Abstract
Objectives:
Our objective was to compare outcomes following combined versus isolated resections for metastatic colorectal cancer and/or liver metastases using a large, contemporary national database.
Background:
Controversy persists regarding optimal timing of resections in patients with synchronous colorectal liver metastases.
Methods:
We analyzed 11,814 patients with disseminated colorectal cancer and/or liver metastases who underwent isolated colon, rectal, or liver resections (CRs, RRs, or LRs) or combined colon/liver or rectal/liver resections (CCLRs or CRLRs) in the National Surgical Quality Improvement Program Participant Use File (2011–2015). We examined associations between resection type and outcomes using univariate/multivariate analyses and used propensity adjustment to account for nonrandom receipt of isolated versus combined resections.
Results:
Two thousand four hundred thirty-seven (20.6%); 2108 (17.8%); and 6243 (52.8%) patients underwent isolated CR, RR, or LR; 557 (4.7%) and 469 (4.0%) underwent CCLR or CRLR. Three thousand three hundred ninety-five patients (28.7%) had serious complications (SCs). One hundred forty patients (1.2%) died, of which 113 (80.7%) were failure to rescue (FTR). One thousand three hundred eighty-six (11.7%) patients experienced unplanned readmission. After propensity adjustment and controlling for procedural complexity, wound class, and operation year, CCLR/CRLR was independently associated with increased risk of SC, as well as readmission (compared with LR). CCLR was also independently associated with increased risk of FTR and death (compared with LR).
Conclusions:
Combined resection uniformly confers increased risk of SC and increased risk of mortality after CCLR; addition of colorectal to LR increases risk of readmission. Combined resections are less safe, and potentially more costly, than isolated resections. Effective strategies to prevent SC after combined resections are warranted.
Keywords: cancer, colon, colorectal, combined, complications, death, isolated, liver, metastases, readmission, rectal, resection, synchronous
Mini-abstract: Using the National Surgery Quality Improvement Program Participant Use Data File (2011–2015), 11,814 patients with disseminated colorectal cancer and/or liver metastases who underwent isolated or combined resection were analyzed. Associations between resection type and outcomes were examined using univariate/multivariate analyses and propensity adjustment. Combined resection was associated with increased risk of death, serious complications, and readmission.
Supplemental Digital Content is available in the text.
INTRODUCTION
Colorectal cancer (CRC) is the third leading cause of cancer and cancer-related deaths in the United States.1 The liver is the most common site of CRC metastasis.2 Approximately half of patients with CRC develop colorectal liver metastases (CRLMs); in a third, the liver will be the sole site of distant disease.3,4 Although systemic therapy for metastatic CRC is associated with median survival of approximately 2 years, long-term survival is rare.5–7 In contrast, complete negative-margin resection of CRLM is associated with median 5-year overall survival of 38%, and 5-year survival rates as high as 71% with a solitary CRLM.3–5,8
Approximately 20%–34% of CRC patients present with synchronous liver metastases.8 Curative resection requires complete extirpation of both the primary CRC and CRLM, either at the same time (combined resection) or in a staged fashion (isolated resections). Benefits of combined resection include single-step cytoreduction and avoidance of a second operation and hospital stay. Several retrospective studies have asserted combined resections are safe, whereas others have reported higher risks of perioperative morbidity and mortality.9–12 Larger studies using national datasets have also compared these strategies, but did not differentiate between patients with colon or rectal cancer, consistently exclude patients with nonmetastatic disease, or include patients operated on since 2009.13–19
National Comprehensive Cancer Network guidelines recommend several surgical options in patients with CRC and resectable synchronous CRLM: (1) synchronous or staged colorectal resection with liver resection, followed by adjuvant chemotherapy; (2) neoadjuvant chemotherapy followed by synchronous or staged colorectal resection with liver resection; and (3) colorectal resection, followed by adjuvant chemotherapy and staged liver resection.8 The presence of multiple acceptable choices reflects persistent lack of consensus and ongoing controversy regarding optimal timing of colorectal and liver resection in this common clinical scenario.20
The objective of this study was to compare perioperative outcomes following combined versus isolated resections for metastatic CRC and/or liver metastases using a large, contemporary national database. We performed separate analyses for patients who underwent colon versus rectal resections. To account for selection bias, we used propensity adjustment to account for nonrandom receipt of isolated versus combined resections.
MATERIALS AND METHODS
Study Population
We conducted a retrospective analysis of patients who underwent combined versus isolated resections for metastatic CRC and/or liver metastases in the American College of Surgeons National Surgery Quality Improvement Program (ACS-NSQIP) Participant Use Data File to evaluate association between resection type and perioperative outcomes. Patient data were collected by trained, certified surgical clinical reviewers at each site. The study was reviewed and exempt by our Institutional Review Board.
Patients who underwent colon, rectal, composite colorectal, and/or liver resection in the ACS-NSQIP database from 2011 to 2015 were identified (Fig. 1). Patients were included if they had a diagnosis of disseminated CRC or secondary malignant neoplasm of the liver, and excluded if they underwent pelvic exenteration or local excision of rectal cancer. The analysis was limited to patients with American Society of Anesthesiologists (ASA) score 1–4 who were independent or partially dependent. Patients on dialysis, transferred from an outside facility, and those who underwent emergency or nonelective surgery were excluded.
FIGURE 1.
Flow diagram of patients selected for analysis. ACS-NSQIP indicates American College of Surgeons National Surgery Quality Improvement Program; ASA, American Society of Anesthesiologists.
Variables and Outcomes of Interest
The independent variable of interest was resection type. For each operation, surgical clinical reviewers at each ACS-NSQIP site used available Current Procedural Terminology codes to record whether patients underwent colon, rectal, composite colorectal, and/or liver resection. International Classification of Diseases, 9th Revision, Clinical Modification codes were then used to further limit the study cohort to patients with disseminated CRC and/or secondary malignant neoplasm of the liver (Table 1). Resection type was categorized as isolated colon resection (CR), rectal resection (RR), or liver resection (LR), versus combined colon/liver resection (CCLR) or combined rectal/liver resection (CRLR).
Table 1.
Definitions of Selected Variables, Inclusion Criteria, and Outcomes of Interest.
| Variable/Inclusion Criteria/Outcome of Interest | Data Source | Definition |
|---|---|---|
| Resection type | ||
| Colon | CPT codes | 44140, 44204, 44141, 44143, 44206, 44144, 44150, 44210, 44151, 44160, 44205 |
| Rectal | CPT codes | 44145, 44207, 44146, 44208, 44147, 45110, 45395, 45111, 45112, 45113, 45114, 45116, 45119, 45397, 45123 |
| Composite colorectal* | CPT codes | 44155, 44212, 44156, 44157, 44158, 44211 |
| Liver | CPT codes | 47120, 47122, 47125, 47130 |
| Diagnosis | ||
| Disseminated CRC | ICD-9-CM | 153, 153.0, 153.1, 153.2, 153.3, 153.4, 153.6, 153.7, 153.8, 153.9 or 154.0, 154.1 |
| Secondary malignant neoplasm of the liver | ICD-9-CM | 197.7 |
| Serious complication | ||
| Neurologic | NSQIP PUF | Stroke or coma greater than 24 h |
| Cardiac | NSQIP PUF | Myocardial infarction or cardiac arrest |
| Respiratory | NSQIP PUF | Pneumonia; unplanned intubation; ventilator-dependence greater than 48 h |
| Renal | NSQIP PUF | Acute renal failure requiring dialysis |
| Wound | NSQIP PUF | Deep incisional SSI; organ space SSI; wound dehiscence |
| Venous thromboembolism | NSQIP PUF | Pulmonary embolism |
| Other | NSQIP PUF | Return to the operating room; graft, prosthesis, or flap failure; perioperative blood loss requiring transfusion; postoperative sepsis |
| Complication subtypes | ||
| Renal | NSQIP PUF | Progressive renal insufficiency (rise in creatinine >2 mg/dL from preoperative value not requiring dialysis); acute renal failure requiring dialysis |
| Wound | NSQIP PUF | Superficial incisional SSI; deep incisional SSI; organ space SSI; wound dehiscence |
| Venous thromboembolism | NSQIP PUF | DVT requiring therapy; pulmonary embolism |
| Sepsis | NSQIP PUF | Sepsis; septic shock |
| Minor | NSQIP PUF | Superficial incisional SSI; DVT requiring therapy; UTI; peripheral nerve injury |
*Treated as colon resections in the base case analyses and rectal resections in the sensitivity analysis (which did not impact study results or conclusions [data not shown]).
CPT indicates Current Procedural Terminology; CRC, colorectal cancer; DVT, deep venous thromboembolism; ICD-9-CM, International Classification of Diseases, 9th Revision, Clinical Modification; NSQIP PUF, American College of Surgeons National Surgery Quality Improvement Program Participant Use Data File; SSI, surgical site infection; UTI, urinary tract infection.
Covariates of interest included patient and procedure characteristics previously reported in the literature to be associated with adverse perioperative outcomes after colorectal surgery, as well as those associated with these outcomes in recent ACS-NSQIP Semiannual Report Supplement Model Reports. The sum of the work relative value units (wRVUs) for each patient’s procedure was used to adjust for the complexity of resections performed.21
Postoperative outcomes were evaluated in patients with complete 30-day follow-up. Primary outcome of interest was serious complication (SC) within 30 days of resection (Table 1).22 Secondary outcomes of interest included Clavien-Dindo score 3–4 SC, death, failure to rescue (FTR) after any SC (or after Clavien-Dindo score 3–4 SC), and unplanned readmission.23 We also analyzed the association between resection type and subtypes of SC (Table 1), as well as measures of healthcare utilization. FTR was defined as death following SC.22 With the exception of operative time and length of stay (LOS), primary and secondary outcomes were recorded as binary outcomes.
Statistical Analysis
In unadjusted analyses, associations between resection type, patient/procedure characteristics, and perioperative outcomes, were examined using χ2 tests for categorical variables and Wilcoxon tests for continuous variables. To account for possible selection bias and nonrandom receipt of resection type, propensity adjustment was performed using inverse probability of treatment weights (IPTWs) developed using all theoretically and empirically identified, patient-related covariates.24,25 We separately estimated propensity score weights for each comparison of isolated resection types versus the relevant combined resection, for a total of 4 pairwise comparisons between resection types. For each perioperative outcome, we used IPTW logistic regression models to determine the association between isolated versus combined resection and the outcome, additionally controlling for procedural complexity (total wRVU), wound class, and operation year. We excluded 8.4% of the initial study cohort from the final propensity score-based analyses due to missing data for the following covariates: age, sex, ethnicity, body mass index, serum sodium, serum creatinine, white blood cell count, hematocrit, or platelet count (Fig. 1).
Laboratory values were categorized as binary variables based on previous studies and ACS-NSQIP Semiannual Report Supplement Model Reports. Covariates with missing data > 5% but < 30% of the cohort (ie, blood urea nitrogen, total bilirubin, serum glutamic oxaloacetic transaminase, alkaline phosphatase, albumin, and international normalized ratio) were imputed using multiple imputation methods with 5 imputed datasets.26 A P value <0.05 (2-sided) was used as the cutoff point for statistical significance; a Bonferroni adjustment (P < 0.0125) was used for 4 pairwise comparisons involving the primary outcome. All analyses were completed using SAS 9.4 (Cary, NC).
RESULTS
A total of 11,814 patients were included in the initial cohort, with up to 10,826 included in propensity score-based analyses. Among the patients, 20.6% underwent CR, 17.8% underwent RR, 52.8% underwent LR, 4.7% underwent CCLR, and 4.0% underwent CRLR. Patient and procedure characteristics according to resection type are shown in Tables 2 and 3. Supplementary Tables 1–4 (http://links.lww.com/AOSO/A22) demonstrate that use of IPTW sufficiently balanced patient and procedure characteristics across resection types. We assessed IPTW weighted groups using standardized differences and found that the groups were well-balanced (d < 0.1).27,28
Table 2.
Patient and Procedure Characteristics in Patients Who Underwent Combined Versus Isolated Colon and Liver Resections (Unadjusted Values, N [%] Unless Otherwise Specified)
| Characteristic (% of Patients With Missing Data: Colon/Liver, Colon, Liver) | Colon/Liver | Colon | Liver | P |
|---|---|---|---|---|
| Overall | 557 (6.0) | 2437 (26.4) | 6243 (67.6) | |
| Age* (0.2, 1.8, 0.1) | 59.0 (18.0) | 65.0 (18.0) | 59.0 (17.0) | <0.0001 |
| Female sex (0.2, 0, 0) | 279 (50.2) | 1203 (49.4) | 2891 (46.3) | 0.0142 |
| Race (10.2, 10.1, 9.5) | ||||
| White | 415 (74.5) | 1798 (73.8) | 4935 (79.1) | <0.0001 |
| Black | 62 (11.1) | 271 (11.1) | 470 (7.5) | |
| Other | 23 (4.1) | 121 (5.0) | 247 (4.0) | |
| Hispanic (1.6, 3.2, 1.7) | 33 (6.0) | 109 (4.6) | 322 (5.3) | 0.3130 |
| BMI* (0.0, 0.7, 0.6) | 27.0 (7.3) | 27.0 (7.7) | 27.6 (7.6) | <0.0001 |
| Hypertension (0, 0, 0) | 231 (41.5) | 1269 (52.1) | 2760 (44.2) | <0.0001 |
| CHF (0, 0, 0) | 1 (0.2) | 15 (0.6) | 9 (0.1) | 0.0007 |
| Dyspnea (0, 0, 0) | 37 (6.6) | 259 (10.6) | 314 (5.0) | <0.0001 |
| COPD (0, 0, 0) | 15 (2.7) | 143 (5.9) | 143 (2.3) | <0.0001 |
| Ascites (0, 0, 0) | 2 (0.4) | 43 (1.8) | 11 (0.2) | <0.0001 |
| Diabetes (0, 0, 0) | ||||
| Noninsulin | 46 (8.3) | 288 (11.8) | 569 (9.1) | 0.0002 |
| Insulin | 21 (3.8) | 140 (5.7) | 306 (4.9) | |
| Bleeding disorder (0, 0, 0) | 20 (3.6) | 100 (4.1) | 194 (3.1) | 0.0686 |
| Weight loss (0, 0, 0) | 38 (6.8) | 271 (11.1) | 223 (3.6) | <0.0001 |
| Functional status (0, 0, 0) | ||||
| Independent | 553 (99.3) | 2381 (97.7) | 6212 (99.5) | <0.0001 |
| Partially dependent | 4 (0.7) | 56 (2.3) | 31 (0.5) | |
| Steroid use (0, 0, 0) | 27 (4.9) | 109 (4.5) | 237 (3.8) | 0.2153 |
| Smoking (0, 0, 0) | 79 (14.2) | 380 (15.6) | 782 (12.5) | 0.0007 |
| ASA class (0, 0, 0) | ||||
| 1–2 | 150 (26.9) | 745 (30.6) | 1416 (22.7) | <0.0001 |
| 3 | 382 (68.6) | 1534 (63.0) | 4510 (72.2) | |
| 4 | 25 (4.5) | 158 (6.5) | 317 (5.1) | |
| Sodium, mEq/L* (3.1, 4.9, 3.7) | 140 (3.0) | 139 (4.0) | 140 (3.0) | <0.0001 |
| Creatinine, mg/dL* (1.8, 4.1, 2.8) | 0.8 (0.3) | 0.8 (0.3) | 0.8 (0.3) | 0.1122 |
| WBC, ×103/μL* (1.3, 2.8, 2.2) | 6.5 (3.0) | 7.3 (3.5) | 6.0 (2.6) | <0.0001 |
| Hematocrit, %* (1.3, 2.2, 2.0) | 38.2 (6.1) | 36.0 (7.9) | 39.2 (5.8) | <0.0001 |
| Platelets, ×103/μL* (1.3, 3.2, 2.2) | 225 (105.0) | 270 (143.5) | 207 (87.0) | <0.0001 |
| Albumin, mg/dL* (10.4, 20.8, 11.1) | 4.0 (0.6) | 3.8 (0.7) | 4.0 (0.5) | <0.0001 |
| SGOT, u/L* (10.1, 21.5, 10.1) | 25.0 (15.0) | 23.0 (14.0) | 26.0 (13.0) | <0.0001 |
| Alkaline phosphatase, IU/L* (9.2, 19.9, 8.7) | 90.0 (46.0) | 88.0 (49.0) | 89.0 (47.0) | 0.6973 |
| INR* (16.9, 42.8, 15.3) | 1.0 (0.1) | 1.0 (0.1) | 1.0 (0.1) | <0.0001 |
| Total bilirubin, mg/dL* (7.7, 19.5, 7.3) | 0.5 (0.3) | 0.5 (0.3) | 0.5 (0.3) | <0.0001 |
| BUN, mg/dL* (5.4, 7.2, 7.8) | 13.0 (6.0) | 13.0 (7.1) | 14.0 (6.0) | <0.0001 |
| Total wRVU* (0, 0, 0) | 61.6 (14.0) | 23.0 (3.8) | 39.0 (18.2) | <0.0001 |
| Type of liver resection (0, 0, 0) | ||||
| None | 0 (0.0) | 2437 (100) | 0 (0.0) | <0.0001 |
| Minor | 395 (70.9) | 0 (0) | 3897 (62.4) | |
| Major | 162 (29.1) | 0 (0) | 2346 (37.6) | |
| Operation year (0, 0, 0) | ||||
| 2011 | 76 (13.6) | 310 (12.7) | 969 (15.5) | 0.0075 |
| 2012 | 91 (16.3) | 425 (17.4) | 1092 (17.5) | |
| 2013 | 137 (24.6) | 525 (21.5) | 1409 (22.6) | |
| 2014 | 125 (22.4) | 646 (26.5) | 1474 (23.6) | |
| 2015 | 128 (23.0) | 531 (21.8) | 1299 (20.8) | |
| Wound classification (0, 0, 0) | ||||
| Clean/contaminated | 518 (93.0) | 2151 (88.3) | 5989 (95.9) | <0.0001 |
| Contaminated | 33 (5.9) | 196 (8.0) | 220 (3.5) | |
| Dirty | 6 (1.1) | 90 (3.7) | 34 (0.5) | |
*Median (IQR).
ASA indicates American Society of Anesthesiologists; BMI, body mass index; BUN, blood urea nitrogen; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; INR, international normalized ratio; IQR, interquartile range; SGOT, serum glutamic oxaloacetic transaminase; WBC, white blood cell; wRVU, work relative value units.
Table 3.
Patient and Procedure Characteristics in Patients Who Underwent Combined Versus Isolated Rectal and Liver Resections (Unadjusted Values, N [%] Unless Otherwise Specified)
| Characteristic (% of Patients With Missing Data: Rectal/Liver, Rectal, Liver) | Rectal/Liver | Rectal | Liver | P |
|---|---|---|---|---|
| Overall | 469 (5.3) | 2108 (23.9) | 6243 (70.8) | |
| Age* (0.0, 0.4, 0.1) | 56.0 (15.0) | 58.5 (17.0) | 59.0 (17.0) | <0.0001 |
| Female sex (0, 0, 0) | 195 (41.6) | 879 (41.7) | 2891 (46.3) | 0.0004 |
| Race (8.1, 10.8, 9.5) | ||||
| White | 377 (80.4) | 1643 (77.9) | 4935 (79.1) | 0.0589 |
| Black | 26 (5.5) | 145 (6.9) | 470 (7.5) | |
| Other | 28 (6.0) | 92 (4.4) | 247 (4.0) | |
| Hispanic (1.7, 2.2, 1.7) | 33 (7.2) | 116 (5.6) | 322 (5.3) | 0.1981 |
| BMI* (0.4, 0.6, 0.6) | 26.6 (7.2) | 26.7 (7.5) | 27.6 (7.6) | <0.0001 |
| Hypertension (0, 0, 0) | 158 (33.7) | 859 (40.8) | 2760 (44.2) | <0.0001 |
| CHF (0, 0, 0) | 0 (0.0) | 13 (0.6) | 9 (0.1) | 0.0005 |
| Dyspnea (0, 0, 0) | 21 (4.5) | 112 (5.3) | 314 (5.0) | 0.9214 |
| COPD (0, 0, 0) | 9 (1.9) | 71 (3.4) | 143 (2.3) | 0.0168 |
| Ascites (0, 0, 0) | 6 (1.3) | 15 (0.7) | 11 (0.2) | <0.0001 |
| Diabetes (0, 0, 0) | ||||
| Noninsulin | 39 (8.3) | 174 (8.3) | 569 (9.1) | 0.0718 |
| Insulin | 14 (3.0) | 82 (3.9) | 306 (4.9) | |
| Bleeding disorder (0, 0, 0) | 13 (2.8) | 68 (3.2) | 194 (3.1) | 0.8740 |
| Weight loss (0, 0, 0) | 31 (6.6) | 187 (8.9) | 223 (3.6) | <0.0001 |
| Functional status (0, 0, 0) | ||||
| Independent | 467 (99.6) | 2088 (99.1) | 6212 (99.5) | 0.0594 |
| Partially dependent | 2 (0.4) | 20 (1.0) | 31 (0.5) | |
| Steroid use (0, 0, 0) | 21 (4.5) | 76 (3.6) | 237 (3.8) | 0.6682 |
| Smoking (0, 0, 0) | 83 (17.7) | 444 (21.1) | 782 (12.5) | <0.0001 |
| ASA class (0, 0, 0) | ||||
| 1–2 | 140 (30.0) | 796 (37.8) | 1416 (22.7) | <0.0001 |
| 3 | 312 (66.5) | 1224 (58.1) | 4510 (72.2) | |
| 4 | 17 (3.6) | 88 (4.2) | 317 (5.1) | |
| Sodium, mEq/L* (3.4, 6.0, 3.7) | 140 (4.0) | 139 (3.0) | 140 (3.0) | <0.0001 |
| Creatinine, mg/dL* (2.8, 4.8, 2.8) | 0.8 (0.2) | 0.8 (0.3) | 0.8 (0.3) | 0.0003 |
| WBC, ×103/μL* (2.8, 3.0, 2.2) | 5.7 (2.9) | 6.2 (3.1) | 6.0 (2.6) | 0.0001 |
| Hematocrit, %* (2.1, 2.7, 2.0) | 38.2 (6.2) | 38.1 (6.5) | 39.2 (5.8) | <0.0001 |
| Platelets, ×103/μL* (2.8, 3.1, 2.2) | 215 (102.5) | 233 (115.0) | 207 (87.0) | <0.0001 |
| Albumin, mg/dL* (11.3, 23.6, 11.1) | 4.0 (0.6) | 3.9 (0.6) | 4.0 (0.5) | <0.0001 |
| SGOT, u/L* (10.2, 24.5, 10.1) | 24.0 (13.0) | 22.0 (13.5) | 26.0 (13.0) | <0.0001 |
| Alkaline phosphatase, IU/L* (9.4, 22.2, 8.7) | 81.0 (39.0) | 86.0 (43.0) | 89.0 (47.0) | <0.0001 |
| INR* (24.7, 45.3, 15.3) | 1.0 (0.1) | 1.0 (0.1) | 1.0 (0.1) | <0.0001 |
| Total bilirubin, mg/dL* (8.7, 21.2, 7.3) | 0.5 (0.4) | 0.5 (0.3) | 0.5 (0.3) | <0.0001 |
| BUN, mg/dL* (6.6, 8.2, 7.8) | 12.0 (5.0) | 13.3 (6.0) | 14.0 (6.0) | <0.0001 |
| Total wRVU* (0, 0, 0) | 69.8 (6.5) | 31.9 (4.2) | 39.0 (18.2) | <0.0001 |
| Type of liver resection (0, 0, 0) | ||||
| None | 0 (0.0) | 2108 (100) | 0 (0.0) | <0.0001 |
| Minor | 370 (78.9) | 0 (0.0) | 3897 (62.4) | |
| Major | 99 (21.1) | 0 (0.0) | 2346 (37.6) | |
| Operation year (0, 0, 0) | ||||
| 2011 | 59 (12.6) | 211 (10.0) | 969 (15.5) | <0.0001 |
| 2012 | 84 (17.9) | 329 (15.6) | 1092 (17.5) | |
| 2013 | 93 (19.8) | 466 (22.1) | 1409 (22.6) | |
| 2014 | 123 (26.2) | 590 (28.0) | 1474 (23.6) | |
| 2015 | 110 (23.5) | 512 (24.3) | 1299 (20.8) | |
| Wound classification (0, 0, 0) | ||||
| Clean/contaminated | 429 (91.5) | 1804 (85.6) | 5989 (95.9) | <0.0001 |
| Contaminated | 32 (6.8) | 236 (11.2) | 220 (3.5) | |
| Dirty | 8 (1.7) | 68 (3.2) | 34 (0.5) | |
*Median (IQR).
ASA indicates American Society of Anesthesiologists; BMI, body mass index; BUN, blood urea nitrogen; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; INR, international normalized ratio; IQR, interquartile range; SGOT, serum glutamic oxaloacetic transaminase; WBC, white blood cell; wRVU, work relative value units.
Among 9237 patients who underwent (isolated or combined) colon and/or liver resection, 2594 (28.1%) had a SC and 121 patients (1.3%) died. Of 557 patients who underwent CCLR, 253 (45.4%) had a SC and 9 (1.6%) died (Table 4). In contrast, of 2437 patients who underwent isolated CR, 668 (27.4%) patients developed a SC and 60 (2.5%) died, whereas among 6243 patients who underwent isolated LR, 1673 (26.8%) developed a SC and 52 (0.8%) died. In addition, there were significant differences with respect to rates of FTR and health care utilization across resection types. On univariate subgroup analyses, rates of respiratory, wound, venous thromboembolism (VTE), and sepsis complications were significantly higher in patients who underwent combined versus isolated colon and/or liver resection (Table 5).
Table 4.
Univariate and Multivariate Adjusted/Inverse Probability of Treatment-Weighted (Propensity Score-Based Weights) Associations between Resection Type and Perioperative Outcomes
| Outcome Variable | Unadjusted Probabilities | Adjusted Odds Ratios (95% CI) | |||||
|---|---|---|---|---|---|---|---|
| Colon/Liver | Colon | Liver | P | Colon/Liver | Colon | Liver | |
| Serious complication (%) | 45.42 | 27.41 | 26.80 | < 0.001 | Ref | 0.340 (0.301–0.384) | 0.487 (0.451–0.525) |
| Serious complication, Clavien-Dindo 3 or 4 (%) | 24.42 | 13.13 | 10.14 | < 0.001 | Ref | 0.438 (0.375–0.513) | 0.355 (0.320–0.394) |
| Death (%) | 1.62 | 2.46 | 0.83 | < 0.001 | Ref | 0.745 (0.512–1.084) | 0.454 (0.327–0.630) |
| Failure to rescue (%) | 3.56 | 6.44 | 2.75 | < 0.001 | Ref | 0.802 (0.509–1.263) | 0.596 (0.411–0.863) |
| Failure to rescue, Clavien-Dindo 3 or 4 (%) | 5.88 | 11.25 | 6.32 | 0.02 | Ref | 1.346 (0.735–2.464) | * |
| CNS complication (%) | 0.36 | 0.33 | 0.19 | 0.421 | Ref | * | * |
| Cardiac complication (%) | 2.15 | 0.98 | 0.91 | 0.019 | Ref | 0.202 (0.126–0.324) | 0.487 (0.354–0.669) |
| Respiratory complication (%) | 8.26 | 4.72 | 3.75 | < 0.001 | Ref | 0.449 (0.349–0.578) | 0.441 (0.376–0.517) |
| Renal complication (%) | 1.62 | 1.52 | 0.88 | 0.018 | Ref | * | 0.387 (0.280–0.535) |
| Wound complication (%) | 27.47 | 13.95 | 8.79 | < 0.001 | Ref | 0.419 (0.359–0.489) | 0.275 (0.248–0.305) |
| VTE complication (%) | 4.85 | 2.95 | 2.34 | 0.001 | Ref | 0.445 (0.332–0.596) | 0.439 (0.359–0.536) |
| Sepsis complication (%) | 15.44 | 6.57 | 4.13 | < 0.001 | Ref | 0.434 (0.353–0.533) | 0.214 (0.186–0.246) |
| Minor complication (%) | 14.18 | 10.22 | 5.72 | < 0.001 | Ref | 0.727 (0.607–0.870) | 0.400 (0.352–0.456) |
| Unplanned readmission (%) | 18.13 | 13.75 | 9.15 | < 0.001 | Ref | 0.920 (0.785–1.077) | 0.417 (0.376–0.464) |
| Operative time (min) | 287 | 156 | 225 | < 0.001 | Ref | –101.741 (–111.306 to –92.176) | –67.583 (–73.852 to –61.314) |
| Length of stay (d) | 7 | 6 | 5 | < 0.001 | Ref | –2.528 (–3.077 to –1.979) | –3.071 (–3.420 to –2.722) |
| Outcome Variable | Rectal/Liver | Rectal | Liver | P | Rectal/Liver | Rectal | Liver |
| Serious complication (%) | 41.36 | 28.80 | 26.80 | < 0.001 | Ref | 0.537 (0.471–0.612) | 0.787 (0.720–0.860) |
| Serious complication, Clavien-Dindo 3 or 4 (%) | 20.04 | 14.37 | 10.14 | < 0.001 | Ref | 0.628 (0.534–0.738) | 0.676 (0.573–0.798) |
| Death (%) | 0.64 | 0.76 | 0.83 | 0.871 | Ref | * | * |
| Failure to rescue (%) | 1.55 | 1.98 | 2.75 | 0.398 | Ref | * | * |
| Failure to rescue, Clavien-Dindo 3 or 4 (%) | 3.19 | 3.30 | 6.32 | 0.1 | Ref | * | * |
| CNS complication (%) | 0.43 | 0.19 | 0.19 | 0.548 | Ref | * | * |
| Cardiac complication (%) | 1.07 | 0.81 | 0.91 | 0.834 | Ref | * | * |
| Respiratory complication (%) | 5.76 | 2.70 | 3.75 | 0.003 | Ref | 0.369 (0.268–0.506) | 0.859 (0.703–1.049) |
| Renal complication (%) | 0.85 | 1.90 | 0.88 | < 0.001 | Ref | * | * |
| Wound complication (%) | 20.26 | 16.60 | 8.79 | < 0.001 | Ref | 0.714 (0.611–0.834) | 0.437 (0.381–0.501) |
| VTE complication (%) | 4.05 | 1.76 | 2.34 | 0.010 | Ref | 0.377 (0.253–0.562) | 0.998 (0.782–1.274) |
| Sepsis complication (%) | 9.81 | 5.83 | 4.13 | < 0.001 | Ref | 0.511 (0.405–0.644) | 0.572 (0.471–0.695) |
| Minor complication (%) | 9.81 | 11.34 | 5.72 | < 0.001 | Ref | 1.133 (0.932–1.378) | 0.427 (0.367–0.498) |
| Unplanned readmission (%) | 15.78 | 14.47 | 9.15 | < 0.001 | Ref | 0.869 (0.738–1.024) | 0.704 (0.589–0.841) |
| Operative time (min) | 354 | 248 | 225 | < 0.001 | Ref | –92.012 (–103.417 to –80.607) | –112.353 (–119.849 to –104.856) |
| Length of stay (d) | 7 | 6 | 5 | < 0.001 | Ref | –2.282 (–2.826 to –1.737) | –2.467 (–2.814 to –2.120) |
*Unable to calculate due to insufficient number of patients who experienced outcome.
CI indicates confidence interval; CNS, central nervous system; Ref, reference group; VTE, venous thromboembolism.
Table 5.
Univariate Associations Between Resection Type and Perioperative Outcomes (Subgroup Analyses)
| Outcome Variable | Unadjusted Probabilities | |||
|---|---|---|---|---|
| Colon/Liver | Colon | Liver | P | |
| Respiratory complication | ||||
| Postoperative pneumonia (%) | 5.2 | 2.9 | 2.3 | < 0.001 |
| Unplanned intubation (%) | 4.1 | 2.3 | 1.8 | < 0.001 |
| Failure to wean (%) | 3.8 | 1.5 | 1.6 | < 0.001 |
| Wound complication | ||||
| Superficial SSI (%) | 8.8 | 6.5 | 2.9 | < 0.001 |
| Deep incisional SSI (%) | 3.6 | 1.8 | 1.0 | < 0.001 |
| Organ space SSI (%) | 16.9 | 5.7 | 5.0 | < 0.001 |
| VTE complication | ||||
| DVT (%) | 3.2 | 1.9 | 1.5 | 0.009 |
| PE (%) | 1.6 | 1.6 | 1.2 | 0.313 |
| Sepsis complication | ||||
| Sepsis (%) | 12.6 | 4.6 | 3.3 | < 0.001 |
| Septic shock (%) | 3.4 | 2.1 | 0.9 | < 0.001 |
| Outcome Variable | Rectal/Liver | Rectal | Liver | P |
| Respiratory complication | ||||
| Postoperative pneumonia (%) | 3.0 | 2.1 | 2.3 | 0.497 |
| Unplanned intubation (%) | 3.0 | 1.0 | 1.8 | 0.005 |
| Failure to wean (%) | 2.6 | 0.8 | 1.6 | 0.003 |
| Wound complication | ||||
| Superficial SSI (%) | 7.0 | 7.5 | 2.9 | < 0.001 |
| Deep incisional SSI (%) | 1.1 | 2.2 | 1.0 | < 0.001 |
| Organ space SSI (%) | 13.7 | 7.1 | 5.0 | < 0.001 |
| VTE complication | ||||
| DVT (%) | 2.1 | 1.3 | 1.5 | 0.375 |
| PE (%) | 2.1 | 0.5 | 1.2 | 0.003 |
| Sepsis complication | ||||
| Sepsis (%) | 8.3 | 4.6 | 3.3 | < 0.001 |
| Septic shock (%) | 1.5 | 1.3 | 0.9 | 0.239 |
DVT indicates deep venous thrombosis requiring treatment; PE, pulmonary embolism; SSI, surgical site infection; VTE, venous thromboembolism.
After propensity adjustment, both isolated CR and isolated LR were associated with decreased risk of SC (overall, as well as Clavien-Dindo score 3–4 SC) compared with CCLR (Table 4). Isolated LR was significantly associated with decreased risks of death and FTR compared with CCLR. Additionally, both isolated CR and LR were associated with decreased risks of cardiac, respiratory, wound, VTE, sepsis, and minor complications after propensity adjustment. Although both isolated CR and LR were associated with significantly shorter operative times and LOS compared with CCLR, only LR was associated with decreased risk of unplanned readmission.
Among 8820 patients who underwent (isolated or combined) rectal and/or liver resection, 2474 (28.1%) developed a SC and 71 patients (0.8%) died (Table 4). Of 469 patients who underwent CRLR, 194 (41.4%) had a SC and 3 (0.6%) died. In contrast, of 2108 patients who underwent RR, 607 (28.8%) patients developed a SC and 16 (0.8%) died. Of note, respiratory, wound, VTE, and sepsis complications were also significantly higher in patients who underwent combined versus isolated rectal and/or liver resections (Table 5).
After propensity adjustment, both isolated RR and isolated LR were associated with decreased risk of SC (overall, as well as Clavien-Dindo score 3–4), as well as wound and sepsis complications (Table 4). Compared with CCLR, isolated RR was associated with decreased risk of respiratory and VTE complications, whereas isolated LR was associated with decreased risk of minor complications. Although both isolated RR and LR were associated with significantly shorter operative times and LOS compared with CCLR, only LR was associated with decreased risk of unplanned readmission.
DISCUSSION
Significant controversy persists regarding optimal timing of resections in patients with synchronous CRLM. To our knowledge, this is the first study to-date that has used a large, national, contemporary sample to evaluate perioperative clinical and healthcare utilization outcomes of isolated versus combined colorectal and/or liver resections and uniformly applied a robust methodological approach to control for patient and procedure characteristics, as well as selection bias with respect to type of resection performed (ie, isolated vs combined). In the current study, 20.6%, 17.8%, and 52.8% of patients underwent isolated CR, RR, or LR; 4.7% and 4.0% underwent CCLR or CRLR. Overall, 28.7% of the patients in our cohort had a SC; 1.2% of patients died (of which 80.7% were FTRs) and 11.7% experienced unplanned readmission. After propensity adjustment and controlling for procedural complexity, wound class, and operation year, CCLR/CRLR was associated with increased risk of SC, as well as readmission (compared with LR). CCLR was associated with increased risk of death and FTR (compared with LR). Of note, our study further demonstrated that combined resections are specifically associated with significantly higher rates of respiratory, wound, and sepsis complications after adjustment.
Patient characteristics were markedly different between patients who underwent CR compared with those who underwent LR or CRLR (Table 2). Patients who underwent CR were significantly older and more likely to have hypertension, dyspnea, chronic obstructive pulmonary disease, diabetes, and/or be partially dependent. Selection bias due to similar, systematic “assignment” of younger and/or healthier patients to combined resection may have contributed to apparently comparable perioperative outcomes (compared with patients who underwent isolated and/or staged resections) in previous retrospective series.18,19,29 Of note, some clinically modest (albeit statistically significant) differences were observed in patients who underwent RR, LR, or RRLR in the current study, likely due to more uniform and/or stringent preoperative patient selection across these resection groups (Table 3). As such, it is unlikely that underlying differences in age, comorbidity, and/or functional status across our cohort accounted for the markedly higher rate of SC in patients who underwent combined resections.
Given that combined resection has historically been associated with worse outcomes, it is unsurprising that probable patient selection with respect to extent of liver resection (ie, minor vs major) was also evident in our study.9–11,13,19,29–34 More specifically, only 29.1% and 21.1% of CRLR and RRLR patients in our cohort underwent major liver resections (respectively), compared with 37.6% of patients who underwent LR. Our use of propensity-adjusted, pairwise comparisons allowed us to more effectively analyze the comparative risks of isolated versus combined colorectal and liver resection in this setting, while controlling for the above differences in patient and procedure characteristics, as well as nonrandom treatment assignment (which otherwise, might have significantly confounded our results). Although stratification and weighting via propensity scores has increasingly been used to reduce bias in retrospective studies (and in particular, comparative-effectiveness analyses), recent work suggest that prospective nonrandomized studies with appropriate propensity score analyses can provide reasonable evidence of treatment effects when randomized controlled trials of surgical procedures are not feasible or ethical.35
The overall rate of any SC was 28.7% for our cohort; rates of SC among patients who underwent CR, RR, and LR were relatively comparable (Table 4). In contrast, the addition of a CR to a LR (or vice versa) increased the rate of postoperative SC and Clavien-Dindo 3–4 SC by twofold to 2.9-fold and 2.3- to 2.8-fold, respectively. Similarly, the addition of a RR to a LR (or vice versa) increased the rate of postoperative SC and Clavien-Dindo 3–4 SC by 1.3- to 1.9-fold and 1.5- to 1.6-fold, respectively. The higher rates of SC in patients who underwent combined resection in our cohort were apparently largely driven by increased rates of postoperative respiratory complication, wound complication, VTE complication, and sepsis complication (Table 5). In patients who underwent CRLR, extended (or additional) upper abdominal incisions and bowel manipulation/anastomoses may have resulted in respiratory compromise due to splinting and postoperative ileus, which perhaps increased the risk of pneumonia and/or unplanned intubation. Prolonged operative times after CRLR and RRLR may have resulted in worse postoperative sedation and atelectasis, which perhaps also contributed to unplanned intubations and/or failure to wean from the ventilator.
Combined resection almost doubled or tripled the rate of organ space surgical site infection (SSI) (compared with colorectal or liver resection alone) in our cohort. In a recent study, concomitant bowel surgery increased the risk of organ space SSI by more than fivefold.36 Bile leakage is an independent risk factor for organ space SSI after hepatectomy for hepatocellular carcinoma.37 It is unclear whether the markedly higher rate of organ space SSI after combined resection in our study may be explained by inoculation of post-hepatectomy dead space by colorectal flora and/or bile leakage in the setting of concomitant bowel resection. The increased rate of organ space SSI after combined resection (as well as the increased rate of pneumonia, particularly after CRLR) may have in-turn increased rates of sepsis and sepsis complications in these patients.
Controversy persists regarding the safety of combined resection in patients with synchronous CRLMs. On the basis of a series of retrospective single-institutional studies published in the 1990s (which reported higher rates of morbidity and/or mortality after combined resection), surgical dogma initially favored isolated, staged resections.10–12 Over the past 2 decades, several single- and multi-institutional retrospective studies have suggested that combined resection is not only safe (ie, results in comparable perioperative outcomes) but also potentially preferable (from a “cost-effectiveness” standpoint).13,16,30–34,38–42 An inherent limitation of single-institutional and smaller multi-institutional series is their limited generalizability. By design, retrospective studies comparing surgical procedures and approaches are also particularly vulnerable to bias due to patient selection and nonrandom treatment assignment, which are only partially accounted for via multivariate regression analyses. For example, in a 2003 single-institutional study which compared perioperative outcomes after simultaneous versus staged resections for synchronous CRLMs performed over a 17-year period, simultaneous resections tended to include less complex colorectal resections (ie, right colectomies) and less extensive liver resections (67% minor liver resections, compared with 28% minor liver resections in the staged resection group).42 Perhaps not surprisingly, complications were less common in the simultaneous resections group (49% vs 67%, P < 0.003), while mortality was comparable. Although numerous single- and multi-institutional retrospective studies have subsequent asserted that simultaneous/combined resections are as safe as staged/isolated resections, it is important to note that failure to detect a statistically significant difference between groups is not adequate proof of equivalence. Based on post hoc power analyses (using their respective sample sizes and rates of SC after isolated/staged resection), the vast majority of the above studies were underpowered (3.4%–65.9%) to detect even a large clinically significant (eg, 20%) difference in SC between treatment groups.13,16,30–34,38–42 Apparently, comparable (ie, statistically not different) perioperative outcomes after combined versus isolated resections reported in these studies may have resulted not only from imbalances in patient and procedure characteristics and nonrandom treatment assignment, as well as inadequate sample sizes.
More recent, secondary analyses of large national datasets have reported conflicting conclusions regarding the safety of combined resection.18,19,29,43 In a study using the National Inpatient Sample, CCLR was not associate with increased in-patient morbidity or mortality (compared with CR); however, the analysis did not control for cancer stage, classified liver ablations as resections, and (because it relied on claims data) had limited sensitivity to detect relevant perioperative outcomes.29 Two studies using NSQIP datasets reported higher rates of perioperative morbidity after combined resection (including organ space SSI and sepsis), but not perioperative mortality, while a third NSQIP study using stratified univariate analyses failed to detect a difference.18,19,43 Unlike these previous studies, the current work relied on a larger, more recent sample of patients who underwent combined resection; was strictly limited to patients who underwent colorectal and/or liver resections for metastatic disease; and controlled for surgical complexity of colorectal and/or liver resection (as well as other relevant patient and procedure characteristics) using used propensity-adjusted, multivariate analyses.
Our study has other numerous strengths. Our use of a large, contemporary cohort from the private sector provided us with sufficient sample size to adequately analyze the association between resection type and a broad range of postoperative outcomes and enhanced the generalizability of our findings. In 2011, NSQIP allowed (for the first time) for identification of nonelective cases; as noted above, our cohort was limited to patients operated on/after 2011 to optimize exclusion of these cases (and in particular, nonelective CR cases which would be expected to potentially have more SC and bias the analyses “towards” combined resection). Given the inherent differences and treatment paths of patients with colon and rectal tumors, we performed separate analyses for patients who underwent colon versus rectal resections (alone or in combination with LR) and also controlled for the inherent complexity and risk profiles of the various colon, rectal, and liver procedures performed. To account for differences in patient and procedure characteristics, probable selection bias, and nonrandom treatment assignment, we used propensity score-based, logistic regression models, which also controlled for temporal trends during the study period (operation year), as well as factors inherent to each resection type known to influence perioperative outcomes (procedural complexity, wound class).
Our study also has potential limitations. Although most liver resections for “secondary malignant neoplasms of the liver” are performed for CRC, it is possible that some of the LR patients in our cohort with this “post-op diagnosis” (as reported in NSQIP) did not have CRLM. Because NSQIP does not track patients over time, it is impossible to know if the various isolated resections were performed for synchronous or metachronous disease. Furthermore, the primary and secondary procedures abstracted by the surgical clinical reviewer may not have accurately reflected the actual nature and scope of the procedures performed in each patient. A small percentage of patients underwent “contaminated” or “dirty” resections, potentially suggesting some misclassification with respect to wound class or type of case (resulting in failure to exclude some nonelective or emergent cases). There is a large amount of missing data in NSQIP with respect to receipt of chemotherapy and/or radiation therapy; as such, we could not account for it in our study. In order to propensity adjust across the various resection types and allow for the above pairwise comparisons (irrespective of whether or not a liver resection was performed), we indirectly controlled for extent of liver resection via procedure complexity (total wRVU), rather “minor” versus “major” liver resection. It is highly unlikely that the higher rates of adverse clinical outcomes after combined resection in our study were primarily driven by concomitant major resections, given that the majority of the liver resection in our 2 study subcohorts (ie, 70.9% and 78.9%) were classified as “minor,” and we consistently controlled for procedural complexity in our statistical models.
CONCLUSIONS
Combined resection uniformly confers increased risk of SC and increased risk of FTR and death after CCLR, even after controlling for complexity of colorectal and/or liver resection. Addition of colorectal to LR also increases the risk of readmission. Combined resections increase the risk of Clavien-Dindo 3–4 SC, which often require further surgical, endoscopic, or radiologic interventions and/or can result in life-threatening, single- or multi-organ dysfunction. In addition, they increase the risk of specific SC associated with substantial, previously reported, incremental health care costs, including pulmonary complications ($25,494), SSI ($30,400–40,000), and sepsis ($26,972), and potentially adverse oncologic outcomes due to perioperative immunosuppression.44–47 Previous studies have asserted that single combined resections may be more “cost-effective” than staged isolated resections.18,31 In contrast, our work suggests that combined resections are less safe (as noted in a recent multidisciplinary international consensus statement), and in turn, potentially more costly from both a clinical and economic perspective.48 Testing of targeted strategies to prevent adverse perioperative outcomes after combined resections (such as nutritional and physical “pre-habilitation,” regional and/or nonnarcotic multimodal analgesia, mechanical bowel preparation with oral antibiotics, and minimally invasive surgical approaches) are warranted.49,50 In the interim, combined resections should be approached with great caution, and if performed, limited to highly selected cases at high-volume centers with appropriate expertise and clinical infrastructure.
Supplementary Material
Footnotes
Disclosure: N.F.E. has received honoraria from Celgene, Merck, and AngioDynamics. W.H.W. is a military service member. The other authors declare that they have nothing to disclose. This work was supported by United States Public Health Services grant P30 CA006927 for analysis of the data via support of our Biostatistics and Bioinformatics Facility. This work was prepared as part of his official duties.
Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.annalsofsurgery.com).
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