A Prospective Outcomes and Cost-Effective Analysis of Surgery Compared to Stereotactic Body Radiation Therapy for Stage I Non-Small Cell Lung Cancer

doi:10.21203/rs.3.rs-4693878/v1

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Research Article

A Prospective Outcomes and Cost-Effective Analysis of Surgery Compared to Stereotactic Body Radiation Therapy for Stage I Non-Small Cell Lung Cancer

https://doi.org/10.21203/rs.3.rs-4693878/v1

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Background

To evaluate long-term outcomes, treatment costs, and quality of life associated with curative treatment of newly diagnosed stage I non-small cell lung cancer (NSCLC), by comparing surgery to stereotactic body radiation therapy (SBRT).

Methods

Multicenter consecutive prospective study of newly diagnosed stage I NSCLC patients independently assigned surgery or SBRT by a multidisciplinary tumor board, recruited prior to therapy initiation (n=59). Outcomes included total hospital charges, toxicities, complications, readmissions, and patient satisfaction/ quality of life (FACT-L). Multivariable logistic regression models analyzed the association of treatment type with dichotomous endpoints controlling for age, Charlson Comorbidity Index (CCI), and pre-treatment FACT-L; multiple linear regression was used for delta FACT-L.

Results

Of the 55 evaluable patients, 19 (35%) were males and 36 (65%) females. Thirty (55%) patients received SBRT and 25 (45%) received surgery with a mean age of 73 (57-85) and 67 (55-84) years, respectively. Median follow-up time was 514 days after SBRT and 648 days after surgery. The mean CCI for SBRT and surgery patients was 3.87 and 2.36, respectively. SBRT patients experienced significantly greater improvement in quality of life compared to surgery (delta FACT-L, 14, 95%CI, 2 to 26, p=0.0232) after adjusting for baseline FACT-L. CCI but not age, treatment type, or baseline FACT-L was significantly associated with readmissions (OR, 1.42, 95%CI, 1.08 to 2.00, p=0.0226). Interestingly, CCI was significantly lower (2.36±1.66, 3.87±2.84, p=0.0418) yet total hospital charges were significantly greater ($251,759±$215,643, $129,238±$86,588, p=0.0009) for patients receiving surgery verses SBRT.

Conclusions

Although limitations include small sample size and absence of recurrence data, these analyses justify further evaluation of long-term outcomes, including cost and quality of life, to optimize treatment assignment of early stage NSCLC patients. These observations reveal that, despite targeting patients with higher CCI, SBRT is more cost-effective, with a greater improvement in quality of life than surgery.

Trial Registration

Central Institutional Review Board (IRB) approval was obtained under expedited review and deemed minimal risk to patients (WCG Clinical IRB00000533 Study 1171593). All participating sites obtained local IRB approval before study initiation. Informed consent was obtained from all patients prior to study entry.

Stereotactic ablative radiotherapy (SABR)

Cost-effective

Surgery

Quality of Life

FACT-L

The standard of care for medically operable clinical stage I NSCLC is lobectomy with sampling or dissection of mediastinal lymph nodes. Stereotactic body radiation therapy (SBRT), also referred to as Stereotactic Ablative Radiation Therapy (SABR), is an accepted approach for clinical stage I NSCLC lesions in patients deemed medically inoperable. In addition, current clinical practice is to offer SBRT to patients with early stage lung cancer that are operable but at increased risk of post-surgical complications.

Sufficient evidence exists of efficacy and safety for inoperable patients with stage I NSCLC to receive SBRT instead of surgery. However, the benefit and/or risk of SBRT replacing surgery in the operable population is less clear. Three randomized controlled trials were attempted in the past 10 years (STARS, ROSEL and ACOSOG Z4099) comparing SBRT and surgery in stage I NSCLC patients.¹ Unfortunately, all three trials closed early due to insufficient patient accrual. A potential answer to this question is still years away provided a fourth randomized trial, VALOR, is able to achieve accrual goals. Single arm, phase II, and retrospective analyses have shown effectiveness and safety of SBRT in operable, stage I NSCLC.^2–5 Non-randomized studies of SBRT in early stage lung cancers suggest operable patients appreciate a similar overall survival as surgery.⁶ Additionally, population-based and propensity-matched studies support that both overall survival and disease-specific survival after SBRT are similar to those after surgery in the operable population.^6–11

Guiding our approach to the current study were multiple factors which will impact patient care in the near future. Enhanced screening for lung cancer, along with increased numbers of aging Americans, is expected to result in a rapid rise in lung cancer diagnoses with estimates showing a 50% increase by 2030.¹² There is also a significant and immediate need for data relating to cost-effectiveness, patient satisfaction, and quality of life resulting from both surgical and SBRT approaches in early stage NSCLC to inform not only clinicians, but also payers, hospital systems, patients, and legislators. It is critically important to patients and medical care organizations to “get it right” regarding the optimal treatment approach for early stage NSCLC.

This study was conducted by the Sarah Cannon, the global Cancer Institute of HCA Healthcare, which is developing community-based centers of excellence in thoracic malignancies. It was designed to compare multidisciplinary treatment selection and outcomes of SBRT to surgery using prospective data on patient satisfaction, quality of life, treatment costs, toxicity and complications in patients newly diagnosed with stage I NSCLC.

Site Selection and Regulatory

The study was conducted at 6 Sarah Cannon sites including Centennial Medical Center (Nashville, TN), Summit Medical Center (Hermitage, TN), Skyline Medical Center (Nashville, TN), Stonecrest Medical Center (Smyrna, TN), CJW Medical Center (Richmond, VA), and Henrico Doctor’s Hospital (Richmond, VA) in accordance with US regulations, applicable ICH E6 international standards of Good Clinical Practice, and institutional research policies and procedures. Sites were selected based on (1) presence of a prospective multidisciplinary thoracic tumor board; (2) Thoracic Oncology Nurse Navigation; (3) Radiation Oncology and (4) Thoracic Oncology services. Central Institutional Review Board (IRB) approval was obtained under expedited review and deemed minimal risk to patients (WCG Clinical IRB00000533 Study 1171593). All participating sites obtained local IRB approval before study initiation. Informed consent was obtained from all patients prior to study entry.

The design, analysis, and data interpretations were conducted independently by the investigators. All authors testify to the accuracy and completeness of the data with acknowledgement that there are limitations to real-world, retrospective data collection.

Participants

Patients with newly diagnosed stage I NSCLC were consecutively and prospectively enrolled to study after treatment assignment but before therapy initiation. Patients were independently assigned to one of two treatment arms, SBRT or surgical resection, based on operability, risk status, and standard practice by a multidisciplinary tumor board at each participating site. Those considered medically eligible for surgery consulted with a thoracic surgeon to determine the optimal surgical approach for a stage I NSCLC. All patients underwent interventional pulmonology evaluation with bronchoscopy, endobronchial ultrasound (EBUS) and directed biopsies of the primary tumor and regional lymph nodes. Those identified as medically inoperable with tumors stage I disease were evaluated for SBRT. Patients planning to receive a non-surgical ablative treatment other than SBRT such as radiofrequency ablation (RFA), cryotherapy, or microwave therapy were ineligible for participation. Planning for SBRT involved free-breathing 4DCT simulation, or deep inspiration breath-hold (DIBH), daily pre-treatment image guided radiation therapy (IGRT) via on-board linac cone-beam computed tomography (CBCT) and intrafraction motion monitoring with surface guided radiotherapy (SGRT).

Patients were required to be at least 18 years of age and functionally able to complete a quality of life assessment at baseline to participate in the study. Patients from vulnerable populations were not actively recruited nor excluded. The intent was for the SBRT cohort to be administered radiotherapy on 360-degree rotational gantry-based linear accelerators (TrueBeam™, Varian Medical Systems, Palo Alto, CA). However, two patients in the SBRT group were administered SBRT by a robotic linear accelerator. Under “intent-to-treat,” these two patients remained in the analyses.

Data Sources and Management

Electronic Health Records Data

Data for the study was obtained through HCA Healthcare’s Electronic Data Warehouse (EDW) which houses detailed and structured clinico-demographic, medical, medical history, pharmacy, laboratory, outcomes, and charge data from electronic health records (EHR) affiliated with HCA Healthcare, including Sarah Cannon Cancer Centers. Clinico-demographics such as age, sex, race, ethnicity, smoking status, and comorbidities were extracted as structured data from the EDW. Surgical procedures (e.g., wedge resection, pneumonectomy, and lobectomy), post-surgical complications (e.g., pneumonia, prolonged air leak, deep vein thrombosis, chest wall pain, pneumonitis, and cardiac conditions), and readmissions within 90 days after surgery or 365 days after SBRT were extracted. All charges associated with the initial treatment for stage I NSCLC (SBRT or surgery) and any charges for readmissions occurring during the post-treatment follow-up were extracted. The Charlson Comorbidity Index (CCI) was calculated according to established literature using International Classification of Diseases 10th revision codes (ICD-10-CM), excluding the primary lung cancer diagnosis.¹³

Radiotherapy characteristics of SBRT were manually abstracted from each site EHR by research study staff and included target location, central or peripheral lung tumor location, PTV (Planning Target Volume), number of fractions, fraction size, total dose, elapsed days for SBRT treatment, PTV100%, minimum dose, maximum dose, mean dose, lungs V20%, and conformality index.

Quality of Life Data (FACT-L)

After informed consent, participants were administered the Functional Assessment of Cancer Therapy for Lung cancer (FACT-L) questionnaire, which was to be completed before SBRT or surgery and between 90 to 180 days after completing treatment. The FACT-L tool is patient validated and includes both satisfaction and quality of life measures. Environmental exposures were not captured. Data coordinators manually abstracted questionnaire results into the study database.

Outcome Measures

Complications and Readmissions

Complications were defined as any of the following occurring during the course of treatment or within the defined follow-up period after each treatment completion: pneumonia, air leak/pneumothorax, deep vein thrombosis, chest pain, arrhythmia, or hemorrhage. All-cause admissions occurring after treatment at any HCA Healthcare-affiliated facility, but within the defined follow-up period, were considered readmissions. Post-surgical complications are typically acute and occur within the first 90 days, while complications for SBRT are observed up to 365 days after treatment completion.¹⁴ Thus, the defined follow-up period for readmissions and complications was 365 days for patients undergoing SBRT and 90 days for those receiving surgical resection.

Total Charges

Total charges were separated into three categories for inclusion and sub-analyses; pre-treatment charges, treatment charges, and post-treatment charges. All dollar amounts from 2017 to 2019 were scaled up to 2020 dollars using the U.S. Bureau of Labor Statistics Consumer Price Index (CPI) for All Urban Consumers (https://www.bls.gov/cpi/data.htm).¹⁵ Pre-treatment charges were defined as all charges occurring during the 14 days preceding surgery or initiation of SBRT. Treatment charges were defined as charges occurring on the day of surgery or inclusive of the dates between SBRT initiation and final dosing. Post-treatment charges were defined as all charges up to 365 days after the final radiotherapy dosing or the date of surgery for SBRT and surgery, respectively. Finally, the sum of pre-treatment, treatment, and post-treatment charges make up the total charges reported.

Post-Treatment FACT-L

The FACT-L score (Version 4) consists of 36 self-reported quality of life measures with questions related to 5 categories including emotional, social, physical, and functional well-being as well as lung cancer specific symptomology and cognitive function. Each question is assigned to a five-point scale from 0 (not at all) to 4 (very much). The total FACT-L score ranges from 0 to 144, where minimal meaningful differences of 5 to 7 have been reported.¹⁶ Post-treatment FACT-L will be used as the outcome measure in multivariable analyses looking at the association of treatment type with quality of life.

Statistical Analyses

All statistical analyses were performed using R v3.6.3 utilizing the psych and comorbidity packages; whereas, pwr and powerMediation packages were used for post-hoc power analyses. All statistical tests were two-tailed with a 0.05 alpha level, except for Chi-squared and Fisher’s Exact tests which are inherently one-tailed.

Descriptors and Frequencies

Age, CCI, pre-FACT-L, post-FACT-L, pre-treatment charges, treatment charges, post-treatment charges, and total charges were all reported as means with standard deviation. Wilcoxon rank sum tests, or t-tests when approximately normal, were used to evaluate differences between those receiving SBRT vs. surgery. The number and frequency distribution of sex, race, smoking status, complications, and readmissions were also reported. Significant differences between distributions of these categorical variables were assessed with Chi-square or Fisher’s exact tests where applicable.

Cost-Effectiveness and Quality of Life

For those patients with both pre- and post-treatment FACT-L completed (n = 38), the difference in total cost between SBRT and surgery as well as the change in quality of life from pre- to post-treatment was assessed using Wilcox rank sum tests.

In addition, the cost-effectiveness ratio was calculated as the difference in means of total charges for SBRT and surgery divided by the difference in means of the change in pre- and post-treatment FACT-L scores according to the following equation: (mean (Total Charges_SBRT) – mean (Total Charges_Surgery)) / (mean (FACT-L_SBRT(Pre) – FACT-L_SBRT(Post)) – mean (FACT-L_Surgery(Pre) – FACT-L_{Surgery(Post)}))

$$\:CE=\frac{{\stackrel{-}{T}}_{sbrt}-{\stackrel{-}{T}}_{surgery}}{{\stackrel{-}{{\Delta\:}F}}_{sbrt}-{\stackrel{-}{{\Delta\:}F}}_{surgery}}$$

Where $\:CE$ represents the cost-effectiveness ratio, $\:\stackrel{-}{T}$ represents the mean total charges, and $\:\stackrel{-}{{\Delta\:}F}$ represents the mean change in FACT-L between pre and post-treatment assessments.

The cost-effectiveness ratio was reported as charges in dollars per unit increase in the FACT-L score.

Multivariable Analyses

Multivariable logistic regression models were utilized to analyze the association of treatment with complication and readmission, controlling for age, CCI, and pre-treatment FACT-L score for patients that completed the pre-treatment FACT-L assessment (n = 52). The association of treatment type (SBRT vs. Surgery) with total charges and post-treatment FACT-L were assessed with multivariable linear regression models controlling for age, CCI, and pre-treatment FACT-L score. Only patients completing both the pre- and post-treatment FACT-L questionnaires were included in the analyses for total charges and post-treatment FACT-L (n = 38). For all models, the following interaction terms were assessed: age x treatment, surgery x CCI, CCI x age.

Patient Characteristics

Between 09/07/2017 and 11/11/2020, 59 patients were consented for the study. Four patients were excluded from the analysis due to patient withdrawal after consent or screen failure. Therefore, a total of 55 stage I NSCLC patients were included in the analysis. Thirty (55%) patients received SBRT and 25 (45%) patients underwent surgical removal of small lung tumors; all but three patients completed at least the baseline FACT-L (Fig. 1).

Radiotherapy technique, dosimetric constraints, and fractionation schedules were as per the RTOG published trials (0236, 0618, 0915, and 0813) for peripheral^17–19 and central²⁰ tumor locations. Lesions considered within 2 cm of the proximal bronchial tree were defined as ‘central’ targets and 5 fractions were used. Key details of SBRT are summarized in Table 1.

Table 1

SBRT Tumor Location and Treatment Details
SBRT Tumor Location (n = 30)	SBRT Target Lesion Number (n = 60)^a
Right	19 (32%)
Left	11 (18%)
Central	10 (17%)
Peripheral	20 (33%)
SBRT Treatment Details (n = 30)	SBRT Cohort Median (Range)
PTV Volume (cc)	26.4 (4.0 to 175.37)
Elapsed Time SBRT (days)	7 (3 to 13)
PTV Coverage (%)	95 (94 to 100.5)
Minimum Dose (cGy)	4474 (2518 to 4906)
Maximum Dose (cGy)	6182 (5562 to 7328)
Mean Dose (cGy)	5429 (5176 to 6338)
Lung V20% (cc)	4.9 (0.8 to 26.3)
Conformality Index	1.0 (0.97 to 1.27)
BED10 (Gy)	105.6 (100.0 to 151.2)
EQD2Gy (Gy)	83
a, patients can have multiple target lesions so numbers do not add up to 30 but rather 60.

The mean age of the SBRT and surgery patients was 73.1 (range 57 to 85) and 66.8 (range 55 to 84) years, respectively (Table 2). The majority of patients were white (89%) and 87% of patients had some smoking history (Table 2). The mean weighted CCI for the SBRT and surgery patients was 3.87 and 2.36, respectively (p = 0.0418; Table 2). The predominant comorbidities for patients in the SBRT cohort were chronic obstructive pulmonary disease (COPD) (73%), diabetes (36%), and peripheral vascular disease (25%). The mean follow-up time for patients receiving SBRT was 514 days and 648 days for patients in the surgical cohort (Fig. 2).

Table 2

Descriptive Statistics Comparing SBRT and Surgery Patient Clinicodemographics
	SBRT n = 30	Surgery n = 25	p-value
Age in Years (Mean, SD)^b	73.1 (7.4)	66.8 (8.9)	0.0534
Sex^a			0.3514
Male	12 (40.0%)	7 (28.0%)
Female	18 (60.0%)	18 (72.0%)
Race^a			0.9723
White	27 (90.0%)	22 (88.0%)
Black	2 (06.7%)	2 (08.0%)
Other	1 (03.3%)	1 (04.0%)
Smoking Status^a			0.6421
Ever Smoked	26 (86.7%)	22 (88.0%)
Never Smoked	3 (10.0%)	3 (12.0%)
Unknown	1 (03.3%)	0 (00.0%)
CCI (Mean, SD)^b	3.87 (2.84)	2.36 (1.66)	0.0418
a, chi square test; b, T-test for normally distributed (passed Shapiro Wilks test) or Wilcoxon sum rank test (failed Shapiro Wilks test)

Cost-Benefit Analysis

To complete a cost-benefit analysis, the following definitions were established: 1) treatment charges included all charges occurring between the first and last SBRT date or the day of surgery for a medically eligible patient; 2) Pre-treatment charges included all charges up to 14 days prior to the start of treatment; and 3) post-treatment charges included all charges up to 365 days after the final treatment date. The sum of all 3 charges is the total charges. Dollar amounts were scaled up from 2017 through 2019 to 2020 dollars to analyze the charges of both treatment modalities over time.

Although mean pre-treatment charges were significantly greater for SBRT (2.4-fold, p < 0.0001) by univariable analyses, charges at time of treatment (2.2-fold, p < 0.0001) and post-treatment (2.4-fold, p = 0.0074) were significantly greater for surgery, which resulted in total charges approximately two times greater in the surgery cohort (p = 0.0009; Table 3).

Table 3

Univariable FACT-L and Treatment Charge Comparisons
Total Cohort (n = 55)	SBRT n = 30	Surgery n = 25	p-value
Pre-Treatment FACT-L (Mean, SD) (n = 52)	102 (20)	110 (17)	0.1143
Post-Treatment FACT-L (Mean, SD) (n = 38)	108 (20)	101 (22)	0.3072
Delta FACT-L (Mean, SD) (n = 38)	9.5 (15.8)	-8.2 (20.0)	0.007
Pre-Treatment Charges, 2020 (Mean, SD)	$27,006 ($15,284)	$11,039 ($20,179)	< 0.0001
Treatment Charges, 2020 (Mean, SD)	$43,889 ($31,669)	$98,097 ($39,797)	< 0.0001
Post-Treatment Charges, 2020 (Mean, SD)	$58,334 ($82,302)	$142,623 ($211,718)	0.0074
Total Charges 2020 (Mean, SD)	$129,238 ($86,588)	$251,759 ($215,643)	0.0009

Complications

NCI CTCAE Grade < 2 complications occurred in 18 (60%) patients who received SBRT within 365 days of completing radiotherapy. Complications observed in individual patients were: pneumonia 7, air leak 1 (due to marker placement), chest pain 3, arrhythmia 6, and hemorrhage 1. These complications were not necessarily directly related to SBRT and were likely due to biopsies and procedures unrelated to treatment. However, indirect cause could not be excluded so all complications were reported. SBRT-related complications are likely to be less than 60%. All SBRT patients recovered and none died due to complications. Complications after surgery were observed in 16 (64%) patients during the 90-day follow-up period and included pneumonia 3, air leak 7, chest pain 1, arrhythmia 5, and hemorrhage 0. All surgery patients recovered, and none died due to complications.

No variable was found to have any significant association with development of a complication. Age (p = 0.937) and/or CCI score (p = 0.643) were expected to approach significance, but this was not the case (Table 3). A strong and significant interaction between treatment type and age was found, but controlling for this interaction did not appreciably improve significance. A post hoc analysis revealed that dichotomizing by treatment type would allow us to recover some age and CCI signals expected in the two cohorts, though significance was not reached in either case. A univariable regression model also failed to demonstrate an association of treatment type with complications.

Readmissions

Readmissions for any reason occurred in 7 (23.3%) of the SBRT patients during the post-SBRT 365-day follow-up period. Readmissions were not related to SBRT. All 7 patients recovered, were discharged to home and 0 patients died due to complications of cancer therapy. Similarly, readmissions for any reason occurred in 5 (20.0%) of the surgery patients during the initial 30-day post-operative follow-up period and were not related to surgery. All 5 patients recovered, were discharged to home and 0 patients died due to complications of cancer therapy. Thus, readmissions were not significantly impacted by treatment modality.

Furthermore, the Charlson Comorbidity Index score was significantly correlated with readmission (OR, 1.43, 95% CI, 1.08 to 2.00, p = 0.0226), while the treatment type was not (p = 0.7462), adjusting for age and pre-treatment FACT-L (Table 4). No significant interactions were identified; however, the study was not statistically powered to detect small or medium effect sizes.

Table 4

Multivariable Regression Models Complications Logistic Regression Model
Complications^a	Odds Ratio	95% CI	p-value
Surgery	Ref.	Ref.
SBRT	0.964	0.232 to 3.955	0.959
Age (years)	0.997	0.919 to 1.081	0.937
CCI	0.946	-0.838 to 1.362	0.643
Pre-Treatment FACT-L	1.006	0.973 to 1.041	0.705
Readmissions^b	Odds Ratio	95% CI	p-value
Surgery SBRT	Ref. 0.748	Ref. 0.121 to 4.464	0.7462
Age (years)	0.986	0.882 to 1.096	0.7978
CCI	1.425	1.077 to 2.002	0.0226
Pre-Treatment Fact-L	1.005	0.963 to 1.054	0.8359
Delta FACT-L^c	Linear Coefficient	95% CI	p-value
Surgery SBRT	Ref. 13.81	Ref. 2.01 to 25.62	0.0232
Pre-Treatment FACT-L	-0.36	-0.66 to -0.08	0.0147
a, Multivariable Logistic Regression, 28 of 52 patients had complications, SBRT (n = 15) and surgery (n = 13); b, Multivariable Logistic Regression, 12 of 52 patients were readmitted, SBRT (n = 7) and surgery (n = 5); c, Multivariable Linear Regression, 38 of 55 patient responded to both pre-treatment and post-treatment FACT-L in order to calculate delta FACT-L or change in QoL, SBRT (n = 16) and surgery (n = 22)

FACT-L

Of the 55 patients in the study, 3 (5.5%) patients failed to complete the first FACT-L assessment, and 17 (31%) patients failed to complete the second FACT-L. Thirty-eight (69%) of the patients completed both of the FACT-L assessments. Although pre-treatment FACT-L was not significantly different between SBRT and surgery (102 vs. 110, p = 0.1143), patients receiving SBRT on average showed an improvement in their quality of life (QoL) as measured by the change in FACT-L from pre-treatment to 3- to 6-months post-treatment (delta FACT-L), while those receiving surgery experienced decline (9.5 vs. -8.2, p = 0.007; Table 3). This association was validated by multivariable linear regression (Table 4, Delta Fact-L), where treatment type was significantly and independently associated with change in delta FACT-L (SBRT 13.81, 95% CI 2.01 to 25.62, p = 0.0232) after adjusting for pre-treatment FACT-L which was also significantly associated with delta FACT-L (-0.36, 95% CI -0.66 to -0.08, p = 0.0147).

Surgical resection remains the standard of care for curative therapy in early stage lung cancer.²¹ However, for patients who either do not want, or cannot safely receive, curative lobectomy, stereotactic body radiotherapy (SBRT) delivering ablative doses (biologically effective dose [BED] > 100 Gy) provides safe, effective and well-tolerated outpatient treatment.^{1,3,17,18,21,22} While SBRT has become the standard of care for stage I non-small cell lung carcinoma (NSCLC) in medically inoperable patients, it is unclear if SBRT is equivalent to surgical outcomes in patients able to undergo curative-intent lobectomy.^1,21 Evidence suggests SBRT (retrospective and prospective studies) produces similar overall survival as that achieved in operable patients undergoing definitive surgery for stage I NSCLC. The question is thus far not clearly answered for operable patients, not due to lack of effort in initiating phase III randomized trials – ACOSOG 4099 (RTOG 1021), SABR, ROSEL, STARS, SABRTooth, and POSTILV (RTOG 3502) – all failed to adequately enroll patients over the past decade and closed early. Physician and patient biases in preferring surgical resection are believed to be the main reason these studies did not complete accrual as designed.

It was, therefore, not our intent to prospectively compare SBRT versus surgery directly in operable patients. Rather, the goal was to gain understanding of outcomes in nationwide, community-based, thoracic oncology programs. Key factors supporting this effort were integrated oncology programs and the oncology infrastructure that includes thoracic oncology nurse navigation, prospective tumor board consensus, patient reported outcomes, and cost-data from the network.

Over the past decade, multiple investigators have reported cost-effectiveness analyses of SBRT compared to surgery.^{1,9,10,12,23–25} Others have analyzed SBRT compared to conventional external beam radiotherapy.^26–28 Each report, although not always utilizing the same methodology or metrics, reached the same conclusion, which is that SBRT is cost-effective compared to surgery, conventional external beam radiotherapy, radiofrequency ablation and best supportive care. ²⁹

Published cost-effectiveness and patient satisfaction-quality of life (PS-QoL) data for cancer have several gaps and limitations that should be addressed including, biased development from the payer perspective, minimal PS-QoL provided, short follow-up, and are mainly retrospective; thus, most cost and quality studies in cancer have high likelihood of understating both toxicity and overall costs of care and resultant complications. Furthermore, compared to conventional fractionation using 3D conformal radiation therapy (3DCRT),^26,30,31 radiofrequency ablation (RFA),³² and sublobar resection (surgery),³³ SBRT has been reported to be the more cost-effective and equally clinically effective modality.^9,10,27,28 Given the limitations of these studies, as stated above, there is a call by the medical community to design and implement prospective studies to optimally evaluate PS-QoL for both SBRT and surgery in lung cancer care. Unknown is the future impact on this patient group of two recent landmark randomized surgical trials showing sublobar resection is non-inferior to lobectomy for small tumors (2cm or less) with 1.5-2.0 cm margins.^34,35

Given the sample size limitations and dissimilar selection criteria for each treatment modality, it is not possible to conclude that SBRT is superior to surgery in terms of readmissions or complications. SBRT is definitively the less expensive treatment over one year of patient care, but it is not clear if the improvement in patient reported QoL (FACT-L) is primarily driven by treatment type. Univariate analysis showed that only treatment modality and pre-treatment FACT-L were significant predictors of FACT-L change. In a post-hoc analysis, the change in FACT-L was modelled using only treatment type and post-treatment FACT-L as a method of reducing variance. In the linear model, both were significant and had a negative impact on the final score. The pre-treatment significance is expected because the potential for improvement is smaller with a higher initial score. When controlling for pre-treatment score, surgery still has a negative effect on patient quality of life for the 3 to 6-month window measured.

These results suggest that there may be a relationship between treatment methodology and an improvement in QoL, but a lack of statistical power makes a firm conclusion impossible from this study alone. A prior propensity score matched study³⁶ showed that QoL for SBRT and surgery patients was not significantly different, but baseline QoL was not the same for both groups, and it is not clear why, given that they were matched. The authors note that a previous literature review³⁷ showed that, of the studies included in the review, surgery generally resulted in a reduction in QoL. However, a global improvement in QoL was shown in their study for all groups. The only study to date that contains comparative groups including both QoL measurements and monetary comparisons³⁸ has a participant count of 11 in the SBRT group and 11 in the surgery group. They found a significant difference in global health status after treatment in favor of SBRT. However, there is information about the histology, pathology, and stage of the lung cancer that can only be obtained by biopsy, which is understandably missing for the SBRT group, potentially reducing the strength of the comparison.

A limitation in our study was the number of patients who completed the initial FACT-L questionnaire but did not complete the second FACT-L assessment. Our team made many attempts to have the patients complete the second FACT-L, including phone calls, emails, and contacting family members who had accompanied the patients to previous appointments.

These data support our observations to-date that offering SBRT in appropriate patients, for the populations we serve in the community, provides similar patient satisfaction and cost-effective care. Complications, readmissions, and FACT-L scoring was related more to a patient’s Charlson Comorbidity Index than the modality of treatment selected. Important factors leading to patient selection for each modality are based on closely aligned multidisciplinary oncology specialties, prospective tumor board discussion with consensus, and patient navigation services.

It is critically important to patients and their medical teams to “get it right” regarding the optimal treatment approach for early stage NSCLC. The stakes have never been higher to optimize resource utilization and reduce financial toxicity associated with treating cancer within our communities, which will require a balance between quality, cost, outcomes, and dwindling resources.

Ethics approval and consent to participate

Ethics approval was granted per the Central Institutional Review Board (IRB) approval. This study approval was obtained under expedited review and deemed to have only minimal risk to patients (WCG Clinical IRB00000533 Study 1171593). All participating sites obtained local IRB approval before study initiation. Informed consent was obtained from all patients prior to study entry.

Consent for publication

Not applicable

Availability of data and materials

The data that support the findings of this study are available upon reasonable request from the corresponding author. The data are not publicly available due to privacy restrictions.

Competing interests

The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare, Sarah Cannon or any of its affiliated entities. None of the authors declare any conflict of interest related to the current study beyond current or prior employment with an affiliate of HCA Healthcare.

Funding

Supported, in part, by a grant from Varian Medical Systems, Palo Alto, CA 94304 as well as HCA Healthcare and Sarah Cannon.

Authors' contributions

All authors have made substantial contributions as outlined below and approved this submitted version of the study and agree to be personally accountable for the author’s own contributions and ensures that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved are appropriately investigated, resolved and the resolution documented in the literature.

Andrew Kennedy, - conception, design, acquisition, analysis, interpretation, drafting the work and substantively revising the manuscript including personally submitting it to the journal.
Shanna A. Arnold Egloff, - design, acquisition, analysis, interpretation, drafting the work.
Casey Martin, - design, acquisition, analysis, interpretation, drafting the work.
Denis Gilmore, - acquisition, analysis, interpretation, of the work.
Susan Garwood, - acquisition, analysis, interpretation, of the work.
Tammy Baxter, - acquisition, analysis, interpretation, of the work.
David Spigel, - acquisition, analysis, interpretation, of the work.
Melissa Johnson, - acquisition, analysis, interpretation, of the work.
David Randolph II, - acquisition, analysis, interpretation, of the work.
Casey Chollet-Lipscomb, - acquisition, analysis, interpretation, of the work.
Laurie Cuttino, - acquisition, analysis, interpretation, of the work.
Eleanor Osborne, - acquisition, analysis, interpretation, of the work.
Jenifer Marks, - acquisition, analysis, interpretation, of the work.
Pratik Doshi, - acquisition, analysis, interpretation, of the work.
Meredith Mattlin,- acquisition, analysis, interpretation, of the work.
Richard Geer, - acquisition, analysis, interpretation, of the work.
Dax Kurbegov, - design, acquisition, analysis, interpretation.
Howard Skip Burris III, - design, analysis, interpretation.

Acknowledgements (all are part of Sarah Cannon or Genospace)

Medical Writing - Joan Erland

Design and Conception - Lindsay Sears, Jared Holder, Angela Junglen

Data Engineering – Ryan Patrick, Cecile Roman

Project Management - Lindsey Cossel, Molly Altman, Emily Pless

Program Management and Operations - Jessica Heritage, Michael Frost

Research Coordination - Jameela Riggins, Inngellimar Beasley

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No competing interests reported.

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You are reading this latest preprint version

A Prospective Outcomes and Cost-Effective Analysis of Surgery Compared to Stereotactic Body Radiation Therapy for Stage I Non-Small Cell Lung Cancer

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Version 1

Abstract

Figures

BACKGROUND

METHODS

Site Selection and Regulatory

Participants

Data Sources and Management

Electronic Health Records Data

Quality of Life Data (FACT-L)

Outcome Measures

Complications and Readmissions

Total Charges

Post-Treatment FACT-L

Statistical Analyses

Descriptors and Frequencies

Cost-Effectiveness and Quality of Life

Multivariable Analyses

RESULTS

Patient Characteristics

Cost-Benefit Analysis

Complications

Readmissions

FACT-L

DISCUSSION

Declarations

References

Additional Declarations

Status:

Version 1