Pre-surgical lung biopsy in management of solitary pulmonary nodules: a cost effectiveness analysis

Abstract

Objectives: Tissue diagnosis prior to thoracic surgery with curative intent is vital in thoracic lesions concerning for lung cancer. Methods of obtaining tissue diagnosis are variable within the United Kingdom.

Methods: We performed a model-based analysis to identify the most efficient method of diagnosis using both a health care perspective. Our analysis concerns adults in the UK presenting with a solitary pulmonary nodule suspicious for a primary lung malignancy, patients with more advanced disease (for example lymph node spread) were not considered. Model assumptions were derived from published sources and expert reviews, cost data were obtained from healthcare research group cost estimates (2016–17). Outcomes were measured in terms of costs experienced to healthcare trusts.

Results: Our results show that CT guided percutaneous lung biopsy using an ambulatory approach, is the most cost-effective method of diagnosis. Indeed, using this approach, trust experience approximately half of the cost of an approach of surgical lung biopsy performed at the time of potential resection (‘frozen section’).

Limitations and conclusions: Whilst this analysis is limited to the specific scenario of a solitary pulmonary nodule, these findings have implications for the implementation of lung cancer screening in the UK, which is likely to result in increased numbers of patients with such early disease.

Keywords:

• Lung cancer
• diagnosis
• ambulatory lung biopsy
• cost effectiveness

Introduction

Lung cancer represents the leading cause of cancer-related death in the world¹. Non-small cell lung cancer (NSCLC) constitutes a heterogeneous group of pulmonary malignancies, the most common histological subtype of which is adenocarcinoma². Unfortunately, a significant proportion of patients with NSCLC present with advanced disease, conferring a poor prognosis, and are managed non-surgically, often with palliative intent. A smaller proportion of patients present with early-stage disease, including small solitary nodules limited to the lung. Such patients can be managed by curative surgical resection – with or without adjuvant chemotherapy. Patients with early-stage disease have significantly better prognosis with survival rates of 77–92% at 5 years³.

There is a wide differential diagnosis, including benign and malignant pathologies, of a solitary lung nodule; the definitive management of such lesions is contingent on tissue diagnosis⁴. Whilst surgery with curative intent is indicated in the majority of thoracic malignancies, surgical resection of benign lesions is not⁵ and could potentially be the subject of litigation⁶.

Methods for obtaining tissue prior to definitive resection consist of image-guided biopsy or intraoperative sampling of lesions.

CT-guided percutaneous lung biopsy (PLB) is a widely available technique of image-guided biopsy. This is typically performed with the patient admitted to a hospital bed (for between 3–6 h) for post-procedure monitoring to detect potential pneumothorax, the most common major complication⁷. Symptomatic or significant pneumothoraces are usually treated with inpatient admission and an underwater seal chest drain until the pneumothorax resolves. This approach is contingent on hospital bed availability and incurs costs associated with hospital admission, as well as patient inconvenience. Recently, a new method of outpatient management of pneumothorax has emerged in the UK using a highly portable Heimlich Valve Chest Drain (HVCD), which avoids hospital admission in the vast majority (>99%) of cases of PLB⁶. This ambulatory technique is gradually being adopted in UK centers.

An alternative approach to tissue diagnosis is to perform tissue sampling at the time of surgery. Limited resection of the lesion is performed with histopathological interpretation provided on an urgent basis (∼45 min), whilst the patient remains under general anesthetic. Surgery resumes once a diagnosis has been secured, with cases of proven malignancy proceeding to a definitive operation whilst cases of benign disease typically lead to conclusion of the surgery.

The advantages of combining diagnosis and management in one procedure are potentially negated by longer operative times and a rate of patients with a benign lesion undergoing surgery under general anesthetic for a diagnosis, which could have potentially been avoided with low morbidity pre-operative PLB under local anesthetic.

We sought to define the most economically efficient pathway for obtaining tissue diagnosis and radical treatment in patients with solitary pulmonary nodules suspicious for lung cancer amenable to potentially curative treatment with thoracic surgery.

Methods

Ethical approval

As a model-based analysis of data in the public domain, ethical approval was not sought

Healthcare perspective reference case model parameters

A decision tree model was created, evaluating the expected NHS cost for a nominal cohort of 100 patients with an isolated lung nodule referred for tissue diagnosis prior to definitive treatment. In line with the options described in the previous section, three strategies were evaluated:

1. CT-guided percutaneous lung biopsy, with significant iatrogenic pneumothorax, managed using admission and establishment of a conventional underwater seal drain.

2. CT-guided percutaneous lung biopsy with significant iatrogenic pneumothorax managed using ambulatory HVCD

3. Intraoperative frozen section prior to immediate resection

As the final common pathway – excision of a malignant lesion – is considered to be the same for all three strategies, the model evaluated only the differences in costs associated with reaching a definitive diagnosis. Routine diagnostic imaging (including CT and PET-CT) was considered to be identical amongst each pathway, and the associated costs were not modeled. Navigational and other advanced bronchoscopy techniques were not considered in our scenario, due to the lack of availability and user experience in the UK, and poor diagnostic performance in small and peripheral lesions⁸. In order to make robust comparisons between pathways, the common endpoint was set as the intraoperative point of definitive lesion management.

Care pathway assumptions

For strategy 1, it was assumed that all patients in whom an underwater seal chest drain was inserted would be admitted to hospital until the drain was withdrawn. For strategy 2, 99% of patients with HVCD inserted would be discharged home, returning as outpatients for removal of the drain. A nominal 1% of patients would be admitted to the hospital overnight. For option 3, it was assumed that 75% of patients would require a diagnosis confirmed by frozen section prior to resection, which would add 45 min to the procedure.

Clinical and cost inputs

Inputs for the model were derived, wherever possible, from published sources. Where published data were not available, the advice was sought from relevant clinicians. Costs of healthcare resources were drawn from NHS reference costs, rather than Payment by Results (PbR) tariffs, in order to reflect actual costs incurred by NHS Trusts for each element of each of the three pathways. All key inputs, together with their sources, are listed in Table 1.

Table 1. List of model assumptions and sources for data.

Parameter	Value used	Source
Clinical
Proportion of PLB resulting in pneumothorax	17.8%	Tavare et al.^6
Proportion of patients with pneumothorax discharged  without intervention	40%	Tavare et al.^6
Proportion of patients with chest drain requiring admission
Underwater drain	100%	Manhire et al.^7
HVCD	1%	Tavare et al.^6
Mean length of stay for admitted patients
Underwater drain	4 days	Hospital Admitted Patient Care 2016–17 (HRG DZ26B) [NHS Digital 2016]
HVCD	1 day	Tavare et al.^6
Proportion of surgically diagnosed patients  having frozen section prior to resection	75%	Marchevsky et al.12 Clinician advice
Duration of pre-resection procedure
With frozen section	80 mins	Clinician advice
Without frozen section	35 mins	Clinician advice
Rate of benign lesions	20%	Ginsberg and Rubinstein^17, Aberle et al.^10, van’t Westeinde et al.^11
Costs
PLB (outpatient procedure)	£194	NHS Reference costs 2016–17 (HRG YD03Z) [NHS Improvement]
Hospital stay (per night)	£389	NHS Reference costs 2016–17 (HRGs DX26G-P) [NHS Improvement]
Theatre time (per hour)	£1,200	Theatre – direct costs per hour Thoracic surgery 2016–17 [ISD Scotland]
Chest drain acquisition cost
Underwater drain	£98	Local Trust inventory
HVCD	£50	Local Trust Inventory
Frozen section	£136	Clinician advice: 1 h lab technician time (band 4) + 1 h consultant  pathologist time. Unit costs from [PSSRU]

Sensitivity analysis

In order to explore the impact of parameter uncertainty on comparative results, a deterministic sensitivity analysis was carried out, varying each input variable by ±20%.

Results

In the base case, strategy 1 (PLB and underwater seal drain) was associated with an expected cost of £931 per patient, strategy 2 (PLB with outpatient ambulatory HVCD) with an expected cost of £760 per patient and strategy 3 (intraoperative frozen section) with an expected cost of £1,477 per patient. In a typical unit undertaking 100 procedures per year, projected annual cost for CT-guided biopsy using HVCD versus conventional underwater seal chest drainage would be £17,089; versus intraoperative frozen section, where the projected annual savings would be £71,724. Detailed base case results are shown in Table 2, with the results of the sensitivity analysis shown in Table 3. Sensitivity analysis demonstrates that the conclusions are robust to individual parameter variation. Across a plausible range of input values (±20%), the relative cost performance of the three strategies remains constant, with strategy 2 – CT-directed biopsy with ambulatory HVCD management of incident pneumothorax – representing the lowest cost option across all scenarios. An illustrative diagram of the tree-based model is included in the Supplementary Appendix.

Table 2. Results of base case.

	Strategy 1	Strategy 2	Strategy 3
Patients entering pathway (N)	100	100	100
Pneumothorax (N)	18	18	n/a
Chest drain required (N)	7.2	7.2	n/a
Hospital admission required (N)	7.2	0.07	n/a
Proportion proceeding to surgery (%)	80	80	100
Frozen section required (%)	n/a	n/a	75
Cost of procedure (£)
Biopsy without pneumothorax	£194	£194	n/a
Biopsy with pneumothorax	£1,186	£226	n/a
Resection without frozen section	£700	£700	£700
Resection with frozen section	n/a	n/a	£1,736
Mean expected cost (£)
Overall	£93,065	£75,976	£147,700
Per patient	£931	£760	£1,477

Table 3. Deterministic sensitivity analysis.

Variable	Lower estimate	Upper estimate	Range
Strategy 1
Cost of hospital stay (per night)	£89,741	£96,388	£6,647
Mean length of stay	£89,741	£96,388	£6,647
Cost of biopsy (OP procedure)	£89,185	£96,945	£7,760
Cost of underwater drain	£92,855	£93,274	£419
% resulting in pneumothorax	£89,532	£96,598	£7,066
% of patients with underwater drain requiring admission*	£89,741	£93,065	£6,294
% of pneumothorax discharged without intervention	£90,709	£95,420	£4,711
% of benign lesions	£90,265	£95,865	£5,600
Strategy 2
Mean length of stay	£75,967	£75,984	£17
Cost of hospital stay (per night)	£75,967	£75,984	£17
Cost of biopsy (OP procedure)	£72,096	£79,856	£7,760
Cost of Heimlich drain	£75,869	£76,082	£213
% resulting in pneumothorax	£75,860	£76,091	£231
% of patients with Heimlich valve requiring admission	£75,967	£75,984	£17
% of pneumothorax discharged without intervention	£75,899	£76,052	£153
% of benign lesions	£73,176	£78,776	£5,600
Strategy 3
Cost of theatre time (per hour)	£120,200	£175,200	£55,000
% of VATS patients having frozen section	£131,160	£163,240	£32,080
Duration of biopsy procedure (mins)	£133,700	£161,700	£28,000
Waiting time for frozen section (mins)	£134,200	£161,200	£27,000
Cost of frozen section	£145,660	£149,740	£4,080
% of benign lesions	Not relevant to strategy 3

Discussion

Our results demonstrate that pre-surgical PLB in patients with solitary pulmonary nodules suspicious for lung cancer, as opposed to the intraoperative frozen section, is the most cost-effective management strategy for the NHS. Indeed, PLB performed on an ambulatory basis is associated with approximately half the cost of obtaining tissue at the time of surgery.

The cost savings are effected in two ways: Firstly, a pre-surgical biopsy can prevent patients with benign pathology from undergoing surgery⁹. Secondly, pre-surgical biopsy by any method is more financially efficient than the operating theatre costs associated with the 45-min delay encountered in obtaining intraoperative frozen section diagnosis. When expressed in terms of a time saving, PLB has the potential to save 56 operative hours per 100 patient biopsies.

The recent demonstration of cost-effectiveness and improved mortality of lung cancer screening this into sharp focus. Such screening programs are intended to increase the proportion of patients with early-stage diseases, as modeled above, with the implication that this improves survival. The high rates of resection of benign disease associated with these trials^10,11 are associated with low rates of pre-surgical biopsy. Our findings suggest that the cost-effectiveness of screening programs could be further improved by an ambulatory pre-surgical biopsy approach.

Our economic model has made several assumptions which are supported by published evidence where possible, several of which merit discussion.

Whilst histology is recommended for all patients prior to completion of definitive surgery, in cases of very high a priori of malignant lesions, some surgeons may opt to perform surgical resection without histology. Our model is based on a 75% rate of frozen section in patients undergoing lung resection without pre-operative histology – this is in line with other series examining the rate of frozen section in patients referred for surgery without histology^12,13, and in line with our own local experience, but the lack of national-level data regarding surgical practice is a limitation.

The accuracy of percutaneous CT-guided lung biopsy has not been assessed by our model. The rate of non-diagnostic biopsies in our institution is around 2%⁶, which is consistent with other published series concerning core needle biopsy^14,15. The management of patients following non-diagnostic biopsies is varied, but in a situation of a high pre-test probability of malignancy patients can proceed directly to surgery. In one large series, only 1% of 1116 patients were managed in this manner¹⁶, the exclusion of this from our model is, therefore, unlikely to affect our cardinal findings.

Our methodology is very likely to underestimate the difference between intraoperative tissue diagnosis and PLB, as our model does not concern the postoperative costs. Patients with benign diagnoses undergoing intraoperative tissue sampling would incur such post-operative costs, which are avoided in patients with benign pathology identified without the need for surgery⁹. The rates of benign resection in patients not undergoing pre-surgical biopsy are reported between 9–25%^10,17 in the literature.

Our results are contrary to a prior publication¹⁸, which found that a for a specific form of pulmonary lesion – ground glass nodules – direct surgical resection was associated with reduced total costs as compared with pre-surgical PLB. This result may be explained by the nature of this subtype of pulmonary nodule; slow-growing ground-glass nodules have a very high a priori of representing low-grade adenocarcinoma. The specificity and sensitivity of CT imaging for the final histological diagnosis in such lesions may limit the need for intraoperative frozen section. Our study was designed to represent the more general case, reflecting all possible subtypes of pulmonary nodule.

Whilst this study focused on cost-effectiveness from a health care perspective, consideration should be given to the morbidity and mortality costs of the approaches to tissue diagnosis in suspected lung cancer. Resection of benign disease can be significantly deleterious, exposing patients to both the unnecessary loss of respiratory reserve associated with lung resection and the associated morbidity and mortality of major thoracic surgery. Operative mortality of anatomical resection is around 2.5%¹⁹ and has been reported at around 1.5% in more modern techniques of minimally invasive surgery²⁰. In contrast, mortality from PLB is exceedingly rare, reported at 0.15% in one large survey²¹. Ambulatory lung biopsy has demonstrated comparable safety and diagnostic rates to other published series⁶.

Conclusions

The practice of percutaneous lung biopsy in solitary pulmonary nodules concerning for malignancy is associated with cost savings relative to intraoperative tissue diagnosis. Indeed, when performed on an ambulatory basis, incorporating Heimlich valve chest drain, costs are approximately halved. Even more importantly, when expressed as a total time saving, pre-procedural percutaneous lung biopsy can save 56 operative hours per 100 patient pre-operative biopsies performed.

Transparency

Declaration of funding

No funding was received for this study.

Declaration of financial/other relationships

There are no relevant financial disclosures. JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

JBa, AT, and SH conceived the study; JBe built the financial model with input from the remaining authors. Jba and SH wrote the manuscript with revisions from the remaining authors.

Acknowledgements

None reported.