Surgical outcomes of pulmonary resection for lung cancer after neo-adjuvant treatment

Table 1 Baseline demographic and clinical characteristics

Characteristic	Total n = 4063	Neoadjuvant patients n = 236 (5.81%)	Surgery-only patients n = 3827 (94.19%)	P-value1
Age (yr), median (IQR)	68 (61-75)	66 (55-72)	69 (61-75)	< 0.0012
Male (%)	2003 (49.30)	125 (52.97)	1878 (49.07)	0.246
Race (%)
White	3019 (74.30)	189 (80.08)	2830 (73.95)	0.173
Black	222 (5.46)	12 (5.08)	210 (5.49)
Latino(a)	432 (10.63)	17 (7.20)	415 (10.84)
Other or unknown	390 (9.60)	18 (7.63)	372 (9.72)
ASA classification (%)
1-2 no-mild disturbance	769 (18.97)	38 (16.24)	731 (19.14)	0.523
3 serious disturbance	2888 (71.24)	171 (73.08)	2717 (71.13)
4-5 life threatening/moribund	397 (9.79)	25 (10.68)	372 (9.74)
Functional status
Independent	3985 (98.08)	229 (97.03)	3756 (98.14)	0.227
Partially/totally dependent	78 (1.92)	7 (2.97)	71 (1.86)
Obese, BMI ≥ 30 (%)	1155 (28.65)	58 (24.79)	1097 (28.88)	0.178
Diabetes (%)	598 (14.72)	27 (11.44)	571 (14.92)	0.143
Current smoker (%)	1448 (35.64)	114 (48.31)	1334 (34.86)	< 0.0012
Alcohol consumption (%)	221 (5.44)	15 (6.36)	206 (5.38)	0.522
Dyspnea (%)	1106 (27.22)	57 (24.15)	1049 (27.41)	0.275
History of COPD (%)	1082 (26.63)	54 (22.88)	1028 (26.86)	0.179
History of heart disease (%)	42 (1.03)	3 (1.27)	39 (1.02)	0.734
Hypertension (%)	2375 (58.45)	111 (47.03)	2264 (59.16)	< 0.0012
Previous cardiac surgery (%)	308 (7.58)	11 (4.66)	297 (7.76)	0.081
Weight loss (%)	152 (3.74)	16 (6.78)	136 (3.55)	0.0112
Steroid use (%)	161 (3.96)	22 (9.32)	139 (3.63)	< 0.0012
Year of operation (%)
2005-2008	834 (20.53)	53 (22.46)	781 (20.41)	0.662
2009-2010	1794 (44.15)	105 (44.49)	1689 (44.13)
2011-2012	1435 (35.32)	78 (33.05)	1357 (35.46)
Preoperative WBC (%)
Normal (4.5-11.0 × 109/L)	3364 (85.88)	174 (74.36)	3190 (86.61)	< 0.0012
Abnormal (< 4.5 or > 11.0 × 109/L)	553 (14.12)	60 (25.64)	493 (13.39)
Preoperative hematocrit (%)
Normal (≥ 36)	3147 (80.53)	110 (47.01)	3037 (82.66)	< 0.0012
Abnormal (< 36)	761 (19.47)	124 (52.99)	637 (17.34)
Surgery type (%)
VATS	1203 (29.61)	34 (14.41)	1169 (30.55)	< 0.0012
Open	2860 (70.39)	202 (85.59)	2658 (69.45)

¹P-values taken from χ² tests (Fisher’s exact test in cell counts less than five);

²Two-sided values < 0.05 considered statistically significant. Wilcoxon rank-sum test used to compare rank sum differences in the non-normal distribution of age. Different denominators due to missing data: ASA (n = 4054); obese (n = 4032); WBC (n = 3917), hematocrit (n = 3908). ASA: American Society of Anesthesiology; COPD: Chronic obstructive pulmonary disease; WBC: White blood cell (count); VATS: Video-assisted thoracic surgery; BMI: Body mass index; IQR: Interquartile range.

Table 2 Unadjusted intraoperative and postoperative complications

Characteristic	Total n = 4063	Neoadjuvant patients n = 236 (5.81%)	Surgery-only patients n = 3827 (94.19%)	P-value1
30-d mortality (%)	107 (2.63)	19 (8.05)	88 (2.30)	< 0.0012
Overall morbidity (%)	646 (15.90)	63 (26.69)	583 (15.23)	< 0.0012
Wound infection	4 (0.10)	0 (0.00)	4 (0.10)	0.787
Pneumonia	5 (0.73)	0 (0.00)	5 (0.77)	0.774
Urinary tract infection	1 (0.15)	0 (0.00)	1 (0.16)	0.956
Return to OR	201 (4.95)	22 (9.32)	179 (4.68)	< 0.0012
Venous thromboembolism	80 (1.97)	7 (2.97)	73 (1.91)	0.256
Cardiac complication	60 (1.48)	10 (4.24)	50 (1.31)	< 0.0012
Shock/sepsis	107 (2.63)	11 (4.66)	96 (2.51)	0.0452
Unplanned intubation	207 (5.09)	27 (11.44)	180 (4.70)	< 0.0012
Bleeding transfusion	178 (4.38)	28 (11.86)	150 (3.92)	<0.0012
Renal complication	22 (0.54)	0 (0.00)	22 (0.57)	0.636
On ventilator > 48 h	3 (0.07)	1 (0.42)	2 (0.05)	0.164
Organ space SSI	44 (1.08)	1 (0.42)	43 (1.12)	0.516
Serious morbidity (%)	469 (11.54)	44 (18.64)	425 (11.11)	< 0.0012
Length of stay (d), median (IQR)	6 (4-9)	6 (4-9)	6 (4-8)	0.915
Prolonged length of stay (%)	816 (20.08)	46 (19.49)	770 (20.12)	0.815
Operative time (min), median (IQR)	161 (123-216)	160 (121-214)	192 (147-250)	< 0.0012
Prolonged operative time (%)	1006 (24.76)	91 (38.56)	915 (23.91)	< 0.0012

¹P-values taken from χ² tests (Fisher’s exact test in cell counts less than five);

²Two-sided values < 0.05 considered statistically significant. Wilcoxon rank-sum tests used to compare rank sum differences in non-normal distributions of length of stay and operative time. Overall morbidity: Wound infection, pneumonia, urinary tract infection, venous thromboembolism, bleeding transfusion, renal complication, return to OR, cardiac complication, shock/sepsis, unplanned intubation, on ventilator > 48 h, and organ space SSI. Serious morbidity: Return to OR, cardiac complication, shock/sepsis, unplanned intubation, on ventilator > 48 h, and organ space SSI. Prolonged length of stay and operative time refer to times longer than the 75^th percentiles for the respective distributions; IQR: Interquartile range; SSI: Surgical site infection; OR: Operating room.

Table 3 Intraoperative/postoperative outcomes overall and among propensity-score matched cohorts (results represent odds ratios unless otherwise indicated)

Characteristic	Unadjusted (95%CI)	P-value1	Risk-adjusted(95%CI)	P-value1	Propensity-score matched cohort3 (95%CI)	P-value1
30-d mortality (%)	3.72 (2.22-6.22)	< 0.0011	2.70 (1.54-4.72)	0.0011	1.63 (0.77-3.45)	0.197
Overall morbidity (%)	2.02 (1.50-2.74)	< 0.0011	1.53 (1.12-2.11)	0.0101	1.68 (1.08-2.62)	0.0211
Return to OR	2.09 (1.32-3.33)	0.0011	1.77 (1.08-2.90)	0.0231	3.37 (1.41-8.04)	0.0061
Cardiac complication	3.34 (1.67-6.70)	0.0011	3.11 (1.47-6.57)	0.0031	2.57 (0.79-8.30)	0.116
Shock/sepsis	1.90 (1.00-3.60)	0.0491	1.53 (0.78-3.02)	0.217	3.80 (1.05-13.80)	0.0431
Unplanned intubation	2.62 (1.71-4.02)	< 0.0011	2.03 (1.28-3.22)	0.0021	1.66 (0.88-3.14)	0.116
Bleeding transfusion	3.30 (3.15-5.06)	< 0.0011	1.72 (1.08-2.73)	0.0231	2.31 (1.17-4.58)	0.0161
Serious morbidity (%)	1.83 (1.30-2.58)	0.0011	1.55 (1.08-2.23)	0.0181	1.70 (1.02-2.85)	0.0421
Length of stay (d)2
Predicted difference in means	-0.02 (-0.38 to 0.35)	0.927	-0.93 (-1.32 to -0.55)	< 0.0011	-1.02 (-1.54 to -0.50)	< 0.0011
Prolonged length of stay (%)	0.96 (0.87-1.34)	0.815	0.67 (0.47-0.96)	0.0301	0.63 (0.41-0.97)	0.0371
Operative time (min)2
Predicted difference in means	30.5 (28.8-32.1)	< 0.0011	26.4 (24.7-28.1)	< 0.0011	29.0 (26.5-31.6)	< 0.0011
Prolonged operative time (%)	2.00 (1.52-2.62)	< 0.0011	1.81 (1.36-2.41)	< 0.0011	1.73 (1.17-2.57)	0.0061

¹Two-sided P-values < 0.05 considered statistically significant. Adjusted models controlled for age, being a current smoker within one year, hypertension requiring medication, > 10% loss of body weight in last 6 mo, steroid use for chronic condition, abnormal preoperative WBC, abnormal preoperative hematocrit, abnormal preoperative albumin, operative year, managing specialty, and type of surgery preformed;

²Modified Park tests corresponded to a Poisson distribution. Generalized linear models (family Poisson, link log) were used to model non-normally distributed continuous data, followed by post-estimation average marginal effects to attain predicted mean differences and 95%CI. Interpretation: Patients treated with neo-adjuvant therapy had average operative times that were longer than those of surgery-only patients by 29.0 min (95%CI: 26.5-31.6 min);

³Separate cohorts were generated for each outcome using propensity-score-based 1:1 nearest-neighbor matching without replacement, accounting for significant baseline differences in demographic and clinical characteristics. OR: Operating room.

Table 4 Baseline demographic and clinical characteristics among the unmatched population cohort

Characteristic	Surgery only n = 3593 (94.21%)	Chemotherapy n = 64 (1.68%)	Radiotherapy n = 100 (2.62%)	Chemo and radio n = 57 (1.49%)	P-value1
Age (yr), median (IQR)	69 (61-75)	66 (62-73)	66 (53-69)	62 (52-70)	< 0.0012
Male (%)	1774 (49.59)	35 (54.69)	45 (45.45)	28 (49.12)	0.662
Race (%)
Non-Hispanic White	2678 (78.58)	48 (78.69)	83 (86.46)	46 (85.19)	0.508
Non-Hispanic Black	194 (5.69)	3 (4.92)	5 (5.21)	4 (7.41)
Hispanic	393 (11.53)	7 (11.48)	4 (4.17)	3 (5.56)
Other or unknown	143 (4.20)	3 (4.92)	4 (4.17)	1 (1.85)
ASA classification (%)
1-2 no-mild disturbance	2573 (71.61)	51 (79.69)	71 (71.00)	41 (71.93)	0.445
3 serious disturbance	665 (18.51)	10 (15.63)	19 (19.00)	7 (12.28)
4-5 life threatening/moribund	355 (9.88)	3 (4.69)	10 (10.00)	9 (15.79)
Functional status
Independent	3528 (98.19)	61 (95.31)	98 (98.00)	56 (98.25)	0.413
Partially/totally dependent	65 (1.81)	3 (4.69)	2 (2.00)	1 (1.75)
Obese, BMI ≥ 30 (%)	1093 (30.42)	20 (31.25)	22 (22.00)	14 (24.56)	0.245
Diabetes (%)	546 (15.20)	11 (17.19)	9 (9.00)	5 (8.77)	0.178
Current smoker (%)	1223 (34.04)	29 (45.31)	48 (48.00)	30 (52.63)	< 0.0012
Alcohol consumption (%)	193 (5.37)	5 (7.81)	6 (6.00)	4 (7.02)	0.785
Dyspnea (%)	975 (27.14)	14 (21.88)	24 (24.00)	16 (28.07)	0.711
History of COPD (%)	962 (26.77)	19 (29.69)	21 (21.00)	11 (19.30)	0.317
History of heart disease (%)	38 (1.06)	0 (0.00)	3 (3.00)	0 (0.00)	0.186
Hypertension (%)	2134 (59.39)	31 (48.44)	48 (48.00)	25 (43.86)	0.0042
Previous cardiac surgery (%)	280 (7.79)	2 (3.13)	6 (6.00)	3 (5.26)	0.422
Weight loss (%)	115 (3.20)	0 (0.00)	8 (8.00)	5 (8.77)	0.0032
Steroid use (%)	132 (3.67)	6 (9.38)	10 (10.00)	3 (5.26)	0.0012
Year of operation (%)
2005-2008	728 (20.26)	6 (9.38)	34 (34.00)	9 (15.79)	< 0.0012
2009-2010	1577 (43.89)	21 (32.81)	61 (61.00)	18 (31.58)
2011-2012	1288 (35.85)	37 (57.81)	5 (5.00)	30 (52.63)
Preoperative WBC (%)
Normal (4.5-11.0 × 109/L)	2988 (83.16)	54 (84.38)	73 (73.00)	38 (66.67)	< 0.0012
Abnormal (< 4.5 or > 11.0 × 109/L)	468 (13.03)	10 (15.63)	27 (27.00)	17 (29.82)
Preoperative hematocrit (%)
Normal (≥ 36)	2860 (79.60)	32 (50.00)	52 (52.00)	23 (40.35)	< 0.0012
Abnormal (< 36)	588 (16.37)	32 (50.00)	48 (48.00)	32 (56.14)
Preoperative albumin (%)
Normal (≥ 3.5 g/dL)	3345 (93.10)	58 (90.63)	82 (82.00)	55 (96.49)	< 0.0012
Abnormal (< 3.5 g/dL)	248 (6.90)	6 (9.38)	18 (18.00)	2 (3.51)
Managing specialty (%)
Thoracic	2243 (62.43)	48 (75.00)	48 (48.00)	40 (70.18)	0.0082
General	991 (27.58)	11 (17.19)	42 (42.00)	11 (19.30)
Other specialty	359 (9.99)	5 (7.81)	10 (10.00)	6 (10.53)
Surgery type (%)
Open	2545 (70.83)	51 (79.69)	86 (86.00)	53 (92.28)	< 0.0012
VATS	1048 (29.17)	13 (20.31)	14 (14.00)	4 (7.02)

¹Two-sided P-values taken from χ² tests (Fisher’s exact test in cell counts less than five);

²P< 0.05 considered statistically significant. Kruskal-Wallis one-way analysis of variance was used to compare non-normal distributions of age. ASA: American Society of Anesthesiology; COPD: Chronic obstructive pulmonary disease; CHF: Congestive heart failure; MI: Myocardial infarction; WBC: White blood cell (count); VATS: Video-assisted thoracic surgery; BMI: Body mass index; IQR: Interquartile range.

Table 5 Unadjusted intraoperative/postoperative outcomes among the unmatched population cohort

Characteristic	Surgery only n = 3593 (94.21%)	Chemotherapy n = 64 (1.68%)	Radiotherapy n = 100 (2.62%)	Chemo and radio n = 57 (1.49%)	P-value1
30-d mortality (%)	83 (2.31)	3 (4.69)	9 (9.00)	5 (8.77)	< 0.0012
Overall morbidity (%)	415 (11.55)	13 (20.31)	21 (21.00)	17 (29.82)	< 0.0012
Wound infection	3 (0.08)	0 (0.00)	0 (0.00)	0 (0.00)	--
Pneumonia	4 (0.11)	0 (0.00)	0 (0.00)	0 (0.00)	--
Urinary tract infection	1 (0.03)	0 (0.00)	0 (0.00)	0 (0.00)	--
Return to OR	170 (4.73)	7 (10.94)	10 (10.00)	4 (7.02)	0.0122
Venous thromboembolism	70 (1.95)	0 (0.00)	2 (2.00)	3 (5.26)	0.212
Cardiac complication	47 (1.31)	2 (3.13)	2 (2.00)	4 (7.02)	0.0022
Shock/sepsis	92 (2.62)	2 (3.13)	5 (5.00)	2 (3.51)	0.513
Unplanned intubation	169 (4.70)	5 (7.81)	12 (12.00)	7 (12.28)	< 0.0012
Bleeding transfusion	133 (3.70)	8 (12.50)	7 (7.00)	10 (17.54)	< 0.0012
Renal complication	22 (0.61)	0 (0.00)	0 (0.00)	0 (0.00)	--
On ventilator > 48 h	2 (0.06)	1 (1.56)	0 (0.00)	0 (0.00)	--
Organ space SSI	38 (1.06)	0 (0.00)	1 (1.00)	0 (0.00)	--
Serious morbidity (%)	372 (10.35)	12 (18.75)	19 (19.00)	10 (17.54)	0.0022
Length of stay (d), median (IQR)	6 (4-8)	5 (4-7)	6 (5-9)	5 (4-8)	0.134
Prolonged length of stay (%)	899 (25.02)	10 (15.63)	28 (28.00)	13 (22.81)	0.306
Operative time (min), median (IQR)	160 (121-214)	187 (140-246)	202 (151-253)	182 (142-249)	< 0.0012
Prolonged operative time (%)	858 (23.44)	23 (35.94)	41 (41.00)	20 (35.09)	< 0.0012

¹Two-sided P-values taken from χ² tests (Fisher’s exact test in cell counts less than five);

²P < 0.05 considered statistically significant. Kruskal-Wallis one-way analysis of variance was used to compare non-normal distributions of length of stay and operative time. Overall morbidity: Wound infection, pneumonia, urinary tract infection, venous thromboembolism, bleeding transfusion, renal complication, return to OR, cardiac complication, shock/sepsis, unplanned intubation, on ventilator > 48 h, and organ space SSI. Serious morbidity: Return to OR, cardiac complication, shock/sepsis, unplanned intubation, on ventilator > 48 h, and organ space SSI. Prolonged length of stay, prolonged operative time refers to times longer than the 75^th percentiles for the respective distributions. OR: Operating room; SSI: Surgical site infection; IQR: Interquartile range.

Table 6 Intraoperative/postoperative outcomes among propensity-score matched cohorts³ relative to the surgery only group (results represent odds ratios unless otherwise indicated)

Characteristic	Surgery only varied size with cohort	Chemotherapy n = 64 matched patients	Radiotherapy n = 100 matched patients	Chemo and radio n = 57 matched patients
30-d mortality (%)	1.00 (reference)	0.74 (0.16-3.43)	1.24 (0.73-2.13)	1.38 (0.79-2.43)
Overall morbidity (%)	1.00 (reference)	1.10 (0.46-2.65)	1.14 (0.80-1.62)	1.38 (1.01-1.89)1
Serious morbidity (%)	1.00 (reference)	1.25 (0.50-3.13)	1.00 (0.70-1.42)	1.00 (0.72-1.38)
Length of stay (d)2
Predicted mean difference	0.00 (reference)	-1.43 (-2.19 to -0.68)1	0.34 (0.08-0.60)1	-0.04 (-0.28-0.21)
Prolonged length of stay (%)	1.00 (reference)	0.56 (0.21-1.46)	0.95 (0.68-1.31)	0.78 (0.57-1.06)
Operative time (min)2
Predicted mean difference	0.00 (reference)	13.8 (10.7-17.0)1	19.9 (18.7-21.1)1	9.49 (8.41-10.6)1
Prolonged operative time (%)	1.00 (reference)	2.20 (1.00-4.87)1	1.56 (1.15-2.11)1	1.03 (0.79-1.34)

¹Two-sided P-values < 0.05 considered statistically significant;

²Modified Park tests corresponded to a Poisson distribution. Generalized linear models (family Poisson, link log) were used to model non-normally distributed continuous data, followed by post-estimation average marginal effects to attain predicted mean differences and 95%CI. Interpretation: Patients treated with chemotherapy had average operative times that were longer than those of surgery-only patients by 13.8 min (95%CI: 10.7-17.0); ³Separate cohorts were generated for each outcome using propensity-score-based 1:1 nearest-neighbor matching without replacement, accounting for significant baseline differences in demographic and clinical characteristics.

Table 7 Rates of intraoperative and postoperative complications in cohorts matched for each outcome

Characteristic	Neoadjuvant patients n = 234 (50.00%)3	Surgery-only patients n = 234 (50.00%)3	Odds ratio (95%CI)	P-value1
30-d mortality (%)	19 (8.12)	12 (5.13)	1.63 (0.77-3.45)	0.197
Overall morbidity (%)	63 (26.92)	42 (17.95)	1.68 (1.08-2.62)	0.0211
Return to OR	22 (9.40)	7 (2.99)	3.37 (1.41-8.04)	0.0061
Cardiac complication	10 (4.27)	4 (1.71)	2.57 (0.79-8.30)	0.116
Shock/sepsis	11 (4.70)	3 (1.28)	3.80 (1.05-13.80)	0.0431
Unplanned intubation	27 (11.54)	17 (7.26)	1.66 (0.88-3.14)	0.116
Bleeding transfusion	28 (11.97)	13 (5.56)	2.31 (1.17-4.58)	0.0161
Serious morbidity (%)	44 (18.80)	28 (11.97)	1.70 (1.02-2.85)	0.0421
Length of stay (d)2
Predicted difference in means	--	--	-1.02 (-1.54 to -0.50)	< 0.0011
Prolonged length of stay (%)	44 (18.80)	63 (26.92)	0.63 (0.41-0.97)	0.0371
Operative time (min)2
Predicted difference in means	--	--	29.0 (26.5-31.6)	< 0.0011
Prolonged operative time (%)	90 (38.46)	62 (26.50)	1.73 (1.17-2.57)	0.0061

¹Two-sided P values < 0.05 considered statistically significant;

²Modified Park test found Poisson most appropriate distribution to account for non-normality of the count data; average marginal effects used to calculate predicted difference in the mean;

³Separate cohorts were generated for each outcome using propensity-score-based 1:1 nearest-neighbor matching without replacement, accounting for baseline differences in demographic and clinical characteristics. While all cohorts had an equal distribution of matched neoadjuvant and surgery-only patients (n = 234) by design, no two cohorts necessarily contain the same patients in order to account for cohorts appropriately weighted to each outcome. OR: Operating room.