The value of V/Q SPECT/CT lobar quantitation for pre-treatment assessment of lung malignancy.

Introduction
Lung cancer affects 2.4 million people annually worldwide (1). Prognosis depends on staging and five-year survival ranges from 68–92% in stage I to 0–10% in stage IV (2). Low-dose computed tomography (CT) screening reduces mortality by 20–30% by promoting earlier diagnosis (3-6) and allowing potentially curative surgery for early-stage lung cancer. Screening-detected participants often have emphysema due to the shared risk factor of smoking (7). Participants unfit for surgery may be offered stereotactic ablative body radiotherapy (SABR), definitive radiotherapy or image-guided ablation. Multidisciplinary teams make management recommendations, often informed by a patient’s performance status and lung function.
Operative work-up includes pulmonary function testing (PFT) to calculate predicted post-operative (PPO) forced expiratory volume in 1 second (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO), which can be corrected for haemoglobin (DLCOc). Poor PPO lung function indicates a higher risk, requiring further risk stratification with exercise testing (7). The American College of Chest Physicians (ACCP) method estimates PPO lung function using CT appearances, subtracting the volume contribution of the malignant lobe (8). This approach applies the following formulae:
where FEV1 represents the best measured post-bronchodilator value, y denotes the number of functional, unobstructed lung segments to be removed, and z represents the total number of functional segments (9 in the left lung and 10 in the right lung).
CT-based predictions ignore variability of the amount of air and blood in each lobe available for gas exchange. This variability is likely significant in airways disease and can only be inferred from visible disease on the CT. Existing methods of functional assessment including planar ventilation-perfusion (V/Q) and perfusion single photon emission computed tomography/computed tomography (SPECT/CT) assess ventilation, perfusion and volume often independently, without accounting for the interrelationship between these components (9). There is no current universally applied method for predicting post-treatment lung function for sub-lobar resection or SABR.
The limitations of current prediction models can be addressed using V/Q scan to incorporate the quantification of air and blood in addition to lobar volume for a truer assessment of lobar function. We have developed novel software [RAH V/Q SPECT/CT Quantification (RAHVQSQ)] which can perform lobar quantification of V/Q SPECT/CT data. This program incorporates quantified lobar ventilation radioactivity and lobar perfusion radioactivity from the V/Q scan, and lobar volume from the CT to generate a novel index called Ventilation-Perfusion Capacity Differential Index (VQCDI). This index represents the amount of air and blood per unit lung volume in each lobe expressed as a percentage of both lungs, thus reflecting the differential contribution from each lobe to total lung function. We aim to test the feasibility of using VQCDI to accurately predict PPO reductions in FEV1 and DLCO from pre-operative results by comparing pre-treatment predictions with post-treatment measurements in cases of lobectomy, sub-lobar resection, and SABR. As a comparison, synonymous with current practice of using the CT to estimate residual lung reserve, we also used the CT lobar quantification component of our program (CT-based volumetric predictions, Vol%) to predict post-treatment FEV1 and DLCO. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2205/rc).

Methods

Quantitative V/Q SPECT/CT
RAHVQSQ is an in-house software, developed using Interactive Data Language (IDL). From CT data, a 3-dimensional map is created from which the operator annotates lung fissures, segmenting the lungs into individual lobes. The CT map is then fused with the V/Q SPECT datasets. The program then quantifies the radioactivity in each lobe in the ventilation scan (99mTc Technegas®, Cyclomedica, Kingsgrove, Australia) and the perfusion scan (99mTc MAA, DRAXIMAGE MACROSALB®, Jubilant Radiopharma™, Montreal, Québec, Canada), and the lobar volume from the CT. Within the SPECT/CT matrix of each lobe, the numerical datum of each voxel in the ventilation and perfusion scans is multiplied. The array of product values for each voxel that the lobe occupies is then summed and divided by lobar volume determined from the CT map. The resultant quantity is thus a measure of the amount of air and blood per unit lung volume. For example, the right upper lobe (RUL) is represented by:
The quantity of each lobe is then expressed as a percentage of all 5 lobes. This percentage, which we called VQCDI, is a reflection of the percentage differential contribution to total lung function. For example, for the RUL:
Post-lobectomy FEV1 and DLCO can be predicted from pre-operative PFTs by subtracting the percentage of loss of lung function based on the VQCDI for the lobe that is being resected.
For comparison, based on current practice of using CT alone to estimate post-treatment FEV1 and DLCO, we used the lobar volume quantification of our CT map expressed as a percentage of total lung volume, which we called Vol%.
RAHVQSQ allows the flexibility of separately quantifying sub-lobar resection by annotating surgical resection margins (Figure 1). The software is also able to use CT data from a V/Q SPECT/CT acquired from a hybrid gamma camera, as well as a CT acquired separately. This includes an SABR planning CT. From the latter, we quantified the amount of lung injury based on the isocontour zones that represent 100%, 75%, 50%, and 25% of the prescribed radiotherapy dose (Figure 2).
V/Q scans were acquired using standard SPECT/CT protocol on a Siemens Discovery or Intevo (Siemens Healthcare, Erlangen, Germany) hybrid camera.

Study population
This prospective study sequentially enrolled participants at the Royal Adelaide Hospital. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study obtained Ethics and Governance approval from the Central Adelaide Local Health Network (CALHN) Human Research and Ethics Committee (HREC reference 12150). The Royal Adelaide Hospital is a CALHN institution and the only network site with the required nuclear medicine facilities. Informed consent was obtained from all individual participants for the procedures performed. Included patients had early-stage lung cancer, oligometastatic disease or high-risk nodules undergoing lobectomy, sub-lobar resection (wedge or segmentectomy) or SABR. Exclusion criteria included life expectancy <1 year, age <18 years, pregnancy, inability to consent or egg allergy precluding the Q scan. Recruitment occurred through a multi-disciplinary lung cancer meeting where management recommendations were made.
All participants completed standard pre-treatment PFTs at an accredited lung function laboratory with FEV1 and DLCO measurements.
Once enrolled, participants underwent quantitative V/Q SPECT/CT, using RAHVQSQ to derive VQCDI and Vol% which were used to predict post-treatment FEV1 (PPO FEV1) and DLCO (PPO DLCO). At 6-month post-treatment, PFTs were repeated and participants underwent respirologist assessment to exclude complications that could compromise follow-up assessment. The PPO FEV1 and DLCO were then compared to the post-treatment measurements.
Pre-bronchodilator FEV1 was used preferentially as it was consistently measured pre- and post-procedure in all participants. Many patients did not receive post-bronchodilator testing during the COVID-19 pandemic as part of hospital protocol. DLCO data were analysed with and without haemoglobin correction.

Statistical analysis
To evaluate pre-treatment prediction concordance with post-treatment measurements, a Pearson correlation coefficient (R) was calculated. Intraclass correlation coefficients (ICC’s) were also estimated from 2-way mixed-effects models (subjects as the random effect and measurement technique as the fixed effect) using an absolute agreement definition. Since linear correlation does not necessarily equate to agreement, Bland-Altman analysis was performed.
The analysis was divided into two groups: (I) surgical participants, including those undergoing lobectomy and sub-lobar resections and (II) SABR participants. We sub-analysed smokers and participants with emphysema to assess the model performance in heterogenous lung disease. For SABR cases, we conducted an exploratory evaluation performing sub-analyses of isocontour zones representing the delivery of different percentages of the prescribed radiation dose (Figure 2). Feasibility in using this tool to evaluate the field of radiation that most affects lung function was assessed

Results
Sixty participants were enrolled between May 2021 and February 2024, with follow-up completed in December 2024. Seven participants were excluded, one with unresectable chest wall invasion, one with mediastinal progression precluding operative management, one for metastatic progression requiring systemic treatment, three who declined post-treatment PFTs and one with unilateral diaphragmatic paralysis preventing reliable assessment of lung function post-operatively.
The final analysis included 53 participants (mean age 67.68 years, 62.26% females) (Table 1). Baseline Eastern Cooperative Oncology Group (ECOG) was 0 in 75.47%, 1 in 22.64% and 2 in 1.89% of participants. At diagnosis, 28.30% were active smokers, 49.06% former and 22.64% never-smokers. Among ever-smokers, mean pack-years was 35.20. Mean pre-treatment weight was 75.16 kg, height 1.65 m and body mass index (BMI) 27.43 kg/m2. Mean post-treatment weight and BMI were not significantly different. Pre-treatment PFTs identified obstructive ventilatory disease consistent with emphysema in 25 (47.17%) participants. The mean baseline FEV1 was 2.04±0.67 L, mean DLCO 16±5.10 mL/min/mmHg and mean DLCOc 16.27±4.31 mL/min/mmHg. There were no significant differences in pre- and post-treatment haemoglobin or oxygen saturations.
Surgical resection was performed in 40 participants. Of these, 26 (49.06%) had lobectomy, 13 (24.53%) had sub-lobar resection and 1 (1.89%) had staged lobectomy with SABR for synchronous primary lung cancers (Table 1). Thirteen (24.53%) received SABR alone.
Histopathology was available in 51 patients including all surgical cases and most participants who underwent pre-treatment biopsy. There were 42 participants diagnosed with adenocarcinoma, 3 squamous cell carcinomas, 1 atypical carcinoid, 1 typical carcinoid, 1 large cell carcinoma and 1 oligometastatic urothelial carcinoma. Two had benign diagnoses on excision including one sclerosing pneumocytoma and one organising pneumonia. Two participants proceeded to SABR without diagnostic biopsy (Table 2).
Most cancers were early-stage including 42 (79.25%) with stage I malignancy. Of these, 3 (5.67%) were stage IA1, 23 (43.40%) stage IA2, 6 (11.32%) stage IA3 and 10 (18.87%) stage IB. Five participants (9.43%) were stage IIA, 2 (3.77%) stage IIB, and 1 (1.89%) stage IIIA.

FEV1
Among all surgical participants, there was a strong correlation between the VQCDI predicted and the measured FEV1 (R=0.92, ICC =0.908) with strong agreement [mean difference −0.096 L, limits of agreement (LOA) −0.524 to 0.332 L] (Table 3, Figure 3A). Vol% had lower correlation (R=0.869, ICC =0.830) and lower agreement with a greater mean difference −0.174 L and wider LOA (−0.728 to 0.381) (Figure 3B). VQCDI demonstrated similar degrees of correlation and agreement, with comparable or superior results to Vol%, across the lobectomy and sub-lobar resection subgroups, and among smokers and emphysema subgroups.

DLCO (uncorrected)
Among all surgical participants, there was a strong correlation between the VQCDI predicted and the measured uncorrected DLCO (R=0.899, ICC =0.874) with favourable agreement (mean difference: −0.994 mL/min/mmHg). Limits of agreement were wide (−4.923 to 2.935 mL/min/mmHg) (Table 3, Figure 3A). A similar degree of correlation and agreement were seen across the lobectomy and sub-lobar resection subgroups, and among the smoker and emphysema subgroups. Vol% had a slightly lower correlation (r=0.876, ICC =0.790) in all surgical participants with lower agreement −1.678 mL/min/mmHg (LOA −6.064 to 2.708) (Figure 3B). Similar trends for correlation and agreement were seen for lobectomy and sub-lobar resection groups and among smokers and emphysema participants.

DLCOc
Among all surgical participants, there was strong correlation between VQCDI-predicted and measured DLCOc (R=0.921 and ICC =0.899) with favourable agreement (mean difference of −0.988 mL/min/mmHg). However, LOA were also wide −4.367 to 2.391 mL/min/mmHg (Table 3, Figure 3A). Similar correlation and agreement were observed across lobectomy and sub-lobar resection subgroups, and among smoker and emphysema subgroups. Vol% had slightly lower correlation (R=0.898, ICC =0.824) in all surgical participants with lower agreement (mean difference: −1.668 mL/min/mmHg; LOA: −5.415 to 2.080 mL/min/mmHg). Vol% results were also lower for lobectomy and sub-lobar resection subgroups, and among the smoker and emphysema subgroups.

SABR
Among SABR participants, VQCDI and Vol% demonstrated consistently high correlation and agreement for predicted post-SABR lung function. When predicting FEV1, estimates of post-SABR lung function were similarly strong at the 100%, 75% and 50% isocontour zones (R=0.907, 0.905, 0.892 and ICC =0.907, 0.909, 0.896). The 25% isocontour zone had the lowest correlation (VQCDI: R=0.816, ICC =0.748; Vol%: R=0.838, ICC =0.674) with the highest mean differences (VQCDI: −0.180 L; Vol%: −0.235 L).
Uncorrected and corrected DLCO showed similar patterns across isocontour zones. At the 25% isocontour zone, VQCDI demonstrated correlation and agreement comparable to the other zones (DLCO R=0.896, ICC =0.846, DLCOc R=0.888, ICC =0.840). Vol% produced a slightly higher correlation (DLCO R=0.939 and DLCOc R=0.937) with equivalent ICC values. However, both VQCDI and Vol% showed substantially larger mean differences at the 25% isocontour zone (VQCDI: −1.058 mL/min/mmHg; Vol%: −1.446 mL/min/mmHg and VQCDI: −1.046 mL/min/mmHg; Vol%: −1.430 mL/min/mmHg).

Discussion
We evaluated a novel VQCDI, generated by in-house developed SPECT/CT software, as a measure of lobar differential contribution to total lung function. This is the first prospective study to incorporate three physiological parameters of ventilation, perfusion and volume into a single metric. We prospectively evaluated feasibility of this index by using it to predict the reduction of lung function following curative intent lung cancer treatment with surgery or SABR. Pre-treatment lung function was measured conventionally with FEV1 and DLCO/DLCOc. The reduction in lung function parameters extrapolated from the VQCDI of the region of lung to be treated correlated well with the same measured parameters at least 6 months post-treatment. Qualitative assessment of pre-operative CT is the commonly used method for estimating lobar lung reserve. RAHVQSQ allows the quantification of volume of each lobe expressed as a percentage of the total lung volume or Vol%, which was used as the gold-standard for comparison. Our results signal that VQCDI may have more value in predicting the degree of loss of lung function than Vol%.
The strongest predictive value in surgical participants was observed for FEV1 using VQCDI. VQCDI achieved a correlation of R=0.92 with strong agreement ICC =0.908. Correlation and agreement were lower with Vol% (R=0.869, ICC =0.830). The strength of correlation and agreement persisted in smokers and patients with emphysema. A key novel finding was that RAHVQSQ enabled reliable sub-lobar functional assessment with high correlation and agreement (R=0.896, ICC =0.892), greater than vol% (R=0.806, ICC =0.770). This flexibility is not achievable with traditional volumetric methods and other commercial programs. Current evidence suggests that wedge resection best preserves lung function compared to segmentectomy or lobectomy, though declines in lung function are still significant, ranging from 8.6–21% for FEV1, and DLCO 11.2–16.0%, respectively (10). This novel flexibility of VQCDI may have a role in contemporary surgical practice, where sub-lobar resections are increasingly utilised.
VQCDI showed strong correlation for PPO DLCO in surgical patients (R=0.899, ICC =0.874) but with wider 95% LOA (−4.923 to 2.935 mL/min/mmHg) and mean difference of −0.994 mL/min/mmHg. DLCOc results were similar overall (R=0.921, ICC =0.899, mean difference −0.988 mL/min/mmHg, 95% LOA: −4.367 to 2.391). Correlation was strong in lobar and sub-lobar resection as well as smokers and emphysema subgroups compared to Vol%. However, the wider LOA for DLCO limits the reliability of VQCDI and Vol% as predictors for this parameter in the clinical setting. VQCDI consistently overestimated reductions in DLCO. A possible explanation is that DLCO reflects both alveolar volume and the transfer coefficient for carbon monoxide (KCO), which represents the efficiency of gas transfer per unit alveolar volume and is influenced by membrane thickness, surface area and gas partial pressure gradient. After resection or SABR, DLCO does not decrease proportionally with volume loss (11) due to redistribution of pulmonary blood flow to the remaining lung, increasing capillary volume and gas partial pressure, raising KCO. Despite reduced surface area, the net effect is a smaller-than-expected DLCO decline. Additional confounders affecting DLCO include the effect of exercise and unmeasured carboxyhaemoglobin from smoking which were not standardised peri-treatment. We intentionally waited 6 months before repeating PFTs to allow recovery. Any lingering post-treatment factors affecting breath-hold capability can also affect the quality of repeated lung function. This study forms the foundation for further quantitative studies using VQCDI to examine PPO redistribution of ventilation and perfusion affecting differential lobar function.
In SABR cohorts, small but significant declines in pulmonary function are reported post-treatment, with DLCO affected more than FEV1 (12-18). Declines up to 10% in slow vital capacity, FEV1 and DLCO have been observed (18). Studies postulate that the larger DLCO decline is attributed to low radiation doses applied to large lung volumes resulting in pulmonary microvascular damage (19), however appropriate multifactorial models predicting post-radiotherapy lung function remain lacking. RAHVQSQ uniquely permits fusion of V/Q SPECT with SABR planning CTs. From this, we could determine the non-segmental regions of the lung that received different amounts of radiation as a percentage of the prescribed dose. Correlation and agreement scores were strong and equivalent for the 50%, 75% and 100% isocontour zones. FEV1 correlation was lower at the 25% radiation dose zone. For DLCO/DLCOc, the 25% isocontour zone had equivalent correlation but larger mean differences compared to the other isocontour zones. Acute radiation pneumonitis post-SABR is well recognised to occur in the first 6 months post-treatment, occurring in up to 62% of patients. The latter fibrotic phase can occur for up to 2 years in 91% (20,21). Whilst the long-term changes of SABR are not captured in this study, VQCDI appears to show promise in predicting 6-month post-treatment changes and may serve as a novel tool for further studies to evaluate how SABR impacts lung function.
Functional imaging has previously been used to predict lung function. Planar V/Q (non-tomographic, 2-dimensional) acquired in anterior and posterior projections is a standard pre-procedural quantification method for lung volume reduction, lung cancer surgery and pre-lung transplant assessment. This method segments both lungs into six geometric zones (upper, middle and lower zone for each lung), which is useful for pneumonectomy planning but limited for lobectomy as these zones do not conform to lobar anatomy (22,23). Perfusion scintigraphy and SPECT-CT offer 3-dimensional lobar assessment and have shown improved prediction of PPO lung function compared to traditional anatomic and planar scintigraphy approaches. However, the existing literature analyses ventilation and/or perfusion datasets independently and does not interpret quantified ventilation, perfusion and volume data together to assess the differential contribution to lung function (24-26). Not accounting for the interdependence of these variables may misrepresent function in conditions such as emphysema, where ventilation-perfusion mismatch results in segments that appear functional but represent alveolar dead space. The same reverse perfusion mismatched defects are also seen in areas of pneumonic consolidation and atelectasis, where perfusion-only studies can overstate functional contribution. To our knowledge, VQCDI is the first scintigraphic-index to overcome this limitation by integrating all three physiological variables. Several recently published studies with similar methodology have evaluated PPO FEV1 and PPO DLCO against PPO measurements (Table 4). Arnon-Sheleg et al. (27) compared non-imaging segment counting, planar perfusion-only scintigraphy and perfusion-only SPECT-CT demonstrating good correlation but wide LOA for both FEV1(%) and DLCO(%) for all techniques. Yokoba et al. (28) assessed perfusion-only scintigraphy in lobectomy patients and demonstrated strong correlation at 12-month for PPO FEV1(L) and PPO DLCO(%) although correlations were slightly lower and mean differences and LOA wider than those observed with VQCDI. Moneke et al. (9) evaluated planar perfusion and perfusion-only SPECT-CT for PPO FEV1(L and %) and DLCO(%) with lower correlation at 3 months post resection than for VQCDI. Fourdrain et al. (29) compared five predictive methods, including segment-based algorithms (Nakahara and Juhl & Frost formulae), planar ventilation-only and perfusion-only, and quantitative CT (qCT) modified to exclude emphysematous parenchyma. qCT had the greatest correlation though all results were lower than VQCDI. The correlation of qCT was marginally higher than that of Vol%. Collectively, these studies suggest that segment counting and ventilation or perfusion-only methods can estimate PPO lung function, though correlation and agreement results appear lower than VQCDI. As segment-based volumetric assessment remains the most commonly used and guideline-recognised approach, Vol% was used as our comparator. Whilst VQCDI appears to show better correlation to post-procedure lung function than Vol%, further evaluation in larger, heterogeneous cohorts may help clarify the relative role of VQCDI among functional assessment methods.
Our V/Q SPECT/CT quantification method has previously demonstrated reproducibility with high intra- and interobserver concordance between 3 blinded readers evaluating participants undergoing transplant assessment for advanced airways disease (30). With no gold standard for V/Q lobar quantification, RAHVQSQ was verified against a commercial program. In blinded evaluation of duplicated studies of participants with end-stage emphysema undergoing bronchoscopic lung volume reduction, RAHVQSQ had close concordance with modified Q-Lung (GE HealthCare, Chicago, IL, USA) for estimated differential lobar ventilation, perfusion and volume percentages (31). These initial validations, performed on grossly abnormal V/Q datasets from participants with advanced airways disease, support the robustness of RAHVQSQ quantification capabilities. We have since applied this quantification process to other clinical areas. A recent, novel RAHVQSQ-derived index, was used to select target lobes for endobronchial valve lung volume reduction. Target lobe selection based on this index was highly concordant with selection based on gold-standard qCT (32).
FEV1 and DLCO were chosen endpoints due to established prognostic value. Low pre-operative FEV1 and DLCO predict higher peri-operative morbidity and mortality (33-37). DLCO also predicts long-term survival and quality of life (38,39), independent of FEV1 (40,41). Guidelines suggest surgery is low-risk if FEV1 and DLCO are >60%, if either is 30–60%, a stair climb or shuttle walk test is advised. If either is <30%, cardiopulmonary exercise test (CPET) with VO2 max measurement is recommended. A VO2 max <10 mL/kg/min or <35% predicted denotes high-risk, favouring minimally invasive surgery, sub-lobar resection or non-operative treatment like SABR. VQCDI may help to understand lung function changes in this group. Similarly, for upper lobe emphysema, combined lung volume reduction with cancer resection may be considered and VQCDI may be helpful in risk-stratifying those with parenchymal disease.
This study has several limitations. Firstly, RAHVQSQ is an in-house software, not generally available which limits reproducibility and generalizability. The concept and method of calculation may be adapted to other centres. The relatively small sample size from a single tertiary centre may introduce selection bias. Cancer type, stage, smoking history varied between individual participants. The use of sequential, prospectively enrolled participants and pre-specified subgroup analyses helps to mitigate these concerns. The study population was intentionally heterogenous, encompassing surgical and SABR cohorts and a spectrum of pulmonary reserve to test VQCDI performance across clinically relevant settings. Future studies in more homogeneous treatment-specific cohorts would help confirm generalisability. VQCDI was also validated against volumetric CT reflecting the historical gold standard used in clinical guidelines. Having demonstrated its accuracy against this technique, this study paves the way for future multicentre studies to compare VQCDI to existing SPECT-CT methods of lobar quantification in larger, homogenous cohorts to confirm clinical utility and reproducibility. We also acknowledge that pre-bronchodilator FEV1 was used for consistency, though post-bronchodilator values may have greater prognostic value in participants with airway obstruction.

Conclusions
This prospective feasibility study demonstrates that VQCDI appears to accurately predict post-treatment lung function reduction from lobectomy and sub-lobar resection in surgical patients. VQCDI also appears to be able to predict changes in lung function from acute radiation pneumonitis 6 months post-SABR. VQCDI outperforms volume-based Vol%, with higher correlations and agreement for FEV1 and DLCO, including in participants with smoking history and emphysema. Wider LOA for DLCO could reflect confounding test technical factors and post-treatment physiological adaptations. Larger, multi-centre studies with longer follow-up are required to further evaluate the utility and value of VQCDI in early-stage lung cancer treatment assessment.

Supplementary
The article’s supplementary files as