Natural growth and disease progression of non-small cell lung cancer evaluated with 18F-fluorodeoxyglucose PET/CT

doi:10.1016/j.lungcan.2012.06.010

Lung Cancer

Volume 78, Issue 1, October 2012, Pages 51-56

https://doi.org/10.1016/j.lungcan.2012.06.010 Get rights and content

Abstract

Purpose

The aims of this study were to: (1) estimate the volumetric and metabolic growth rate of non-small cell lung cancer (NSCLC), (2) evaluate disease progression prior to treatment, and (3) explore the effects of tumor growth rate and time to treatment (TTT) on survival outcome.

Methods

Patients with inoperable stages I–III NSCLC with serial pre-treatment PET/CT scans were eligible for this study. PET-derived metabolic tumor volumes (PET-MTV) and CT-derived gross tumor volumes (CT-GTV) were contoured using PET/CT information. Normalized standardized uptake values (NSUV) in tumors including the NSUVmean and NSUVmax were measured. Tumor growth rates expressed as doubling time (DT) were estimated using an exponential model. Pre-treatment disease progression defined as the development of any new site of disease on PET/CT and change in TNM stage (AJCC 7th ed.) were recorded. Growth rate and tumor progression were analyzed with respect to overall (OS) and progression free survival (PFS).

Results

Thirty-four patients with a median inter-scan interval (ISI) of 43 days and TTT of 48 days were analyzed. Tumor volumes showed remarkable inter-scan growth while NSUV did not increase significantly. The DT for PET-MTV, CT-GTV, NSUVmean and NSUVmax were 124, 139, 597, and 333 days, respectively. Pre-treatment disease progression occurred in 20.6% patients with longer ISI being a significant risk factor (OR = 1.027, p = 0.02). The optimal threshold ISI to predict progression was 58 days (4.8% vs. 46.2%, p = 0.007). Neither tumor growth rates nor TTT were significantly correlated to OS or PFS.

Conclusions

NSCLC displays rapid tumor volume growth whereas NSUVmean and NSUVmax are relatively stable over the same time period. Longer delays before initiation of treatment are associated with higher risk of pre-treatment disease progression.

Introduction

Non-small cell lung cancer (NSCLC) is a biologically aggressive tumor, with rapid growth and metastatic spread leading to dismal survival outcomes. By the time tumor is detected on imaging modalities, it is likely to have been present as microscopic disease for a longer duration. Treatment delay in cancer patients is not an uncommon occurrence in daily practice often with multiple contributing factors such as scheduling delay during the diagnosis and staging process, patient delay related to anxiety or hesitation, and even issues relating to insurance policies [1]. Lung cancer genotyping is being increasingly performed prior to starting treatment and can contribute to delays as well. Excessive waiting time may lead to interval tumor growth and metastatic spread which can consequently alter treatment intent and strategy as well as clinical outcome. Therefore a more detailed understanding of the natural time-course of growth and disease progression in untreated NSCLC would assist with clinical decision making, determination of appropriate treatment strategies and surveillance protocols, and defining acceptable waiting time without compromise to patient outcomes [2], [3].

Several studies of lung cancer presenting initially as a small pulmonary nodule detected by X-ray or CT based screening programs have shown great heterogeneity in tumor volume doubling time (VDT) [4], [5], [6], [7], [8]. However, there is little published data on the natural growth of lung cancer detected by routine medical care, when tumor size is generally larger and regional nodal metastases may already be present. Changes in tumor volumes and metabolic activity for untreated NSCLC on ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) have not been well-described.

The aims of this study, through serial PET/CT scans prior to administration of any active treatment, were to: (1) estimate the volumetric and metabolic growth rate of NSCLC, (2) evaluate disease progression prior to treatment, and (3) explore the effects of tumor growth rate and time to treatment (TTT) on survival outcome including overall survival (OS) and progression free survival (PFS).

Section snippets

Study population

This is a secondary analysis of a subgroup of patients prospectively enrolled in a series of functional imaging-related studies at the University of Michigan. These investigational studies were approved by the local institutional review board (IRB). Patients with either unresectable or inoperable stages I–III NSCLC treated with radiation therapy (RT), with or without concurrent chemotherapy, were eligible. Per protocol, pre-RT PET/CT scans were performed within two weeks of the CT simulation.

Patients characteristics

A total of 118 patients were enrolled in a series of functional imaging-related studies between 2003 and 2010 and eventually 34 patients were eligible for this analysis. Thirty patients received both scans at the same institution and 4 patients had crossover PET/CT studies at both UMH and VA-AA. The demographics and tumor characteristics of the patients in this secondary analysis were similar to those who were not included. General patient demographics and tumor characteristics are shown in

Discussion

In this study of NSCLC diagnosed during routine clinical care, tumor volumetric measurements increased remarkably in a short interval. In contrast, tumor metabolic activity (NSUVmean and NSUVmax) remained relatively stable during the same period of time. VDT of early stage lung cancer has been widely studied based on X-ray and CT evaluations of pulmonary nodules and has a strikingly broad range [3], [4], [5], [6], [7], [8], [13], [14]. One study found that the mean VDT of pulmonary nodule was

Conclusions

The natural history of NSCLC diagnosed at routine clinical care based on FDG-PET/CT is that of rapid growth in tumor volume with relatively stable tumor metabolic activity (NSUVmean and NSUVmax). Longer waiting time before treatment is associated with higher risk of pre-treatment disease progression. For treatment delays of longer than 2 months after initial PET/CT examination, repeated staging workup is recommended.

Funding

This work was funded in part by R21CA127057 and R01 CA142840.

Conflict of interest statement

None declared.

Acknowledgements

We sincerely thank Yue Cao, Ph.D., Randall K Ten Haken, Ph.D., and Marc Kessler Ph.D. for the establishment and maintenance of FIAT work station.

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A long interval between 4D-CT and PFT was due to the fact that several patients received PFT as part of the standard of care rather than specifically for the study. However, the effect is considered small because the intervals were much shorter than the tumor volume doubling time of 139 days (median) reported by Wang et al (45). SPECT provides respiration-averaged ventilation images, which may be better compared with 4D-CT ventilation images averaged over a respiratory cycle.
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In an institutional review board–approved prospective clinical trial, 4D-CT imaging and PFT and/or SPECT ventilation imaging were performed in thoracic cancer patients. Regional ventilation (V_4DCT) was calculated by deformable image registration of 4D-CT images and quantitative analysis for regional volume change. V_4DCT defect parameters were compared with the PFT measurements (forced expiratory volume in 1 second (FEV₁; % predicted) and FEV₁/forced vital capacity (FVC; %). V_4DCT was also compared with SPECT ventilation (V_SPECT) to (1) test whether V_4DCT in V_SPECT defect regions is significantly lower than in nondefect regions by using the 2-tailed t test; (2) to quantify the spatial overlap between V_4DCT and V_SPECT defect regions with Dice similarity coefficient (DSC); and (3) to test ventral-to-dorsal gradients by using the 2-tailed t test.
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^☆: Disclosures: This work was presented as a poster presentation at the 52nd Annual Meeting of American Society for Therapeutic Radiology and Oncology (ASTRO) held in San Diego, California, October 31–November 4, 2010.

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Published by Elsevier Ireland Ltd.

Natural growth and disease progression of non-small cell lung cancer evaluated with 18F-fluorodeoxyglucose PET/CT☆

Abstract

Purpose

Methods

Results

Conclusions

Introduction

Section snippets

Study population

Patients characteristics

Discussion

Conclusions

Funding

Conflict of interest statement

Acknowledgements

Int J Radiat Oncol Biol Phys

Chest

Clin Radiol

Clin Radiol

J Thorac Oncol

Int J Radiat Oncol Biol Phys

Eur J Cancer

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Validation of two models to estimate the probability of malignancy in patients with solitary pulmonary nodules

Thorax

On the growth rates of human malignant tumors: implications for medical decision making

J Surg Oncol

Natural growth and disease progression of non-small cell lung cancer evaluated with ¹⁸F-fluorodeoxyglucose PET/CT☆