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Quality of life after treatment of neuroendocrine liver metastasis
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e1 0
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Quality of life after treatment of neuroendocrine liver metastasis Gaya Spolverato, MD, Fabio Bagante, MD, Doris Wagner, MD, Stefan Buettner, MD, Rohan Gupta, MD, Yuhree Kim, MD, Hadia Maqsood, MD, and Timothy M. Pawlik, MD, MPH, PhD* Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland
article info
abstract
Article history:
Background: A large subset of patients with neuroendocrine liver metastasis (NELM) is
Received 27 April 2015
symptomatic at the time of presentation. In addition to improving survival, treatment of
Received in revised form
NELM seeks to provide palliation of symptoms. However, data on health-related quality of
15 May 2015
life (QoL) are uncommon. We sought to define patient-reported QoL after treatment of
Accepted 22 May 2015
NELM.
Available online xxx
Methods: Patients who underwent treatment of NELM at Johns Hopkins Hospital between
Keywords:
were invited to complete a QoL survey designed using validated assessment tools, to assess
NELM
their physical, mental, and general health before treatment, after the most recent treat-
QoL
ment and at the time of the study. Clinicopathologic data were collected and correlated
Surgery
with QoL data.
1998 and 2013 and who were alive as of March 2014 were identified (n ¼ 125). These patients
Survey
Results: The response rate was 68.0% (n ¼ 85). Median patient age was 55 y and most were male (59.2%). Most patients had a pancreatic (24.7%) or a small bowel (37.7%) primary tumor; the overwhelming majority had multiple NELM (83.5%). Patient-reported symptoms before any treatment included diarrhea (41.1%), flushing (34.1%), fatigue (36.5%), and osteoarticular pain (18.8%). Initial treatment of NELM consisted of surgery in 55 patients (64.7%) and nonsurgical treatment in 30 patients (35.3%). Many patients reported an overall improvement in physical health and mental health. Specifically, the proportion of patients reporting diarrhea (before any treatment, 41.1% versus currently, 25.9%; P ¼ 0.019) and flushing (before any treatment, 34.1% versus currently, 10.5%; P < 0.001) tended to decrease over time and a lower proportion of patients reported to be currently sad about being ill (before any treatment, 31.8% versus currently, 23.2%; P ¼ 0.009). Patients with a very poor QoL at the time of the diagnosis were more likely to experience an improvement in QoL after treatment. Interestingly, there was no difference in the improvement in overall QoL whether the initial treatment for NELM was surgical or nonsurgical; however, a lower proportion of patients were dissatisfied with surgery versus nonsurgical therapy (5.4% versus 9.4%; P ¼ 0.001). Conclusions: Less than one-fourth of patients experienced a significant improvement in QoL after treatment of NELM. The patients who benefit the most of treatment were those who were more symptomatic before any treatment. ª 2015 Elsevier Inc. All rights reserved.
* Corresponding author. Department of Surgery, Johns Hopkins Hospital, 600 N. Wolfe Street, Blalock 688, Baltimore, MD 21287. Tel.: þ1 410 502 2387; fax: þ1 410 502 2388. E-mail address: [email protected] (T.M. Pawlik). 0022-4804/$ e see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2015.05.048
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1.
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e1 0
Introduction
Gastrointestinal neuroendocrine tumors (NETs) form a group of relatively rare neoplasms arising mostly from the pancreas and the luminal gastrointestinal tract, which are often characterized by the secretion of bioactive hormones [1]. Although the natural history of NETs is often indolent, up to 60%e90% of gastrointestinal NETs metastasize to the liver during the course of their disease [2]. Treatment of neuroendocrine liver metastasis (NELM) therefore represents an important component in the management of NETs not only for the therapeutic effect of treating the metastatic disease, but also the possible palliative effect of treating the severe hormonal symptoms that some patients can experience secondary to the hepatic tumor burden [3]. Although there is consensus on the necessity of surgical resection of primary NETs in the absence of metastatic disease, the role of surgery in patients with NELM is still controversial. While several series have reported 5-y survival after surgical resection ranging from 60%e75%, few patients are actually cured of their disease [4e8]. In fact, in a large series of patients undergoing surgical management for NELM, Mayo et al. [9] reported recurrence in >90% of patients at 5 y. As such, some investigators have suggested that nonsurgical approaches such as intra-arterial (IAT) or systemic targeted agents may be more appropriate for patients with NELMdespecially those with extensive disease [9e15]. In fact, in a different study examining the role of IAT for NELM, Mayo et al. noted that asymptomatic patients with a large >25% burden of liver disease benefited the least from surgical management and suggested that nonsurgical treatment strategies may be preferred in this clinical situation [9]. To this end, other studies have noted that octreotide and tyrosine kinases including everolimus and sunitinib can improve disease-free survival in patients with advanced NET disease [12e14]. Because NELM can be associated with symptoms and can adversely impact potential survival, treatment goals of NELM often include both symptomatic relief, in addition to improved survival. Although many previous studies have examined the impact of treatment on survival, minimal data exist on the impact of surgical and nonsurgical therapy on patient quality of life (QoL). Given that surgery rarely can achieve a complete cure, data on QoL after surgery relative to nonsurgical therapies are important. Therefore, the objective of the present study was to define patientreported outcomes after surgical and nonsurgical therapy for NELM. Specifically, we sought to assess whether QoL after therapy for NELM improved over a range of selfreported symptoms including physical, emotional, and social functioning.
2.
Methods
2.1.
Patients and data collection
Patients who underwent treatment for NELM at Johns Hopkins Hospital between 1998 and 2013 and who were alive as of March 2014 were identified. Patients with histologically
confirmed NELM or with radiological and clinical features highly suspicious for NELM were included in the study cohort. Only patients with NELM who were alive and who had complete follow-up at the time of the analysis were included (n ¼ 125). Patients were categorized based on initial treatment regimen delivered: surgical treatment (e.g., hepatic resection alone, hepatic resection plus ablation, and open ablation alone) versus nonsurgical treatment (e.g., IAT and received somatostatin analogs). In most instances, IAT consisted of transarterial chemoembolization, bland transarterial embolization, drug eluting beads, or yttrium-90. The Johns Hopkins University Institutional Review Board approved the study. Standard patient demographic and clinicopathologic data such as age, gender, race, intent of treatment, symptoms, location of primary tumor, time to development of liver metastasis, number of hepatic lesions, and the presence of extrahepatic metastasis were collected. Regarding the liver-directed therapy, data on procedure type, number of liver-directed interventions, and timing between primary resection and diagnosis or treatment of NELM were recorded. Specifically, operative data for hepatic resection, such as type of surgery, intent of surgery, indication for hepatic resection, extent of hepatic resection, were collected.
2.2.
QoL assessment
All eligible patients were invited via mail to complete a QoL survey sent to each patient’s home address. Patients were asked to evaluate their QoL before treatment, after the last treatment administered, and at the “current” time. Because no specific questionnaire exists to evaluate QoL after NELM treatment, a survey was constructed using elements of validated assessment tools, including the Norfolk Quality of Life tool for Neuroendocrine Tumors (Norfolk QoL-NETs) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30/GI.NET-21) [16e18]. The questions from Norfolk QoL-NETs were used to assess specific hormone-induced symptoms associated with NELM, whereas elements from EORTC QLQ-C30/GI.NET-21 were used to assess general health perception and well-being. The survey consisted of 28 questions aimed at evaluating physical health, mental health, and general health perceptions using standard Likert scale assessments. Patientreported information was also collected on each patient’s subjective feeling toward the decision to have undergone treatment for NELM.
2.3.
Statistical analysis
Continuous variables were presented as the median with the interquartile range. Categorical variables were reported both as integers and percentages. The distributions of categorical and numerical variables between independent groups were compared using Fisher’s exact test and a ManneWhitney Utest, respectively. Comparisons of QoL parameters were assessed using t-test for paired observation. For statistical analyses, P values <0.05 (two-tailed) were deemed significant. All analyses were carried out with STATA 13.0 (StataCorp, College Station, TX).
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Table 1 e Clinicopathologic characteristics of cohort, stratified by response status. Variable
Age Gender Female Male Race White Black Other N/A Location of primary tumor Pancreas Colon-rectum Small-bowel Bronchus Unknown Type of surgery for primary Intestinal resection Distal pancreatectomy Whipple Other Primary not resected Histology Carcinoid Nonfunctioning islet cell Insulinoma Gastrinoma Glucagonoma N/A Grade Low Medium High N/A Presentation Not symptomatic Symptomatic N/A Symptoms Abdominal cramping Weight loss Flushing Diarrhea or steatorrhoea Palpitations Rash Diabetes mellitus Synchronous liver metastasis No Yes N/A Number of liver metastasis Single Multiple N/A Indication for liver operation Pain Hormonal symptoms Mechanical symptoms Indication based on stage and resectability Treatment of liver metastasis Liver resection Liver resection and ablation
Median (interquartile range) or n (%) 55 y (47e61) 39 (40.8%) 45 (59.2%) 65 8 3 9
(76.5%) (9.4%) (3.5%) (10.6%)
21 9 32 3 20
(24.7%) (10.6%) (37.7%) (3.5%) (23.5%)
39 10 4 20 12
(45.9%) (11.7%) (4.7%) (23.6%) (14.1%)
50 14 2 1 1 17
(58.8%) (16.7%) (2.3%) (1.1%) (1.1%) (20.0%)
18 9 13 45
(21.2%) (10.6%) (15.3%) (52.9%)
22 (25.9%) 45 (52.9%) 18 (21.2%) 16 6 24 22 4 1 2
(18.8%) (7.1%) (28.2%) (25.9%) (4.7%) (1.2%) (2.4%)
32 (37.6%) 42 (49.4%) 11 (13.0%) 8 (9.4%) 71 (83.5%) 6 (7.1%) 12 13 5 25
(21.8%) (23.6%) (9.2%) (45.4%)
50 (58.8%) 5 (5.9%) (continued)
Table 1 e (continued ) Variable
Other Type of resection Minor or nonanatomic resection Hemihepatectomy Nonsurgical treatment* IAT Targeted agents Systemic chemotherapy None
Median (interquartile range) or n (%) 30 (35.3%) 30 (54.5%) 25 (45.5%) 22 18 7 3
(73.3%) (60.0%) (23.3%) (10.0%)
IAT ¼ intra-arterial therapy; N/A ¼ not available or missing. * Some patients received multiple nonsurgical treatments.
3.
Results
3.1.
Description of cohort
Among a total of 125 patients who were identified with NELM, 85 patients returned the questionnaire for a response rate of 68.0%. Overall, median age was 55 y (interquartile range 47, 61) with most patients being male (n ¼ 45, 59.2%) and white (n ¼ 65, 76.5%; Table 1). Most patients had a primary tumor located in the small intestine (n ¼ 32, 37.7%) or in the pancreas (n ¼ 21, 24.7%). Most patients had a carcinoid tumor (n ¼ 50, 58.8%), whereas nonfunctioning islet cell tumors, gastrinomas, insulinomas, and glucagonomas were less common (Table 1). Most patients (n ¼ 45, 52.9%) had symptomatic primary tumors, with the most common symptoms being flushing (n ¼ 24, 28.2%) and diarrhea (n ¼ 22, 25.9%). Almost half of the patients had synchronous liver metastasis (n ¼ 42, 49.4%) and most patients presented with multiple NELM (n ¼ 71, 83.5%). Of the 85 patients, 55 (64.7%) underwent surgery as initial therapy, whereas 30 (35.3%) patients received nonsurgical treatment as primary therapy. The clinicopathologic and tumor characteristics of the patients who underwent surgical versus nonsurgical therapy were largely comparable (Table 1). Among patients who received surgical treatment for NELM, 50 patients (58.8%) underwent resection alone, whereas five patients (5.9%) received both resection and ablation. The most common type of procedure was a minor or nonanatomic resection (n ¼ 30, 54.5%), whereas 25 patients (45.5%) had a formal hemihepatectomy. Among patients who underwent surgery, preoperative symptoms included diarrhea (moderate to extreme, n ¼ 35, 41.1%), flushing (moderate to extreme, n ¼ 29, 34.1%), and general abdominal pain (moderate to extreme, n ¼ 17, 20.0%). After surgery, nine patients (16.3%) experienced a recurrence at a median time of 32.8 mo; four patients (44.4%) who recurred were eventually treated with somatostatin-analog or tyrosine kinase inhibitors. Overall survival among surgical patients was 50.7 mo (range, 35.4e115.9 mo). Among 30 patients (35.3%) who received nonsurgical therapy as their initial modality of care, IAT (n ¼ 22, 73.3%) was most often used, followed by medical treatment with targeted
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Table 2 e Quality of life of patients receiving treatment for neuroendocrine liver metastasis. Before first treatment Physical symptoms Flushing None or mild Moderate Severe to extreme No response Osteoarticular pain None or mild Moderate Severe to extreme No response Other pain None or mild Moderate Severe to extreme No response Diarrhea or constipation None or mild Moderate Severe to extreme No response Rash None or mild Moderate Severe to extreme No response Blue discoloration of skin None or mild Moderate Severe to extreme No response Red spot on skin None or mild Moderate Severe to extreme No response Whistling sound None or mild Moderate Severe to extreme No response Cough None or mild Moderate Severe to extreme No response Swelling of hands or feet None or mild Moderate Severe to extreme No response Fatigue None or mild Moderate Severe to extreme No response Mental symptoms Sex life None or mild Moderate Severe to extreme No response Trouble for sleeping None or mild
After last treatment
P value*
At the time of the study
<0.001 51 20 9 5
(60.0%) (23.5%) (10.6%) (5.9%)
66 9 2 8
(77.7%) (10.6%) (2.3%) (9.4%)
62 12 4 7
(73.0%) (14.1%) (4.7%) (8.2%)
59 13 4 9
(69.4%) (15.3%) (4.7%) (10.6%)
59 13 4 9
(69.4%) (15.3%) (4.7%) (10.6%)
61 9 4 11
(71.8%) (10.6%) (4.7%) (12.9%)
45 20 15 5
(52.9%) (23.5%) (17.6%) (5.9%)
50 21 8 6
(58.8%) (24.7%) (9.4%) (7.1%)
72 4 2 7
(84.8%) (4.7%) (2.3%) (8.2%)
72 5 0 8
(84.7%) (5.9%) (0%) (9.4%)
74 5 0 6
(87.1%) (5.9%) (0%) (7.1%)
77 1 0 7
(90.6%) (1.2%) (0%) (8.2%)
73 5 1 6
(85.9%) (5.9%) (1.2%) (7.1%)
75 5 0 5
(85.9%) (5.9%) (0%) (8.2%)
77 2 0 6
(90.6%) (2.4%) (0%) (7.1%)
77 1 0 7
(90.6%) (1.2%) (0%) (8.2%)
72 8 0 5
(84.7%) (9.4%) (0%) (5.9%)
74 4 1 6
(87.1%) (4.7%) (1.2%) (7.1%)
73 5 3 4
(85.9%) (5.9%) (3.5%) (4.7%)
77 2 0 6
(90.6%) (2.3%) (0%) (7.1%)
49 25 6 5
(57.6%) (29.4%) (7.1%) (5.9%)
46 26 7 6
(54.1%) (30.6%) (8.2%) (7.1%)
60 10 6 9
(70.6%) (11.8%) (7.1%) (10.6%)
50 18 7 10
(58.8%) (21.2%) (8.2%) (11.8%)
<0.001 71 (83.5%) 7 (8.2%) 2 (2.3%) 5 (5.9%)
0.658
0.070 63 (74.1%) 13 (15.3%) 4 (4.7%) 5 (5.9%)
0.717
0.113 70 (82.3%) 9 (10.6%) 0 (0%) 6 (7.1%) 0.019
0.101 60 (70.6%) 16 (18.8%) 6 (7.1%) 3 (3.5%) 0.373
0.642 73 (85.9%) 6 (7.1%) 1 (1.2%) 5 (5.9%)
0.159
0.070 80 (94.1%) 1 (1.2%) 0 (0%) 4 (4.7%)
0.409
0.596 75 (88.2%) 6 (7.1%) 0 (0%) 4 (4.7%)
0.798
0.899 79 (92.9%) 2 (2.4%) 0 (0%) 4 (4.7%)
0.820
0.320 78 (91.8%) 4 (4.7%) 0 (0%) 3 (3.5%)
0.436
0.726 79 (92.9%) 3 (3.5%) 0 (0%) 3 (3.5%)
0.357
0.150 58 (68.2%) 20 (23.5%) 4 (4.7%) 3 (3.5%)
0.004
0.045 55 (64.7%) 18 (21.2%) 4 (4.7%) 8 (9.4%) 0.021
0.252 62 (72.9%)
59 (69.4%)
P valuey
59 (69.4%) (continued)
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Table 2 e (continued )
Moderate Severe to extreme No response Physical or emotional health interference with family life None or mild Moderate Severe to extreme No response Physical or emotional health interference with social activities None or mild Moderate Severe to extreme No response Have to take pain medication None or mild Moderate Severe to extreme No response Tense or irritable or depressed or worried None or mild Moderate Severe to extreme No response Sad about being ill None or mild Moderate Severe to extreme No response Worried about dying None or mild Moderate Severe to extreme No response Hopeful about future None or mild Moderate Severe to extreme No response Happy with life None or mild Moderate Severe to extreme No response General health Limited in daily life None or mild Moderate Severe to extreme No response Limited in leisure None or mild Moderate Severe to extreme No response Satisfied with quality of life None or mild Moderate Severe to extreme No response
Before first treatment
After last treatment
17 (20.0%) 1 (1.2%) 5 (5.9%)
18 (21.2%) 1 (1.2%) 7 (8.2%)
P value*
At the time of the study 21 (24.7%) 1 (1.2%) 4 (4.7%)
0.006 69 (81.2%) 9 (10.6%) 3 (3.5%) 4 (4.7%)
60 17 3 5
(70.6%) (20.0%) (5.5%) (5.9%)
0.625 64 16 2 3
(75.3%) (18.9%) (2.4%) (3.5%)
<0.001 67 (78.8%) 11 (12.9%) 3 (3.5%) 4 (4.7%)
56 19 4 6
(65.9%) (22.4%) (4.7%) (7.1%)
69 (81.2%) 8 (9.4%) 3 (3.5%) 5 (5.9%)
62 13 4 6
(72.9%) (15.3%) (4.7%) (7.1%)
0.077 67 14 1 3
(78.8%) (16.5%) (1.2%) (3.5%)
71 10 2 2
(83.5%) (11.8%) (2.4%) (2.4%)
<0.001
0.172
0.003 67 (78.8%) 11 (12.9%) 4 (4.7%) 3 (3.5%)
58 18 4 5
(68.2%) (21.2%) (4.7%) (5.9%)
55 (64.7%) 17 (20.0%) 10 (11.8%) 3 (3.5%)
55 17 8 5
(64.7%) (20.0%) (9.4%) (5.9%)
56 (65.9%) 18 (21.2%) 8 (9.4%) 2 (3.5%)
63 11 6 5
(74.1%) (12.9%) (7.1%) (5.9%)
31 (36.5%) 28 (32.9%) 23 (27.1%) 3 (3.5%)
28 30 22 5
(32.9%) (35.3%) (25.9%) (5.9%)
18 (21.2%) 36 (41.3%) 28 (32.9%) 3 (3.5%)
20 38 22 5
(23.5%) (44.7%) (25.9%) (5.9%)
59 (69.4%) 18 (21.2%) 4 (4.7%) 4 (4.7%)
49 23 7 6
(57.6%) (27.1%) (8.2%) (7.1%)
62 (72.9%) 14 (16.5%) 5 (5.9%) 4 (4.7%)
50 24 5 6
(58.8%) (28.2%) (5.9%) (7.1%)
21 (24.7%) 40 (47.1%) 24 (28.2%) 0 (0%)
23 35 22 5
(27.0%) (41.2%) (25.9%) (5.9%)
0.260 70 11 2 2
(82.4%) (12.9%) (2.4%) (2.4%)
65 16 2 2
(76.5%) (18.8%) (2.4%) (2.4%)
68 13 2 2
(80.0%) (15.3%) (2.4%) (2.4%)
27 33 23 2
(31.8%) (38.8%) (27.1%) (2.4%)
17 44 22 2
(20.0%) (51.8%) (25.9%) (2.4%)
57 22 3 3
(67.1%) (25.9%) (3.5%) (3.5%)
70 11 2 2
(82.3%) (12.9%) (2.4%) (2.4%)
0.009
0.783
0.296
0.094
0.775
0.559
0.163
0.593
0.001
0.390
0.004
0.892
0.581
Bold values indicate significant P values. * Comparison between before first treatment and after last treatment. y Comparison between before first treatment and at the time of the study.
P valuey
0.117 17 (20.0%) 40 (47.1%) 28 (32.9%) 0 (0%)
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agents (n ¼ 18, 60.0%) and systemic chemotherapy (n ¼ 7, 23.3%). As expected some patients received multiple nonsurgical treatments. Among patients who received IAT, transarterial chemoembolization was used in 13 patients, whereas drug eluting beads (n ¼ 4, 28.6%) and yttrium-90 (n ¼ 5, 35.7) were used less frequently. The median number of IAT treatments administered was 3 (range, 1e6). Overall survival among nonsurgical patients was 47.9 mo (range, 30.7e95.8 mo).
3.2.
QoL assessment
Patient-reported symptoms before any treatment included diarrhea (n ¼ 35, 41.1%), flushing (n ¼ 29, 34.1%), fatigue (n ¼ 31, 36.5%), and osteoarticular pain (n ¼ 16, 18.8%), and did not differ among patients treated with surgery versus nonsurgical therapy (P > 0.05). A substantial number of patients also complained of mental health (i.e., depressed mood, n ¼ 15, 17.6%; sad about being ill, n ¼ 27, 31.8%; worried about dying, n ¼ 36, 30.6%) and general health (i.e., limitations in daily life, n ¼ 22, 25.9% versus limitations in leisure, n ¼ 19, 22.4%) issues. In particular, one-fourth of patients (n ¼ 21, 24.7%) reported being unsatisfied with their QoL. After the most recent treatment of NELM, the proportion of patients reporting moderate-to-extreme fatigue (before any treatment, 36.5% versus after the most recent treatment, 38.8%) and diarrhea (before any treatment, 41.1% versus after the most recent treatment, 34.1%) had not significantly changed (both P > 0.05); in contrast, self-reported complaints of flushing decreased (before any treatment, 34.1% versus after the most recent treatment, 12.9%; P < 0.001). Mental health issues remained, however, a matter of concern for patients after therapy, with a larger number of patients stating that family life (before any treatment, 14.1% versus after the most recent treatment, 25.5%; P ¼ 0.006) and social activities (before any treatment, 16.4% versus after the most recent treatment, 27.1%; P < 0.001) were affected adversely by the treatments (Table 2). General health was also compromised after the most recent treatment with 35.3% of patients reporting limitations in daily life (compared with 25.9% before any treatment; P ¼ 0.001) and 34.1% noting limitations in leisure activities
(compared with 22.4% before any treatment; P ¼ 0.004). Overall satisfaction with QoL did not change after treatment, with only 57 patients (67.1%) reporting to be satisfied with their QoL after treatment, compared with 64 patients (75.3%) before any treatment (P ¼ 0.581). Patients were asked to assess their QoL before any treatment versus “currently.” In general, patients reported a slight increase in satisfaction with their QoL, although this improvement was not statistically significant (before any treatment, 75.3% versus currently, 80%; P ¼ 0.117). Examination of specific QoL domains revealed improvements in both physical and mental health. Specifically, the proportion of patients reporting diarrhea (before any treatment, 41.1% versus currently, 25.9%; P ¼ 0.019) and flushing (before any treatment, 34.1% versus currently, 10.5%; P < 0.001) tended to decrease over time. A decreasing trend (P < 0.05) was also reported for fatigue (before any treatment, 36.5% versus currently, 28.2%), other pain (before any treatment, 20.0% versus currently, 10.6%), and skin discoloration (before any treatment, 5.9% versus currently, 1.2%). There was also a modest improvement in mental health. Although a lower proportion of patients self-reported to be sad about being ill (before any treatment, 31.8% versus currently, 23.2%; P ¼ 0.009), other self-reported outcome such as being tense or irritable or depressed or worried (before any treatment, 17.6% versus currently, 14.3%; P ¼ 0.260) or worried about dying (before any treatment, 30.6% versus currently, 17.7%; P ¼ 0.094) were not much different. Limitations in daily life (29.4%) and in leisure (15.3%) were also comparable with those reported preoperatively (P > 0.05). Patients with a very poor QoL at the time of the diagnosis were more likely to experience an improvement in QoL after treatment. For example, patients who reported the worst initial QoL at diagnosis reported a 55.0% improvement in QoL at last follow-up (Table 3). In contrast, patients who selfreported a moderate QoL at the time of diagnosis had only a 7.7% improvement in overall QoL at last follow-up (P < 0.001). Interestingly, there was no difference in the improvement in overall QoL whether the initial treatment for NELM was surgical or nonsurgical (Fig. 1). Specifically, 18.9% of patients who
Table 3 e Improvement in QoL after treatment for neuroendocrine liver metastasis.
Whole cohort of patients* Type of treatment Surgery patients Other therapy QoL at diagnosis None or mild Moderate QoL none or mild at diagnosis Surgery patients Other therapy QoL moderate at diagnosis Surgery patients Other therapy
N
QoL equal
QoL improved
83
69 (83.3%)
14 (16.7%)
54 29
44 (81.8%) 25 (86.2%)
10 (18.1%) 4 (13.8%)
20 39
9 (45.0%) 36 (92.3%)
11 (55.0%) 3 (7.7%)
11 9
4 (36.4%) 5 (55.6%)
7 (63.6%) 4 (44.4%)
25 13
22 (88.0%) 13 (100%)
3 (12.0%) 0 (0%)
P value 0.559
<0.001
0.653
0.538
Bold value indicate significant P value. QoL ¼ quality of life. * Eighty-three were the patients who answered to a specific question on perception of their QoL, 54 were surgical, and 29 were nonsurgical.
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Fig. 1 e Improvement of QoL after treatment for neuroendocrine liver metastasis stratified by different type of treatment and QoL at diagnosis. QoL, quality of life.
underwent a surgical procedure reported an improvement in QoL versus 13.8% of patients who received nonsurgical treatment (P ¼ 0.559). Despite the modest improvements in overall QoL, overall satisfaction with treatment was high. In fact, only 5.4% of patients were dissatisfied with surgery versus 9.4% of patients who had been initially treated with nonsurgical therapy (P ¼ 0.001). Of interest, many patients reported having ongoing financial difficulties as a result of their NELM (59.3% and 57.6%).
4.
Discussion
Although NETs can often be indolent, a subset of patients has NELM either at presentation or develops metastatic disease sometime during the course of their disease. Unlike most other secondary malignancies of the liver, NELM not only can threaten long-term survival, but also can adversely impact patient QoL. Specifically, in a subset of patients, NELM can be associated with hormonal symptoms including flushing, palpitations, and diarrhea, which can be debilitating for some patients [5,6,19e22]. As such, treatment goals associated with surgical extirpation of NELM often not only include prolongation of survival, but also an attempt to alleviate NET-related symptoms. The treatment for NELM can be varied, including resection, ablation, locoregional IAT, and the use of targeted or systemic agents [4e8,10,15,23e25]. Previous data on the effect of NELM management have largely focused on oncologic outcomes such as recurrence and disease-free and overall survival [9,15]. The present study is important because
it provides an assessment of QoL among patients undergoing treatment for NELM. Data on how treatment of NELM may affect QoL is of great value from the patient’s perspective and may be helpful in counselling patients. Although improvement in QoL might be anticipated after treatment of NELM, there are scant data in the literature on the topic. In the present study, although patients reported improvements in certain QoL domains and certain symptoms such as diarrhea and flushing, most patients reported only a modest improvement in their overall QoL satisfaction. Perhaps not surprisingly, patients with the worst initial QoL were more likely to experience an improvement in QoL after treatment. Furthermore, there was no difference in the improvement in overall QoL whether the initial treatment for NELM was surgical or nonsurgical (Fig. 1). The treatment of NELM, especially among patients with extensive liver disease, remains somewhat varied [9,15]. Surgical management of NELM has been an important therapeutic option for many patients with NELM, as it holds the best promise of cure. However, even when all measurable disease is resected, a high majority of patients with NELM will experience recurrence after resection [7,9,15]. As such, although some groups have advocated for debulking of NELM even in the presence of extensive disease [5,26], other groupsdincluding our owndhave suggested that surgical management of NELM be reserved for patients with low-volume disease or those patients with symptomatic disease [9,27], as debulking may help alleviate symptoms in this latter group of patients. Other studies have advocated, however, for the potential beneficial effects of nonsurgical approaches such as IAT [10,11].
Fig. 2 e Comparison of physical health before and after treatment of neuroendocrine liver metastasis.
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Fig. 3 e Comparison of mental health before and after treatment of neuroendocrine liver metastasis.
Specifically, several reports have documented the potential of IAT to reduce tumor burden and hormonal output [28e31]. IAT may, therefore, provide symptomatic relief by “debulking” the intrahepatic tumor burden. Furthermore, systemic targeted agents such as somatostatin analogs, as well as sunitinib and everolimus, have both anticancer and antisymptomatic effects. As such, multiple options exist to treat patients with NELM, with each option potentially impacting both cancerspecific outcomes and patient QoL. Despite anticipated improvements in QoL being among one of the main indications for treatment of NELM, minimal data are available on the effect of treatment on health-related QoL of patients with NELM. Patient-reported outcomes are, however, an important area of research as many patients with NELM have symptoms. Flushing and diarrhea are common presenting symptoms among patients with hormonally active NELM [5,6,19e22]. In fact, data from prospective studies have noted that up to 70% and 74% of patients with NELM complain of grade 2e3 flushing and diarrhea, respectively [12,32,33]. Similarly, in the present study, we noted that more than twothirds of patients had flushing or diarrhea as one of their main complaints. Other commonly reported physical symptoms included fatigue and osteoarticular pain (Fig. 2). Of note, a subset of patients self-reported that many of their physical symptoms improved after therapy. Specifically, 21% and 7% of patients reported that their flushing or diarrhea improved after the initial treatment for their NELM. In addition, 24% and 15% reported that this improvement persisted currently at the time of the survey administration (Fig. 2). Of note, those patients who had the most significant symptoms before initial
treatment had the biggest incremental improvement in QoL. However, the improvement in QoL did not seem to be different based on the type of initial therapy employed (e.g., resection, IAT, targeted agents). Collectively, these data demonstrate that many patients with NELM can expect to have only a modest improvement in QoL, with the largest benefit among those patients who are most symptomatic. In addition to physical symptoms, several other QoL domains were evaluated, including emotional, social, and general health perceptions. Several previous studies have examined these QoL domains among patients undergoing liver surgery for hepatocellular carcinoma [34,35], secondary metastatic liver tumors [36e38], and benign liver tumors [39]. Each of these studies noted that patients who underwent resection had improved QoL scores in emotional and social domains. The present report expands on these previous data by examining QoL in patients with NELM treated not only with surgical resection, but also other modalities of care. Interestingly, many patients with NELM self-reported significant concerns with daily life before treatment, including social and also emotional problems. Of note, although patients selfreported improvements in physical symptoms after treatment of NELM, other domains such as sexual and family life, social activities, and general mental health remained compromised (Figs. 3 and 4). In fact, less than one in five patients reported an improvement in their emotional status after treatment. Furthermore, many patients reported having ongoing financial difficulties as a result of their NELM (59.3% and 57.6%). In sum, although self-reported physical symptoms such as flushing and diarrhea improved in a subset of patients
Fig. 4 e Comparison of general health before and after treatment of neuroendocrine liver metastasis.
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e1 0
after NELM-directed therapy, the effect of therapy on other aspects of QoL was more negligible. The present study had several limitations. Survey data were collected in a retrospective fashion and therefore the collection of the data was likely subject to some degree of recall bias. Patients who had more severe initial symptoms may have been more likely to remember details regarding their symptoms compared with patients who had no or only mild symptoms. Moreover, the recall bias would impact more on QoL perception before the first treatment and after the most recent treatment, rather than on current QoL. Despite possible recall bias, the present study provides relevant data on self-reported patient perceptions on their current QoL after treatment of NELM. Another important limitation of the present study is that only patients who were alive as of March 2014 were included; in turn, patients who had more aggressive disease and dieddand possibly had a worse QoLdwere excluded.
5.
Conclusions
In the present study, we showed that treatment of NELM was associated with improvements in certain patient-reported outcomes. Specifically, a subset of patients reported improvement in diarrhea and flushing, although patients only noted more modest improvement in their mental and general health. Patients with a very poor QoL at the time of the diagnosis were more likely to experience an improvement in QoL after treatment. Our results may help facilitate discussions around QoL at the time of treatment for NELM and assist in counselling patients regarding treatment options and QoL expectations.
Acknowledgment Author contributions: Spolverato, Bagante, Maqsood, and Pawlik contributed toward study conception and design; Spolverato, Bagante, Maqsood, Wagner, Buettner, Gupta, Kim, and Pawlik contributed toward acquisition of data; Spolverato, Bagante, Maqsood, and Pawlik contributed toward analysis and interpretation of data; Spolverato, Maqsood, and Pawlik contributed toward drafting of the manuscript; and critical revision was done by Spolverato, Bagante, Maqsood, Wagner, Buettner, Gupta, Kim, and Pawlik.
Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in the article.
references
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[2] Vogl TJ, Naguib NN, Zangos S, Eichler K, Hedayati A, NourEldin NE. Liver metastases of neuroendocrine carcinomas: interventional treatment via transarterial embolization, chemoembolization and thermal ablation. Eur J Radiol 2009; 72:517. [3] Reddy SK, Clary BM. Neuroendocrine liver metastases. Surg Clin North Am 2010;90:853. [4] Scigliano S, Lebtahi R, Maire F, et al. Clinical and imaging follow-up after exhaustive liver resection of endocrine metastases: a 15-year monocentric experience. Endocr Relat Cancer 2009;16:977. [5] Sarmiento JM, Heywood G, Rubin J, Ilstrup DM, Nagorney DM, Que FG. Surgical treatment of neuroendocrine metastases to the liver: a plea for resection to increase survival. J Am Coll Surg 2003;197:29. [6] Chamberlain RS, Canes D, Brown KT, et al. Hepatic neuroendocrine metastases: does intervention alter outcomes? J Am Coll Surg 2000;190:432. [7] Mayo SC, de Jong MC, Pulitano C, et al. Surgical management of hepatic neuroendocrine tumor metastasis: results from an international multi-institutional analysis. Ann Surg Oncol 2010;17:3129. [8] Pavel M, Baudin E, Couvelard A, et al. ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 2012;95:157. [9] Mayo SC, de Jong MC, Bloomston M, et al. Surgery versus intra-arterial therapy for neuroendocrine liver metastasis: a multicenter international analysis. Ann Surg Oncol 2011;18: 3657. [10] Ho AS, Picus J, Darcy MD, et al. Long-term outcome after chemoembolization and embolization of hepatic metastatic lesions from neuroendocrine tumors. AJR Am J Roentgenol 2007;188:1201. [11] Liapi E, Geschwind JF, Vossen JA, et al. Functional MRI evaluation of tumor response in patients with neuroendocrine hepatic metastasis treated with transcatheter arterial chemoembolization. AJR Am J Roentgenol 2008;190:67. [12] Anthony LB, Pavel ME, Hainsworth JD, et al. Impact of previous somatostatin analogue use on the activity of everolimus in patients with advanced neuroendocrine tumors: analysis from the phase III RADIANT-2 Trial. Neuroendocrinology; 2015. [13] Lee SY, Choi YJ, Chang WJ, Shin SW, Kim YH, Kim ST. The role of chemotherapy and/or octreotide in patients with metastatic gastroenteropancreatic and hepatobiliary neuroendocrine carcinoma. J Gastrointest Oncol 2014;5:457. [14] Mohamed A, Blanchard MP, Albertelli M, et al. Pasireotide and octreotide antiproliferative effects and sst2 trafficking in human pancreatic neuroendocrine tumor cultures. Endocr Relat Cancer 2014;21:691. [15] Mayo SC, Herman JM, Cosgrove D, et al. Emerging approaches in the management of patients with neuroendocrine liver metastasis: role of liver-directed and systemic therapies. J Am Coll Surg 2013;216:123. [16] Vinik E, Carlton CA, Silva MP, Vinik AI. Development of the Norfolk quality of life tool for assessing patients with neuroendocrine tumors. Pancreas 2009;38:e87. [17] Davies AH, Larsson G, Ardill J, et al. Development of a disease-specific quality of life questionnaire module for patients with gastrointestinal neuroendocrine tumours. Eur J Cancer 2006;42:477. [18] Yadegarfar G, Friend L, Jones L, et al. Validation of the EORTC QLQ-GINET21 questionnaire for assessing quality of life of patients with gastrointestinal neuroendocrine tumours. Br J Cancer 2013;108:301.
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[19] Thompson GB, van Heerden JA, Grant CS, Carney JA, Ilstrup DM. Islet cell carcinomas of the pancreas: a twentyyear experience. Surgery 1988;104:1011. [20] Chen H, Hardacre JM, Uzar A, Cameron JL, Choti MA. Isolated liver metastases from neuroendocrine tumors: does resection prolong survival? J Am Coll Surg 1998;187:88. discussion 92e3. [21] Knox CD, Anderson CD, Lamps LW, Adkins RB, Pinson CW. Long-term survival after resection for primary hepatic carcinoid tumor. Ann Surg Oncol 2003;10:1171. [22] Osborne DA, Zervos EE, Strosberg J, et al. Improved outcome with cytoreduction versus embolization for symptomatic hepatic metastases of carcinoid and neuroendocrine tumors. Ann Surg Oncol 2006;13:572. [23] O’Toole D, Hentic O, Corcos O, Ruszniewski P. Chemotherapy for gastro-enteropancreatic endocrine tumours. Neuroendocrinology 2004;80(Suppl 1):79. [24] Engstrom PF, Lavin PT, Moertel CG, Folsch E, Douglass HO Jr. Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor. J Clin Oncol 1984;2:1255. [25] Liapi E, Geschwind JF. Chemoembolization for primary and metastatic liver cancer. Cancer J 2010;16:156. [26] Lesurtel M, Nagorney DM, Mazzaferro V, Jensen RT, Poston GJ. When should a liver resection be performed in patients with liver metastases from neuroendocrine tumours? A systematic review with practice recommendations. HPB 2015;17:17. [27] Mayo SC, de Jong MC, Pawlik TM. Surgical management and emerging therapies to prolong survival in metastatic neuroendocrine cancer. Ann Surg Oncol 2011;18(Suppl 3): S220. author reply S222e3. [28] Gupta S, Johnson MM, Murthy R, et al. Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumors: variables affecting response rates and survival. Cancer 2005;104:1590. [29] Roche A, Girish BV, de Baere T, et al. Trans-catheter arterial chemoembolization as first-line treatment for hepatic metastases from endocrine tumors. Eur Radiol 2003;13:136.
[30] Eriksson BK, Larsson EG, Skogseid BM, Lofberg AM, Lorelius LE, Oberg KE. Liver embolizations of patients with malignant neuroendocrine gastrointestinal tumors. Cancer 1998;83:2293. [31] Gupta S, Yao JC, Ahrar K, et al. Hepatic artery embolization and chemoembolization for treatment of patients with metastatic carcinoid tumors: the M.D. Anderson experience. Cancer J 2003;9:261. [32] Yao JC, Phan AT, Chang DZ, et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol 2008;26:4311. [33] Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 2011;378:2005. [34] Arnberger M, Vogt A, Studer P, et al. Evaluation of physical and mental recovery status after elective liver resection. Eur J Anaesthesiol 2009;26:559. [35] Poon RT, Fan ST, Yu WC, Lam BK, Chan FY, Wong J. A prospective longitudinal study of quality of life after resection of hepatocellular carcinoma. Arch Surg 2001;136: 693. [36] Martin RC, Eid S, Scoggins CR, McMasters KM. Health-related quality of life: return to baseline after major and minor liver resection. Surgery 2007;142:676. [37] Wiering B, Oyen WJ, Adang EM, et al. Long-term global quality of life in patients treated for colorectal liver metastases. Br J Surg 2011;98:565. discussion 571e2. [38] Banz VM, Inderbitzin D, Fankhauser R, Studer P, Candinas D. Long-term quality of life after hepatic resection: health is not simply the absence of disease. World J Surg 2009;33:1473. [39] Kneuertz PJ, Marsh JW, de Jong MC, et al. Improvements in quality of life after surgery for benign hepatic tumors: results from a dual center analysis. Surgery 2012;152:193.
Available online at www.sciencedirect.com
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Quality of life after treatment of neuroendocrine liver metastasis Gaya Spolverato, MD, Fabio Bagante, MD, Doris Wagner, MD, Stefan Buettner, MD, Rohan Gupta, MD, Yuhree Kim, MD, Hadia Maqsood, MD, and Timothy M. Pawlik, MD, MPH, PhD* Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland
article info
abstract
Article history:
Background: A large subset of patients with neuroendocrine liver metastasis (NELM) is
Received 27 April 2015
symptomatic at the time of presentation. In addition to improving survival, treatment of
Received in revised form
NELM seeks to provide palliation of symptoms. However, data on health-related quality of
15 May 2015
life (QoL) are uncommon. We sought to define patient-reported QoL after treatment of
Accepted 22 May 2015
NELM.
Available online xxx
Methods: Patients who underwent treatment of NELM at Johns Hopkins Hospital between
Keywords:
were invited to complete a QoL survey designed using validated assessment tools, to assess
NELM
their physical, mental, and general health before treatment, after the most recent treat-
QoL
ment and at the time of the study. Clinicopathologic data were collected and correlated
Surgery
with QoL data.
1998 and 2013 and who were alive as of March 2014 were identified (n ¼ 125). These patients
Survey
Results: The response rate was 68.0% (n ¼ 85). Median patient age was 55 y and most were male (59.2%). Most patients had a pancreatic (24.7%) or a small bowel (37.7%) primary tumor; the overwhelming majority had multiple NELM (83.5%). Patient-reported symptoms before any treatment included diarrhea (41.1%), flushing (34.1%), fatigue (36.5%), and osteoarticular pain (18.8%). Initial treatment of NELM consisted of surgery in 55 patients (64.7%) and nonsurgical treatment in 30 patients (35.3%). Many patients reported an overall improvement in physical health and mental health. Specifically, the proportion of patients reporting diarrhea (before any treatment, 41.1% versus currently, 25.9%; P ¼ 0.019) and flushing (before any treatment, 34.1% versus currently, 10.5%; P < 0.001) tended to decrease over time and a lower proportion of patients reported to be currently sad about being ill (before any treatment, 31.8% versus currently, 23.2%; P ¼ 0.009). Patients with a very poor QoL at the time of the diagnosis were more likely to experience an improvement in QoL after treatment. Interestingly, there was no difference in the improvement in overall QoL whether the initial treatment for NELM was surgical or nonsurgical; however, a lower proportion of patients were dissatisfied with surgery versus nonsurgical therapy (5.4% versus 9.4%; P ¼ 0.001). Conclusions: Less than one-fourth of patients experienced a significant improvement in QoL after treatment of NELM. The patients who benefit the most of treatment were those who were more symptomatic before any treatment. ª 2015 Elsevier Inc. All rights reserved.
* Corresponding author. Department of Surgery, Johns Hopkins Hospital, 600 N. Wolfe Street, Blalock 688, Baltimore, MD 21287. Tel.: þ1 410 502 2387; fax: þ1 410 502 2388. E-mail address: [email protected] (T.M. Pawlik). 0022-4804/$ e see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2015.05.048
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Introduction
Gastrointestinal neuroendocrine tumors (NETs) form a group of relatively rare neoplasms arising mostly from the pancreas and the luminal gastrointestinal tract, which are often characterized by the secretion of bioactive hormones [1]. Although the natural history of NETs is often indolent, up to 60%e90% of gastrointestinal NETs metastasize to the liver during the course of their disease [2]. Treatment of neuroendocrine liver metastasis (NELM) therefore represents an important component in the management of NETs not only for the therapeutic effect of treating the metastatic disease, but also the possible palliative effect of treating the severe hormonal symptoms that some patients can experience secondary to the hepatic tumor burden [3]. Although there is consensus on the necessity of surgical resection of primary NETs in the absence of metastatic disease, the role of surgery in patients with NELM is still controversial. While several series have reported 5-y survival after surgical resection ranging from 60%e75%, few patients are actually cured of their disease [4e8]. In fact, in a large series of patients undergoing surgical management for NELM, Mayo et al. [9] reported recurrence in >90% of patients at 5 y. As such, some investigators have suggested that nonsurgical approaches such as intra-arterial (IAT) or systemic targeted agents may be more appropriate for patients with NELMdespecially those with extensive disease [9e15]. In fact, in a different study examining the role of IAT for NELM, Mayo et al. noted that asymptomatic patients with a large >25% burden of liver disease benefited the least from surgical management and suggested that nonsurgical treatment strategies may be preferred in this clinical situation [9]. To this end, other studies have noted that octreotide and tyrosine kinases including everolimus and sunitinib can improve disease-free survival in patients with advanced NET disease [12e14]. Because NELM can be associated with symptoms and can adversely impact potential survival, treatment goals of NELM often include both symptomatic relief, in addition to improved survival. Although many previous studies have examined the impact of treatment on survival, minimal data exist on the impact of surgical and nonsurgical therapy on patient quality of life (QoL). Given that surgery rarely can achieve a complete cure, data on QoL after surgery relative to nonsurgical therapies are important. Therefore, the objective of the present study was to define patientreported outcomes after surgical and nonsurgical therapy for NELM. Specifically, we sought to assess whether QoL after therapy for NELM improved over a range of selfreported symptoms including physical, emotional, and social functioning.
2.
Methods
2.1.
Patients and data collection
Patients who underwent treatment for NELM at Johns Hopkins Hospital between 1998 and 2013 and who were alive as of March 2014 were identified. Patients with histologically
confirmed NELM or with radiological and clinical features highly suspicious for NELM were included in the study cohort. Only patients with NELM who were alive and who had complete follow-up at the time of the analysis were included (n ¼ 125). Patients were categorized based on initial treatment regimen delivered: surgical treatment (e.g., hepatic resection alone, hepatic resection plus ablation, and open ablation alone) versus nonsurgical treatment (e.g., IAT and received somatostatin analogs). In most instances, IAT consisted of transarterial chemoembolization, bland transarterial embolization, drug eluting beads, or yttrium-90. The Johns Hopkins University Institutional Review Board approved the study. Standard patient demographic and clinicopathologic data such as age, gender, race, intent of treatment, symptoms, location of primary tumor, time to development of liver metastasis, number of hepatic lesions, and the presence of extrahepatic metastasis were collected. Regarding the liver-directed therapy, data on procedure type, number of liver-directed interventions, and timing between primary resection and diagnosis or treatment of NELM were recorded. Specifically, operative data for hepatic resection, such as type of surgery, intent of surgery, indication for hepatic resection, extent of hepatic resection, were collected.
2.2.
QoL assessment
All eligible patients were invited via mail to complete a QoL survey sent to each patient’s home address. Patients were asked to evaluate their QoL before treatment, after the last treatment administered, and at the “current” time. Because no specific questionnaire exists to evaluate QoL after NELM treatment, a survey was constructed using elements of validated assessment tools, including the Norfolk Quality of Life tool for Neuroendocrine Tumors (Norfolk QoL-NETs) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30/GI.NET-21) [16e18]. The questions from Norfolk QoL-NETs were used to assess specific hormone-induced symptoms associated with NELM, whereas elements from EORTC QLQ-C30/GI.NET-21 were used to assess general health perception and well-being. The survey consisted of 28 questions aimed at evaluating physical health, mental health, and general health perceptions using standard Likert scale assessments. Patientreported information was also collected on each patient’s subjective feeling toward the decision to have undergone treatment for NELM.
2.3.
Statistical analysis
Continuous variables were presented as the median with the interquartile range. Categorical variables were reported both as integers and percentages. The distributions of categorical and numerical variables between independent groups were compared using Fisher’s exact test and a ManneWhitney Utest, respectively. Comparisons of QoL parameters were assessed using t-test for paired observation. For statistical analyses, P values <0.05 (two-tailed) were deemed significant. All analyses were carried out with STATA 13.0 (StataCorp, College Station, TX).
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Table 1 e Clinicopathologic characteristics of cohort, stratified by response status. Variable
Age Gender Female Male Race White Black Other N/A Location of primary tumor Pancreas Colon-rectum Small-bowel Bronchus Unknown Type of surgery for primary Intestinal resection Distal pancreatectomy Whipple Other Primary not resected Histology Carcinoid Nonfunctioning islet cell Insulinoma Gastrinoma Glucagonoma N/A Grade Low Medium High N/A Presentation Not symptomatic Symptomatic N/A Symptoms Abdominal cramping Weight loss Flushing Diarrhea or steatorrhoea Palpitations Rash Diabetes mellitus Synchronous liver metastasis No Yes N/A Number of liver metastasis Single Multiple N/A Indication for liver operation Pain Hormonal symptoms Mechanical symptoms Indication based on stage and resectability Treatment of liver metastasis Liver resection Liver resection and ablation
Median (interquartile range) or n (%) 55 y (47e61) 39 (40.8%) 45 (59.2%) 65 8 3 9
(76.5%) (9.4%) (3.5%) (10.6%)
21 9 32 3 20
(24.7%) (10.6%) (37.7%) (3.5%) (23.5%)
39 10 4 20 12
(45.9%) (11.7%) (4.7%) (23.6%) (14.1%)
50 14 2 1 1 17
(58.8%) (16.7%) (2.3%) (1.1%) (1.1%) (20.0%)
18 9 13 45
(21.2%) (10.6%) (15.3%) (52.9%)
22 (25.9%) 45 (52.9%) 18 (21.2%) 16 6 24 22 4 1 2
(18.8%) (7.1%) (28.2%) (25.9%) (4.7%) (1.2%) (2.4%)
32 (37.6%) 42 (49.4%) 11 (13.0%) 8 (9.4%) 71 (83.5%) 6 (7.1%) 12 13 5 25
(21.8%) (23.6%) (9.2%) (45.4%)
50 (58.8%) 5 (5.9%) (continued)
Table 1 e (continued ) Variable
Other Type of resection Minor or nonanatomic resection Hemihepatectomy Nonsurgical treatment* IAT Targeted agents Systemic chemotherapy None
Median (interquartile range) or n (%) 30 (35.3%) 30 (54.5%) 25 (45.5%) 22 18 7 3
(73.3%) (60.0%) (23.3%) (10.0%)
IAT ¼ intra-arterial therapy; N/A ¼ not available or missing. * Some patients received multiple nonsurgical treatments.
3.
Results
3.1.
Description of cohort
Among a total of 125 patients who were identified with NELM, 85 patients returned the questionnaire for a response rate of 68.0%. Overall, median age was 55 y (interquartile range 47, 61) with most patients being male (n ¼ 45, 59.2%) and white (n ¼ 65, 76.5%; Table 1). Most patients had a primary tumor located in the small intestine (n ¼ 32, 37.7%) or in the pancreas (n ¼ 21, 24.7%). Most patients had a carcinoid tumor (n ¼ 50, 58.8%), whereas nonfunctioning islet cell tumors, gastrinomas, insulinomas, and glucagonomas were less common (Table 1). Most patients (n ¼ 45, 52.9%) had symptomatic primary tumors, with the most common symptoms being flushing (n ¼ 24, 28.2%) and diarrhea (n ¼ 22, 25.9%). Almost half of the patients had synchronous liver metastasis (n ¼ 42, 49.4%) and most patients presented with multiple NELM (n ¼ 71, 83.5%). Of the 85 patients, 55 (64.7%) underwent surgery as initial therapy, whereas 30 (35.3%) patients received nonsurgical treatment as primary therapy. The clinicopathologic and tumor characteristics of the patients who underwent surgical versus nonsurgical therapy were largely comparable (Table 1). Among patients who received surgical treatment for NELM, 50 patients (58.8%) underwent resection alone, whereas five patients (5.9%) received both resection and ablation. The most common type of procedure was a minor or nonanatomic resection (n ¼ 30, 54.5%), whereas 25 patients (45.5%) had a formal hemihepatectomy. Among patients who underwent surgery, preoperative symptoms included diarrhea (moderate to extreme, n ¼ 35, 41.1%), flushing (moderate to extreme, n ¼ 29, 34.1%), and general abdominal pain (moderate to extreme, n ¼ 17, 20.0%). After surgery, nine patients (16.3%) experienced a recurrence at a median time of 32.8 mo; four patients (44.4%) who recurred were eventually treated with somatostatin-analog or tyrosine kinase inhibitors. Overall survival among surgical patients was 50.7 mo (range, 35.4e115.9 mo). Among 30 patients (35.3%) who received nonsurgical therapy as their initial modality of care, IAT (n ¼ 22, 73.3%) was most often used, followed by medical treatment with targeted
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Table 2 e Quality of life of patients receiving treatment for neuroendocrine liver metastasis. Before first treatment Physical symptoms Flushing None or mild Moderate Severe to extreme No response Osteoarticular pain None or mild Moderate Severe to extreme No response Other pain None or mild Moderate Severe to extreme No response Diarrhea or constipation None or mild Moderate Severe to extreme No response Rash None or mild Moderate Severe to extreme No response Blue discoloration of skin None or mild Moderate Severe to extreme No response Red spot on skin None or mild Moderate Severe to extreme No response Whistling sound None or mild Moderate Severe to extreme No response Cough None or mild Moderate Severe to extreme No response Swelling of hands or feet None or mild Moderate Severe to extreme No response Fatigue None or mild Moderate Severe to extreme No response Mental symptoms Sex life None or mild Moderate Severe to extreme No response Trouble for sleeping None or mild
After last treatment
P value*
At the time of the study
<0.001 51 20 9 5
(60.0%) (23.5%) (10.6%) (5.9%)
66 9 2 8
(77.7%) (10.6%) (2.3%) (9.4%)
62 12 4 7
(73.0%) (14.1%) (4.7%) (8.2%)
59 13 4 9
(69.4%) (15.3%) (4.7%) (10.6%)
59 13 4 9
(69.4%) (15.3%) (4.7%) (10.6%)
61 9 4 11
(71.8%) (10.6%) (4.7%) (12.9%)
45 20 15 5
(52.9%) (23.5%) (17.6%) (5.9%)
50 21 8 6
(58.8%) (24.7%) (9.4%) (7.1%)
72 4 2 7
(84.8%) (4.7%) (2.3%) (8.2%)
72 5 0 8
(84.7%) (5.9%) (0%) (9.4%)
74 5 0 6
(87.1%) (5.9%) (0%) (7.1%)
77 1 0 7
(90.6%) (1.2%) (0%) (8.2%)
73 5 1 6
(85.9%) (5.9%) (1.2%) (7.1%)
75 5 0 5
(85.9%) (5.9%) (0%) (8.2%)
77 2 0 6
(90.6%) (2.4%) (0%) (7.1%)
77 1 0 7
(90.6%) (1.2%) (0%) (8.2%)
72 8 0 5
(84.7%) (9.4%) (0%) (5.9%)
74 4 1 6
(87.1%) (4.7%) (1.2%) (7.1%)
73 5 3 4
(85.9%) (5.9%) (3.5%) (4.7%)
77 2 0 6
(90.6%) (2.3%) (0%) (7.1%)
49 25 6 5
(57.6%) (29.4%) (7.1%) (5.9%)
46 26 7 6
(54.1%) (30.6%) (8.2%) (7.1%)
60 10 6 9
(70.6%) (11.8%) (7.1%) (10.6%)
50 18 7 10
(58.8%) (21.2%) (8.2%) (11.8%)
<0.001 71 (83.5%) 7 (8.2%) 2 (2.3%) 5 (5.9%)
0.658
0.070 63 (74.1%) 13 (15.3%) 4 (4.7%) 5 (5.9%)
0.717
0.113 70 (82.3%) 9 (10.6%) 0 (0%) 6 (7.1%) 0.019
0.101 60 (70.6%) 16 (18.8%) 6 (7.1%) 3 (3.5%) 0.373
0.642 73 (85.9%) 6 (7.1%) 1 (1.2%) 5 (5.9%)
0.159
0.070 80 (94.1%) 1 (1.2%) 0 (0%) 4 (4.7%)
0.409
0.596 75 (88.2%) 6 (7.1%) 0 (0%) 4 (4.7%)
0.798
0.899 79 (92.9%) 2 (2.4%) 0 (0%) 4 (4.7%)
0.820
0.320 78 (91.8%) 4 (4.7%) 0 (0%) 3 (3.5%)
0.436
0.726 79 (92.9%) 3 (3.5%) 0 (0%) 3 (3.5%)
0.357
0.150 58 (68.2%) 20 (23.5%) 4 (4.7%) 3 (3.5%)
0.004
0.045 55 (64.7%) 18 (21.2%) 4 (4.7%) 8 (9.4%) 0.021
0.252 62 (72.9%)
59 (69.4%)
P valuey
59 (69.4%) (continued)
5
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Table 2 e (continued )
Moderate Severe to extreme No response Physical or emotional health interference with family life None or mild Moderate Severe to extreme No response Physical or emotional health interference with social activities None or mild Moderate Severe to extreme No response Have to take pain medication None or mild Moderate Severe to extreme No response Tense or irritable or depressed or worried None or mild Moderate Severe to extreme No response Sad about being ill None or mild Moderate Severe to extreme No response Worried about dying None or mild Moderate Severe to extreme No response Hopeful about future None or mild Moderate Severe to extreme No response Happy with life None or mild Moderate Severe to extreme No response General health Limited in daily life None or mild Moderate Severe to extreme No response Limited in leisure None or mild Moderate Severe to extreme No response Satisfied with quality of life None or mild Moderate Severe to extreme No response
Before first treatment
After last treatment
17 (20.0%) 1 (1.2%) 5 (5.9%)
18 (21.2%) 1 (1.2%) 7 (8.2%)
P value*
At the time of the study 21 (24.7%) 1 (1.2%) 4 (4.7%)
0.006 69 (81.2%) 9 (10.6%) 3 (3.5%) 4 (4.7%)
60 17 3 5
(70.6%) (20.0%) (5.5%) (5.9%)
0.625 64 16 2 3
(75.3%) (18.9%) (2.4%) (3.5%)
<0.001 67 (78.8%) 11 (12.9%) 3 (3.5%) 4 (4.7%)
56 19 4 6
(65.9%) (22.4%) (4.7%) (7.1%)
69 (81.2%) 8 (9.4%) 3 (3.5%) 5 (5.9%)
62 13 4 6
(72.9%) (15.3%) (4.7%) (7.1%)
0.077 67 14 1 3
(78.8%) (16.5%) (1.2%) (3.5%)
71 10 2 2
(83.5%) (11.8%) (2.4%) (2.4%)
<0.001
0.172
0.003 67 (78.8%) 11 (12.9%) 4 (4.7%) 3 (3.5%)
58 18 4 5
(68.2%) (21.2%) (4.7%) (5.9%)
55 (64.7%) 17 (20.0%) 10 (11.8%) 3 (3.5%)
55 17 8 5
(64.7%) (20.0%) (9.4%) (5.9%)
56 (65.9%) 18 (21.2%) 8 (9.4%) 2 (3.5%)
63 11 6 5
(74.1%) (12.9%) (7.1%) (5.9%)
31 (36.5%) 28 (32.9%) 23 (27.1%) 3 (3.5%)
28 30 22 5
(32.9%) (35.3%) (25.9%) (5.9%)
18 (21.2%) 36 (41.3%) 28 (32.9%) 3 (3.5%)
20 38 22 5
(23.5%) (44.7%) (25.9%) (5.9%)
59 (69.4%) 18 (21.2%) 4 (4.7%) 4 (4.7%)
49 23 7 6
(57.6%) (27.1%) (8.2%) (7.1%)
62 (72.9%) 14 (16.5%) 5 (5.9%) 4 (4.7%)
50 24 5 6
(58.8%) (28.2%) (5.9%) (7.1%)
21 (24.7%) 40 (47.1%) 24 (28.2%) 0 (0%)
23 35 22 5
(27.0%) (41.2%) (25.9%) (5.9%)
0.260 70 11 2 2
(82.4%) (12.9%) (2.4%) (2.4%)
65 16 2 2
(76.5%) (18.8%) (2.4%) (2.4%)
68 13 2 2
(80.0%) (15.3%) (2.4%) (2.4%)
27 33 23 2
(31.8%) (38.8%) (27.1%) (2.4%)
17 44 22 2
(20.0%) (51.8%) (25.9%) (2.4%)
57 22 3 3
(67.1%) (25.9%) (3.5%) (3.5%)
70 11 2 2
(82.3%) (12.9%) (2.4%) (2.4%)
0.009
0.783
0.296
0.094
0.775
0.559
0.163
0.593
0.001
0.390
0.004
0.892
0.581
Bold values indicate significant P values. * Comparison between before first treatment and after last treatment. y Comparison between before first treatment and at the time of the study.
P valuey
0.117 17 (20.0%) 40 (47.1%) 28 (32.9%) 0 (0%)
6
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agents (n ¼ 18, 60.0%) and systemic chemotherapy (n ¼ 7, 23.3%). As expected some patients received multiple nonsurgical treatments. Among patients who received IAT, transarterial chemoembolization was used in 13 patients, whereas drug eluting beads (n ¼ 4, 28.6%) and yttrium-90 (n ¼ 5, 35.7) were used less frequently. The median number of IAT treatments administered was 3 (range, 1e6). Overall survival among nonsurgical patients was 47.9 mo (range, 30.7e95.8 mo).
3.2.
QoL assessment
Patient-reported symptoms before any treatment included diarrhea (n ¼ 35, 41.1%), flushing (n ¼ 29, 34.1%), fatigue (n ¼ 31, 36.5%), and osteoarticular pain (n ¼ 16, 18.8%), and did not differ among patients treated with surgery versus nonsurgical therapy (P > 0.05). A substantial number of patients also complained of mental health (i.e., depressed mood, n ¼ 15, 17.6%; sad about being ill, n ¼ 27, 31.8%; worried about dying, n ¼ 36, 30.6%) and general health (i.e., limitations in daily life, n ¼ 22, 25.9% versus limitations in leisure, n ¼ 19, 22.4%) issues. In particular, one-fourth of patients (n ¼ 21, 24.7%) reported being unsatisfied with their QoL. After the most recent treatment of NELM, the proportion of patients reporting moderate-to-extreme fatigue (before any treatment, 36.5% versus after the most recent treatment, 38.8%) and diarrhea (before any treatment, 41.1% versus after the most recent treatment, 34.1%) had not significantly changed (both P > 0.05); in contrast, self-reported complaints of flushing decreased (before any treatment, 34.1% versus after the most recent treatment, 12.9%; P < 0.001). Mental health issues remained, however, a matter of concern for patients after therapy, with a larger number of patients stating that family life (before any treatment, 14.1% versus after the most recent treatment, 25.5%; P ¼ 0.006) and social activities (before any treatment, 16.4% versus after the most recent treatment, 27.1%; P < 0.001) were affected adversely by the treatments (Table 2). General health was also compromised after the most recent treatment with 35.3% of patients reporting limitations in daily life (compared with 25.9% before any treatment; P ¼ 0.001) and 34.1% noting limitations in leisure activities
(compared with 22.4% before any treatment; P ¼ 0.004). Overall satisfaction with QoL did not change after treatment, with only 57 patients (67.1%) reporting to be satisfied with their QoL after treatment, compared with 64 patients (75.3%) before any treatment (P ¼ 0.581). Patients were asked to assess their QoL before any treatment versus “currently.” In general, patients reported a slight increase in satisfaction with their QoL, although this improvement was not statistically significant (before any treatment, 75.3% versus currently, 80%; P ¼ 0.117). Examination of specific QoL domains revealed improvements in both physical and mental health. Specifically, the proportion of patients reporting diarrhea (before any treatment, 41.1% versus currently, 25.9%; P ¼ 0.019) and flushing (before any treatment, 34.1% versus currently, 10.5%; P < 0.001) tended to decrease over time. A decreasing trend (P < 0.05) was also reported for fatigue (before any treatment, 36.5% versus currently, 28.2%), other pain (before any treatment, 20.0% versus currently, 10.6%), and skin discoloration (before any treatment, 5.9% versus currently, 1.2%). There was also a modest improvement in mental health. Although a lower proportion of patients self-reported to be sad about being ill (before any treatment, 31.8% versus currently, 23.2%; P ¼ 0.009), other self-reported outcome such as being tense or irritable or depressed or worried (before any treatment, 17.6% versus currently, 14.3%; P ¼ 0.260) or worried about dying (before any treatment, 30.6% versus currently, 17.7%; P ¼ 0.094) were not much different. Limitations in daily life (29.4%) and in leisure (15.3%) were also comparable with those reported preoperatively (P > 0.05). Patients with a very poor QoL at the time of the diagnosis were more likely to experience an improvement in QoL after treatment. For example, patients who reported the worst initial QoL at diagnosis reported a 55.0% improvement in QoL at last follow-up (Table 3). In contrast, patients who selfreported a moderate QoL at the time of diagnosis had only a 7.7% improvement in overall QoL at last follow-up (P < 0.001). Interestingly, there was no difference in the improvement in overall QoL whether the initial treatment for NELM was surgical or nonsurgical (Fig. 1). Specifically, 18.9% of patients who
Table 3 e Improvement in QoL after treatment for neuroendocrine liver metastasis.
Whole cohort of patients* Type of treatment Surgery patients Other therapy QoL at diagnosis None or mild Moderate QoL none or mild at diagnosis Surgery patients Other therapy QoL moderate at diagnosis Surgery patients Other therapy
N
QoL equal
QoL improved
83
69 (83.3%)
14 (16.7%)
54 29
44 (81.8%) 25 (86.2%)
10 (18.1%) 4 (13.8%)
20 39
9 (45.0%) 36 (92.3%)
11 (55.0%) 3 (7.7%)
11 9
4 (36.4%) 5 (55.6%)
7 (63.6%) 4 (44.4%)
25 13
22 (88.0%) 13 (100%)
3 (12.0%) 0 (0%)
P value 0.559
<0.001
0.653
0.538
Bold value indicate significant P value. QoL ¼ quality of life. * Eighty-three were the patients who answered to a specific question on perception of their QoL, 54 were surgical, and 29 were nonsurgical.
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7
Fig. 1 e Improvement of QoL after treatment for neuroendocrine liver metastasis stratified by different type of treatment and QoL at diagnosis. QoL, quality of life.
underwent a surgical procedure reported an improvement in QoL versus 13.8% of patients who received nonsurgical treatment (P ¼ 0.559). Despite the modest improvements in overall QoL, overall satisfaction with treatment was high. In fact, only 5.4% of patients were dissatisfied with surgery versus 9.4% of patients who had been initially treated with nonsurgical therapy (P ¼ 0.001). Of interest, many patients reported having ongoing financial difficulties as a result of their NELM (59.3% and 57.6%).
4.
Discussion
Although NETs can often be indolent, a subset of patients has NELM either at presentation or develops metastatic disease sometime during the course of their disease. Unlike most other secondary malignancies of the liver, NELM not only can threaten long-term survival, but also can adversely impact patient QoL. Specifically, in a subset of patients, NELM can be associated with hormonal symptoms including flushing, palpitations, and diarrhea, which can be debilitating for some patients [5,6,19e22]. As such, treatment goals associated with surgical extirpation of NELM often not only include prolongation of survival, but also an attempt to alleviate NET-related symptoms. The treatment for NELM can be varied, including resection, ablation, locoregional IAT, and the use of targeted or systemic agents [4e8,10,15,23e25]. Previous data on the effect of NELM management have largely focused on oncologic outcomes such as recurrence and disease-free and overall survival [9,15]. The present study is important because
it provides an assessment of QoL among patients undergoing treatment for NELM. Data on how treatment of NELM may affect QoL is of great value from the patient’s perspective and may be helpful in counselling patients. Although improvement in QoL might be anticipated after treatment of NELM, there are scant data in the literature on the topic. In the present study, although patients reported improvements in certain QoL domains and certain symptoms such as diarrhea and flushing, most patients reported only a modest improvement in their overall QoL satisfaction. Perhaps not surprisingly, patients with the worst initial QoL were more likely to experience an improvement in QoL after treatment. Furthermore, there was no difference in the improvement in overall QoL whether the initial treatment for NELM was surgical or nonsurgical (Fig. 1). The treatment of NELM, especially among patients with extensive liver disease, remains somewhat varied [9,15]. Surgical management of NELM has been an important therapeutic option for many patients with NELM, as it holds the best promise of cure. However, even when all measurable disease is resected, a high majority of patients with NELM will experience recurrence after resection [7,9,15]. As such, although some groups have advocated for debulking of NELM even in the presence of extensive disease [5,26], other groupsdincluding our owndhave suggested that surgical management of NELM be reserved for patients with low-volume disease or those patients with symptomatic disease [9,27], as debulking may help alleviate symptoms in this latter group of patients. Other studies have advocated, however, for the potential beneficial effects of nonsurgical approaches such as IAT [10,11].
Fig. 2 e Comparison of physical health before and after treatment of neuroendocrine liver metastasis.
8
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Fig. 3 e Comparison of mental health before and after treatment of neuroendocrine liver metastasis.
Specifically, several reports have documented the potential of IAT to reduce tumor burden and hormonal output [28e31]. IAT may, therefore, provide symptomatic relief by “debulking” the intrahepatic tumor burden. Furthermore, systemic targeted agents such as somatostatin analogs, as well as sunitinib and everolimus, have both anticancer and antisymptomatic effects. As such, multiple options exist to treat patients with NELM, with each option potentially impacting both cancerspecific outcomes and patient QoL. Despite anticipated improvements in QoL being among one of the main indications for treatment of NELM, minimal data are available on the effect of treatment on health-related QoL of patients with NELM. Patient-reported outcomes are, however, an important area of research as many patients with NELM have symptoms. Flushing and diarrhea are common presenting symptoms among patients with hormonally active NELM [5,6,19e22]. In fact, data from prospective studies have noted that up to 70% and 74% of patients with NELM complain of grade 2e3 flushing and diarrhea, respectively [12,32,33]. Similarly, in the present study, we noted that more than twothirds of patients had flushing or diarrhea as one of their main complaints. Other commonly reported physical symptoms included fatigue and osteoarticular pain (Fig. 2). Of note, a subset of patients self-reported that many of their physical symptoms improved after therapy. Specifically, 21% and 7% of patients reported that their flushing or diarrhea improved after the initial treatment for their NELM. In addition, 24% and 15% reported that this improvement persisted currently at the time of the survey administration (Fig. 2). Of note, those patients who had the most significant symptoms before initial
treatment had the biggest incremental improvement in QoL. However, the improvement in QoL did not seem to be different based on the type of initial therapy employed (e.g., resection, IAT, targeted agents). Collectively, these data demonstrate that many patients with NELM can expect to have only a modest improvement in QoL, with the largest benefit among those patients who are most symptomatic. In addition to physical symptoms, several other QoL domains were evaluated, including emotional, social, and general health perceptions. Several previous studies have examined these QoL domains among patients undergoing liver surgery for hepatocellular carcinoma [34,35], secondary metastatic liver tumors [36e38], and benign liver tumors [39]. Each of these studies noted that patients who underwent resection had improved QoL scores in emotional and social domains. The present report expands on these previous data by examining QoL in patients with NELM treated not only with surgical resection, but also other modalities of care. Interestingly, many patients with NELM self-reported significant concerns with daily life before treatment, including social and also emotional problems. Of note, although patients selfreported improvements in physical symptoms after treatment of NELM, other domains such as sexual and family life, social activities, and general mental health remained compromised (Figs. 3 and 4). In fact, less than one in five patients reported an improvement in their emotional status after treatment. Furthermore, many patients reported having ongoing financial difficulties as a result of their NELM (59.3% and 57.6%). In sum, although self-reported physical symptoms such as flushing and diarrhea improved in a subset of patients
Fig. 4 e Comparison of general health before and after treatment of neuroendocrine liver metastasis.
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after NELM-directed therapy, the effect of therapy on other aspects of QoL was more negligible. The present study had several limitations. Survey data were collected in a retrospective fashion and therefore the collection of the data was likely subject to some degree of recall bias. Patients who had more severe initial symptoms may have been more likely to remember details regarding their symptoms compared with patients who had no or only mild symptoms. Moreover, the recall bias would impact more on QoL perception before the first treatment and after the most recent treatment, rather than on current QoL. Despite possible recall bias, the present study provides relevant data on self-reported patient perceptions on their current QoL after treatment of NELM. Another important limitation of the present study is that only patients who were alive as of March 2014 were included; in turn, patients who had more aggressive disease and dieddand possibly had a worse QoLdwere excluded.
5.
Conclusions
In the present study, we showed that treatment of NELM was associated with improvements in certain patient-reported outcomes. Specifically, a subset of patients reported improvement in diarrhea and flushing, although patients only noted more modest improvement in their mental and general health. Patients with a very poor QoL at the time of the diagnosis were more likely to experience an improvement in QoL after treatment. Our results may help facilitate discussions around QoL at the time of treatment for NELM and assist in counselling patients regarding treatment options and QoL expectations.
Acknowledgment Author contributions: Spolverato, Bagante, Maqsood, and Pawlik contributed toward study conception and design; Spolverato, Bagante, Maqsood, Wagner, Buettner, Gupta, Kim, and Pawlik contributed toward acquisition of data; Spolverato, Bagante, Maqsood, and Pawlik contributed toward analysis and interpretation of data; Spolverato, Maqsood, and Pawlik contributed toward drafting of the manuscript; and critical revision was done by Spolverato, Bagante, Maqsood, Wagner, Buettner, Gupta, Kim, and Pawlik.
Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in the article.
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