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Impact of presence and degree of pretreatment weight loss in locally-advanced pancreatic cancer patients treated with definitive concurrent chemoradiotherapy
Pancreatology xxx (2016) 1e6
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Original article
Impact of presence and degree of pretreatment weight loss in locally-advanced pancreatic cancer patients treated with definitive concurrent chemoradiotherapy a € Berna Akkus Yildirim a, *, Yurday Ozdemir , Tamer Colakoglu b, Erkan Topkan a a b
Baskent University Adana Medical Faculty, Department of Radiation Oncology, Adana, Turkey Baskent University Adana Medical Faculty, Department of General Surgery, Adana, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history: Available online xxx
Background: To assess the impact of the presence and degree of pretreatment weight loss (WL) on the survival of locally-advanced pancreas cancer (LAPC) patients treated with concurrent chemoradiotherapy (C-CRT). Methods: Seventy-three patients who received 50.4 Gy C-CRT were analyzed. All patients underwent laparoscopy (n ¼ 18) or laparotomy (n ¼ 55), and biopsies were obtained for histologic examination of the primary tumor and enlarged/metabolically active regional lymph nodes. Pretreatment WL and percentage WL (PWL) were calculated by utilizing data obtained 6 months prior to and during hospital admission. The primary objective was to assess the influence WL status on overall survival (OS), and the secondary objective was the identification of a PWL cut-off value, if available. Results: Forty-five (61.6%) patients had WL. Median OS was 14.4 months for the entire study population which was significantly longer in the non-WL than the WL cohort (21.4 vs. 11.3 months; p < 0.003). On further analysis a cut-off value of 3.1% was identified for WL. Accordingly, patients with WL < 3.1% had significantly longer OS than those with WL 3.1% (25.8 vs. 10.1 months; p < 0.001). In multivariate analysis, both the WL status (p < 0.001) and PWL (p ¼ 0.002) retained their independent significance. Conclusion: Both the presence and degree of WL prior to C-CRT had strong adverse effects on the survival of LAPC patients, even if they presented with a BMI > 20 kg/m2. Additionally, a WL of 3.1% in the last 6 months appeared to be a strong cut-off for the stratification of such patients into distinctive survival groups. Copyright © 2016, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Keywords: Locally-advanced pancreatic carcinoma Pretreatment weight loss Survival Concurrent chemoradiotherapy Percentage weight loss Weight loss degree
Introduction Definitive concurrent chemoradiotherapy (C-CRT) or induction chemotherapy followed by C-CRT is the preferred treatment options for patients with locally-advanced pancreatic cancer (LAPC), which accounts for 30e40% of all pancreatic cancers (PC) [1]. However, despite the advances in diagnostic, staging, and treatment methodologies, the prognosis of such patients remains poor, with an estimated median survival of 8e12 months. For LAPC, the conventional prognosticators include gender, age, performance
* Corresponding author. Department of Radiation Oncology, Baskent University, Adana Medical Faculty, Kisla Saglik Yerleskesi, 01120 Adana, Turkey. Tel.: þ90 5337381069. E-mail address: [email protected] (B.A. Yildirim).
status, presence/absence of pain, pancreatic location of the tumor, tumor size, extension of the primary tumor to neighboring organs/ vasculature, tumor grade, lymph node involvement status, serum CA19-9 and CEA levels, weight loss (WL) status before C-CRT, and previous experience of the hospital team [2,3]. Involuntary WL, one of the cardinal signs of anorexia-cachexia syndrome, is present in up to 85% of LAPC patients at the time of diagnosis. The fundamental drivers for involuntary WL in LAPC are complex and are triggered by tumor products and proinflammatory cytokines. Regardless of the exact cause, WL does not only lead to decreased personal physical function and increased psychological distress in patients and their care takers, but also leads to increased rates of severe toxicity and reduces the tolerance to any oncologic treatment [4]. Obligatory reductions in chemotherapy and/or RT doses, treatment delays, or total
http://dx.doi.org/10.1016/j.pan.2016.03.006 1424-3903/Copyright © 2016, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Please cite this article in press as: Yildirim BA, et al., Impact of presence and degree of pretreatment weight loss in locally-advanced pancreatic cancer patients treated with definitive concurrent chemoradiotherapy, Pancreatology (2016), http://dx.doi.org/10.1016/j.pan.2016.03.006
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abandonment of treatment due to intolerance issues have been shown to lead to reduced tumor control and worse survival outcomes [5,6]. To the best of our knowledge, no study has concentrated specifically on the extent of WL and searched for an objective cut-off value in patients in the era of definitive C-CRT. Moreover, in past studies the research populations were exceedingly heterogeneous in terms of basal weight and body mass index (BMI) measures; namely, both underweight (BMI < 20 kg/m2), ordinarily weighted (BMI > 20e25 kg/m2), and overweight (BMI > 25 kg/m2) individuals were included, which raises problems in interpretation of their outcomes. Therefore, in this retrospective cohort study, we investigated the influence of both the presence and degree of pretreatment WL on survival outcomes of LAPC patients with BMI > 20 kg/m2 who were treated with definitive CRT, and sought to ascertain a cut-off value for WL that may be utilized as a clinical indicator of survival in conjunction with promptly used traditional factors.
Methods Patient population A retrospective database search was performed to identify surgically unresectable LAPC patients that underwent definitive C-CRT between February 2008 and December 2013. In accordance with the AJCC staging system (6th ed.), our institutional definition for technically unresectable PC included patients with celiac axis and/ or superior mesenteric artery involvement, namely stage III (T4N01M0) disease. In all patients, the disease extent was determined by radiological studies and laparotomy or laparoscopic examination. Standard radiological work-up included contrast-enhanced abdominal tomography (CT), magnetic resonance imaging (MRI), and/or MR-cholangiopancreaticography (MRCP). Additionally, all patients were re-staged via fusion of previous CT images (obtained 1 week before position-emission tomography/ computerized tomography (FDG-PETeCT) scan) with FDG-PETeCT images obtained for radiation therapy planning (RTP). In accordance with the current standard institutional staging procedure for PC, all patients underwent laparoscopic (n ¼ 18) or laparotomic (n ¼ 55) examination and biopsies were obtained for histologic diagnosis of the primary tumor. Biopsies of enlarged/metabolically active regional lymph nodes and isolated single organ metastasis were also obtained if suspected radiologically or if identified during laparotomy/laparoscopy. Patients with a previous history of chemotherapy or abdominal irradiation were considered ineligible. Further eligibility criteria included the following requirements: an age of 18e70 years, a diagnosis of histologically proven adenocarcinoma, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0e2, presence of a measurable or evaluable lesion, no contraindications for FDG-PET-CT imaging, an adequate bone marrow reserve (hemoglobin value of 10 g/dL, leukocyte count of 4000 cells/mL, and thrombocyte count of 100,000 cells/mL), hepatic (aspartate aminotransferase or alanine aminotransferase of <5 times the upper limit) and renal function (serum creatinine < 2 mg/dL), BMI > 20, and available pretreatment weight and height measures just prior to C-CRT and at 6 months prior to referral. The latter information was readily obtained, as it is common at any oncologic examination to question first degree relatives about the relative weight change status of the patient during the last six months. The study design was approved by the Institutional Ethical Committee before any data collection. The study was performed in accordance with the Helsinki Declaration and Rules of Good Clinical Practice.
Treatment planning and chemoradiotherapy The tumor volumes included the primary tumor and involved LNs and were delineated on the FDG-PET/CT fusion. For each patient, the gross tumor volume (GTV) included the primary tumor (GTV-P) and involved lymph nodes (GTV-N) apparent on contrastenhanced CT (short axis 1.0 cm) and/or PET images. Nodes < 1.0 cm were only included in the GTV if they were judged to be metabolically active (SUVmax > 2.5) on PET scan. Based on literature [7] depicting nearly 1.5 cm of pancreas movement with respiration and considering the lack of a motion tracking system and image guidance at our department, planning target volume (PTV) was defined by adding 2 cm to GTV in all directions, except for intersecting organs at risk (OAR) restrictions or natural barriers with minimal movement risk (e.g. vertebral bodies), to allow for microscopic extension, organ motion, and set-up errors. Elective nodal irradiation was prohibited in the study. All OAR volumes were contoured from the CT because of the inherent difficulties in edge detection with PET-based contouring. All patients received 50.4 Gy (1.8 Gy/fx) RT, which was prescribed to encompass the defined PTV with isodose lines between 95% and 107%. Target volume coverage and OAR doses were assessed by utilizing the dose-volume histograms generated for each patient. The maximum dose limits for normal tissues were 45 Gy for spinal cord; 50 Gy for small bowel and stomach; 50 Gy for one-third, 35 Gy for two-thirds, and 30 Gy for three-thirds of the liver; and 20 Gy for at least two-thirds of one functioning kidney. All patients received 1e2 courses of cisplatin (n ¼ 24), continuously infused 5-fluorouracil (n ¼ 24), gemcitabine (n ¼ 11), and cisplatinbased doublet chemotherapy (n ¼ 14) concurrent with radiotherapy. Additionally, 57 patients received 4e6 courses of maintenance gemcitabine or 2e4 courses of adjuvant cisplatin-based doublet chemotherapy following C-CRT. Weight measures Body weight and height measures just prior to and 6 months before (baseline) the C-CRT were used to calculate the relative weight change (WC) and body mass index (BMI) changes during this time period. However, WC, which by definition independently reflects the absolute difference during the last 6 months, has the potential to underestimate the value of baseline body mass. For this reason, in addition to absolute change (kg), we also calculated the change in percentage relative to baseline, namely the percentage weight change (PWC). For the purposes of this study, patients with no WL or with any degree of weight gain during the last 6 months were assigned to the no weight loss (NWL) group, while patients with any degree of WL were assigned to the WL group. Toxicity and response assessments Toxicity during the course of C-CRT was evaluated by reviewing the treatment charts of all patients, who were examined at weekly intervals, or more frequently if necessary. After completion of the CCRT, patients were examined bimonthly for the first year, every 3 months for the second year, and at 6 month intervals, or more frequently if needed, thereafter. Both the acute and late toxicity were graded by a radiation oncologist according to the Common Terminology Criteria for Adverse Events scale (version 3.0). The recorded grade reflected the worst grade observed. Response evaluation and follow-up Response to treatment was assessed by restaging PET/CT scans 12 weeks after the end of CRT in accordance with the Positron
Please cite this article in press as: Yildirim BA, et al., Impact of presence and degree of pretreatment weight loss in locally-advanced pancreatic cancer patients treated with definitive concurrent chemoradiotherapy, Pancreatology (2016), http://dx.doi.org/10.1016/j.pan.2016.03.006
B.A. Yildirim et al. / Pancreatology xxx (2016) 1e6
Emission Tomography Response Criteria in Solid Tumors (PERCIST) [8]. The 12-week time interval for the first follow-up PET/CT was the shortest possible time mandated by our national health insurance policy, rather than being evidence-based. Thereafter, all patients were monitored every 8e12 weeks by blood count/chemistry and PET/CT. If indicated, patients also underwent abdominal US and/or CT, chest CT, or cranial MRI. Statistical analysis The primary objective of this study was assessment of the overall survival (OS) difference between patients with or without any WL prior to the initiation of C-CRT. The OS was defined as the interval between the first day of C-CRT and death/last visit. The secondary objective was the identification of a significant WL cutoff value in terms of absolute WC or PWL, if present. For this purpose we used receiver operating characteristic (ROC) curve analysis to determine the PWL cut-off value for discrimination of outcomes. The ROC analysis represents the area under the curve (AUC) of sensitivity vs. the false-positive rate, and is equivalent to the probability that the predictive model will assign a higher probability of an event to subjects who subsequently have an event. Patients were further grouped into three WL groups according to the 5% WL cut-off for cachexia, as defined by the Delphi Consensus: Group 1, <5%; Group 2, 5.01e10% WL; Group 3, >10% WL (severe WL) [9]. Survival analysis was performed using the KaplaneMeier method, and the survival outcomes of subsets were compared with two-sided log-rank tests. For multivariate analysis, the Cox proportional hazard model was used to assess the simultaneous interaction among multiple clinical variables and survival. A twosided p < 0.05 was considered significant. Bonferroni's correction was utilized following comparisons between three or more groups, as indicated. Results We evaluated the records of 73 consecutive LAPC patients who were treated with C-CRT and met the specified inclusion criteria. The pretreatment characteristics of the entire study population are depicted in Table 1. Of these patients, 45 (61.6%) experienced WL in the pre-C-CRT 6 month period (Table 2). Of the surviving 22 patients, 13 (46.4%) were in the non-WL (NWL) and 9 (20%) were in the WL groups (p ¼ 0.017). WL was significantly more common in patients with N1 (27/34; 79.4%) than N0 (18/39; 46.2%) nodal disease (p ¼ 0.02) and ECOG 2 (14/17; 82.4%) than 0e1 (31/56; 55.4%) performance status (p ¼ 0.03). In regression analysis, both N1 (p ¼ 0.008) and ECOG 2 (p ¼ 0.006) were found to correlate independently with WL. At a median follow-up of 16.7 months (95% CI: 8.8e18.6), 22 (30.1%) patients were alive. The median survival time was 14.4 months (95% CI: 8.8e18.6), and the 2- and 3-year OS rates for the entire cohort were 30.3% and 13.6%, respectively. Median absolute WL and PWL were 5.7 kg (12.7 to 4.1 kg) and 8.7% (range: 20.2 to 7.8%) during the last 6 months before the initiation of C-CRT. As shown in Fig. 1, comparative survival analysis revealed significantly longer median OS in the NWL than in the WL cohort (21.4 vs. 11.3 months; p < 0.003) with respective 2- (47.5% vs. 19.6%) and 3-year (27.1% vs. 7.3%) OS rates also favoring the NWL group. Although WL could stratify patients into two groups with significantly differing OS, we also searched for the presence of a cut-off value by utilizing PWC as an objective measure of WL. ROC curve analysis identified a PWC of 3.1% (AUC 70.5, sensitivity 78.4, specificity 70.2) as a cut-off point for obtaining distinctive OS results (Fig. 2). Further grouping of patients according to this value [<3.1% (n ¼ 39) vs. 3.1% WL (n ¼ 34)] showed that patients with no or <3.1% WL had
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Table 1 Pretreatment patient and disease characteristics. Characteristic
N (%)
Median age, y (range) Gender Female Male ECOG 0e1 2 Diabetes mellitus Absent Present Fatty stool Absent Present Nodal status 0 1 Concurrent chemotherapy Cisplatinum 5-Fluorouracil Gemcitabine Cisplatinum-based doublet WL status Absent Present WL-ROC analysis cut-off <3.1% 3.1% Cachexia statusa Non-cachectic (no WL) Precachectic (5% WL) Cachectic (>5% WL) WL group Group 1 Group 2 Group 3
57 (39e69) 16 (21.9) 57 (78.1) 56 (76.7) 17 (23.3) 54 (74.0) 19 (26.0) 52 (71.24) 21 (28.76) 39 (53.0) 34 (47.0) 24 24 11 14
(32.8) (32.8) (15.0) (19.4)
28 (38.4) 45 (61.6) 39 (53.4) 34 (46.6) 28 (38.4) 19 (26.0) 26 (35.6) 47 (64.4) 15 (20.5) 11 (15.1)
Abbreviations: WL: weight loss; Group 1: <5%, Group 2: 5.01e10%, and Group 3: >10%, ROC: receiver operating characteristic, ECOG: Eastern Cooperative Oncology Group. a According to Delphi Consensus definition (9).
significantly longer median OS times than those with 3.1% WL (25.8 vs. 10.1 months; p < 0.0001) (Fig. 3). With an end goal of recognizing the group with the worst outcomes, we stratified our study population into three further groups according to the Delphi Consensus: Group 1, <5% WL; Group 2, 5.01e10% WL; and Group 3, >10% WL. The 10% value was chosen because of its wide acceptance as the definition of severe WL in the literature (9, 11). As demonstrated in Fig. 4, comparative long-rank analysis revealed significant and step-wise decrements in median OS times with the worsening of WL: 25.8 vs. 12.9 vs. 6.4 months (p < 0.001) for Groups 1, 2, and 3, respectively. Similarly, the 3-year OS rate also decreased with the worsening of WL (27.1% vs. 9.7% vs. 0% for Groups 1, 2, and 3, respectively). As demonstrated in Table 2, univariate analyses revealed that OS associated significantly with ECOG status (0e1 vs. 2), N stage (0 vs. 1), WL status (absent vs. present), WL grouping according to the ROC defined cut-off (<3.1% vs. 3.1%), and WL grouping (<5% vs. 5.01e10% vs. >10%), all favoring the precedent values. In multivariate analysis, which exclusively included the factors that were significant in univariate analysis, each factor retained its independent significant association with OS outcomes (Table 2). Discussion The results of the present retrospective cohort analysis demonstrated that both the presence and degree of WL prior to CCRT had strong adverse effects on survival outcomes of LAPC
Please cite this article in press as: Yildirim BA, et al., Impact of presence and degree of pretreatment weight loss in locally-advanced pancreatic cancer patients treated with definitive concurrent chemoradiotherapy, Pancreatology (2016), http://dx.doi.org/10.1016/j.pan.2016.03.006
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Table 2 Outcomes of univariate and multivariate analysis. Characteristic Age <65 65 Gender Female Male ECOG 0e1 2 Nodal status 0 1 WL status Absent Present ROC analysis cut-off <3.1% 3.1% WL group Group 1 Group 2 Group 3
Patients N (%)
Survival (months)
Univariate p-value
Multivariate p-value
59 (80.82) 14 (19.18)
14.4 15.7
0.32
e
16 (21.9) 57 (78.1)
12.9 15.7
0.72
e
56 (76.7) 17 (23.3)
17.5 11.2
<0.001
<0.001
39 (53.0) 34 (47.0)
20.2 11.2
<0.001
0.006
54 (74.0) 19 (26.0)
21.4 11.3
0.003
<0.001
39 (53.4) 34 (46.6)
25.8 10.1
<0.001
<0.001
47 (64.4) 15 (20.5) 11 (15.1)
25.8 12.9 6.4
<0.001
0.002
Abbreviations: ECOG: Eastern Cooperative Oncology Group; WL: weight loss; ROC: receiver operating characteristic, Group 1: <5%, Group 2: 5.01e10%, and Group 3: >10%.
Fig. 2. Receiver operating curve analysis results searching weight loss cut-off correlated with overall survival status (AUC: area under the curve). Fig. 1. Overall survival according to weight loss status.
patients treated with C-CRT, even they presented with a BMI above the cachexia range (>20 kg/m2). Additionally, a WL of greater than 3.1% in the 6 months prior to C-CRT appeared to be a strong cut-off for the stratification of such patients into distinctive survival groups, and may be utilized as an additional surrogate marker of poorer prognosis. WL, experienced by up to 85% of patients with advanced gastrointestinal cancers [12], reflects tumor-induced increased catabolism [10], and its presence has repeatedly been demonstrated to indicate poorer prognosis in various tumor types, including LAPC. Although WL has been proposed to onset in the
early phases of tumorigenesis and to progress in parallel with tumor progression, no strict cut-off value for WL and the time interval for this loss has gained universal acceptance. For example, in the 2008 Washington Consensus reported by Evans et al., WL of 5% in the last 12 months was recommended as the cardinal parameter for the diagnosis of cancer cachexia, whereas in the 2011 Delphi Consensus, the same WL cut-off was recommended for the last 6 months [9,11]. Additionally, as cancer cachexia is usually an irreversible medical condition with no well-defined treatment, it may be more important to define the critical degree of WL in the precachectic time period when treatment, or at least a delay of cachexia, may be possible with supportive interventions.
Please cite this article in press as: Yildirim BA, et al., Impact of presence and degree of pretreatment weight loss in locally-advanced pancreatic cancer patients treated with definitive concurrent chemoradiotherapy, Pancreatology (2016), http://dx.doi.org/10.1016/j.pan.2016.03.006
B.A. Yildirim et al. / Pancreatology xxx (2016) 1e6
Fig. 3. Overall survival according to the ROC analysis-defined weight loss cut-off of 3.1% (ROC: receiver operating curve).
Interestingly, to date, there has been no universally accepted consensus definition or even a suggestion for a pre-cachectic WL cut-off for any tumor type. Considering the fact that cancer progression and increased catabolic activity/WL are strongly interrelated, we herein planned to evaluate the prognostic significance of any WL present before the onset of C-CRT and search for a LAPC specific cut-off beyond the aforementioned ones that may be utilized for the further stratification of such patients who present with a BMI > 20 and are planned to undergo radical C-CRT into different prognostic groups.
Fig. 4. Overall survival outcomes for patients following grouping according to the Delphi Consensus cachexia definition and severe cachexia.
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Although all patients had a BMI > 20 in our current series, in accordance with previous LAPC studies reporting that up to 85% of cases experience some degree of WL, we noted up to 20.7% WL in 61.6% cases [12]. Of these patients, 26 (35.6%) were cachectic according to the Delphi Consensus definition [9], as they had >5% WL, while 19 (26.0%) were non-cachectic but had some degree of WL (0.1e5%), and therefore were pre-cachectic. The high WL incidence and rate of precachectic patients reported herein and elsewhere by others underscores the importance of the diagnosis of WL as a marker of both cachexia and precachexia, particularly in the detection and treatment of precachexia before its transformation to irreversible and lethal cancer cachexia. In an unresected LAPC study by Wesseltoft-Rao et al., the authors found that patients with cancer cachexia and precachexia had poorer survival than those with noncachexia [13]. In this study the corresponding OS ratio between precachectic and noncachectic groups was 0.44 (95% CI: 0.17e1.14) [13]. Although we methodologically grouped patients into different groups than Wesseltoft-Rao et al., our present results confirm their results in terms of demonstrating a strong relationship between the extent of WL and OS outcomes. Accordingly, the OS ratios for Group 3 vs. 2, Group 2 vs. 1, and Group 3 vs. 1 were 0.50 (p < 0.001), 0.50 (p < 0.001), and 0.49 (p < 0.001), respectively (Fig. 4). Interestingly, the median OS of 6.4 months observed in patients with >10% WL was similar to the median survival of 3e11.1 months that was reported for metastatic pancreatic cancer patients treated with the best available chemotherapy regimens [14,15]. Although the study population size and the retrospective nature of the present study does not permit us to remark conclusively on this finding, it may indicate that a rapidly progressing LAPC subtype with PET-CT occult distant metastases is present in patients with >10% WL, and mandates a rethinking of the potentially unnecessary early use of C-CRT or limited courses of neoadjuvant chemotherapy. This point needs to be further investigated in appropriately designed future studies. Importantly, our search primary end goal of determining a LAPC-specific PWL cut-off by utilizing ROC analysis identified 3.1% as the cut-off point for stratifying patients into two different groups with distinct survival outcomes (25.8 months for <3.1% vs. 10.1 months for 3.1% WL patients; p < 0.001). Although this value needs to be further confirmed in larger series, to the best of our knowledge, this is the first cut-off value that has been identified specifically for definitively treated LAPC patients with prognostic importance beyond the generally used consensus-based value of 5% [9,11]. Furthermore, it may be difficult to attribute this result to a single exact cause, but it may be related to an early and aggressive WL course in LAPC patients. Providing support for this assumption is a relative older study in which Wigmore et al. demonstrated that at 3 months pre-illness, none of the 20 eligible LAPC patients had WL, but had a median weight of 63.7 kg that decreased to 53.2 kg at the time of diagnosis, representing a 14.2% WL. Additionally, 17 (85%) patients became cachectic during this relatively short time period. This finding emphasizes the need for the identification of critical WL values for each tumor type rather than using a common cut-off value, as suggested by consensus statements, for any cancer type irrespective its inherent biological behavior [16]. Two additional important, but not surprising, findings of the present study was the confirmation of lymph node involvement (9.1 vs. 21.4 months; p ¼ 0.008) and ECOG 2 performance score (11.2 vs. 17.5 months; p ¼ 0.006) as strong surrogates of poor prognosis in such patients. Numerous studies have demonstrated that patients with lymph node involvement have significantly worse survival than lymph node-negative patients, with a median survival range of 7.9e15.5 months [17e22]. Likewise, poor ECOG performance status, which reflects poor overall health, has also
Please cite this article in press as: Yildirim BA, et al., Impact of presence and degree of pretreatment weight loss in locally-advanced pancreatic cancer patients treated with definitive concurrent chemoradiotherapy, Pancreatology (2016), http://dx.doi.org/10.1016/j.pan.2016.03.006
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been associated with worse prognosis in radically treated LAPC patients [23]. This may be associated with the decreased tolerance of such LAPC patients to definitive C-CRT, may reflect a poor physical condition as a consequence of more aggressive tumor behavior, or both [2,24,25]. Interestingly, in our study, both lymph node involvement (79.4% vs. 46.2%; p ¼ 0.02) and poor ECOG (82.4% vs. 55.4%; p ¼ 0.03) performance status were associated with a higher extent of WL. Although it is difficult to explain the exact mechanism by which patients with WL have a poorer performance status and higher rates of lymph node involvement, it is reasonable to anticipate that patients with WL have inherently more aggressive tumor phenotypes and possibly poorer immunologic status, which may add to the poorer prognosis observed in this patient group [26e28]. However, further well-designed studies that include a larger number of patients are warranted to determine the exact causeeresult relationship between these three factors. Besides several strengths, such as the use of PET-CT for staging in all patients and the exclusive inclusion of LAPC patients that were treated in a similar fashion, our study also has considerable limitations. First, as with any retrospective cohort analysis, unpredictable biases may have influenced our results. Second, since the patients were highly selected in terms of BMI, our results cannot be generalized to all LAPC patients undergoing C-CRT. Third, the limited cohort size mandates the confirmation of the results observed herein in similarly designed future studies with larger study cohorts to remark conclusively on this highly specific and important issue. In conclusion, although it represents the findings of a retrospective cohort analysis with a relatively small study population size, the results presented here demonstrated that both the presence and degree of WL prior to C-CRT had strong adverse effects on survival outcomes of LAPC patients even if they presented with a BMI > 20 kg/m2. Additionally, a WL of 3.1% in the last 6 months appeared to be a strong cut-off value for the stratification of such patients into distinctive survival groups, and this cut-off may be utilized as an additional surrogate marker of poorer prognosis. Funding None. References [1] Pliarchopoulou K, Pectasides D. Pancreatic cancer: current and future treatment strategies. Cancer Treat Rev 2009;35(5):431e6. [2] Peixoto RD, Speers C, McGahan CE, Renouf DJ, Schaeffer DF, Kennecke HF. Prognostic factors and sites of metastasis in unresectable locally advanced pancreatic cancer. Cancer Med 2015;4(8):1171e7. [3] Gobbi PG, Bergonzi M, Comelli M, Villano L, Pozzoli D, Vanoli A, et al. The prognostic role of time to diagnosis and presenting symptoms in patients with pancreatic cancer. Cancer Epidemiol 2013;37:186e90. [4] Hopkinson JB, Wright DN, McDonald JW, Corner JL. The prevalence of concern about weight loss and change in eating habits in people with advanced cancer. J Pain Symptom Manag 2006;32(4):322e31. [5] Dalal S, Hui D, Bidaut L, Lem K, Del Fabbro E, Crane C, et al. Relationships among body mass index, longitudinal body composition alterations, and survival in patients with locally advanced pancreatic cancer receiving chemoradiation: a pilot study. J Pain Symptom Manag 2012;44(2):181e91.
[6] Mueller TC, Burmeister MA, Bachmann J, Martignoni ME. Cachexia and pancreatic cancer: are there treatment options? World J Gastroenterol 2014;20(28):9361e73. [7] Gwynne S, Wills L, Joseph G, John G, Staffurth J, Hurt C, et al. Respiratory movement of upper abdominal organs and its effect on radiotherapy planning in pancreatic cancer. Clin Oncol R Coll Radiol 2009;21(9):713e9. [8] Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med 2009;50(Suppl. 1):122Se50S. [9] Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 2011;12:489e95. [10] Barber MD, Ross JA, Fearon KC. Changes in nutritional, functional, and inflammatory markers in advanced pancreatic cancer. Nutr Cancer 1999;35: 106e10. s J, Bales C, Baracos V, Guttridge D, et al. Cachexia: [11] Evans WJ, Morley JE, Argile a new definition. Clin Nutr 2008;27(6):793e9. [12] Wigmore SJ, Todorov PT, Barber MD, Ross JA, Tisdale MJ, Fearon KC. Characteristics of patients with pancreatic cancer expressing a novel cancer cachectic factor. Br J Surg 2000;87(1):53e8. [13] Wesseltoft-Rao N, Hjermstad MJ, Ikdahl T, Dajani O, Ulven SM, Iversen PO, et al. Comparing two classifications of cancer cachexia and their association with survival in patients with unresected pancreatic cancer. Nutr Cancer 2014;24:1e9. [14] Vaccaro V, Sperduti I, Vari S, Bria E, Melisi D, Garufi C, et al. Metastatic pancreatic cancer: is there a light at the end of the tunnel? World J Gastroenterol 2015;21(16):4788e801. O, Guimbaud R, Be couarn Y, et al. [15] Conroy T, Desseigne F, Ychou M, Bouche FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817e25. [16] Wigmore SJ, Plester CE, Richardson RA, Fearon KC. Changes in nutritional status associated with unresectable pancreatic cancer. Br J Cancer 1997;75(1): 106e9. [17] Liu ZQ, Xiao ZW, Luo GP, Liu L, Liu C, Xu J, et al. Effect of the number of positive lymph nodes and lymph node ratio on prognosis of patients after resection of pancreatic adenocarcinoma. Hepatobiliary Pancreat Dis Int 2014;13(6): 634e41. [18] Li J, Zhang B, Cui G, Dai D. Correlation between characteristics of lymph node metastases and prognosis in pancreatic cancer treated with pancreaticoduodenectomy. Zhonghua Zhong Liu Za Zhi 2014;36(9):688e92. [19] Lim JE, Chien MW, Earle CC. Prognostic factors following curative resection for pancreatic adenocarcinoma: a population-based, linked database analysis of 396 patients. Ann Surg 2003;237:74e85. [20] Sohn TA, Yeo CJ, Cameron JL, Koniaris L, Kaushal S, Abrams RA, et al. Resected adenocarcinoma of the pancreas 616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 2000;4:567e79. [21] Pawlik TM, Abdalla EK, Barnett CC, Ahmad SA, Cleary KR, Vauthey JN, et al. Feasibility of a randomized trial of extended lymphadenectomy for pancreatic cancer. Arch Surg 2005;140:589e91. [22] Yeo CJ, Cameron JL, Sohn TA, Lillemoe KD, Pitt HA, Talamini MA, et al. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. Ann Surg 1997;226:248e57. discussion 57e60. [23] Cao N, Zhao A, Zhao G, Wang X, Han B, Lin R, et al. Survival analysis of 272 patients with pancreatic cancer undergoing combined treatment. Integr Cancer Ther 2015;14(2):133e9. [24] Maisey NR, Norman AR, Hill A, Massey A, Oates J, Cunningham D. CA19-9 as a prognostic factor in inoperable pancreatic cancer: the implication for clinical trials. Br J Cancer 2005;93:740e3. [25] Ikeda M, Okada S, Tokuuye K, Ueno H, Okusaka T. Prognostic factors in patients with locally advanced pancreatic carcinoma receiving chemoradiotherapy. Cancer 2001;91:490e5. [26] Acunzo M, Croce CM. MicroRNA in cancer and cachexia e a mini-review. J Infect Dis 2015;15(212 Suppl. 1):S74e7. [27] McMillan DC. Systemic inflammation, nutritional status and survival in patients with cancer. Curr Opin Clin Nutr Metab Care 2009;12(3):223e6. [28] Fearon KC, Voss AC, Hustead DS, Cancer Cachexia Study Group. Definition of cancer cachexia: effect of weight loss, reduced food intake, and systemic inflammation on functional status and prognosis. Am J Clin Nutr 2006;83(6): 1345e50.
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Original article
Impact of presence and degree of pretreatment weight loss in locally-advanced pancreatic cancer patients treated with definitive concurrent chemoradiotherapy a € Berna Akkus Yildirim a, *, Yurday Ozdemir , Tamer Colakoglu b, Erkan Topkan a a b
Baskent University Adana Medical Faculty, Department of Radiation Oncology, Adana, Turkey Baskent University Adana Medical Faculty, Department of General Surgery, Adana, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history: Available online xxx
Background: To assess the impact of the presence and degree of pretreatment weight loss (WL) on the survival of locally-advanced pancreas cancer (LAPC) patients treated with concurrent chemoradiotherapy (C-CRT). Methods: Seventy-three patients who received 50.4 Gy C-CRT were analyzed. All patients underwent laparoscopy (n ¼ 18) or laparotomy (n ¼ 55), and biopsies were obtained for histologic examination of the primary tumor and enlarged/metabolically active regional lymph nodes. Pretreatment WL and percentage WL (PWL) were calculated by utilizing data obtained 6 months prior to and during hospital admission. The primary objective was to assess the influence WL status on overall survival (OS), and the secondary objective was the identification of a PWL cut-off value, if available. Results: Forty-five (61.6%) patients had WL. Median OS was 14.4 months for the entire study population which was significantly longer in the non-WL than the WL cohort (21.4 vs. 11.3 months; p < 0.003). On further analysis a cut-off value of 3.1% was identified for WL. Accordingly, patients with WL < 3.1% had significantly longer OS than those with WL 3.1% (25.8 vs. 10.1 months; p < 0.001). In multivariate analysis, both the WL status (p < 0.001) and PWL (p ¼ 0.002) retained their independent significance. Conclusion: Both the presence and degree of WL prior to C-CRT had strong adverse effects on the survival of LAPC patients, even if they presented with a BMI > 20 kg/m2. Additionally, a WL of 3.1% in the last 6 months appeared to be a strong cut-off for the stratification of such patients into distinctive survival groups. Copyright © 2016, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Keywords: Locally-advanced pancreatic carcinoma Pretreatment weight loss Survival Concurrent chemoradiotherapy Percentage weight loss Weight loss degree
Introduction Definitive concurrent chemoradiotherapy (C-CRT) or induction chemotherapy followed by C-CRT is the preferred treatment options for patients with locally-advanced pancreatic cancer (LAPC), which accounts for 30e40% of all pancreatic cancers (PC) [1]. However, despite the advances in diagnostic, staging, and treatment methodologies, the prognosis of such patients remains poor, with an estimated median survival of 8e12 months. For LAPC, the conventional prognosticators include gender, age, performance
* Corresponding author. Department of Radiation Oncology, Baskent University, Adana Medical Faculty, Kisla Saglik Yerleskesi, 01120 Adana, Turkey. Tel.: þ90 5337381069. E-mail address: [email protected] (B.A. Yildirim).
status, presence/absence of pain, pancreatic location of the tumor, tumor size, extension of the primary tumor to neighboring organs/ vasculature, tumor grade, lymph node involvement status, serum CA19-9 and CEA levels, weight loss (WL) status before C-CRT, and previous experience of the hospital team [2,3]. Involuntary WL, one of the cardinal signs of anorexia-cachexia syndrome, is present in up to 85% of LAPC patients at the time of diagnosis. The fundamental drivers for involuntary WL in LAPC are complex and are triggered by tumor products and proinflammatory cytokines. Regardless of the exact cause, WL does not only lead to decreased personal physical function and increased psychological distress in patients and their care takers, but also leads to increased rates of severe toxicity and reduces the tolerance to any oncologic treatment [4]. Obligatory reductions in chemotherapy and/or RT doses, treatment delays, or total
http://dx.doi.org/10.1016/j.pan.2016.03.006 1424-3903/Copyright © 2016, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.
Please cite this article in press as: Yildirim BA, et al., Impact of presence and degree of pretreatment weight loss in locally-advanced pancreatic cancer patients treated with definitive concurrent chemoradiotherapy, Pancreatology (2016), http://dx.doi.org/10.1016/j.pan.2016.03.006
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abandonment of treatment due to intolerance issues have been shown to lead to reduced tumor control and worse survival outcomes [5,6]. To the best of our knowledge, no study has concentrated specifically on the extent of WL and searched for an objective cut-off value in patients in the era of definitive C-CRT. Moreover, in past studies the research populations were exceedingly heterogeneous in terms of basal weight and body mass index (BMI) measures; namely, both underweight (BMI < 20 kg/m2), ordinarily weighted (BMI > 20e25 kg/m2), and overweight (BMI > 25 kg/m2) individuals were included, which raises problems in interpretation of their outcomes. Therefore, in this retrospective cohort study, we investigated the influence of both the presence and degree of pretreatment WL on survival outcomes of LAPC patients with BMI > 20 kg/m2 who were treated with definitive CRT, and sought to ascertain a cut-off value for WL that may be utilized as a clinical indicator of survival in conjunction with promptly used traditional factors.
Methods Patient population A retrospective database search was performed to identify surgically unresectable LAPC patients that underwent definitive C-CRT between February 2008 and December 2013. In accordance with the AJCC staging system (6th ed.), our institutional definition for technically unresectable PC included patients with celiac axis and/ or superior mesenteric artery involvement, namely stage III (T4N01M0) disease. In all patients, the disease extent was determined by radiological studies and laparotomy or laparoscopic examination. Standard radiological work-up included contrast-enhanced abdominal tomography (CT), magnetic resonance imaging (MRI), and/or MR-cholangiopancreaticography (MRCP). Additionally, all patients were re-staged via fusion of previous CT images (obtained 1 week before position-emission tomography/ computerized tomography (FDG-PETeCT) scan) with FDG-PETeCT images obtained for radiation therapy planning (RTP). In accordance with the current standard institutional staging procedure for PC, all patients underwent laparoscopic (n ¼ 18) or laparotomic (n ¼ 55) examination and biopsies were obtained for histologic diagnosis of the primary tumor. Biopsies of enlarged/metabolically active regional lymph nodes and isolated single organ metastasis were also obtained if suspected radiologically or if identified during laparotomy/laparoscopy. Patients with a previous history of chemotherapy or abdominal irradiation were considered ineligible. Further eligibility criteria included the following requirements: an age of 18e70 years, a diagnosis of histologically proven adenocarcinoma, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0e2, presence of a measurable or evaluable lesion, no contraindications for FDG-PET-CT imaging, an adequate bone marrow reserve (hemoglobin value of 10 g/dL, leukocyte count of 4000 cells/mL, and thrombocyte count of 100,000 cells/mL), hepatic (aspartate aminotransferase or alanine aminotransferase of <5 times the upper limit) and renal function (serum creatinine < 2 mg/dL), BMI > 20, and available pretreatment weight and height measures just prior to C-CRT and at 6 months prior to referral. The latter information was readily obtained, as it is common at any oncologic examination to question first degree relatives about the relative weight change status of the patient during the last six months. The study design was approved by the Institutional Ethical Committee before any data collection. The study was performed in accordance with the Helsinki Declaration and Rules of Good Clinical Practice.
Treatment planning and chemoradiotherapy The tumor volumes included the primary tumor and involved LNs and were delineated on the FDG-PET/CT fusion. For each patient, the gross tumor volume (GTV) included the primary tumor (GTV-P) and involved lymph nodes (GTV-N) apparent on contrastenhanced CT (short axis 1.0 cm) and/or PET images. Nodes < 1.0 cm were only included in the GTV if they were judged to be metabolically active (SUVmax > 2.5) on PET scan. Based on literature [7] depicting nearly 1.5 cm of pancreas movement with respiration and considering the lack of a motion tracking system and image guidance at our department, planning target volume (PTV) was defined by adding 2 cm to GTV in all directions, except for intersecting organs at risk (OAR) restrictions or natural barriers with minimal movement risk (e.g. vertebral bodies), to allow for microscopic extension, organ motion, and set-up errors. Elective nodal irradiation was prohibited in the study. All OAR volumes were contoured from the CT because of the inherent difficulties in edge detection with PET-based contouring. All patients received 50.4 Gy (1.8 Gy/fx) RT, which was prescribed to encompass the defined PTV with isodose lines between 95% and 107%. Target volume coverage and OAR doses were assessed by utilizing the dose-volume histograms generated for each patient. The maximum dose limits for normal tissues were 45 Gy for spinal cord; 50 Gy for small bowel and stomach; 50 Gy for one-third, 35 Gy for two-thirds, and 30 Gy for three-thirds of the liver; and 20 Gy for at least two-thirds of one functioning kidney. All patients received 1e2 courses of cisplatin (n ¼ 24), continuously infused 5-fluorouracil (n ¼ 24), gemcitabine (n ¼ 11), and cisplatinbased doublet chemotherapy (n ¼ 14) concurrent with radiotherapy. Additionally, 57 patients received 4e6 courses of maintenance gemcitabine or 2e4 courses of adjuvant cisplatin-based doublet chemotherapy following C-CRT. Weight measures Body weight and height measures just prior to and 6 months before (baseline) the C-CRT were used to calculate the relative weight change (WC) and body mass index (BMI) changes during this time period. However, WC, which by definition independently reflects the absolute difference during the last 6 months, has the potential to underestimate the value of baseline body mass. For this reason, in addition to absolute change (kg), we also calculated the change in percentage relative to baseline, namely the percentage weight change (PWC). For the purposes of this study, patients with no WL or with any degree of weight gain during the last 6 months were assigned to the no weight loss (NWL) group, while patients with any degree of WL were assigned to the WL group. Toxicity and response assessments Toxicity during the course of C-CRT was evaluated by reviewing the treatment charts of all patients, who were examined at weekly intervals, or more frequently if necessary. After completion of the CCRT, patients were examined bimonthly for the first year, every 3 months for the second year, and at 6 month intervals, or more frequently if needed, thereafter. Both the acute and late toxicity were graded by a radiation oncologist according to the Common Terminology Criteria for Adverse Events scale (version 3.0). The recorded grade reflected the worst grade observed. Response evaluation and follow-up Response to treatment was assessed by restaging PET/CT scans 12 weeks after the end of CRT in accordance with the Positron
Please cite this article in press as: Yildirim BA, et al., Impact of presence and degree of pretreatment weight loss in locally-advanced pancreatic cancer patients treated with definitive concurrent chemoradiotherapy, Pancreatology (2016), http://dx.doi.org/10.1016/j.pan.2016.03.006
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Emission Tomography Response Criteria in Solid Tumors (PERCIST) [8]. The 12-week time interval for the first follow-up PET/CT was the shortest possible time mandated by our national health insurance policy, rather than being evidence-based. Thereafter, all patients were monitored every 8e12 weeks by blood count/chemistry and PET/CT. If indicated, patients also underwent abdominal US and/or CT, chest CT, or cranial MRI. Statistical analysis The primary objective of this study was assessment of the overall survival (OS) difference between patients with or without any WL prior to the initiation of C-CRT. The OS was defined as the interval between the first day of C-CRT and death/last visit. The secondary objective was the identification of a significant WL cutoff value in terms of absolute WC or PWL, if present. For this purpose we used receiver operating characteristic (ROC) curve analysis to determine the PWL cut-off value for discrimination of outcomes. The ROC analysis represents the area under the curve (AUC) of sensitivity vs. the false-positive rate, and is equivalent to the probability that the predictive model will assign a higher probability of an event to subjects who subsequently have an event. Patients were further grouped into three WL groups according to the 5% WL cut-off for cachexia, as defined by the Delphi Consensus: Group 1, <5%; Group 2, 5.01e10% WL; Group 3, >10% WL (severe WL) [9]. Survival analysis was performed using the KaplaneMeier method, and the survival outcomes of subsets were compared with two-sided log-rank tests. For multivariate analysis, the Cox proportional hazard model was used to assess the simultaneous interaction among multiple clinical variables and survival. A twosided p < 0.05 was considered significant. Bonferroni's correction was utilized following comparisons between three or more groups, as indicated. Results We evaluated the records of 73 consecutive LAPC patients who were treated with C-CRT and met the specified inclusion criteria. The pretreatment characteristics of the entire study population are depicted in Table 1. Of these patients, 45 (61.6%) experienced WL in the pre-C-CRT 6 month period (Table 2). Of the surviving 22 patients, 13 (46.4%) were in the non-WL (NWL) and 9 (20%) were in the WL groups (p ¼ 0.017). WL was significantly more common in patients with N1 (27/34; 79.4%) than N0 (18/39; 46.2%) nodal disease (p ¼ 0.02) and ECOG 2 (14/17; 82.4%) than 0e1 (31/56; 55.4%) performance status (p ¼ 0.03). In regression analysis, both N1 (p ¼ 0.008) and ECOG 2 (p ¼ 0.006) were found to correlate independently with WL. At a median follow-up of 16.7 months (95% CI: 8.8e18.6), 22 (30.1%) patients were alive. The median survival time was 14.4 months (95% CI: 8.8e18.6), and the 2- and 3-year OS rates for the entire cohort were 30.3% and 13.6%, respectively. Median absolute WL and PWL were 5.7 kg (12.7 to 4.1 kg) and 8.7% (range: 20.2 to 7.8%) during the last 6 months before the initiation of C-CRT. As shown in Fig. 1, comparative survival analysis revealed significantly longer median OS in the NWL than in the WL cohort (21.4 vs. 11.3 months; p < 0.003) with respective 2- (47.5% vs. 19.6%) and 3-year (27.1% vs. 7.3%) OS rates also favoring the NWL group. Although WL could stratify patients into two groups with significantly differing OS, we also searched for the presence of a cut-off value by utilizing PWC as an objective measure of WL. ROC curve analysis identified a PWC of 3.1% (AUC 70.5, sensitivity 78.4, specificity 70.2) as a cut-off point for obtaining distinctive OS results (Fig. 2). Further grouping of patients according to this value [<3.1% (n ¼ 39) vs. 3.1% WL (n ¼ 34)] showed that patients with no or <3.1% WL had
3
Table 1 Pretreatment patient and disease characteristics. Characteristic
N (%)
Median age, y (range) Gender Female Male ECOG 0e1 2 Diabetes mellitus Absent Present Fatty stool Absent Present Nodal status 0 1 Concurrent chemotherapy Cisplatinum 5-Fluorouracil Gemcitabine Cisplatinum-based doublet WL status Absent Present WL-ROC analysis cut-off <3.1% 3.1% Cachexia statusa Non-cachectic (no WL) Precachectic (5% WL) Cachectic (>5% WL) WL group Group 1 Group 2 Group 3
57 (39e69) 16 (21.9) 57 (78.1) 56 (76.7) 17 (23.3) 54 (74.0) 19 (26.0) 52 (71.24) 21 (28.76) 39 (53.0) 34 (47.0) 24 24 11 14
(32.8) (32.8) (15.0) (19.4)
28 (38.4) 45 (61.6) 39 (53.4) 34 (46.6) 28 (38.4) 19 (26.0) 26 (35.6) 47 (64.4) 15 (20.5) 11 (15.1)
Abbreviations: WL: weight loss; Group 1: <5%, Group 2: 5.01e10%, and Group 3: >10%, ROC: receiver operating characteristic, ECOG: Eastern Cooperative Oncology Group. a According to Delphi Consensus definition (9).
significantly longer median OS times than those with 3.1% WL (25.8 vs. 10.1 months; p < 0.0001) (Fig. 3). With an end goal of recognizing the group with the worst outcomes, we stratified our study population into three further groups according to the Delphi Consensus: Group 1, <5% WL; Group 2, 5.01e10% WL; and Group 3, >10% WL. The 10% value was chosen because of its wide acceptance as the definition of severe WL in the literature (9, 11). As demonstrated in Fig. 4, comparative long-rank analysis revealed significant and step-wise decrements in median OS times with the worsening of WL: 25.8 vs. 12.9 vs. 6.4 months (p < 0.001) for Groups 1, 2, and 3, respectively. Similarly, the 3-year OS rate also decreased with the worsening of WL (27.1% vs. 9.7% vs. 0% for Groups 1, 2, and 3, respectively). As demonstrated in Table 2, univariate analyses revealed that OS associated significantly with ECOG status (0e1 vs. 2), N stage (0 vs. 1), WL status (absent vs. present), WL grouping according to the ROC defined cut-off (<3.1% vs. 3.1%), and WL grouping (<5% vs. 5.01e10% vs. >10%), all favoring the precedent values. In multivariate analysis, which exclusively included the factors that were significant in univariate analysis, each factor retained its independent significant association with OS outcomes (Table 2). Discussion The results of the present retrospective cohort analysis demonstrated that both the presence and degree of WL prior to CCRT had strong adverse effects on survival outcomes of LAPC
Please cite this article in press as: Yildirim BA, et al., Impact of presence and degree of pretreatment weight loss in locally-advanced pancreatic cancer patients treated with definitive concurrent chemoradiotherapy, Pancreatology (2016), http://dx.doi.org/10.1016/j.pan.2016.03.006
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Table 2 Outcomes of univariate and multivariate analysis. Characteristic Age <65 65 Gender Female Male ECOG 0e1 2 Nodal status 0 1 WL status Absent Present ROC analysis cut-off <3.1% 3.1% WL group Group 1 Group 2 Group 3
Patients N (%)
Survival (months)
Univariate p-value
Multivariate p-value
59 (80.82) 14 (19.18)
14.4 15.7
0.32
e
16 (21.9) 57 (78.1)
12.9 15.7
0.72
e
56 (76.7) 17 (23.3)
17.5 11.2
<0.001
<0.001
39 (53.0) 34 (47.0)
20.2 11.2
<0.001
0.006
54 (74.0) 19 (26.0)
21.4 11.3
0.003
<0.001
39 (53.4) 34 (46.6)
25.8 10.1
<0.001
<0.001
47 (64.4) 15 (20.5) 11 (15.1)
25.8 12.9 6.4
<0.001
0.002
Abbreviations: ECOG: Eastern Cooperative Oncology Group; WL: weight loss; ROC: receiver operating characteristic, Group 1: <5%, Group 2: 5.01e10%, and Group 3: >10%.
Fig. 2. Receiver operating curve analysis results searching weight loss cut-off correlated with overall survival status (AUC: area under the curve). Fig. 1. Overall survival according to weight loss status.
patients treated with C-CRT, even they presented with a BMI above the cachexia range (>20 kg/m2). Additionally, a WL of greater than 3.1% in the 6 months prior to C-CRT appeared to be a strong cut-off for the stratification of such patients into distinctive survival groups, and may be utilized as an additional surrogate marker of poorer prognosis. WL, experienced by up to 85% of patients with advanced gastrointestinal cancers [12], reflects tumor-induced increased catabolism [10], and its presence has repeatedly been demonstrated to indicate poorer prognosis in various tumor types, including LAPC. Although WL has been proposed to onset in the
early phases of tumorigenesis and to progress in parallel with tumor progression, no strict cut-off value for WL and the time interval for this loss has gained universal acceptance. For example, in the 2008 Washington Consensus reported by Evans et al., WL of 5% in the last 12 months was recommended as the cardinal parameter for the diagnosis of cancer cachexia, whereas in the 2011 Delphi Consensus, the same WL cut-off was recommended for the last 6 months [9,11]. Additionally, as cancer cachexia is usually an irreversible medical condition with no well-defined treatment, it may be more important to define the critical degree of WL in the precachectic time period when treatment, or at least a delay of cachexia, may be possible with supportive interventions.
Please cite this article in press as: Yildirim BA, et al., Impact of presence and degree of pretreatment weight loss in locally-advanced pancreatic cancer patients treated with definitive concurrent chemoradiotherapy, Pancreatology (2016), http://dx.doi.org/10.1016/j.pan.2016.03.006
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Fig. 3. Overall survival according to the ROC analysis-defined weight loss cut-off of 3.1% (ROC: receiver operating curve).
Interestingly, to date, there has been no universally accepted consensus definition or even a suggestion for a pre-cachectic WL cut-off for any tumor type. Considering the fact that cancer progression and increased catabolic activity/WL are strongly interrelated, we herein planned to evaluate the prognostic significance of any WL present before the onset of C-CRT and search for a LAPC specific cut-off beyond the aforementioned ones that may be utilized for the further stratification of such patients who present with a BMI > 20 and are planned to undergo radical C-CRT into different prognostic groups.
Fig. 4. Overall survival outcomes for patients following grouping according to the Delphi Consensus cachexia definition and severe cachexia.
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Although all patients had a BMI > 20 in our current series, in accordance with previous LAPC studies reporting that up to 85% of cases experience some degree of WL, we noted up to 20.7% WL in 61.6% cases [12]. Of these patients, 26 (35.6%) were cachectic according to the Delphi Consensus definition [9], as they had >5% WL, while 19 (26.0%) were non-cachectic but had some degree of WL (0.1e5%), and therefore were pre-cachectic. The high WL incidence and rate of precachectic patients reported herein and elsewhere by others underscores the importance of the diagnosis of WL as a marker of both cachexia and precachexia, particularly in the detection and treatment of precachexia before its transformation to irreversible and lethal cancer cachexia. In an unresected LAPC study by Wesseltoft-Rao et al., the authors found that patients with cancer cachexia and precachexia had poorer survival than those with noncachexia [13]. In this study the corresponding OS ratio between precachectic and noncachectic groups was 0.44 (95% CI: 0.17e1.14) [13]. Although we methodologically grouped patients into different groups than Wesseltoft-Rao et al., our present results confirm their results in terms of demonstrating a strong relationship between the extent of WL and OS outcomes. Accordingly, the OS ratios for Group 3 vs. 2, Group 2 vs. 1, and Group 3 vs. 1 were 0.50 (p < 0.001), 0.50 (p < 0.001), and 0.49 (p < 0.001), respectively (Fig. 4). Interestingly, the median OS of 6.4 months observed in patients with >10% WL was similar to the median survival of 3e11.1 months that was reported for metastatic pancreatic cancer patients treated with the best available chemotherapy regimens [14,15]. Although the study population size and the retrospective nature of the present study does not permit us to remark conclusively on this finding, it may indicate that a rapidly progressing LAPC subtype with PET-CT occult distant metastases is present in patients with >10% WL, and mandates a rethinking of the potentially unnecessary early use of C-CRT or limited courses of neoadjuvant chemotherapy. This point needs to be further investigated in appropriately designed future studies. Importantly, our search primary end goal of determining a LAPC-specific PWL cut-off by utilizing ROC analysis identified 3.1% as the cut-off point for stratifying patients into two different groups with distinct survival outcomes (25.8 months for <3.1% vs. 10.1 months for 3.1% WL patients; p < 0.001). Although this value needs to be further confirmed in larger series, to the best of our knowledge, this is the first cut-off value that has been identified specifically for definitively treated LAPC patients with prognostic importance beyond the generally used consensus-based value of 5% [9,11]. Furthermore, it may be difficult to attribute this result to a single exact cause, but it may be related to an early and aggressive WL course in LAPC patients. Providing support for this assumption is a relative older study in which Wigmore et al. demonstrated that at 3 months pre-illness, none of the 20 eligible LAPC patients had WL, but had a median weight of 63.7 kg that decreased to 53.2 kg at the time of diagnosis, representing a 14.2% WL. Additionally, 17 (85%) patients became cachectic during this relatively short time period. This finding emphasizes the need for the identification of critical WL values for each tumor type rather than using a common cut-off value, as suggested by consensus statements, for any cancer type irrespective its inherent biological behavior [16]. Two additional important, but not surprising, findings of the present study was the confirmation of lymph node involvement (9.1 vs. 21.4 months; p ¼ 0.008) and ECOG 2 performance score (11.2 vs. 17.5 months; p ¼ 0.006) as strong surrogates of poor prognosis in such patients. Numerous studies have demonstrated that patients with lymph node involvement have significantly worse survival than lymph node-negative patients, with a median survival range of 7.9e15.5 months [17e22]. Likewise, poor ECOG performance status, which reflects poor overall health, has also
Please cite this article in press as: Yildirim BA, et al., Impact of presence and degree of pretreatment weight loss in locally-advanced pancreatic cancer patients treated with definitive concurrent chemoradiotherapy, Pancreatology (2016), http://dx.doi.org/10.1016/j.pan.2016.03.006
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B.A. Yildirim et al. / Pancreatology xxx (2016) 1e6
been associated with worse prognosis in radically treated LAPC patients [23]. This may be associated with the decreased tolerance of such LAPC patients to definitive C-CRT, may reflect a poor physical condition as a consequence of more aggressive tumor behavior, or both [2,24,25]. Interestingly, in our study, both lymph node involvement (79.4% vs. 46.2%; p ¼ 0.02) and poor ECOG (82.4% vs. 55.4%; p ¼ 0.03) performance status were associated with a higher extent of WL. Although it is difficult to explain the exact mechanism by which patients with WL have a poorer performance status and higher rates of lymph node involvement, it is reasonable to anticipate that patients with WL have inherently more aggressive tumor phenotypes and possibly poorer immunologic status, which may add to the poorer prognosis observed in this patient group [26e28]. However, further well-designed studies that include a larger number of patients are warranted to determine the exact causeeresult relationship between these three factors. Besides several strengths, such as the use of PET-CT for staging in all patients and the exclusive inclusion of LAPC patients that were treated in a similar fashion, our study also has considerable limitations. First, as with any retrospective cohort analysis, unpredictable biases may have influenced our results. Second, since the patients were highly selected in terms of BMI, our results cannot be generalized to all LAPC patients undergoing C-CRT. Third, the limited cohort size mandates the confirmation of the results observed herein in similarly designed future studies with larger study cohorts to remark conclusively on this highly specific and important issue. In conclusion, although it represents the findings of a retrospective cohort analysis with a relatively small study population size, the results presented here demonstrated that both the presence and degree of WL prior to C-CRT had strong adverse effects on survival outcomes of LAPC patients even if they presented with a BMI > 20 kg/m2. Additionally, a WL of 3.1% in the last 6 months appeared to be a strong cut-off value for the stratification of such patients into distinctive survival groups, and this cut-off may be utilized as an additional surrogate marker of poorer prognosis. Funding None. References [1] Pliarchopoulou K, Pectasides D. Pancreatic cancer: current and future treatment strategies. Cancer Treat Rev 2009;35(5):431e6. [2] Peixoto RD, Speers C, McGahan CE, Renouf DJ, Schaeffer DF, Kennecke HF. Prognostic factors and sites of metastasis in unresectable locally advanced pancreatic cancer. Cancer Med 2015;4(8):1171e7. [3] Gobbi PG, Bergonzi M, Comelli M, Villano L, Pozzoli D, Vanoli A, et al. The prognostic role of time to diagnosis and presenting symptoms in patients with pancreatic cancer. Cancer Epidemiol 2013;37:186e90. [4] Hopkinson JB, Wright DN, McDonald JW, Corner JL. The prevalence of concern about weight loss and change in eating habits in people with advanced cancer. J Pain Symptom Manag 2006;32(4):322e31. [5] Dalal S, Hui D, Bidaut L, Lem K, Del Fabbro E, Crane C, et al. Relationships among body mass index, longitudinal body composition alterations, and survival in patients with locally advanced pancreatic cancer receiving chemoradiation: a pilot study. J Pain Symptom Manag 2012;44(2):181e91.
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Please cite this article in press as: Yildirim BA, et al., Impact of presence and degree of pretreatment weight loss in locally-advanced pancreatic cancer patients treated with definitive concurrent chemoradiotherapy, Pancreatology (2016), http://dx.doi.org/10.1016/j.pan.2016.03.006