Influence of surgeon specialization upon the results of colon cancer surgery. Usefulness of propensity scores

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1 D. MARTINEZ RAMOS -:Maquetación 1 19/9/08 11:23 Página /2008/100/7/ REVISTA ESPAÑOLA DE ENFERMEDADES DIGESTIVAS Copyright 2008 ARÁN EDICIONES, S. L. REV ESP ENFERM DIG (Madrid) Vol N. 7, pp , 2008 ORIGINAL PAPERS Influence of surgeon specialization upon the results of colon cancer surgery. Usefulness of propensity scores D. Martínez-Ramos, J. Escrig-Sos, J. M. Miralles-Tena, M. I. Rivadulla-Serrano, J. M. Daroca-José and J. L. Salvador Sanchís Service of General and Digestive Surgery. Castellón General Hospital. Spain ABSTRACT Introduction: surgeon influence on colorectal cancer surgery outcomes has been repeatedly studied in the scientific literature, but conclusions have been contradictory. Here we study whether surgeon specialization is a determinant factor for outcome in these patients. The importance of propensity scores (PS) in surgical research is also studied. Patients and methods: a retrospective study was performed and medical records were reviewed for 236 patients who were intervened for colon cancer in Castellon General Hospital (Spain). Cases were divided into two groups (specialist and non-specialist surgeons), and both 5-year surveillance and disease free survival were compared. Comparisons were first made with no adjustments, and then subsequently using PS analysis. Results: the initial (non-adjusted) analysis was clearly favourable for the specialist surgeon group (5-year surveillance, 64.3 vs. 79.3%, p = 0.028). After adjusting for PS no statistical significance was obtained. Conclusions: surgeon specialization had no significant impact on patient outcome after colon cancer surgery. Propensity score analysis is an important tool in the analysis of surgical non-randomized studies, particularly when events under scrutiny are rare. Key words: Colon cancer. Outcomes. Specialization. Propensity scores. RESUMEN Introducción: la influencia del factor cirujano en el cáncer colorrectal se ha estudiado de manera reiterada en literatura científica, pero los resultados han sido contradictorios. Se plantea en este estudio si la especialización del cirujano es un factor determinante del pronóstico en estos pacientes. Asimismo, se valora la importancia de los índices de propensión (PS) en el análisis de los resultados. Pacientes y métodos: se planteó un estudio retrospectivo con revisión de las historias clínicas de 236 pacientes sometidos a cirugía por cáncer de colon en el Hospital General de Castellón. Se establecieron dos grupos de cirujanos (especialista y no especialista), comparando los resultados en cuanto a supervivencia y en cuanto a intervalo libre de enfermedad a los 5 años. Inicialmente, se realizaron las comparaciones sin el ajuste de los resultados y, posteriormente, utilizando los PS. Resultados: el primer análisis de los resultados (sin ajuste) fue claramente favorable al grupo de cirujanos especialistas (supervivencia a los 5 años del 64,3 frente al 79,3%, p = 0,028). No obstante, cuando se ajustó mediante los PS, no se obtuvo dicha significación estadística. Conclusiones: no se ha podido demostrar que la especialización del cirujano sea un factor determinante del pronóstico en los pacientes sometidos a cirugía por cáncer de colon. Los índices de propensión pueden ser de gran utilidad para el ajuste de los resultados en estudios retrospectivos no aleatorizados, especialmente cuando el factor de estudio es poco frecuente. Palabras clave: Cáncer de colon. Resultados. Especialización. Índices de propensión. Martínez-Ramos D, Escrig-Sos J, Miralles-Tena JM, Rivadulla-Serrano MI, Daroca-José JM, Salvador Sanchís JL. Influence of surgeon specialization upon the results of colon cancer surgery. Usefulness of propensity scores. Rev Esp Enferm Dig 2008; 100: Received: Accepted: Correspondence: David Martínez-Ramos. Servicio de Cirugía General y Digestiva. Hospital General de Castellón. Avda. Benicàssim, s/n Castellón, Spain. davidmartinez@comcas.es INTRODUCTION The influence of the surgeon factor upon surgical results has been widely analyzed for different types of cancer in the literature worldwide (1,2). Colon cancer has

2 D. MARTINEZ RAMOS -:Maquetación 1 19/9/08 11:23 Página D. MARTÍNEZ-RAMOS ET AL. REV ESP ENFERM DIG (Madrid) been no exception in this respect, and many authors have examined the potential relationship between extent of surgeon specialization in colorectal surgery and surgical results obtained (3-20). However, these comparative studies (specialized versus non-specialized surgeons) have not always exhibited the methodological guarantees required to draw conclusions based on true scientific evidence. Thus, while it is true that randomized, prospective clinical trials eliminate biases due to the biological characteristics of patients and their tumors (age, sex, tumor stage, comorbidity, etc.) by distributing them in a balanced manner in both study groups, retrospective studies are unable to guarantee such true randomization. In other words, non-randomized studies may present important imbalances in the distribution of characteristics inherent in each tumor and patient, and this in turn can condition and bias the results obtained. In order to lessen the influence of confounding factors in non-randomized analyses, in 1983 Rosenbaum and Rubin (21) introduced the concept of propensity score (PS). This score is a value of between 0 and 1 indicating the probability that a given patient (with certain biological characteristics) will be allotted to one study branch or another in the absence of randomization (22,23). With certain limitations, when results are adjusted using this probability, it can be assumed that the characteristics of patients capable of influencing study results will be distributed in a quasi-randomized manner. The present study analyzes the influence of the surgeon factor (specialist versus non-specialist) upon the results of colon cancer surgery, and examines the importance of PSs in this type of comparative analysis. MATERIAL AND METHODS In order to secure the study objectives, we used data corresponding to 236 patients operated upon for colon cancer in Castellón General Hospital (Castellón, Spain) between years 1995 and All patients included were subjected to tumor resection with either healing or palliative intent. We therefore excluded all interventions without resection of the primary tumor, and cases of rectal cancer. The purpose of selecting this study period was to ensure a minimum follow-up of 5 years. To establish propensity scores (PSs), use was made of logistic regression in which the outcome variable was type of surgeon. As predictive variables we used those parameters in our database which theoretically could influence the outcome of surgery, and thus of the disease. Likewise, the selected variables were not allowed to depend on surgeon choice or intervention, and could not correspond to case outcome in terms of survival and disease-free interval since both patient survival and disease-free interval constituted the primary endpoints of the analysis. The selected variables were related to patients (e.g., age and serious comorbidity); potential difficulty of the operation; tumor localization; and tumor baseline characteristics (e.g., Dukes stage and histological grade). A new variable was then entered in the database, consisting of the probability derived from the logistic model i.e., the probability, given these predictive variables, that each case was treated by the corresponding surgeon. In this study, the aforementioned probability constitutes the PS. Serious comorbidity was taken to be the presence of risk disorders under treatment at the time of surgery: heart or liver disease, renal failure, diabetes, chronic pulmonary disease, and peripheral vascular accidents. Right-side tumors were defined as those primary lesions located between the cecum and the two proximal thirds of the transverse colon, while left-side tumors were taken to be those primary tumors located between the distal third of the transverse colon and the zone immediately proximal to the rectosigmoid junction. The Dukes classification comprised the classical Stages A, B and C, along with another group (Stage D) comprising cases with metastasis synchronic to surgery, and which in all cases affected the liver. Specialized surgeons were taken to be those belonging to the Coloproctology Section (3 surgeons), while nonspecialized surgeons were taken to be the rest of surgeons in the Service that had performed some surgery for colon cancer (8 surgeons). In our Service there is no formal pre-established protocol for distributing elective colon cancer surgery between the two surgeon groups. We first analyzed the variables corresponding to baseline characteristics for patients and tumors, as well as the results of treatment in terms of patient survival and disease-free interval, without any type of adjustment, for both groups of surgeons. Quantitative variables were expressed as mean ± standard deviation (SD), while qualitative variables were expressed as frequency and relative percentage. Student s t-test was used for quantitative variables, Fisher s exact test for qualitative variables, and the Kaplan- Meier method with log-rank for analyzing survival. Subsequently we analyzed general patient survival and disease-free interval (time to disease relapse in cases without initially diagnosed metastases) based on Cox s regression analysis. In this multivariate test we only included as predictive variable the type of surgeon, and the PS as adjusting element. The STATA version 9 package was used for the statistical analyses. Statistical significance was accepted for p < RESULTS Of the 236 patients included in the study, 127 (53.8%) were males and 109 (46.2%) females. Mean age was 67.7 ± 12 years, with a minimum of 30 years and a maximum of 92 years. Tumors were located in 154 cases (65.3%) on the left side of the colon, and in 82 cases (34.7%) on the right side. In 148 patients (62.7%) we identified some type of comorbidity prior to surgery. The distribution by

3 D. MARTINEZ RAMOS -:Maquetación 1 19/9/08 11:23 Página 389 Vol N. 7, 2008 INFLUENCE OF SURGEON SPECIALIZATION UPON THE RESULTS 389 OF COLON CANCER SURGERY. USEFULNESS OF PROPENSITY SCORES Dukes stages was as follows: Stage A, 31 patients (13%); Stage B, 105 patients (44%); Stage C, 72 patients (31%); and Stage D, 28 patients (12%). The histological grading of tumors was as follows: GX, 2 patients; G1, 140 patients (59.3%); G2, 85 patients (36%); G3, 9 patients (4%). Mean anesthetic time was ± 51 minutes. In 97 patients (41%) some positive lymph node was isolated the mean number of lymph nodes examined per patient was 10.4 ± 7 nodes. No immediate postoperative complications were recorded in 191 patients (80.9%). Six cases of surgical wound infection were documented, along with 3 cases of evisceration, 4 suture failures, 18 other complications, and 14 deaths (6%). In relation to follow-up, the overall 5-year survival rate was 64.1%, with death due to tumor disease in 72 cases (31%). The global 5-year disease-free survival rate was 71.5%. The group of specialized surgeons carried out a total of 111 operations, representing an average of 7.4 operations a year per surgeon, while the non-specialized surgeons performed a total of 125 operations (3 operations/year/surgeon on average). Tables I and II show the results obtained after a comparative analysis of both groups, with no adjustment for patient distribution. This study showed the only factors reaching statistical significance to be Dukes stage (more synchronic metastases in the group of non-specialized surgeons, and more cases of positive lymph nodes among the specialists) and the global 5-year survival rate (greater in the group of specialized surgeons) (Fig. 1). In other words, in the absence of PS adjustment of results, specialized surgeons yielded better results in terms of the probability of 5-year survival, with a difference of 15% (64.3 versus 79.3% in the case of non-specialized surgeons). Other factors, such as the Table I. Baseline characteristics of the patients and tumors Non-specialized Specialized P surgeon surgeon value Number of patients Age 67.9 ± ± * Comorbidity Yes 77 (52%) 71 (48%) No 48 (55%) 40 (45%) 0.788** Tumor location Right 40 (49%) 42 (51%) Left 85 (55%) 69 (45%) 0.411** Dukes stage A 18 (58%) 13 (42%) B 59 (56%) 46 (44%) C 29 (40%) 43 (60%) 0.049** D 19 (68%) 9 (32%) Histological grade Indeterminate 2 0 G1 (well differentiated) 74 (53%) 66 (47%) G2 (Intermediate) 45 (53%) 40 (47%) 0.710** G3 (poorly differentiated) 4 (44%) 5 (56%) Expressed as mean ± standard deviation (SD); *Student t-test; **Fisher exact test. number of lymph nodes analyzed and postoperative complications, bordered on statistical significance. This could be interpreted as indicating a certain tendency in the group of specialized surgeons to obtain a comparatively larger number of lymph nodes and different postoperative complications. In this analysis there were no differences in disease-free survival between the two study groups. Despite these results clearly favorable to the group of specialized surgeons, PS adjustment in the Cox regression analysis for survival and disease relapse yielded the Table II. Results of surgical treatment prior to propensity scores adjustment Non-specialized Specialized P surgeon surgeon value Number of patients Anesthesia time (minutes) ± ± * Lymph nodes studied 9,6 ± ± * Positive lymph nodes 1.2 ± ± * Postoperative complications No 101 (81%) 90 (81%) Wound infection 1 (1%) 5 (4%) Evisceration 1 (1%) (2%) 0.078** Suture failure ( ) 4 (3%) 0 Death ( ) 10 (8%) 4 (4%) Other 8 (6%) 10 (9%) Death due to disease No 79 (48%) 85 (52%) Yes 46 (64%) 26 (36%) 5-year survival rate (Kaplan-Meier) 64.3% 79.3% 0.028*** Tumor relapse No 102 (56%) 79 (43%) Yes 23 (42%) 32 (58%) 5-year disease-free survival (Kaplan-Meier) 77.8% 75.4% 0.197*** Expressed as mean ± standard deviation (SD); ( ): particular for suture failure, p = 0.177**; ( ): particular for death, p = 0,125**; *Student t-test; **Fisher exact test; ***Log-rank test. Fig. 1. Probability of patient survival according to the Kaplan-Meier method for specialized and non-specialized surgeons. Results prior to adjustment.

4 D. MARTINEZ RAMOS -:Maquetación 1 19/9/08 11:23 Página D. MARTÍNEZ-RAMOS ET AL. REV ESP ENFERM DIG (Madrid) results shown in table III. After adjustment, it was seen that the p-value for PS in relation to tumor relapse was close to 1 (p = 0.92), i.e., clearly no significant, while in the case of survival, the value was under (i.e., highly significant). In other words, the distribution of patients between both types of surgeons exerted very little influence upon the results in relation to relapsing disease, but it strongly conditioned differences in global survival. Thus, the differences obtained as a result of the analysis of results without adjustment would not be attributable to the extent of surgeon specialization but to differences in the probability of patients being allotted to one surgeon group or the other, according to their baseline characteristics (age, comorbidity, side of tumor location, Dukes stage and histological grade, jointly grouped in the PS). In sum, we have not been able to demonstrate that the surgeon factor (relating to specialization) influences general survival and disease-free interval in our colon cancer patients. Table III. Cox regression and propensity scores adjustments for tumor relapse and patient survival Hazard 95% confidence P ratio interval value Tumor relapse Specialized surgeon to * Propensity score 0.921* Survival Specialized surgeon to * Propensity < 0.001** *Non significant; **Very significant. DISCUSSION The degree of surgeon specialization has been shown to be an independent prognostic factor for different types of complex and infrequent surgical procedures such as pancreatectomy, esophagectomy, pneumonectomy, liver resection or pelvic exenteration (1). In colorectal cancer, however, findings are contradictory. McArdle and Hole (10), among other authors (7,20), reported that surgeons with greater experience or specialized in colorectal surgery obtained better results in terms of patient survival and disease relapse versus non-specialized surgeons. Similar findings were published by Harmon et al. (5) and Schrag et al. (17,19), though unlike in the case of McArdle and Hole (10), these authors considered the volume of patients attended in the hospital to be a more important factor than the degree of surgeon specialization. However, while statistically significant, the difference in postoperative mortality after colon cancer surgery between hospitals with a greater or lesser volume of patients was only 2% (16). These results are in contrast with those obtained by Hermanek et al. (6), who reported a similar disease relapse rate between surgeons with fewer than (15) rectal surgical operations and those with comparatively greater experience. Two additional studies (8,13) likewise reported no statistically significant relationship between number of cases per surgeon and patient survival. Likewise, Mella et al. (11), in a series of 3,221 patients with colorectal cancer, found no differences in postoperative survival between a group of surgeons self-defined as being experts and another group considered to lack such expertise. Simunovic et al. (19) recorded no differences in the survival of patients subjected to specific colon cancer surgery in Ontario (Canada) between hospitals with a greater or lesser volume of treated patients. In this context, the present study identified no statistically significant differences in terms of the global 5-year survival rate or disease-free survival between the group of specialized surgeons and the group of non-specialized surgeons. However, the main limitation of our study is the definition of the concept of a surgeon specialized in colorectal surgery. In effect, at present there are no national or international criteria for defining such specialization or expertise in oncological colon surgery. In some cases, the definition of a specialized surgeon has been based on the number of patients operated upon by the surgeon (9) or hospital (18), membership in some specific coloproctology association (16,20), years as a specialist (7), possession of a board title in coloproctology (14,15), or even self-definition as specialist with a particular interest in coloproctology (11). In other cases, as in our study, the distinction between specialized and non-specialized surgeons is based on peer assessment according to certain previously established criteria (10). In the present study, the classification was exclusively based on whether a surgeon belonged to the Coloproctology Section of our Service of General Surgery. Although it is logically necessary to define what is meant by a surgeon specialized in coloproctology, due consideration is also required of the limitations differences in concept may impose upon the comparative analysis of the results obtained. Another difference to be taken into account is that the present study refers only to colon cancer with the exclusion of all rectal lesions. As is well known, rectal malignancies present important differences in terms of technical difficulty and as regards adjuvant and neoadjuvant treatments, compared with cancers located in the colon. As a result, our findings cannot be applied to rectal tumors. On the other hand, the present study has demonstrated the usefulness of applying propensity scores (PSs). In effect, in the initial analysis without adjustment for confounding factors, the results were clearly favorable to specialized surgeons (5-year survival rate 64.3% vs. 79.3% among the non-specialists, p = 0.028). However, such statistical significance was lost after applying a PS adjustment. According to this analysis, certain patients had an a priori greater probability of being assigned to one surgeon group or the other a fact that introduced an important bias in the initial results. Following PS adjustment, the surgeon factor was not found to exert an impor-

5 D. MARTINEZ RAMOS -:Maquetación 1 19/9/08 11:23 Página 391 Vol N. 7, 2008 INFLUENCE OF SURGEON SPECIALIZATION UPON THE RESULTS 391 OF COLON CANCER SURGERY. USEFULNESS OF PROPENSITY SCORES tant influence in the prognosis of patients subjected to colon cancer surgery. The slight and no significant tendency towards improved patient survival in the specialized surgeon group that remained after adjustment (hazard ratio < 1, table III) could have been related to the fact that these surgeons operated on fewer cases presenting with metastases at the time of surgery. In contrast, the group of specialists showed a slight and again no significant tendency towards poorer performance (hazard ratio > 1, table III), in terms of time to disease relapse. This may have been because they operated upon more cases with positive lymph nodes (Dukes Stage C), and upon fewer patients in Stages A and B. An added advantage of propensity scores is that they consider the influence (no matter how small) of variables which individually show no significant differences with respect to compared groups. Although the comparison of surgical results is one of the elements required for evidence-based surgical practice, such comparisons must be established with rigor in order to avoid biased conclusions and dire consequences for patients. Thus, when comparisons are made in the context of randomized and controlled clinical trials, patients are randomly allotted to the different study groups or arms, and it therefore can be assumed that differences between groups are minimal in terms of confounding factors. However, these studies cannot always be conducted in a randomized and prospective manner due to a number of reasons (particularly ethical and organizational in nature). In such situations use must be made of case series, cohorts or case-control designs, as in our study. In these non-randomized studies, confounding factors are generally an important problem, and a multivariate analysis is often used to adjust for such factors. However, in some cases this type of analysis, applied directly to the study objective, may exceed its applicability - particularly when the study result is unusual (e.g., death of patients in early tumor stages) or (in other words) when the number of confounding factors is too large for the sample used. In these cases, propensity scores (PSs) offer a mathematically valid alternative to direct multivariate analysis (22,23). Thus, PSs represent the probability (between 0 and 1) that a given patient will receive one treatment instead of the treatment of the other control group, i.e., the probability of being assigned to a given study group on the basis of a series of baseline characteristics (potential confounding factors) using a logistic regression model as intermediate step towards the definitive analysis. The main difference between direct multivariate analysis and PS adjustment is that the former involves adjustment according to a series of baseline characteristics paying special attention to the relationship between these characteristics and the final result while propensity scoring focuses on the relationship between baseline characteristics and the primary endpoint of the study (in our case type of surgeon), with use in a second step as an element for adjustment in the final analysis of the primary endpoint. In this way, propensity scoring attempts an a posteriori reconstruction of a situation similar to randomization, known as quasi-randomization (22). The analytical techniques most commonly used for calculating PS in medicine are matching, stratification and logistic regression. In the present study we used the latter approach, since it is simpler to apply versus the other techniques, and we deliberately included age, comorbidity, side of tumor location, tumor stage, and histological grade as potential confounding factors since these are the factors commonly used for the adjustment of surgical results in this disease (16). However, it is important to take into account that propensity scoring, in the same way as the direct multivariate analysis, is unable to adjust for unknown or unavailable confounding factors, and the presence of any such factor could alter the final result (22). This constitutes another limitation of the study, but is exclusively inherent to the methodology. The usefulness of PS goes well beyond what has been presented here for the comparison of results between specialized and non-specialized surgeons, since the technique can be used for comparing results in any setting, such as two surgical techniques (laparoscopic versus open surgery), two adjuvant therapies (adjuvant chemotherapy versus neoadjuvant chemotherapy) or two hospital centers (reference versus secondary), etc. Knowledge of the indications for PS, and the consequences and limitations involved, may be of great help for avoiding important errors when drawing conclusions from studies. In general, on comparing two groups in non-randomized studies, some type of adjustment for potential confounding factors must be established. Am analysis of the distribution of these factors between the two groups, with the observation of no statistically significant differences, does not guarantee that groups are comparable and can be analyzed with conventional inferential (non-multivariate) statistical tests. This erroneous approach is quite widespread in the literature (9,24,25), and should be avoided. Thus, while propensity scores are not the only adjustment tool available, in studies such as our own they may be very useful. CONCLUSION In the present study we were unable to show extent of surgeon specialization as a determining factor for the prognosis of patients subjected to colon cancer surgery. Rather, the results were found to be influenced by the baseline characteristics of patient and tumor. On the other hand, our study demonstrates the usefulness of propensity scores in adjusting the results of non-randomized retrospective studies, particularly when the study factor is infrequent, and illustrates how findings can be drastically modified as a result. Such propensity scores can be applied in many clinical research settings, avoiding biases introduced by the non-randomized distribution of patients in one study group or another.

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