ORIGINAL ARTICLE. Clinical Calculator of Conditional Survival Estimates for Resected and Unresected Survivors of Pancreatic Cancer

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1 ONLINE FIRST ORIGINAL ARTICLE Clinical Calculator of Conditional Survival Estimates for Resected and Unresected Survivors of Pancreatic Cancer Matthew H. G. Katz, MD; Chung-Yuan Hu, PhD; Jason B. Fleming, MD; Peter W. T. Pisters, MD; Jeffrey E. Lee, MD; George J. Chang, MD, MS Objective: To calculate conditional survival estimates for patients with pancreatic adenocarcinoma. Design: We constructed separate multivariate survival models adjusted for 7 clinicopathologic factors for patients who did and did not undergo radical surgical resection. Participants: Patients with pancreatic adenocarcinoma diagnosed between 1988 and 2005 included in the Surveillance Epidemiology End Results cancer registry. Main Outcome Measure: Internet browser based calculator to compute personalized survival estimates. Results: Conditional survival probabilities increased over time for all patients with pancreatic cancer regardless of patient characteristics, disease stage, or treatment. For patients with resected stage I, II, or III disease, 3-year conditional cancer-specific survival increased from 38% to 70%, 19% to 54%, and 8% to 39%, respectively, over the 3 years following diagnosis. The relative improvement in survival over time was larger for patients with advanced disease. A customizable, Internet browser-based clinical calculator was implemented that may be used to compute in real time personalized conditional survival estimates based on an individual s unique clinicopathologic profile. Conclusions: Conditional survival estimates provide a more accurate and typically more optimistic assessment of prognosis for patients with pancreatic cancer than traditional survival estimates that apply only at the initial diagnosis. Arch Surg. 20;147(6): Published online February 20, 20. doi: /archsurg Author Affiliations: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston. PANCREATIC DUCTAL ADENOcarcinoma (PDA) represents the fourth leading cause of cancer-related death in the United States. 1 Pancreatic ductal adenocarcinoma has aggressive tumor biology and high metastatic potential, with less than 20% of patients with newly diagnosed PDA surviving 1 year following the initial diagnosis. Only 4% of patients survive 5 years. 2 These statistics often contribute to a sense of nihilism among patients with pancreatic cancer and their medical practitioners. However, it is increasingly recognized that the probability of future survival of patients with PDA is determined by multiple clinical factors including disease stage at presentation and the use of surgical resection. Even long-term survival is no longer uncommon following multimodality therapy for localized cancer. 3-6 Furthermore, because the risk of cancer recurrence and death from PDA change significantly over time, the probability of a patient s future survival is also dependent on the amount of time that has elapsed since the initial diagnosis. For cancers associated with a significant rate of early death, traditional survival estimates applicable to patients with a new cancer diagnosis rapidly become inaccurate and irrelevant. Therefore, the median or 5-year overall survival estimates that are routinely reported cannot be directly applied to survivors of pancreatic cancer. To the extent that personalized survival probability estimates have a critical influence on personal decision making, diseaserelated anxiety, and quality of life, the clinical relevance of such estimates depends on the degree to which they reflect not only that patient s unique clinicopathologic characteristics but also the time that has elapsed since the diagnosis of cancer. Conditional survival is defined as the future survival probability or duration that is calculated after a given period of survival. 7 Unlike standard survival estimates, estimates of conditional survival are time dependent and change significantly during the survivorship period for pa- 513

2 tients with cancer particularly those with cancers associated with a low long-term survival probability at diagnosis. 8 Conditional survival estimates have been reported for patients with various solid cancers including colon, 8 rectum, 9 stomach, 10 skin, 11 and breast cancer. In this study, we sought to calculate personalized and clinically relevant conditional survival estimates for individual patients with PDA. Furthermore, we sought to implement an interactive, Internet browser based calculator to facilitate clinical application of these data. METHODS DATA SOURCE AND STUDY POPULATION Data from the Surveillance, Epidemiology, and End Results (SEER) 17 program of the National Cancer Institute released in 2011 were used in this study. 13 The Surveillance, Epidemiology, and End Results program collects cancer incidence, cancer-related variables, and survival data from regional registries that cover approximately 26% of the US population. We evaluated all patients with a histopathologic diagnosis of PDA as their only malignancy (SEER primary site recodes C250-3 or C257-9 and International Classification of Diseases for Oncology, Third edition histology codes 8140, 8480, 8481, 8490, or 8500). To allow for at least 3 years of follow-up in December 2008, the patients included in our study were diagnosed from January 1988 through December Tumor extension codes from SEER were used to assign T, N, and M stages, according to the seventh edition of the American Joint Commission on Cancer algorithm. 14 Tumors were classified as being confined to the pancreas (T1 and T2), extending beyond the pancreas (T3), or extending to the mesenteric vessels (T4). The program does not provide specific information regarding whether mesenteric vascular involvement is confined to the superior mesenteric or portal vein or involves the superior mesenteric artery. Therefore, our approach likely upstaged a small number of patients with isolated involvement of the superior mesenteric vein or portal vein who would be considered T3 (stage II) using the American Joint Commission on Cancer system but T4 (stage III) using this recoding system. Tumors at distant sites were assessed and coded as metastatic disease (M1). Any lymph node involvement was coded as N1. We evaluated separately patients who underwent surgical resection and those who did not. We considered patients with nonmetastatic disease who had undergone pancreaticoduodenectomy, distal pancreatectomy, or total pancreatectomy to have received a radical oncologic resection. 15 Patients with stage IV cancers who had undergone 1 of these procedures as well as all patients who had undergone other nonanatomic operations were not considered to have had oncologic resection because these operations do not influence survival. 16 Exclusion criteria included patients aged younger than years or older than 90 years, in situ disease, and lack of histologic or overall survival information. Occurrences also were excluded if the cancer-reporting source was a nursing home, hospice, autopsy, or death certificate; survival time was less than 1 month; or incomplete data precluded American Joint Commission on Cancer stage assignment. STATISTICAL ANALYSES Survival outcomes for all patients in the study cohort were determined using SEER data through December Cancerspecific survival was calculated using SEER cause of death recodes. Occurrences were censored if death was due to other causes or the patient was alive at the last follow-up. Cancer-specific survival probabilities were estimated by the Kaplan-Meier method. The multiplicative law of probability was used to calculate conditional survival probability estimates among patients with a minimum of 3 years of actual followup, as previously described. 8 Conditional survival represents the probability that a patient with cancer will survive an additional number of years (x) given that the patient has already survived a given number of years (y). For example, to compute the x-year conditional survival for patients who have survived y years, the (x y)-year cancer-specific survival is divided by the y-year cancer-specific survival. To adjust for the simultaneous effect of multiple variables on survival, we employed multivariate Cox regression analyses. Covariates adjusted in the prediction model were based on factors identified on univariate analysis as well as those we determined to be clinically relevant. These factors were age, sex, race/ethnicity, tumor site, tumor grade, tumor stage, and radiotherapy. We graphically assessed the proportional hazards assumption on the basis of Schoenfeld residuals. 17 Because of the importance of surgical therapy on survival outcomes, adjusted survival functions stratified by the same 7 factors were evaluated separately for patients who had undergone oncologic pancreatic resection and those who had not. Adjusted cancer-specific survival rates were calculated up to 78 months (6.5 years) for patients who had undergone surgery and up to 45 months (3.75 years) for patients who had not. These survival statistics formed the basis for calculating the adjusted conditional survival. For example, conditional survival probabilities stratified by sex were calculated on the basis of the adjusted survival function for men and women and were controlled for the influence from the other covariates in the final model. Once the final models had been established, we developed a browser-based clinical application that can be used to compute individualized cancer-specific survival and conditional survival probabilities. The calibration of the online application was validated graphically through the goodness-of-fit statistics for Cox proportional hazards models. The agreement between the observed and model-predicted expected risk of cancerspecific death was plotted on the calibration plot for each decile of the survival outcome. We performed all analyses with Stata MP software version 11.0 (Stata). This study was exempt from review by our institutional review board. RESULTS In the SEER database, patients had been diagnosed with a first and only primary pancreatic adenocarcinoma between 1988 and Following exclusions, patients were included in the final analysis. Baseline clinicopathologic characteristics of the cohort are reported in Table 1. In all, 5736 patients (15%) had undergone an oncologic resection and (85%) had not. Among patients who had undergone resection, 15% of the tumors were stage I, 78% were stage II, and 7% were stage III. Among the patients with stage I, II, or III tumors, 41%, 44%, and %, respectively, had undergone an oncologic resection. Radiotherapy had been administered to a substantially higher percentage of patients who had undergone resection (47%) than those who had not (19%). The median follow-up was 58 months (range, months) for patients with resected cancer and 48 months 514

3 (range, months) for patients with unresected cancer. Kaplan-Meier cancer-specific survival plots for patients with PDA who had and had not undergone surgery, stratified by disease stage and adjusted for age, sex, race/ethnicity, tumor site, tumor grade, and radiotherapy, are presented in Figure 1. The results of the separate multivariate survival models are shown in Table 2. The calibration plot indicated good agreement between the observed and modelpredicted outcomes (efigure, For each disease stage, the median cancerspecific survival of patients who had undergone resection was more favorable than of those who had not. Among patients who had undergone surgery, advanced disease stage and grade, advanced age, and tumor site in the body/ tail of the pancreas were all associated with a higher risk of cancer-specific death. Radiotherapy was associated with a lower risk of cancer-specific death. Among patients who had not undergone resection, patients who had been diagnosed with stage IV disease had the highest risk of cancer-specific death. Advanced age, male sex, black race, advanced disease stage and grade, tumor site in the body/ tail, and absence of radiotherapy were additional independent factors associated with a higher risk of cancerrelated death. Adjusted conditional survival probabilities were calculated separately for patients who had undergone oncologic resection and those who had not. We developed an interactive browser-based conditional survival calculator to facilitate the estimation of conditional survival probabilities for individual patients on the basis of clinicopathologic factors and time parameters that may be selected by the operator. Here we report conditional survival using time parameters we felt to be most relevant to each clinical cohort. The adjusted probability of 3 years of future survival stratified by disease stage given that patients have already survived 6 to 42 months in 6-month intervals are depicted in Figure 2A for patients who had undergone surgery. For patients who had not undergone this operation, the adjusted probabilities of 1 year of future survival are reported for patients who have survived 3 to 21 months in 3-month intervals (Figure 2B). Conditional survival probabilities increased over time for each disease stage whether surgery had been performed. The relative increase was larger for patients with advanced disease. For example, the probability of 3 years of future survival for patients with resected stage I cancer relatively increased by 85% (from 38% to 70%) between diagnosis and 3 years, whereas that of patients with resected stage III cancer increased 388% (from 8% to 39%). Our browser-based conditional survival calculator has been implemented and is available for clinical use at http: // COMMENT Table 1. Baseline Clinicopathologic Characteristics of Study Cohort Overall and by Disease Stage Characteristic Patient Total No. (%) Resected Unresected, or V No. of Patients (100) 5736 (15) (85) Age at diagnosis, y (8) 538 (9) 2496 (8) (68) 4317 (75) (67) (24) 881 (15) 79 (25) Sex Male 923 (51) 2921 (51) (51) Female 2 (49) 2815 (49) (49) Race/ethnicity White (81) 4774 (83) (81) Black 4295 () 567 (10) 3728 () Asian/Pacific Islander 2789 (7) 395 (7) 2394 (8) Tumor stage a I 2061 (6) 835 (15) 26 (4) II (27) 4479 (78) 5653 () III 3403 (9) 422 (7) 2981 (9) IV (58) NA (69) Tumor site Head (55) 4975 (87) (50) Body/tail 7673 (21) 706 () 6967 (22) Site unknown 8924 (24) 55 (1) 8869 (28) Tumor grade 1 and (28) 3432 (60) 7043 (22) 3 and (23) 56 (32) 6501 (21) Unknown 303 (49) 448 (8) (57) Radiotherapy No (76) 3049 (53) (81) Yes 8766 (24) 2687 (47) 6079 (19) Abbreviation: NA, not applicable. a Modified from the seventh edition of the American Joint Commission on Cancer algorithm. In this study, we identified a clinically significant association between time after diagnosis and conditional cancer-specific survival probability among patients with PDA. Using data from more than patients with cancer treated nationwide, we demonstrated that pancreatic cancer specific survival improves for all patients over time regardless of patient characteristics, disease stage, or treatment. Furthermore, we developed a browser-based calculator that can be used to compute personalized conditional survival estimates based on an individual s unique clinicopathologic profile. The survival estimates derived from this tool may be recalculated in real time to inform the personal and clinical decision making of survivors of pancreatic cancer and their caregivers. Prior reports of long-term survival for patients with PDA have focused on cancer survivors who have lived more than 5 years after surgical resection and have shown that the relatively infrequent event of 5-year survival is associated with an improved future prognosis. 19 It is increasingly accepted that cancer survivorship begins at the time of diagnosis, however, not at an arbitrarily chosen future milestone. 20 We demonstrated that the future life expectancy of all patients with PDA continually improves relative to that at diagnosis over time regardless of disease stage, age, sex, race/ethnicity, tumor grade, tumor site, or treatment. For patients who undergo resection, the absolute improvement in conditional survival over time is dramatic and reflects both the significant risk for early recurrence and the existence of an established subgroup of patients with favorable cancer biology who 515

4 A Adjusted Cancer-Specific Survival Time Following Diagnosis, mo I No. of patients at risk Months I B Adjusted Cancer-Specific Survival Time Following Diagnosis, mo I V No. of patients at risk Months I V Figure 1. Kaplan-Meier plots of adjusted cancer-specific survival stratified by disease stage for patients with pancreatic ductal adenocarcinoma diagnosed between 1998 and 2005 who had (A) and had not (B) undergone an oncologic resection. Note that the survival curves of patients with unresected stage II and III cancers are superimposed. survive long-term. 3 Indeed, the probability of 3 years of future survival improves from 8% to 38% to 39% to 70% for survivors of cancer over the first 3 years. However, it must be emphasized that we did not observe a plateau in the conditional survival estimates of these patients, reflecting the potential for cancer recurrence and subsequent cancer-specific death we previously reported as occurring as late as 7 years following diagnosis. 3 Relative to the group of patients who undergo surgery, far fewer long-term survivors exist among patients who do not undergo resection. However, even among patients with advanced stage or inoperable disease, the relative increase in conditional survival is significant over periods that are clinically relevant to the patient. For example, the adjusted probability of 1 year of future survival of patients with stage IV disease increases by a relative 73% (11% to 19%) over the first year (Figure 2B). Therefore, real-time conditional survival estimates provide a more accurate assessment of prognosis for all patients with pancreatic cancer than do the routinely cited 5-year survival rates or median survival statistics that apply only at the time of initial diagnosis of cancer. The clinical importance of personalized prognostication is well established. Indeed, considerable effort has been expended in the creation of risk nomograms with which the survival probability of individual patients with pancreatic cancer can be calculated on the basis of clinicopathologic variables. 21,22 Existing survival nomograms are inexpensive and easy to use but were constructed using data from highly selected patients treated at single, specialized centers; therefore, they may not be generalizable to larger populations. Moreover, they can be applied only to patients with early stage cancer immediately following surgical resection and do not reflect the continuous changes in survival probability that we have demonstrated among survivors of pancreatic cancer over time. For these reasons, those clinical tools have limited clinical use for most patients with pancreatic cancer. 516

5 Table 2. Results of Multivariate Cox Regression Analysis by Disease Stage Characteristic Resected Hazard (95% CI) Unresected, or V Age at diagnosis, y 50 1 [Ref] 1 [Ref] ( ) 1.16 ( ) ( ) 1.49 ( ) Sex Male 1 [Ref] 1 [Ref] Female 0.96 ( ) 0.95 ( ) P value Race/ethnicity White 1 [Ref] 1 [Ref] Black 1.11 ( ) 1.09 ( ) Asian/Pacific Islander 1.06 ( ) 0.90 ( ) P value Tumor stage a I 1 [Ref] 1 [Ref] II 1.74 ( ) 1. ( ) III 2.68 ( ) 1.11 ( ) IV NA 1.68 ( ) Tumor site Head 1 [Ref] 1 [Ref] Body/tail 1.11 ( ) 1.10 ( ) Site unknown 1.23 ( ) 1.11 ( ) P value Tumor grade 1 and 2 1 [Ref] 1 [Ref] 3 and ( ) 1.31 ( ) Unknown 1.08 ( ) 1. ( ) Radiotherapy No 1 [Ref] 1 [Ref] Yes 0.71 ( ) 0.71 ( ) Abbreviation: NA, not applicable. a Modified from the seventh edition of the American Joint Commission on Cancer algorithm. Our online conditional survival calculator addresses these limitations. This clinical calculator is applicable to all patients with PDA regardless of disease stage or treatment. It accurately reflects the simultaneous effect of multiple clinicopathologic factors on survival, and it may be used at any point following diagnosis. Furthermore, our calculator allows the user to input the desired duration of time for which future survival probability is computed an important consideration given the limited relevance of the 3- or 5-year overall survival estimates traditionally reported for patients with PDA. 8,9 Indeed, customization of both time parameters and critical clinicopathologic variables allows clinicians to calculate in real time the conditional survival probability estimate specific to a unique patient and relevant to a specific clinical scenario. These estimates can be updated at each surveillance visit and may facilitate personalized decision making. For example, the personal, economic, and treatment-related decisions made by a young white man with well-differentiated stage II disease following resection and AAdjusted Cancer-Specific Survival BAdjusted Cancer-Specific Survival I I V Survival After Diagnosis, mo Survival After Diagnosis, mo Figure 2. Chart of adjusted cancer-specific survival. (A) Three-year conditional, cancer-specific survival by disease stage (adjusted for age, sex, race/ethnicity, tumor grade, tumor site, and radiotherapy) of patients with stages I through III pancreatic ductal adenocarcinoma who had undergone surgical resection. (B) One-year, conditional, cancer-specific survival by stage (adjusted for the same factors) of patients with stages I through III pancreatic ductal adenocarcinoma who had not undergone resection or who had stage IV disease. The x-axis represents the duration of survival to date (6-month intervals for surgical patients and 3-month intervals for nonsurgical patients). radiation (who has a 31% chance of surviving 3 years) might differ considerably from those of the same patient who is still alive 3 years later (who has approximately a 65% chance of surviving 3 additional years). Appreciation of improvements in conditional survival over time may gradually reduce the anxiety and fear of disease progression that exert a negative impact on the quality of life of survivors of cancer and their caregivers Our analysis has important strengths and limitations. We evaluated data from a population-based representation of patients with all stages of PDA. This is a distinction from previously developed tools based on data generated by single institutions with highly selected patients. Although the observed experience of individual centers may differ slightly, our analysis is applicable to the US population of patients diagnosed with PDA. Furthermore, because of the unselected nature of the study 517

6 cohort, we were able to develop separate survival models for patients who had and had not undergone resection, which is a critical determinant of long-term outcome. This bears emphasizing given that a minority of patients with PDA undergo surgery even those with American Joint Commission on Cancer stage I or II disease who would otherwise be considered surgical candidates on the basis of tumor anatomy However, some relevant data including whether systemic chemotherapy was administered are not available in SEER. This may have influenced our model because chemotherapy may prolong overall survival both as adjuvant therapy for patients with resected cancer and as primary therapy for patients with advanced disease. 31,32 Interestingly, we did identify a survival advantage associated with the administration of radiotherapy even among patients who underwent surgery. Although adjuvant chemoradiation is well accepted in many American high-volume pancreatic centers, its benefit has not been clearly demonstrated in randomized clinical trials A second limitation is that clinical stage assignment may be difficult to determine in the absence of a resected pathologic specimen and may affect the stage-dependent estimates for patients who did not undergo cancerdirected surgery. However, the use of cancer-directed surgery was a more important determinant of outcome, and in fact the survival estimates for unresected localized tumors were similar to each other. By developing separate models for the resected and unresected cohorts, our analysis separately informs prognosis for patients who were unable to undergo resection and is applicable to the real-world scenario of caring for patients with best available clinical stage assignment. The performance of our model might be improved by the addition of clinical variables not currently available within the SEER database such as performance status, which is known to be of clinical significance for patients with any stage of PDA, 37 or more specific anatomic descriptions of the relationship between the tumor and the superior mesenteric artery and vein. However, as performance status is an important determinant of surgical resection candidacy, stratifying by resection status can be expected to minimize this effect. In summary, we have shown that conditional survival estimates are a more useful measure of future survival for survivors of pancreatic cancer than traditionally reported survival estimates, which are applicable only at diagnosis. We have further shown that the survival expectancy of all patients with PDA improves over time regardless of patient characteristics or the pathologic variables associated with the primary cancer. Finally, we have developed a powerful, interactive clinical calculator for generating clinically relevant estimates of future survival that are individualized to patients with PDA. These estimates may have significant effects on the quality of life of survivors of pancreatic cancer. Accepted for Publication: November 28, Published Online: February 20, 20. doi: /archsurg Correspondence: Matthew H. G. Katz, MD, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Unit 1484, PO Box , Houston, TX (mhgkatz@mdanderson.org). Author Contributions: Study concept and design: Chang and Katz. Acquisition of data: Katz, Hu, and Fleming. Analysis and interpretation of data: Katz, Hu, Fleming, Pisters, Lee, and Chang. Drafting of the manuscript: Hu, Pisters, and Chang. Critical revision of the manuscript for important intellectual content: Katz, Hu, Fleming, Pisters, Lee, and Chang. Statistical analysis: Hu and Chang. Obtained funding: Katz, Fleming, and Chang. Administrative, technical, and material support: Lee. Study supervision: Pisters, Lee, and Chang. Financial Disclosure: None reported. Funding/Support: This study was supported in part by an American Society of Clinical Oncology Foundation Career Development Award and K07-CA1337 research grant from the National Cancer Institute to Dr Chang. Online-Only Material: The efigure is available at http: // REFERENCES 1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, CA Cancer J Clin. 2010; 60(5): Survival rates for pancreatic cancer. American Cancer Society Web site. http: // Accessed May 20, Katz MH, Wang H, Fleming JB, et al. Long-term survival after multidisciplinary management of resected pancreatic adenocarcinoma. Ann Surg Oncol. 2009; 16(4): Howard TJ, Krug JE, Yu J, et al. A margin-negative R0 resection accomplished with minimal postoperative complications is the surgeon s contribution to longterm survival in pancreatic cancer. 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