specific survival rate was 73.5% and median survival of IAC patients is 13.5 years (Table 2).

Table 2

Clinicopathological characteristics of pre-/minimally invasive adenocarcinomas and invasive adenocarcinomas after propensity score matching
Variables (n, %)	AIS/MIA (n = 124)	IAC (n = 124)
Average age (year)	53.6 ± 9.5	58.2 ± 9.8
Sex			P = 0.905
Male	39 (31.5)	38 (30.6)
Female	85 (68.5)	86 (69.4)
Smoke status			P = 1.000
Ever	16 (12.9)	16 (12.9)
Never	108 (87.1)	108 (87.1)
Median survival (year)	-	13.5
5 -year DFS rate	100%	73.5%
AIS: Adenocarcinoma in situ MIA: Minimally invasive adenocarcinoma IAC: Invasive adenocarcinoma GGO: Ground-glass opacity DFS: Disease-specific survival

The average age of AIS/MIA group and IAC group are 53.6 years and 58.2 years, respectively (Table 2). The lead time between diagnosis of AIS/MIA and IAC is 4.6 years. Referring to the estimation of Chinese life expectancy from Centre for Health and Information, the life expectancy of people aging 50 to 54 years old are 28.9 years¹⁸. Life expectancy of AIS/MIA patients was regarded as life expectancy of normal population for excellent survival and no recurrence. If the patient with adenocarcinoma diagnosed at pre-/minimally invasive stage, survival benefit seems to be 15.4 years (28.9 years minus 13.5 years). With adjustment for the lead time, the gain of life years is 10.8 years (15.4 years minus 4.6 years) (Fig. 2).

In the National Lung Screening Trial research, there were 58.8% detected lung adenocarcinomas were stage I in low dose CT group and 38.4% detected lung adenocarcinomas were stage I in radiography group⁴. In the Multicentric Italian Lung Detection trial, a significantly larger proportion of stage I lung adenocarcinoma was detected in screening arm (50%) compared with control arm (21.7%)⁵. In Nelson trials, screening-detected 58.6% lung cancers were diagnosed in stage I, while only 14.2% of non–screening detected lung cancers were diagnosed in stage I¹². Thus, the shift to early-stage lung cancer at detection by low-dose CT screening may cause lead time of diagnosis.

In radiology, AIS majorly featured as pure ground-glass opacity (GGO) nodule and MIA mostly contained ground-glass component^19,20. Along with the widely using of low-dose CT screening, a rising number of GGO nodules are detected²¹. It can be concluded that low-dose CT screening allows lung adenocarcinoma to be earlier diagnosed at pre- and minimally invasive stage. Similarly, low-dose CT screening made a shift to early-invasive-stage lung cancer at the time of diagnosis. That is the reason why this study focused on the role of lead-time bias in earlier detection of AIS/MIA.

In this investigation, the 5-year disease-specific survival rate of AIS/MIA was 100% and no recurrence were observed. Furtherly, our previous study found no lymph node metastasis was revealed in AIS/MIA²². Many studies founded the same consequences. Notably, the latest research of Yotsukura reported no recurrence was observed in AIS/MIA patient cohort during long-term follow-up and 10-year postoperative disease-specific survival rate was 100%¹⁴. As the long-term postoperative survival of AIS/MIA is extremely excellent, we regard the life expectancy of patients with AIS/MIA to be equal to the life expectancy of the normal Chinese population at the same age. Comparably, five-year overall survival of invasive stage I adenocarcinoma is approximately 78.4% and five-year disease-free survival of stage IA and stage IB adenocarcinoma are nearly 95.4% and 64.8%^20,23−25. In 2019, Okami et al found the five-year overall survival and disease-free survival of stage IA1, IA2, IA3, IB were 91.6%, 81.4%, 74.8%, 71.5% and 88.2%, 73.6%, 64.5%, 60.1%, respectively²⁶. These results reveal that even comparing with stage IA1 invasive adenocarcinoma, AIS/MIA show a much better survival.

As the diagnosis time point is in advance, the surgical intervention followed by earlier detection can seem to falsely increase survival even though death point time is not delayed. Since the biologically progression pattern of lung cancer from pre- and minimal invasive stage to invasive stage is still unaddressed, we try to estimate if survival is truly prolonged by surgical treatment for AIS/MIA from the view of clinical statistics. Our estimation model regards that lung cancer will develop from pre- and minimal invasive stage into invasive stage without resection based on several reasons: a) The stepwise progression of lung adenocarcinoma proposed by Noguchi revealed that AIS/MIA would develop into IAC¹⁶. b) We follow the lead time estimating method in the work of Yang, which regards lung cancer will develop from stage I to stage IV¹⁷.

In our study, after being adjusted for the lead time, the gain in life years for adenocarcinoma diagnosed at pre-/minimally invasive stage is remarkable. In addition, once AIS/MIA progress to IAC, the 5-year disease-specific survival rate will significantly reduce from 100–73.5%. On one hand, surgical treatment performed at pre-/minimal invasive stage indeed provide excellent survival. On the other hand, AIS/MIA can develop into an invasive stage without surgical intervention²⁷. Resection of AIS/MIA can be regarded as a cure at pre- and minimally invasive stage for improving life expectancy. It is convincing that the excellent survival of AIS/MIA is not lead-time bias.

A recent study found that surgery approach made no influence on survival of AIS/MIA. and the overall surgical complication rate was significantly lower for patients with receiving wedge resection²⁰. These results indicated that sublobar resection without lymph node dissection might be the generally suitable surgical procedure for AIS/MIA. The exact diagnosis of AIS/MIA cannot be confirmed by radiology but requires the tumor being completely sampled by histology²⁷, a previous study demonstrated that the concordance rate between intraoperative frozen section diagnosis and final pathology for AIS/MIA was 95.9%²⁸. A followed study focused on the errors of frozen section and discovered that patients undergoing limited resection of invasive adenocarcinoma underestimated as AIS/MIA still had excellent prognoses²⁹. Thus, limited resection following intraoperative frozen section is enough to cure high-like AIS/MIA on image and guarantees the excellent survival benefit.

There are some limitations of our study. First, some AIS/MIA remains indolent and will not progress to invasive stage. According to the newest histological classification and linear progression proposed by Noguchi^15,16, we acknowledge that invasive lung adenocarcinomas are all developed from AIS/MIA. There will be a lead time of diagnosis if a lung adenocarcinoma was detected at pre-/minimal invasive stage. Second, we admit that the progression speed of AIS/MIA are different. In clinic, solid components and size growth were related with high probability of invasiveness^30–32. We also have observed stable pure GGOs grew after follow-up over 5 years and 10 years (Fig. 3), which indicated that AIS/MIA could grow slowly and develop into invasive stage after a long time. We cannot predict the speed of cancer progression and describe a specific model of cancer development for each AIS/MIA. For a certain patient, AIS/MIA may not progress in his/her life time. However, for entire group of patients with AIS/MIA featured as small GGO nodules, we can provide the information that there is a risk of cancer progression and once the adenocarcinoma progresses into invasive stage, the 5-year disease-specific survival rate will not be 100% and general life lost is 10.8 years.

In conclusion, with adjustment for the lead time between diagnosis of AIS/MIA and IAC, resecting lung adenocarcinoma at pre-/minimally invasive stage can improve life expectancy. Thus, the excellent survival of AIS/MIA is not lead time bias.

Computed Tomography

AIS

Adenocarcinoma in Situ

MIA

Minimally Invasive Adenocarcinoma

IAC

Invasive Adenocarcinoma

IASLC

International Association for the Study of Lung Cancer

ATS

American Thoracic Society

ERS

European Respiratory Society

GGO

Ground-glass Opacity

PSM

Propensity Score Matching

Statement: The investigation was conducted based on the Declaration of Helsinki and approved by the Institutional Review Board of the Fudan University Shanghai Cancer Center (No. 090977-1). Each patient signed informed consent to allow biological samples to be pathologically examined.

Funding: This work was supported by the National Natural Science Foundation of China (81930073), Shanghai Municipal Science and Technology Major Project (Grant No. 2017SHZDZX01), Shanghai Shenkang Hospital Development Center City Hospital Emerging Cutting-edge Technology Joint Research Project (SHDC12017102) and Shanghai Municipal Health Commission Key Discipline Project (2017ZZ02025 and 2017ZZ01019).

Disclosures: The authors declare no relevant conflicts of interest.

Sung H, Ferlay J, Siegel RL et al (2021) : Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. 71:209–249,
Aberle D, Adams A, Berg C et al (2011) Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365:395–409
de Koning H, van der Aalst C, de Jong P et al (2020) Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial. N Engl J Med 382:503–513
National Lung Screening Trial Research T (2019) Lung Cancer Incidence and Mortality with Extended Follow-up in the National Lung Screening Trial. J Thorac oncology: official publication Int Association Study Lung Cancer 14:1732–1742
Pastorino U, Silva M, Sestini S et al (2019) Prolonged lung cancer screening reduced 10-year mortality in the MILD trial: new confirmation of lung cancer screening efficacy. Ann Oncol 30:1162–1169
Gill RR, Jaklitsch MT, Jacobson FL (2013) Controversies in lung cancer screening. J Am Coll Radiol 10:931–936
Yang S-C, Lai W-W, Lin C-C et al (2017) Cost-effectiveness of implementing computed tomography screening for lung cancer in Taiwan. Lung Cancer
Zojwalla N, Fogelman D, Neugut AI (2004) Cancer Screening. In: Legato MJ (ed) Principles of Gender-Specific Medicine. Academic Press, San Diego, pp 693–702
Rollison DE, Sabel MS (2007) Basic Epidemiologic Methods for Cancer Investigations. In: Sabel MS, Sondak VK, Sussman JJ (eds) Essentials of Surgical Oncology. Mosby, Philadelphia, pp 21–38
Tzung B, Julien PJ (2010) Lung Cancer Screening. In: Lewis MI, McKenna RJ, Falk JA et al (eds) Medical Management of the Thoracic Surgery Patient. W.B. Saunders, Philadelphia, pp 197–200
Aberle D, Adams A, Berg C et al (2011) Reduced lung-cancer mortality with low-dose computed tomographic screening. 365:395–409
de Koning HJ, van der Aalst CM, de Jong PA et al (2020) Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial. 382:503–513
Travis WD, Brambilla E, Noguchi M et al (2011) International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma. J Thorac Oncol 6:244–285
Yotsukura M, Asamura H, Motoi N et al (2021) Long-Term Prognosis of Patients With Resected Adenocarcinoma In Situ and Minimally Invasive Adenocarcinoma of the Lung. J Thorac Oncol 16:1312–1320
Travis WD, Brambilla E, Nicholson AG et al (2015) The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol 10:1243–1260
Noguchi M (2010) Stepwise progression of pulmonary adenocarcinoma–clinical and molecular implications. Cancer Metastasis Rev 29:15–21
Yang S, Lai W, Lin C et al (2017) Cost-effectiveness of implementing computed tomography screening for lung cancer in Taiwan. 108:183–191
Yue C, Meng Q, Wang C et al (2016) The Estimation of Chinese LifeExpectancy in 2015 and 2020 and Influence Factors. Chin J Health Stat 33(1):4
Ishida H, Shimizu Y, Sakaguchi H et al (2019) Distinctive clinicopathological features of adenocarcinoma in situ and minimally invasive adenocarcinoma of the lung: A retrospective study. Lung Cancer
Zhang Y, Ma X, Shen X et al (2020) : Surgery for pre- and minimally invasive lung adenocarcinoma.J Thorac Cardiovasc Surg,
Zhang Y, Fu F, Chen H (2020) Management of Ground-Glass Opacities in the Lung Cancer Spectrum. Ann Thorac Surg
Zhang Y, Sun Y, Shen L et al (2013) Predictive factors of lymph node status in small peripheral non-small cell lung cancers: tumor histology is more reliable. Ann Surg Oncol 20:1949–1954
Kadota K, Villena-Vargas J, Yoshizawa A et al (2014) Prognostic significance of adenocarcinoma in situ, minimally invasive adenocarcinoma, and nonmucinous lepidic predominant invasive adenocarcinoma of the lung in patients with stage I disease. Am J Surg Pathol 38:448–460
Murakami S, Ito H, Tsubokawa N et al (2015) Prognostic value of the new IASLC/ATS/ERS classification of clinical stage IA lung adenocarcinoma. Lung Cancer 90:199–204
Takahashi M, Shigematsu Y, Ohta M et al (2014) Tumor invasiveness as defined by the newly proposed IASLC/ATS/ERS classification has prognostic significance for pathologic stage IA lung adenocarcinoma and can be predicted by radiologic parameters. J Thorac Cardiovasc Surg 147:54–59
Okami J, Shintani Y, Okumura M et al (2019) Demographics, Safety and Quality, and Prognostic Information in Both the Seventh and Eighth Editions of the TNM Classification in 18,973 Surgical Cases of the Japanese Joint Committee of Lung Cancer Registry Database in 2010. J Thorac Oncol 14:212–222
Travis WD, Brambilla E, Riely GJ (2013) New pathologic classification of lung cancer: relevance for clinical practice and clinical trials. J Clin Oncol 31:992–1001
Liu S, Wang R, Zhang Y et al (2016) Precise Diagnosis of Intraoperative Frozen Section Is an Effective Method to Guide Resection Strategy for Peripheral Small-Sized Lung Adenocarcinoma. J Clin Oncol 34:307–313
Zhang Y, Deng C, Fu F et al (2021) Excellent Prognosis of Patients With Invasive Lung Adenocarcinomas During Surgery Misdiagnosed as Atypical Adenomatous Hyperplasia, Adenocarcinoma In Situ, or Minimally Invasive Adenocarcinoma by Frozen Section. Chest 159:1265–1272
Yanagawa M, Johkoh T, Noguchi M et al (2017) Radiological prediction of tumor invasiveness of lung adenocarcinoma on thin-section CT. Med (Baltim) 96:e6331
Saji H, Matsubayashi J, Akata S et al (2015) Correlation between whole tumor size and solid component size on high-resolution computed tomography in the prediction of the degree of pathologic malignancy and the prognostic outcome in primary lung adenocarcinoma. Acta Radiol 56:1187–1195
Lee KH, Goo JM, Park SJ et al (2014) Correlation between the size of the solid component on thin-section CT and the invasive component on pathology in small lung adenocarcinomas manifesting as ground-glass nodules. J Thorac Oncol 9:74–82

Download PDF

Reviews received at journal
01 Apr, 2022
Reviewers invited by journal
30 Mar, 2022
Editor assigned by journal
29 Mar, 2022
First submitted to journal
29 Mar, 2022

You are reading this latest preprint version

Detection and Treatment of Lung Adenocarcinoma at Pre-/minimally Invasive Stage: Is It Lead-time Bias?

Status:

Version 1

Abstract

Figures

Introduction

Methods

Results

Discussion

Abbreviations

Declarations

References

Status:

Version 1