To Biopsy or Not to Biopsy: A Matched Cohort Analysis of Early-Stage Lung Cancer Treated with Stereotactic Radiation with or Without Histologic Confirmation

Journal Pre-proof To biopsy or not to biopsy: A matched cohort analysis of early stage lung cancer treated with stereotactic radiation with or without histologic confirmation Antoine Dautruche, M.D., Edith Filion, M.D., Dominique Mathieu, M.D., Houda Bahig, M.D., David Roberge, M.D., Louise Lambert, M.D., Toni Vu, M.D., Marie-Pierre Campeau, M.D. PII:

S0360-3016(20)30124-3

DOI:

https://doi.org/10.1016/j.ijrobp.2020.01.018

Reference:

ROB 26161

To appear in:

International Journal of Radiation Oncology • Biology • Physics

Received Date: 27 July 2019 Revised Date:

11 January 2020

Accepted Date: 21 January 2020

Please cite this article as: Dautruche A, Filion E, Mathieu D, Bahig H, Roberge D, Lambert L, Vu T, Campeau M-P, To biopsy or not to biopsy: A matched cohort analysis of early stage lung cancer treated with stereotactic radiation with or without histologic confirmation, International Journal of Radiation Oncology • Biology • Physics (2020), doi: https://doi.org/10.1016/j.ijrobp.2020.01.018. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc.

To biopsy or not to biopsy: A matched cohort analysis of early stage lung cancer treated with stereotactic radiation with or without histologic confirmation Antoine Dautruche, M.D. ¹, Edith Filion, M.D. ¹, Dominique Mathieu, M.D. ¹, Houda Bahig, M.D. ¹, David Roberge, M.D. ¹, Louise Lambert, M.D. ¹, Toni Vu, M.D. ¹ and Marie-Pierre Campeau M.D. ¹ ¹ Centre hospitalier de l’Université de Montréal, QC, Canada The authors have no conflict of interest to disclose. There was no outside financial support to report. Statistical analysis by Antoine Dautruche, Kip Brown, Michael Yu Corresponding author: Antoine Dautruche [email protected] +336 33 62 05 58 23, rue de Strasbourg 94230 Cachan FRANCE

To biopsy or not to biopsy: A matched cohort analysis of early stage lung cancer treated with stereotactic radiation with or without histologic confirmation

Short title: Lung stereotactic radiation without biopsy

Abstract Purpose/Objective(s): For non-operable stage I non-small cell lung cancer (NSCLC), stereotactic body radiation therapy (SBRT) has emerged as a standard treatment option. We aimed to compare the clinical outcomes of lung SBRT between patients with versus without pathological cancer diagnosis.

Materials/Methods: We included patients treated by SBRT for a single pulmonary lesion between July 2009 and July 2017. Patients in the clinical diagnosis group had a positron emission tomography computed tomography (PET-CT) showing hypermetabolism, growth of the mass on sequential computed tomography (CT) and were not eligible for biopsy, refused biopsy or had an inconclusive biopsy. For each of those patients, a matched pair in pathological diagnosis group was identified by matching for patient, treatment and tumoral characteristics. We performed a power calculation to estimate the sample size required to detect a difference arising from a 5% or 15% rate of benign processes in the group without pathology.

Results:

A total of 924 lung SBRT treatments were performed on 878 patients from 2009 to 2017. Within this population, 131 patients were treated based on clinical findings. They were matched with 131 patients treated with a pathological diagnosis. No significant differences were observed at 3 years in overall survival (Hazard Ratio [HR], 1.2; 95% confidence interval [CI], 0.7-2.1), local control (HR, 0.9; 95% CI, 0.4-2), regional (HR, 0.5; 95% CI, 0.2-1.4) or distant recurrence (HR, 0.6; 95% CI, 0.3-1.1).

Conclusion: In our population, we found no clinically significant difference in patterns of recurrence or survival after lung SBRT, for clinically versus pathologically diagnosed patients. There was however a trend toward more distant recurrences in the pathological diagnosis group. Our power calculation suggests that data from multiple institutions would be required to rule out a difference in outcomes due to 5 to 15% of clinically diagnosed patients being treated for benign processes.

Introduction For non-operable stage I non-small cell lung cancer (NSCLC), stereotactic body radiation therapy (SBRT) has emerged as a standard treatment option (1). However, in some cases, obtaining pathological confirmation is not feasible due to either a patient’s comorbidities or preference. Most of the large published studies on lung SBRT report outcomes for patients with suspected lung cancer and pathologically proven lung cancer without subgroup analysis. In those studies, there are up to 65% of patients treated without pathological proof of malignancy (2,3). Compared to prospective studies including only pathologically confirmed cases, tumor outcomes seems however to be similar (4,5). Although biopsy is favored whenever possible, biopsy can be hazardous in many inoperable patients (bullae of emphysema, poor lung function, tumor location, other comorbidities or patient’s preference). There is no consensual pulmonary function limit for the realization of a lung biopsy. It is stated in NCCN guidelines (6) that when a biopsy is not felt to be possible, a multidisciplinary evaluation should be performed including radiation oncology, surgery, and interventional pulmonology. This evaluation should take into account that based on previous studies, an approach combining fludeoxyglucose (FDG) PET-CT and serial CTs resulted in less than 5% of false

diagnosis when PET-CT and serials CTs were in accordance using a combination of SUV value and volume doubling time between initial and 3-month rescan, in regions with low rate of benign lung disease (7). Due to those considerations, SBRT is often performed without pathological proof of lung cancer. This has led to some concerns that a part of the oncologic outcomes associated with SBRT is due to the inclusion of potentially nonmalignant nodules. Yet, some prospective protocols excluded patients without pathological diagnosis of lung cancer from SBRT studies, and suggested similar outcomes (8–10). We aimed to compare the outcomes of patients treated with SBRT for a clinically diagnosed, early stage lung cancer, with those of patients with similar characteristics who had a pathologically proven disease.

Material and Methods Patient characteristics We conducted a retrospective matched-cohort analysis on all patients treated for a suspected or proved lung cancer in our institution between July 2009 and June 2017. Patients without pathological evidence of cancer were not eligible

for biopsy due to comorbidities, had inconclusive biopsies, or refused invasive investigations. All patients had T1-3N0M0 tumors as per the American joint Committee on cancer 8th edition and were either ineligible for surgery or refused surgery. We excluded patients who presented with synchronous suspicious lung lesions, had received prior thoracic radiation therapy, or had a history of cancer in the 5 years preceding SBRT. Investigations included serial thoracic CTs, FDG-PET CTs, pulmonary function tests and, when indicated and possible, mediastinal staging by endobronchial ultrasound (EBUS) guided biopsy. The decision to treat the patients without pathological evidence of cancer was considered in a multidisciplinary meeting after considering tumor progression on serial CT scans with an at least 3-month interval and FDG-PET uptake. There was no definitive SUV Cut-off value. Patient history including smoking status or previous lung nodule was also considered. No patient was treated based on imaging at a single time point. Decisions were made based on our patient population in which alternate diagnoses, such as granulomatous diseases, are rare (11). Central tumors were defined as tumors within 2 cm of the tracheobronchial tree or adjacent to the mediastinal or pericardial pleura. Approval by our institutional ethics review board was obtained for this study.

Radiation therapy treatment

All patients had a 3 mm slice thickness non-contrast 4D planning CT-scan. Immobilization included a custom single vacuum cushion for patients treated by robotic SBRT with direct soft tissue tracking (Xsight Lung) or fiducial markers technique, and a customized dual vacuum immobilization device (BodyFIX, Elekta, Stockholm, Sweden) for patients treated with a volumetric modulated arc therapy (VMAT) technique. In highly mobile tumors treated with VMAT (i.e lower lobes tumors), an abdominal compression belt could be used. Treatment technique was determined by tumor size, density, localization, movement on 4D-CT and possibilities of implanting fiducial markers, or previous implantation during biopsy.

Gross tumor volume (GTV) was determined using pulmonary window (width 1500 HU; level −400 HU). For VMAT-SBRT, internal target volume (ITV) was delineated using all respiratory phases of the 4D-CT. An additional planning tumor volume (PTV) margin of 5 mm was added to the GTV for fiducials or Xsight Lung cases or to the ITV for other cases. Dose and fractionation schedules were established according to tumor location, with peripheral tumors treated with 60 Gy in 3 fractions and central tumors with 60 Gy in 5 fractions, 50 Gy in 4 fractions or 50 Gy in 5 fractions, with strict observance of dose constraints to organs at risk according to Radiation Therapy Oncology

Group RTOG 0236 and RTOG 0813 protocols (12,13). Dose was prescribed to an isodose covering at least 95% of the PTV. The prescription dose typically represented 65–85% of the maximum dose, depending on tumor size and location.

Follow-up Follow-up CT scans were performed every 3-6 months in the first year and every 6 months thereafter, unless the patient refused follow-up or developed other medical conditions precluding treatment of a potential recurrence. End of treatment was defined as the date of the last radiation therapy treatment. Survival time was defined as time from end of treatment until death. Local failure was defined as a primary tumor failure or an involved lobe failure. When a biopsy was not feasible, diagnosis of failure was decided during a multidisciplinary tumor board with radiation oncologists, radiologists, nuclear radiologists and surgeons. Regional failure was defined as a recurrence within the ipsilateral hilum or mediastinum. Distant failure was defined as a recurrence at any other location, including ipsilateral lung (other lobe) and contralateral lung. Toxicities were graded as per the Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03

Statistical Analysis Patient treated without pathology were matched with patients treated with pathology on a 1:1 basis. The match was performed using the nearest-neighbor methods based on the propensity score estimated with logistic regression. All covariates were matched to within a standardized mean difference of 10%. Matching was performed using the MatchIt package in R version 3.5.3. The pairing was done based on the following characteristics: gender, age at treatment, smoking status (active, stopped or never), T stage, tumor size, location, initial Standard Uptake Value (SUV) on FDG-PET, dose and fractionation of SBRT treatment, radiation therapy (RT) technique (Robotic SBRT or VMAT), Charlson comorbidity index, Karnofsky performance status (KPS) and forced expiratory volume in one second (FEV1) in percent of the predicted value. Patients and tumor characteristics were tested for differences in distribution between the groups by independent mean t-test for numerical variables, and chi-square test for categorical variables. Kaplan-Meier method was used for estimation of local control (LC), regional control (RC), overall survival (OS), distant metastasis-free survival (DMFS) and progression-free survival (PFS). Estimations were made for three-year endpoints. Log-rank test was performed to test for differences between Kaplan-Meier survival curves. All tests with p values of <0.05 were considered

statistically significant. All statistical analyses were conducted using SPSS v25.0 (IBM SPSS, IBM Corporation, NY, USA). A power calculation was conducted to estimate the sample size needed to find a difference in outcomes based on a 5% or 15% rate of benign disease. A proportional odds assumption was not appropriate, as the hazard ratio changes over time. Power was estimated using a bootstrap of the observed survival curve of the biopsied group, using an alpha of 5%. The bootstrap generated two groups: one with survival characteristics matching the biopsied group, the other in which a proportion of observations were replaced with benign (censored) observations. These groups were compared with a log-rank test. The sample size associated with a target power of 80% was estimated using a search algorithm that ran the bootstrap using a range of different sample sizes, applied an isotonic regression to identify the sample size most likely to produce the desired power, then repeated the process multiple times, each time using a narrower range around the identified sample size. This search was run several times for each sample size calculation to provide an estimate of the error in the search algorithm. Results

Patient and Treatment Characteristics

In our institution, 924 pulmonary SBRT courses were delivered from July 2009 to June 2017 on 878 patients. Among those treatments, 231 (25%) were performed without biopsy, and 64 (7%) with an inconclusive biopsy. One hundred thirty-one patients met our requirements for inclusion in our clinical diagnosis group (Supplementary material 1). They were matched 1:1, from 314 patients with a pathological diagnosis. Median follow-up for overall survival was 26 months (2-84) for patients with a clinical diagnosis vs. 27 months (0-96) for the matched patients with pathological evidence of cancer (p=0.61). The corresponding median age was 73 (53-92) vs. 75 (44- 88) years (p=0.78) Tumor characteristics were comparable in both groups. Median tumor size was respectively 20 mm and 19 mm (p=0.9), for patients without and with pathological evidence of cancer. Median SUV was respectively 6 and 5.3 (p=0.65). Most tumors were peripheral in both groups. Treatment characteristics were comparable in both groups. Patients and tumor characteristics are summarized in Table 1 Tumor Outcomes

Comparison of outcomes between our two cohorts is shown in Figure 1-3. Three-year outcomes did not differ either between patients without and with pathological evidence, with respectively an estimated 3-year LC, OS, RC, DMFS of 85% vs. 80% (HR=0.89; p=0.78), 71% vs. 74% (HR=1.21; p=0.48), 93% vs. 86% (HR=0.47; p=0.15) and 82% vs. 68% (HR=0.59; p=0.11) (Table 2). PFS at 3 years was estimated with an HR of 0.91 (p=0.63). Treating death of all cause as a competing event did not significatively altered those results with HRs for LC, RC, an DFMS of, respectively, 0.89 (p=0.782), 0.46 (p=0.145) and 0.57 (p=0.09) Univariate analysis showed that gender was a prognostic factor for death with 1.74 odds ratio (OR) favoring female gender (1.03-2.9, p=0.04). Tumor stage was associated with distant recurrence (p=0.04). Tumor location was associated with disease progression and regional recurrence, with respective ORs of 0.52 (0.27-0.98, p=0.04,) and 0.37 (0.14-0.95, p=0.03) in favor of peripheral tumors. SUV was a prognostic factor for regional recurrence with a mean SUV of 8.8 versus 6.5 (p=0.03) for patients who had a regional recurrence vs. patients who did not. Age at treatment was a prognosis factor for disease progression with mean age at treatment of 71 vs. 74 years (p=0.004) for patient who progressed versus patients who did not.

Treatment toxicity

Treatment toxicities are listed in Table 3. There was no significant difference in toxicities between the two groups. There was a total of 5 (4%) symptomatic (grade 2 or more) rib fractures in the group without definitive pathology, the grade 3 being a rib fracture associated with a hemothorax that required hospitalization. In the group without definitive pathology, there were 9 (7%) symptomatic rib fractures. There was a death in the group without definitive pathology of a patient with a bacterial pneumonia associated with a radiation pneumonitis two months after SBRT.

Power calculation To obtain 80% power to detect a difference of 15% of benign disease in the no pathology group, 5 156 patients would be needed (95% CI: 4 874 – 5590) based on the distant control. The results for regional and local control are presented in table 4, as well as those in case of 5% of benign disease in the no pathology group. Discussion There were no statistical differences for local, regional, distant recurrence or overall survival between our two groups. There was however a trend in favor of more regional and distant recurrences among patients with a pathological diagnosis. While we unfortunately did not collect the frequency of imaging in

this study, this could be explained by the fact that those patients, despite the matching, might have had more follow-up CT or PET-CT exams, being less prone to decline follow-up imaging. There is also the possibility that our matching did not account fully for the comorbidities of the patients, leading the patients treated without pathology to be less closely watched due to poorer health state precluding further treatments and making follow-up less important. The diagnosis of recurrence being made on the progression of a lesion, not only the last CT or PET-CT but the frequency of those exams can lead to faster discovery of those recurrences and thus the increase of the recurrence rate at a given time point. There might also be a difference between the clinical and pathological-based treatment outcomes that fell short of being statistically significant due to a lack of power. A prospective analysis with a standardized follow-up would be required to test those hypotheses. We can also add that while we classified recurrence in another lobe of the same lung as distant recurrence, as opposed to RTOG 0813, only one patient of our study in the no-pathology group presented such a recurrence. The power calculation shows that a considerable cohort would be needed to find a difference on tumor outcomes, even with a 15% rate of benign disease in the no-pathology group. On biopsy-proven tumors, previous studies report distant metastases-free survival rates at three years of 62-88% versus local

control rates of 89-94% (4,14). Our power calculation showed that distant control would indeed be the most realistic outcome on which a difference arising from benign tumor treatment could be statistically different. It would still require more than 5000 patients if we hypothesized a 15% rate of benign disease in the clinical diagnosis group, thus requiring a multicenter analysis. We did not have enough information on cause of death to run a typical competing risk analysis, in this setting where causes of death other than cancer were likely. Without this analysis, progression free survival might be less relevant as all causes of death are registered as an event. Our study is, to our knowledge, the first matched cohort analysis comparing clinical versus pathological-based treatment for lung SBRT. Verstegen et al. reported in 2011 the outcomes of SBRT following a clinical diagnosis of early lung cancer among 382 patients, compared with a contemporaneous cohort of 209 patients with pathologically proven disease (15). The 3-year OS was 53.7% for patients without pathology vs. 55.4% (p=0.95) and their 3-year local control was 91.2% for patients without pathology vs. 90.4% (p=0.98). They did not specify their definition of the local recurrence, which could explain that we had more recurrence since we counted recurrences in the whole affected lobe, likely including some second primary tumors. Without patient matching, their

3-year regional and distant control were respectively, for clinical versus pathological diagnosis, 88% vs. 90% and 73% vs. 80%, similar to ours. Two studies focused on patients without definitive histology, with no comparison cohort, and included only 22 and 27 patients (16,17). With a follow-up of respectively 15 and 17 months, the authors reported a 2-year OS of 75% and 65%, and a 2-year LC of 91% and 100%. Two

other

studies

did

a

retrospective

comparison

between

clinically/radiologically diagnosed cancer and pathologically proven cancer, but without a matched pairs analysis (18,19). Takeda et al. found among 58 patients treated without pathology versus 15 treated with pathology, a global survival at 3 years of 54% vs. 57% (p=0.48) and a local control at 3 years of 80% vs. 87% (p=0.73), similar to our results. Fischer-Valuck et al. compared 65 patients treated without pathology versus 23 treated with pathology. They found no statistical difference for OS, with a 3-year survival rate of respectively 60% vs. 59% (p=0.46) and 3-year cumulative local progression-free rate of respectively 93% vs. 94% (p=0.98).

Clinical implications & Perspectives The main risk of the strategy of treating a patient without pathological confirmation is the treatment, and thus exposure to side effects, of a non-

malignant nodule. However, even in the context of numerous differential diagnosis existing for solid and subsolid nodules on CT (20), a strategy combining serial CT scans and PET-CT has shown to have very high sensitivity and specificity in regions with a low prevalence of benign lung nodules (granulomatous disease and tuberculosis for example). Used alone, FDG PET-CT have a sensitivity higher than 90%, but a specificity varying from 40% to 78% (21,22) due to a high number of false-positive. Serial CT can help discriminate benign from malignant lesions, even in patients with other lung pathologies such as interstitial pneumonia (23). Our results add some data about the reliability of radiological/metabolic criteria for the diagnosis of lung cancer. PET-CT being a major element of a treatment strategy without pathological diagnosis, efforts have been made to optimize the interpretation of the SUVmax value of a nodule. It is established that the higher the SUVmax is, the higher chance a nodule would be malignant (24). However, while there have been proposition of SUVmax cut-off ranging from 2.0 to 3.6, it currently seems unreasonable to propose such a value (25–27). Efforts are being made to standardize SUV values between different institutions, but major factors such as the patient’s glycemia, the size of the lesion or it’s metabolic activity makes the SUVmax a value to interpret individually.

The concerns about the validity of a diagnosis procedure without pathology have led to questions around the comparison of SABR to surgery for a malignant nodule. For some authors comparing tumoral outcomes among SBRT patients without pathological confirmation versus surgical patients with a definitive diagnosis is unfair (8,28). Unfortunately, there are no completed randomized trial comparing SABR with surgery due to the difficulty or obtaining the patient’s approval for such different treatment strategies (29). A pooled analysis has been made of two randomized trials (STARS and ROSEL), including only 58 patients and failing to find a difference between the two strategies, but with a lack of statistical power to do so (30). Histological confirmation of NSCLC by biopsy or cytological evaluation was required in the STARS trial but was not mandatory in the ROSEL protocol. Interestingly, one patient that received surgery in the ROSEL trial had a benign disease on definitive pathology, leading to some concerns about over-estimating the advantages of SABR (28).

There is also a risk of delaying a treatment until the followed nodule has an evolution and aspect justifying a treatment without biopsy. This delay in the treatment could lead to worsening of the outcomes of the patients in the nonpathologically proven group, leading to less early treatments in this group, or even exclude some patients that could have been treated by SBRT, but

developed a nodal invasion during the time when their nodule was followed by chest imaging. Some authors constructed models suggesting that a SBRT treatment without pathology, when biopsy is not feasible, should be conducted if the estimated probability of lung cancer based on the PET-CT exceeded 85% (31,32). After CT-guided percutaneous transthoracic tumor biopsy, Wang et al. reported, on 1484 patients, a 21% prevalence of hemoptysis and an 8% chance of post-procedure pneumothorax, leading to therapeutic air aspiration in 2% of patients (33). These risks are increased with smaller lesions, basal and middle zone lesions, and longer distances from lesion to pleura (34). In a study over 248 percutaneous interventions, including 42 biopsies followed by Cyberknife fiducial placement, pneumothorax rates were 28% and 43%, with and without fiducial placement respectively, with pneumothorax drainage rates of 7% vs. 17%(35). Other studies report rates as high as 38% of post-procedure pneumothorax, depending on needle size (36). Other possible complications involve hemothorax, air embolism and seeding (37). There is also a risk of false negative estimated to be from 3 to 19% among studies (32,38). In our study, 31% of the 131 patients treated in the group without histology had an history of inconclusive biopsy.

Among the 924 lung SBRT treatment performed in our institution during this study, 32% were performed without a definitive neoplastic pathology. This percentage is to be compared with other reported SBRT results, such as those by Bongers et al (39), where 64% of the patients were treated without pathology, Murray et al (2), with 65% of patients treated without pathology, or Senthi et al (40) with also 65% of patients treated without pathology. Those series with less frequent pathological confirmation were collated in United Kindgom and Netherlands, whereas in Northern America treating without pathology is often regarded as a last resort.

Conclusion We present here the results of a study comparing, with a retrospective patient, treatment and tumor matching, general outcomes between patients treated by lung SBRT for a clinically/radiologically diagnosed cancer versus a pathologically/biopsy proven lung cancer. We found no clinically significant difference in patterns of tumor recurrence or general outcomes between those two groups. A trend toward significance was however noticed for distant control. In this population with a high risk of intercurrent death, our power calculations suggest that distant control would be the most reasonable outcome on which to conduct further analyses on this matter of determining

how many benign lesions are treated when the treatment decision is based on clinical and radiological features. We still recommend that clinically diagnosed tumors be included in prospective studies of lung SBRT, as this is the case for the ongoing Canadian trial testing SBRT versus hypofractionated conventional radiotherapy in inoperable early lung cancer (41).

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Figure 1: Comparison of Local Control (CD: Clinical Diagnosis, PD: Pathological Diagnosis)

Figure 2: Comparison of Metastasis-Free Survival (CD: Clinical Diagnosis, PD: Pathological Diagnosis) Figure 3: Comparison of Overall Survival (CD: Clinical Diagnosis, PD: Pathological Diagnosis)

Supplementary material 1: Flow Chart (CNO: Carcinoma Non Otherwise specified) Supplementary material 2: Comparison of Regional Control (CD: Clinical Diagnosis, PD: Pathological Diagnosis)

No Definitive Pathology (n=131) (%) 73 (53-92)

Age, median (years) Gender Male 64 (49) Female 67 (51) Smoking Status Active 42 (32) Stopped 87 (66) Never 2 (2) Charlson 2-3 53 (40) 4 36 (27) ≥5 42 (32) KPS, median 90 (60-100) FEV1, median (L) 1.16 (0.5-3) RT reason Surgery Refusal 14 (11) Non-operable 117 (89) Tumor Size, median (mm) 20 (8-50) Tumor SUV, median 6 (1-27) Tumor Localization Central 28 (21) Peripheric 103 (79) T stage (TNM 8) 1a 11 (8) 1b 61 (47) 1c 44 (34) 2a 11 (8) 2b 4 (3) 3 0 Pathology No biopsy 90 (69) Inconclusive biopsy 41 (31) Adenocarcinoma Squamous cell Other RT Dose 60Gy/3fr 80 (61) 60Gy/5fr 27 (21) 50Gy/5fr 18 (14) Other 6 (5) RT technique Robotic SBRT 48 (37) VMAT 83 (63) Table 1: Patients and treatment characteristics

Definitive Pathology (n=131) (%) 74 (44-88)

p value 0.775 0.457

58 (44) 73 (56) 0.685 45 (34) 85 (65) 1 (1) 0.56 55 (42) 42 (32) 34 (26) 90 (40-100) 1.22 (0.6-2.9) 19 (15) 112 (85) 19 (8-50) 5.3 (1.21)

0.761 0.832 0.384

0.897 0.649 0.588

25 (19) 106 (81) 0.335 6 (5) 72 (55) 35 (27) 13 (10) 3 (2) 2 (2) nd

67 (51) 51 (39) 13 (10) 0.566 82 (63) 25 (19) 15 (11) 9 (7) 0.787 50 (38) 81 (62)

Three-year endpoints

Definitive Pathology (n=131) (%) 74 (65-83)

p value

Hazard Ratio

Overall Survival

No Definitive Pathology (n=131) (%) 71 (62-80)

0.476

1.21 (0.72-2.05)

Local Control

85 (77-94)

80 (70-90)

0.777

0.89 (0.4-1.99)

Regional Control

93 (86-99)

86 (78-94)

0.154

0.47 (0.16-1.36)

Distant Control

82 (72-91)

68 (56-80)

0.113

0.59 (0.31-1.14)

Progression free survival

51 (41-63)

45 (36-57)

0.63

0.91 (0.62-1.34)

Table 2: Three-year outcomes

No Definitive Pathology (n=131) (%) Radiation Pneumonitis Grade 2 3 (2) Grade 3 1 (1) Grade 5 1 (1) Rib Fracture Grade 1 6 (5) Grade 2 4 (3) Grade 3 1 (1) Cardiac event Grade 2 Grade 3 1 (1) Chest Pain Grade 1 6 (5) Grade 2 4 (3) Table 3: treatment Toxicity

Definitive Pathology (n=131) (%)

p value 0.771

4 (3) 1 (1) 0.370 3 (2) 9 (7) 0.368 1 (1) 0.575 9 (7) 6 (5)

Number of patients needed – 5 % benign disease in the no-histology group

Number of patients needed – 15 % benign disease in the no-histology group

Local control

100,306 (93,478-106,938)

11,016 (9,458-11,176)

Regional control

129,738 (118,904-138,328)

13,628 (12,466 - 14,838)

Distant control

50,622 (44,396-57,250)

5,156 (4,874-5,590)

Table 4: Power calculation (80% power, alpha 5%) estimating the number of patients needed to detect a difference arising from 5% or 15% rate of benign disease in the group without pathology