Low-dose versus standard-dose computed tomography-guided biopsy for pulmonary nodules: a randomized controlled trial

Study design

The study protocol of this single-center RCT was approved by our center’s Institutional Review Board. All participants gave written, informed-consent. In addition, this RCT was listed within ClinicalTrials.gov (NCT04217655).

From June 2020 to December 2020, consecutive eligible patients with PNs were randomly assigned into low-dose and standard-dose groups. Table 1 showed the scanning parameters of the low-dose and standard-dose CT.

Table 1 Scanning parameters between 2 groups

Inclusion criteria: (a) clinical cases with PNs, detected on CT; (b) solid PNs; (c) PNs > 8 mm; (d) PNs having intermediate-high risk for lung cancer, depending upon clinical/radiology-based characteristics [4].

Exclusion criteria: (a) patients who underwent CT-guided biopsy previously; (b) PNs which were stable in size for at least 1 year; (c) PNs that decreased in size during follow-up; (d) clinical cases having a history of intense cardiac, pulmonary, renal or coagulation dysfunctional conditions; and (e) patients who refused to join this RCT.

The primary endpoint of this RCT was diagnostic accuracy. The secondary endpoints included technical success, diagnostic yield, operation time, radiation dose, and biopsy-related complications.

Randomization and blinding

The eligible patients were randomly assigned into 1:1 low-dose and standard-dose groups through the block-randomization technique (block size: 8). The randomized computer-generated numbers were placed within sequentially-numbered, opaque, sealed envelopes. Before the biopsy, envelopes were opened by a member of the Science and Education department without a defined role in the trial. This RCT was single-blinded for the patients.

CT-guided biopsy protocols

All procedures were performed under the guidance of a 16-row CT (Philips™, Cleveland, OH, USA) operated through a CT-guided interventional radiology expert (10+ years). Only the spiral CT was used for guiding the biopsy procedures, while the CT fluoroscopy was not used.

The patient’s position was decided according to the sites of PNs. The needle-paths were chosen depending upon preoperative CT outcomes. The co-axial technique was employed during the procedure. First, a 17G outer needle (DuoSmart™, Modena, Italy) was used to pierce the lung-parenchyma, followed by a second CT scan to establish a needle-tip to displace it accordingly. Once the outer needle-tip touched the PN, an 18G inner semi-automatic core-needle (Wego™, Weihai, China) was inserted via the outer needle to obtain the samples from the PNs. A total of 3–4 samples were obtained from each PN and consequently submerged into 10% formaldehyde until pathology assessment was done.

After biopsy, another CT intervention was conducted to assess the procedure-associated complications.

Image reconstruction

CT raw data were reconstructed by a third-generation image reconstruction technique (iDose, Philips, Hybrid Model Based Iterative Reconstruction) with strength level of 5, slice thickness of 2 mm, and an increment of 1 mm. Reconstructions using a sharp reconstruction filter (Y-sharp) for lung structures and a standard reconstruction filter (B) for soft tissue structures.

Imaging subjectivity

Two radiologists (T.W. and E-L.L.) evaluated imaging standards independently. One radiologist (T.W.) had 15 years of experience in CT-guided intervention and the other (E-L.L.) had 8 years of experience in CT-guided intervention. Imaging-quality was evaluated across four categories according to the previous study for low-dose CT-guided lung biopsy [12]: category A: needle/PN were distinctly observable; category B: needle/PN were adequately observable; category C: needle/PN were only somewhat observable; and category D: needle/PN could not be seen. Therefore, only category A and B could be used for CT-guided biopsy procedures. In the case of category C or D images, tube voltage and/or current were adjusted to obtain higher quality images. However, the procedures should be considered a technical failure.

Evaluation of radiation dose

The radiation dose was assessed by the dose-length product (DLP) value. DLP was measured in mGy*cm and it was a measure of CT tube radiation output/exposure. DLP accounts for the length of the radiation output along the z-axis.

Definitions and diagnoses

PN was defined as a spherical/oval image of non-transparent lesions ≤ 3 cm in diameter with neighboring pulmonary parenchyma/non-linked to atelectasis, mediastinal lymphadenopathy, or pleural effusion [4]. Technical success for CT-guided biopsy was confirmed once pathologists finalised their diagnosis from extracted specimens [12, 13]. Biopsy-based diagnoses could be classified into four categories: (a) malignancy; (b) suspected malignancy; (c) specific benignity; and (d) non-specific benignity. Suspected malignancy was defined as atypical cells suspected of indicated malignancy [14]. Specific benignity was defined as dataset outcomes suggested defined benign-diagnosis, including hamartomas and tuberculosis [14]. Finally, non-specific benignity was defined as benign pathology characteristics that existed through and did not suffice for a formal diagnosis [14].

Resection was used to make the final diagnoses for both malignant and benign PNs. biopsy-based malignancy and specific benignity could be accepted as the final diagnosis [8,9,10,11,12,13]. Biopsy-based suspected malignancy and non-specific benignity could not be accepted as the final diagnoses, if they were not confirmed by resection, the CT medical observation would be useful for attaining a finalized diagnostic outcome. For an PN with ≥ 20% size-reduction (without anticancer treatments), or maintained dimensions (no change or decreased < 20%) for a 12 month-minimum period (with no anti-cancer treatments), the final benign diagnosis could be accepted [6, 14].

True-positive was postulated when biopsy-based malignancy/suspicious was confirmed as malignant at finalized-diagnosis. The true-negative was postulated when biopsy-based benignities confirmed benignities at finalized-diagnosis.

Diagnosis yield = (biopsy-based malignancy + biopsy-based specific benignity)/all cases. Diagnostic accuracy = (true positive + true negative)/all cases with the final diagnosis. Pneumothorax and lung hemorrhage were assessed by chest CT. Lung hemorrhage was considered as a novel consolidating/ground-glass opacity around the needle tract [15]. High-grade hemorrhage was defined as the width of needle tract hemorrhage > 2 cm [15].

Statistical analyses

The sample size was calculated based on diagnostic accuracy with the non-inferiority analysis. Based upon past investigations linked to CT-guided biopsy for PNs, we estimated that the diagnostic accuracy was 94% [6, 8, 12]. Based on the − 10% of non-inferiority margin with the one-sided significance category of 0.025, we estimated that 200 patients (100 patients per group) were needed after considering the 10% dropout rate.

Intention-to-treat (ITT) evaluations were performed depending on the total patient group quantity enrolled in this study. In contrast, per-protocol (PP) evaluations were performed depending on the total number of patients who achieved technical success and definite final-diagnoses.

The continuous data were compared through the independent sample t test when the distribution was normal, while Mann–Whitney U test was used if the distribution was not normal. Categorical data were compared through Pearson χ2/Fisher exact test. Univariate and multivariate logistic regression tests were used for predictive indicators of diagnosis accuracy and complications. Kappa analysis was conducted to assess inter-observer agreement regarding imaging-quality. All statistical analyses were conducted through SPSS® v.16.0 (SPSS Inc™, Chicago, Illinois, USA). The significance level was P < 0.05.

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