Background
Pancreatic cancer remains an aggressive and often fatal malignancy. Approximately one-third of patients present with nonmetastatic disease with extensive vascular involvement, classifying it as locally advanced pancreatic cancer (LAPC).1 The standard of care for LAPC includes multiagent chemotherapy, often in combination with radiotherapy.2 Advances in systemic and local disease control with (m)FOLIFRINOX ([modified] 5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) and gemcitabine + nab-paclitaxel have significantly improved outcomes compared with earlier regimens. As a result, up to 23% (95% CI, 11%–40%) of patients with LAPC may undergo subsequent surgical resection, which is associated with improved 5-year overall survival (OS) rates up to 25%.3–5
However, these systemic and surgical treatments are not without risks. Multiagent chemotherapies, such as (m)FOLFIRINOX, are associated with a high incidence of serious adverse events, ranging from 43% to 76%.6–10 Furthermore, surgical resection of LAPC following induction therapy is associated with significant short-term postoperative complications11–13 and long-term sequelae, such as postarterial divestment diarrhea and endocrine and exocrine pancreatic insufficiency.14–18 Median OS for all patients with LAPC treated with (m)FOLFIRINOX or gemcitabine + nab-paclitaxel ranges from 13 to 17 months due to rapid disease progression during chemotherapy or (early) disease recurrence after resection.3,19 This raises the question of whether these intensified treatment strategies are justified, given that they may negatively impact quality of life (QoL). On the other hand, chemotherapy can decrease tumor burden, alleviating disease-related symptoms such as fatigue and pain, thereby potentially improving QoL.20
Understanding how tumor-directed treatment(s) affect QoL over time is crucial for counseling patients and facilitating shared decision-making by balancing potential benefits and risks.21,22 The importance of this is underscored by the 2016 ASCO guidelines on LAPC and unresectable pancreatic cancer,23 which advised clinicians to proactively discuss QoL with patients. However, prospective studies investigating QoL over time in all-comers with LAPC, regardless of (type of) treatment received, are lacking. Although several studies over the past decade have explored QoL in patients with LAPC, these were either cross-sectional or prospective studies in selected patients who were considered fit for induction therapy or had nonprogressive disease following induction therapy.24–32 As a result, the available evidence is limited and insufficient to support comprehensive patient counseling and shared decision-making.
Therefore, this study aimed to evaluate QoL over time in newly diagnosed patients with LAPC, both in general and within subgroups according to the tumor-directed treatment they received.
Methods
Study Design
This post hoc analysis is based on a prospective multicenter study of patients with LAPC across 13 centers, all of whom were included in the Dutch LAPC registry and the Dutch Pancreatic Cancer Project (PACAP; ClinicalTrials.gov identifier: NCT03513705) for patient-reported outcome measures (PROMs).33,34 Clinical data from the LAPC registry were linked with PACAP data, and all patients provided written informed consent. The study was approved by the scientific committee of the Dutch Pancreatic Cancer Group (DPCG)35 and conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline.36
Study Population
All consecutive patients diagnosed with LAPC between 2015 and 2019, based on cross-sectional imaging, were included when they completed at least one QoL-questionnaire within 12 months after diagnosis. Both patients who received tumor-directed treatment and those who did not were included. LAPC was defined in accordance with the DPCG criteria37 (Supplementary Table S1, available online in the supplementary materials).
Study Endpoints
The primary outcome was the global health status (GHS) from the EORTC QoL Questionnaire-Core 30 (EORTC QLQ-C30) as an indicator of general QoL.38,39 Secondary endpoints included functioning and symptom scores from the EORTC QLQ-C30 and the EORTC QLQ pancreatic cancer–specific module (QLQ-PAN26). QoL outcomes were compared with those of the general (healthy) Dutch population and stratified by age categories matching those of the included QoL cohort.40
Data Collection and Definitions
Clinical Data
The Dutch LAPC registry includes data on patient, tumor, and treatment characteristics, including age, sex, performance status (PS), tumor location, tumor size, baseline CA-19.9 level, type of chemotherapy, resection margin status, lymph node status, major complications, progression/recurrence, and OS measured from the time of diagnosis.
Patients were categorized into 3 subgroups: those who underwent induction chemotherapy followed by resection, those who received palliative/induction chemotherapy (± radiotherapy) without subsequent resection, and those who received best supportive care (BSC). Tumor-directed treatment was defined as chemotherapy (± radiotherapy) and/or resection. Margin status was defined as radical (R0) or irradical (R1/R2) based on The Royal College of Pathologists definition.41 Major complications were defined as Clavien-Dindo grade ≥IIIa.42
QoL Data
Within the PACAP PROMs infrastructure, QoL was assessed at diagnosis (baseline) and subsequently every 3 months until 12 months. After 12 months, assessments were conducted every 6 months until 24 months, followed by an annual assessment death or the end of follow-up. For this study, only measurements from the first 12 months after diagnosis were analysed, focusing on the EORTC QLQ-C30 (version 3.0) and QLQ-PAN26.38,39
The EORTC QLQ-C30 includes the GHS, 5 functioning scales, 8 symptom scales/individual items, and 1 item addressing financial difficulties. The QLQ-PAN26 comprises 9 pancreatic- and treatment-related symptoms and 5 emotional domains. Scores range from 0 to 100, with higher scores on the GHS, functional scales of the QLQ-C30, and emotional scales of the QLQ-PAN-26 indicating better QoL. Higher scores on the symptom scales/items of both the QLQ-C30 and QLQ-PAN-26 indicate more complaints.
Time Intervals of Questionnaires
The time points at which the questionnaires were completed were defined according to the measurements of the PACAP PROMs: baseline, 3 months, 6 months, and so on. Baseline was defined as the period between 0 and 3 months after diagnosis (regardless of treatment initiation), whereas 3 months was defined as the period between 3 and 6 months after diagnosis. This 3-month time window was applied consistently to all subsequent time points. The type of treatment received during each time point was also documented.
Statistical Analysis
Baseline characteristics were presented using descriptive statistics. Categorical variables were reported as proportions and continuous variables were summarized as mean [SD] or median (IQR). Normally distributed data were compared using a Student t test, categorical data using the chi-square test, and non-normally distributed data using the Mann-Whitney U test. Although the questionnaire scores were non-normally distributed, mean [SD] were used due to the relatively large sample size and the common practice of analyzing QoL data parametrically.
First, GHS at baseline was compared across the 3 different treatment groups using one-way analysis of variance. Second, linear mixed model regression analyses using a random slope were performed to assess the effect of time on QoL for all patients. The clinical relevance of absolute score differences was determined using the method of Osoba et al,43 and a “delta” (Δ) of ≥10 points was defined and considered clinically relevant. Third, as for the 3 treatment groups individually, no effect over time could be assessed due to the small sample sizes, and therefore a subgroup analysis was performed to assess the effect of time on QoL for patients receiving tumor-directed treatment (excluding the BSC group). Fourth, the QLQ-C30 outcomes from the overall cohort at baseline were compared with the general Dutch population.40
Outcomes were calculated per the EORTC user manual when >50% of the questions for a (sub)scale were completed. Missing data (ie, <50% of questions answered or questionnaire incomplete at a certain time point) were described but not imputed, because they were not at random. All P values were 2-sided, with values <.05 considered statistically significant. All calculations were performed using RStudio (version 4.0.3; Posit PBC).
Results
Overall, 865 patients were included in the Dutch LAPC registry, of whom 170 (20%) completed at least 1 QoL questionnaire within 12 months after diagnosis and were included in the final cohort. The median number of completed questionnaires in this cohort was 3, with 69 (41%) patients completing at least 4 questionnaires. The response rate of patients completing the questionnaires gradually decreased over time, from 81% (n=137/170) at baseline to 37% (n=63/170) at 12 months. However, accounting for deaths (and the resulting inability to complete questionnaires), the actual response rate at 12 months was 62% (n=63/102), based on the 102 patients who were still alive.
Within the final study cohort, the mean [SD] age was 64.9 [9.5] years and 49% of the patients were female. Overall, 116 (68%) patients received chemotherapy alone, 36 (21%) underwent chemotherapy followed by resection, and 18 (11%) received BSC only. Compared with the broader LAPC registry cohort, patients included in the current study had a more favorable WHO PS at diagnosis, and a higher proportion underwent resection (Supplementary Table S2).
Global Health Status
The mean [SD] GHS at baseline was 62.9 [20.1] (Table 1, Figure 1). Among different treatment strategies, baseline GHS was the highest for patients receiving chemotherapy followed by resection (mean [SD], 69.5 [16.1]), compared with those receiving chemotherapy alone (mean [SD], 63.8 [19.8]) and those receiving BSC (mean [SD], 47.5 [20.8]; P=.001). Over time, GHS did not show a statistically significant (P=.41) or clinically relevant change for all patients. Similarly, no significant change was observed in the subgroup of patients who received tumor-directed therapy (P=.78).
Dynamics in QoL Investigating the Global Health Status
| Baseline Mean [SD] | 3 Months Mean [SD] | 6 Months Mean [SD] | 9 Months Mean [SD] | 12 Months Mean [SD] | P Valuea | Δb 0–3 Months | Δb 0–6 Months | Δb 0–9 Months | Δb 0–12 Months | |
|---|---|---|---|---|---|---|---|---|---|---|
| All patients (N=170) | 62.9 [20.1] n=137 |
65.0 [19.9] n=112 |
68.4 [18.5] n=94 |
69.6 [19.2] n=79 |
65.7 [23.1] n=63 |
.41 | 0.1 n=93 |
2.7 n=73 |
−1.2 n=61 |
−5.0 n=48 |
| Chemotherapy + resection (N=36) | 69.5 [16.1] n=29 |
69.7 [22.2] n=25 |
75.3 [15.6] n=28 |
69.0 [22.2] n=26 |
69.6 [24.1] n=17 |
.78c | −1.6 n=21 |
4.5 n=22 |
−2.4 n=11 |
−0.6 n=15 |
| Chemotherapy only (N=116) | 63.8 [19.8] n=92 |
65.1 [18.1] n=80 |
66.0 [18.8] n=63 |
70.0 [18.1] n=53 |
65.5 [22.6] n=44 |
1.0 n=66 |
2.2 n=49 |
−0.9 n=39 |
−6.7 n=32 |
|
| Best supportive care (N=18) | 47.5 [20.8] n=17 |
51.2 [7.5] n=7 |
52.8 [12.7] n=3 |
66.7 [11.8] n=2 |
37.5 [5.8] n=2 |
NA | −4.2 n=6 |
−4.2 n=2 |
8.3 n=1 |
−16.7 n=1 |
Bold numbers indicate statistical significance or a clinically relevant difference (Δ ≥10).
Abbreviations: n, number of patients who answered the specific question in the questionnaires; NA, not applicable; QoL, quality of life.
Mixed model linear regression investigating the effect of time on global health status.
Δ scores were calculated from the number of patients who completed the questionnaires at both time points. Higher mean scores (0–100) indicate better QoL.
Applies to the statistical differences over time among patients who received tumor-directed therapy (chemotherapy + resection or chemotherapy only).
Global health status over time in patients with locally advanced pancreatic cancer, stratified by treatment strategy. See Table 1 for mean [SD] values. The table under the graph shows which phase of the treatment process the patient is in at a specific timepoint.
aDate of resection until 3 months after resection.
bPatient received adjuvant chemotherapy before 3 months after surgery.
cWhen follow-up was complete or when moment of treatment was unknown.
Citation: Journal of the National Comprehensive Cancer Network 23, 3; 10.6004/jnccn.2024.7091
Functional and Symptom Scales
Tables 2 and 3 present the functional and symptom scales for the overall cohort of included patients. Of the 28 subscales assessed, 13 (46%) showed statistically significant changes over time, but only 9 (32%) demonstrated clinically relevant differences. Improvements were observed in appetite loss, pancreatic pain, and hepatic symptoms (ie, pruritus, jaundice). In contrast, patients reported increases in diarrhea, flatulence, altered bowel habits, and financial difficulties. Over time, fear of future health decreased, but health care satisfaction declined. Additionally, problems with sexuality and insomnia did not change significantly over the entire study period; however, sexuality showed significant deterioration after 3 and 6 months, while insomnia worsened only after 3 months. For changes over time per treatment group, refer to Supplementary Tables S3a–S4c. Statistical analysis of the effect over time by treatment group was not feasible due to the small number of patients; however, clinically relevant differences were noted. Patients in the chemotherapy only group reported improvements in appetite loss and sexuality over time (Supplementary Tables S3b, S4b), whereas patients in the chemotherapy + resection group reported increases in diarrhea and decreases in fear of future health over time (Supplementary Tables S3a, S4a). In both subgroups, financial difficulties increased, and health care satisfaction decreased.
QoL for All Patients Based on Cancer-Related Subscales (EORTC QLQ-C30)
| Baseline Mean [SD] | 3 Months Mean [SD] | 6 Months Mean [SD] | 9 Months Mean [SD] | 12 Months Mean [SD] | P Valuea | Δb 0–3 Months | Δb 0–6 Months | Δb 0–9 Months | Δb 0–12 Months | |
|---|---|---|---|---|---|---|---|---|---|---|
| Physical functioning | 74.9 [12.7] n=138 |
75.2 [19.3] n=112 |
73.6 [20.4] n=95 |
76.0 [23.2] n=81 |
75.0 [6.8] n=63 |
.11 | −2.7 n=95 |
−3.1 n=75 |
−3.9 n=63 |
−5.6 n=47 |
| Role functioning | 61.5 [31.4] n=138 |
64.9 [27.9] n=112 |
64.2 [28.6] n=95 |
67.5 [28.3] n=80 |
65.3 [30.6] n=63 |
.46 | −1.9 n=95 |
−1.6 n=75 |
−0.3 n=62 |
−4.6 n=47 |
| Emotional functioning | 74.1 [21.6] n=137 |
80.2 [18.8] n=112 |
79.5 [21.0] n=95 |
82.4 [19.2] n=79 |
91.5 [21.5] n=63 |
.46 | 6.4 n=93 |
4.6 n=74 |
1.9 n=61 |
−2.1 n=48 |
| Cognitive functioning | 83.9 [20.5] n=137 |
84.2 [16.9] n=112 |
83.9 [19.4] n=95 |
86.1 [17.6] n=79 |
84.7 [18.8] n=63 |
.28 | −1.1 n=93 |
−3.6 n=74 |
−2.5 n=61 |
−3.5 n=48 |
| Social functioning | 72.3 [26.2] n=137 |
75.2 [22.7] n=112 |
75.4 [23.4] n=95 |
76.8 [25.1] n=79 |
76.9 [26.5] n=63 |
.43 | 0.7 n=93 |
−0.7 n=74 |
−2.7 n=61 |
−3.5 n=48 |
| Fatigue | 44.2 [26.8] n=138 |
42.5 [22.1] n=112 |
42.5 [24.7] n=95 |
40.2 [22.8] n=80 |
38.8 [27.7] n=63 |
.85 | 2.5 n=95 |
3.9 n=75 |
4.2 n=62 |
2.8 n=47 |
| Nausea and vomiting | 26.8 [32.2] n=138 |
20.2 [26.6] n=112 |
19.7 [27.7] n=95 |
15.6 [23.2] n=79 |
19.6 [17.8] n=63 |
.03 | −4.9 n=95 |
−3.1 n=75 |
−7.7 n=61 |
0.7 n=47 |
| Pain | 32.5 [26.4] n=139 |
25.0 [23.6] n=112 |
27.2 [26.9] n=95 |
24.8 [24.3] n=80 |
27.5 [27.3] n=63 |
.72 | −3.7 n=95 |
−2.9 n=76 |
0.5 n=63 |
3.5 n=48 |
| Dyspnea | 11.4 [19.1] n=137 |
13.1 [22.1] n=112 |
14.4 [22.6] n=95 |
11.3 [19.1] n=80 |
11.3 [22.5] n=62 |
.56 | 1.4 n=94 |
2.7 n=78 |
−0.5 n=62 |
0.0 n=46 |
| Insomnia | 33.3 [31.8] n=137 |
19.6 [25.1] n=112 |
24.6 [30.8] n=95 |
28.8 [29.9] n=80 |
22.8 [31.6] n=63 |
.21 | −12.4 n=94 |
−8.1 n=74 |
0.5 n=61 |
−4.3 n=47 |
| Appetite loss | 43.8 [35.4] n=137 |
27.3 [29.9] n=111 |
30.9 [30.5] n=95 |
21.8 [28.8] n=78 |
27.4 [30.5] n=152 |
<.001 | −11.4 n=94 |
−6.2 n=75 |
−16.1 n=60 |
−10.9 n=46 |
| Constipation | 33.3 [26.9] n=137 |
9.8 [21.3] n=112 |
11.7 [22.8] n=94 |
9.7 [20.1] n=79 |
10.1 [22.1] n=63 |
.001 | −7.4 n=94 |
−5.9 n=74 |
−7.2 n=60 |
−7.2 n=46 |
| Diarrhea | 20.9 [26.8] n=137 |
26.4 [30.2] n=111 |
27.0 [29.7] n=95 |
32.5 [33.3] n=79 |
25.9 [27.7] n=63 |
.007 | 5.1 n=92 |
5.9 n=74 |
12.6 n=61 |
7.6 n=48 |
| Financial difficulties | 11.0 [24.0] n=136 |
26.4 [30.2] n=111 |
27.0 [29.7] n=95 |
32.5 [33.3] n=79 |
25.9 [27.7] n=63 |
<.001 | 12.5 n=91 |
12.3 n=73 |
20.8 n=61 |
15.3 n=48 |
Bold numbers indicate statistical significance or clinically relevant difference (Δ ≥10).
Abbreviations: EORTC QLQ-C30, EORTC Quality of Life Questionnaire-Core 30; n, number of patients who answered the specific question in the questionnaires; QoL, quality of life.
Mixed model linear regression investigating the effect of time.
Delta scores were calculated from the number of patients who completed the questionnaires at both time points. Higher functioning mean scores (0–100) indicate better QoL. Negative Δ in functioning scales indicate a decline in QoL. Higher symptom scales indicate more symptoms (so worse QoL). Negative Δ in symptom scales indicate improvement in symptoms.
QoL for All Patients Based on Specific Pancreatic Cancer–Related Subscales (QLQ-PAN26)
| Baseline Mean [SD] | 3 Months Mean [SD] | 6 Months Mean [SD] | 9 Months Mean [SD] | 12 Months Mean [SD] | P Valuea | Δb 0–3 Months | Δb 0–6 Months | Δb 0–9 Months | Δb 0–12 Months | |
|---|---|---|---|---|---|---|---|---|---|---|
| Pancreatic pain | 35.6 [24.0] n=138 |
20.9 [20.5] n=111 |
25.2 [22.2] n=95 |
25.1 [20.9] n=79 |
23.8 [18.8] n=64 |
.02 | −14.5 n=94 |
−11.0 n=75 |
−4.8 n=62 |
−5.4 n=49 |
| Eating-related items | 35.9 [30.7] n=138 |
29.1 [28.4] n=111 |
27.2 [26.1] n=95 |
25.9 [27.1] n=79 |
30.2 [31.8] n=64 |
.16 | −5.5 n=94 |
−5.6 n=75 |
−5.6 n=62 |
−2.4 n=49 |
| Ascites | 32.6 [28.9] n=137 |
24.6 [27.2] n=111 |
28.8 [30.6] n=95 |
29.1 [29.4] n=79 |
31.3 [27.1] n=64 |
.46 | −8.2 n=93 |
−1.8 n=74 |
4.3 n=62 |
7.5 n=49 |
| Burden of treatment | 34.2 [25.9] n=138 |
38.6 [21.6] n=111 |
37.1 [19.7] n=95 |
31.7 [24.3] n=79 |
27.9 [23.0] n=64 |
.21 | 5.8 n=94 |
5.1 n=75 |
3.1 n=62 |
0.5 n=49 |
| Indigestion | 34.6 [29.5] n=137 |
29.1 [28.6] n=110 |
30.2 [29.6] n=95 |
33.8 [30.4] n=79 |
34.4 [31.9] n=64 |
.66c | −3.3 n=92 |
0.0 n=75 |
8.1 n=62 |
9.5 n=49 |
| Flatulence | 38.4 [29.3] n=138 |
39.0 [27.7] n=111 |
44.7 [29.6] n=94 |
44.7 [29.7] n=79 |
49.5 [24.5] n=64 |
<.001 | −0.4 n=97 |
3.1 n=78 |
7.5 n=63 |
10.2 n=51 |
| Cachexia | 33.5 [25.2] n=138 |
29.3 [22.6] n=111 |
28.6 [24.8] n=95 |
23.2 [23.2] n=79 |
23.7 [22.9] n=64 |
.03 | −1.8 n=94 |
−0.9 n=75 |
0.5 n=62 |
0.7 n=49 |
| Hepatic symptoms | 16.9 [28.5] n=138 |
8.6 [20.9] n=111 |
3.7 [8.5] n=94 |
5.3 [13.5] n=79 |
4.4 [8.5] n=64 |
<.001 | −9.2 n=94 |
−11.7 n=74 |
−8.3 n=62 |
−10.5 n=49 |
| Altered bowel habits | 32.6 [25.4] n=138 |
31.7 [29.9] n=111 |
36.5 [26.2] n=94 |
44.2 [27.3] n=79 |
37.5 [28.2] n=64 |
<.001 | −3.9 n=94 |
5.2 n=74 |
13.2 n=62 |
11.6 n=49 |
| Body image | 24.9 [27.8] n=139 |
25.9 [25.3] n=111 |
26.1 [26.9] n=94 |
24.9 [25.9] n=79 |
23.2 [24.8] n=64 |
.77 | 1.9 n=95 |
2.7 n=75 |
3.8 n=62 |
5.1 n=49 |
| Fear of future health | 66.7 [28.5] n=139 |
52.1 [30.1] n=110 |
46.8 [33.6] n=94 |
42.9 [31.5] n=77 |
42.7 [29.9] n=64 |
<.001 | −9.6 n=94 |
−15.1 n=75 |
−11.1 n=60 |
−7.5 n=49 |
| Ability to plan the future | 46.0 [32.9] n=139 |
39.0 [29.4] n=111 |
36.3 [33.6] n=91 |
33.3 [30.7] n=79 |
32.8 [35.7] n=63 |
.03 | −5.3 n=95 |
−5.8 n=75 |
−4.8 n=62 |
−9.7 n=48 |
| Health care satisfaction | 64.6 [29.8] n=138 |
59.3 [29.4] n=111 |
53.2 [29.9] n=93 |
54.1 [32.2] n=77 |
52.9 [32.3] n=63 |
.001 | −5.4 n=95 |
−17.1 n=74 |
−16.1 n=60 |
−13.9 n=48 |
| Sexuality | 42.9 [36.8] n=130 |
53.5 [33.5] n=99 |
50.0 [37.8] n=83 |
50.2 [37.4] n=70 |
54.8 [38.5] n=56 |
.07 | 13.8 n=81 |
12.0 n=64 |
4.8 n=52 |
8.3 n=42 |
Bold numbers indicate statistically significant or clinically relevant difference (Δ ≥10).
Abbreviations: n, number of patients who answered the specific question in the questionnaires; QLQ-PAN26, EORTC Quality of Life Questionnaire Pancreatic Cancer Module; QoL, quality of life.
Mixed model linear regression investigating the effect of time.
Δ scores were calculated from the number of patients who completed the questionnaires at both time points. Higher values (0–100) indicate more of the mentioned subscale. Negative Δ in symptom scales indicate decline in subscale.
Measurement at 12 months was not taken into account due to model not reaching convergence.
Comparison With the General Population
The mean GHS at baseline in this cohort was 62.9 (SD, 20.1), compared with 78.6 (SD, 19.5) in the general Dutch population, indicating a clinically relevant difference (Δ −15.7; Table 4). The largest differences compared with the general Dutch population were observed in role functioning (Δ −25.2) and symptoms of fatigue (Δ +24.1), nausea and vomiting (Δ +24.3), appetite loss (Δ +39.0), and constipation (Δ +28.3), all of which were worse in the study cohort.
LAPC QoL Cohort at Baseline Compared With the General Dutch Population
| QoL Cohort (n=170) Mean [SD]a | General Dutch Population (n=200)b Mean [SD]40 | Δ Scorec | |
|---|---|---|---|
| Global health status | 62.9 [20.1] | 78.6 [19.5] | −15.7 |
| Functional scales | |||
| Physical functioning | 74.9 [12.7] | 87.0 [16.7] | −12.1 |
| Role functioning | 61.5 [31.4] | 86.7 [22.6] | −25.2 |
| Emotional functioning | 74.1 [21.6] | 87.3 [17.0] | −13.2 |
| Cognitive functioning | 83.9 [20.5] | 91.3 [13.4] | −7.4 |
| Social functioning | 72.3 [26.2] | 92.2 [16.8] | −19.9 |
| Symptom scales | |||
| Fatigue | 44.2 [26.8] | 20.1 [22.8] | +24.1 |
| Nausea and vomiting | 26.8 [32.3] | 2.5 [9.7] | +24.3 |
| Pain | 32.5 [26.4] | 20.7 [24.7] | +11.8 |
| Dyspnea | 11.4 [19.1] | 13.2 [23.9] | −1.8 |
| Insomnia | 33.3 [31.8] | 22.2 [25.8] | +11.1 |
| Appetite loss | 43.8 [35.4] | 4.8 [14.4] | +39.0 |
| Constipation | 33.3 [26.9] | 5.0 [13.7] | +28.3 |
| Diarrhea | 20.9 [26.8] | 6.3 [17.2] | +14.6 |
| Financial difficulties | 11.0 [24.0] | 4.7 [16.1] | +6.3 |
Bold numbers indicate a clinically relevant difference (Δ ≥10).
Abbreviations: LAPC, locally advanced pancreatic cancer; QoL, quality of life.
Based on baseline value, mean age of 65 years, and 49% female.
Based on general Dutch population stratified by age category 60–69 years (50% female).
Lower scores/negative Δ on the global health status and functional scales indicate worse QoL. Higher scores/positive Δ on the symptom scales indicate more complaints.
Discussion
This is the first prospective multicenter study to evaluate QoL over time among newly diagnosed patients with LAPC undergoing different treatment strategies. In the overall cohort of 170 patients, general QoL was reduced at baseline compared with the general Dutch population and remained stable during the first year after diagnosis, during which 89% of patients received tumor-directed treatment(s). One-third of the QoL subscales showed both statistically significant and clinically relevant changes over time. Appetite loss, pancreatic pain, and hepatic symptoms improved, whereas patients reported increases in diarrhea, flatulence, altered bowel habits, and financial difficulties. Over time, patients experienced reduced fear of future health, but health care satisfaction declined.
Previous studies have investigated QoL in selected patients with LAPC receiving tumor-directed treatment. The SCALOP trial randomized 114 patients with stable disease after 12 weeks of induction gemcitabine + capecitabine to continue this therapy followed by either capecitabine- or gemcitabine-based chemoradiotherapy.28 During chemotherapy, improvements were observed in pancreatic pain, appetite loss, cachexia, and future health perspective.28 These findings align with our results, given that we also observed statistically significant and clinically relevant improvements in these symptoms (except for cachexia) during the first months after chemotherapy. Additionally, in the SCALOP trial, several scores, including fatigue, appetite loss, and gastrointestinal symptoms, worsened during subsequent chemoradiation but recovered within 3 weeks after treatment ended.28 Interestingly, in our study, appetite loss improved in all patients, although several gastrointestinal symptoms, such as diarrhea, flatulence, and altered bowel habits, worsened at 9 and 12 months after diagnosis. This may be related to the postoperative phase after surgery, given that most patients underwent resection at 6 months, or to disease progression or recurrence, during which patients were not receiving treatment anymore.
In advanced disease, the PRODIGE 4/ACCORD 11 trial, which randomized patients with metastatic pancreatic cancer to FOLFIRINOX or gemcitabine, provided a unique perspective on the impact of FOLFIRINOX on QoL over time.20 The trial reported an improvement in QoL due to reductions in pain, constipation, and anorexia—findings that align with our study. However, a significant increase of diarrhea was observed in PRODIGE 4/ACCORD 11, but only during the first 2 months of FOLFIRINOX treatment.20 In our study, a significant increase in diarrhea was also observed over time, with a clinically relevant difference observed at 9 months compared with baseline.
In our study, GHS was worse at baseline compared with the general population and remained stable over time. In contrast, a previous Dutch single-center study evaluated QoL among 41 fit patients with nonprogressive disease after at least 4 courses of (m)FOLFIRINOX, finding that GHS was surprisingly better compared with other patients with cancer and the general Dutch population.29 This illustrates that good QoL can be achieved in selected patients with LAPC who have stable disease/response after palliative/induction chemotherapy. Nevertheless, there remains a need to assess QoL in a nonselective group of patients with LAPC.
The nonrandomized LAPACT study evaluated the safety and efficacy of gemcitabine + nab-paclitaxel in 107 previously untreated patients with LAPC.25 In the LAPACT trial, GHS did not change over time (ie, from baseline to the sixth course of gemcitabine + nab paclitaxel), which aligns with the findings of the present study.25 Furthermore, in a study of patients with metastatic pancreatic cancer who started with first-line chemotherapy (mostly gemcitabine + nab-paclitaxel or [m]FOLFIRINOX), GHS improved over time, particularly in patients with ECOG PS 2 compared with those with ECOG PS 0–1.44 Even when considering the dropout rate due to disease progression or toxicity, the data suggest that these treatments may offer a (temporary) preservation/improvement of QoL, alongside the potential for prolonged OS.
These studies, including the present one, appear unable to fully capture the decline in QoL that undeniably occurs in patients approaching the end of their palliative trajectory. The reason is that it is clearly not possible to obtain a stable response rate over time for patients completing the QoL questionnaires during follow-up, given disease progression. In the 2 previous prospective studies, the response rate for patients completing the questionnaires also gradually decreased over time.25,28 In the SCALOP trial, 69 (93%) patients completed the questionnaire at baseline, but this number decreased to 51 (71%) at 39 weeks of follow-up.28 In the LAPACT trial, 42% of 99 patients who completed the survey at baseline also filled out the questionnaire at restaging.25 This attrition could be caused by disease progression. This trend was also observed in the present study, particularly in the group of patients who received chemotherapy or BSC only. Consequently, this may introduce bias, because it is likely that only the “more fit” patients (those with treatment options) would undertake the task of completing these QoL questionnaires during follow-up. Therefore, there is a potential risk of QoL being overestimated in such study populations. Some studies, such as the PRODIGE trial,6 achieved higher completion rates (78% in PRODIGE vs 62% in our study). This difference in completion rate could also be explained by the fact that the selected group of patients in the PRODIGE trial were intensively followed throughout a certain time period and asked to complete the questionnaire. Furthermore, the present study reflects a real-world cohort comprising a large nonselective group of patients (n=865), in which follow-up is more difficult.
Life expectancy for patients with LAPC remains limited.34 Furthermore, approximately one-third of patients experience early recurrence within 6 months after surgery.19 Given that short-term morbidity11–13 and long-term sequelae such as postdivestment diarrhea and metabolic insufficiencies14–18 can negatively influence QoL, it is important to understand how the benefits (or lack thereof) of resection influence QoL. In the present study, GHS appeared to remain stable among patients who underwent induction chemotherapy followed by resection. However, this could not be confirmed statistically due to the small sample size in this subgroup, but only in the cohort of all patients who received tumor-directed treatment. Nevertheless, it seems that the impact of surgery on QoL is acceptable. This finding aligns with a systematic review on the impact of pancreatoduodenectomy on QoL among patients with localized pancreatic cancer (17 studies, 1,240 patients). This review demonstrated that physical and social functioning, as well as pain, fatigue, and diarrhea scores, worsened within the first 3 months after surgery but recovered after 3 to 6 months.45 Additionally, a prospective single-center study including 137 patients with pancreatic/periampullary malignancy showed that major morbidity did not influence QoL within the first year postoperatively.46 Even after total pancreatectomy, which might be needed for LAPC in cases of concomitant arterial resection,47 patients were able to adapt to the metabolic insufficiencies, resulting in a reduction in QoL comparable to the preoperative situation.48
The findings of this study may provide valuable insights for patient counseling and shared decision-making. First, understanding how different treatment strategies can both negatively and positively influence QoL is important, because it can help inform patients about the potential consequences of proposed treatments. This knowledge can also facilitate discussions between patients and caregivers regarding treatment decisions. However, this information would need to be translated into informative textual and visual tools to make it more accessible to patients and their families.49 This approach has previously shown positive results in the SOURCE trial, which included patients with upper gastrointestinal cancers.50 Currently, a similar approach is being used for patients with LAPC in the ongoing Dutch nationwide PREOPANC-4 trial (ClinicalTrials.gov identifier: NCT05524090). Second, and most importantly, this study found that health care satisfaction decreased over time, suggesting that ongoing support from health care professionals could be improved. Additionally, symptoms such as diarrhea, flatulence, and altered bowel habits should addressed by the treating physician when deterioration is observed because they could impair QoL. Given that most of these symptoms are also indicative of exocrine pancreatic insufficiency (EPI), (adequate) use of pancreatic enzyme replacement therapy is essential. Unfortunately, it is widely known that EPI is currently undertreated.51 These symptoms warrant greater attention. The use of a multidisciplinary approach, including consultations with a dietician/diabetes nurse, remains crucial for managing symptoms (during therapy) in patients with pancreatic cancer.51–53
Several limitations in this study need to be addressed. First, the results must be interpreted with caution, because only a subset of the newly diagnosed patients (with a treatment perspective) completed the questionnaires. Additionally, as previously mentioned, patients who experienced deterioration dur to disease progression and/or treatment-related toxicity likely dropped out, leading to an overestimation of QoL. However, there is still a lack of standardization and no consensus on how to analyze QoL data with informative dropouts. Proposed solutions, such as pattern-mixture models, may yield different results for the same data fit. Furthermore, it is difficult to specify these models with a limited number of patients.54 Second, the number of patients who received chemotherapy with or without resection and BSC only was too small to allow for separate statistical comparisons of QoL outcomes over time among the 3 groups. Nevertheless, the impact of tumor-directed treatment on GHS was evaluated and did not show a statistically significant or clinically relevant change over time. Third, because there was a delay in sending and completing the questionnaires, some patients began induction chemotherapy before completing their baseline questionnaire, and the timing of completing the questionnaires relative to surgery also varied greatly. In future studies, alongside the questionnaires, other methodologies, such as activity monitoring (eg, sleep, steps, heart rate, body weight), should be incorporated to quantify QoL more objectively and gain further insight into (early) deterioration/improvement of QoL. Fourth, no data were available on treatment-related adverse events or local disease control/asymptomatic metastases. This represents an interesting topic for future consideration, to correlate these outcomes to QoL. Nevertheless, this study is the first to prospectively investigate QoL over time in a nonselected group of patients with LAPC. As this is a multicenter study that includes nonselective newly diagnosed patients, the outcomes reflect daily clinical practice.
Conclusions
This multicenter study, which evaluated QoL over time for different treatment strategies among newly diagnosed patients with LAPC, found that general QoL remained stable during the first year for most patients, 89% of whom received tumor-directed treatment(s). Some symptoms worsened over time and deserve more attention. These findings may support patient counseling, shared decision-making, and optimization of symptom management in the treatment of LAPC.
References
- 2.↑
Stoop TF, Theijse RT, Seelen LWF, et al. Preoperative chemotherapy, radiotherapy, and surgical decision-making in patients with borderline resectable and locally advanced pancreatic cancer. Nat Rev Gastroenterol Hepatol 2024;21:101–124.
- 3.↑
Eshmuminov D, Aminjonov B, Palm RF, et al. FOLFIRINOX or gemcitabine-based chemotherapy for borderline resectable and locally advanced pancreatic cancer: a multi-institutional, patient-level, meta-analysis and systematic review. Ann Surg Oncol 2023;30:4417–4428.
- 4.↑
Janssen QP, van Dam JL, Doppenberg D, et al. FOLFIRINOX as initial treatment for localized pancreatic adenocarcinoma. J Natl Cancer Inst 2022;114:695–703.
- 5.↑
Brown ZJ, Heh V, Labiner HE, et al. Surgical resection rates after neoadjuvant therapy for localized pancreatic ductal adenocarcinoma: meta-analysis. Br J Surg 2022;110:34–42.
- 6.↑
Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817–1825.
- 7.↑
Suker M, Beumer BR, Sadot E, et al. FOLFIRINOX for locally advanced pancreatic cancer. Lancet Oncol 2016;17:801–810.
- 8.↑
Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med 2018;379:2395–2406.
- 9.↑
Janssen QP, Buettner S, Suker M, et al. Neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer. J Natl Cancer Inst 2019;111:782–794.
- 10.↑
Fong ZV, Verdugo FL, Fernandez-Del Castillo C, et al. Tolerability, attrition rates, and survival outcomes of neoadjuvant FOLFIRINOX for non-metastatic pancreatic adenocarcinoma: intent-to-treat analysis. J Am Coll Surg 2023;236:1126–1136.
- 11.↑
Hartwig W, Gluth A, Hinz U, et al. Outcomes after extended pancreatectomy in patients with borderline resectable and locally advanced pancreatic cancer. Br J Surg 2016;103:1683–1694.
- 12.↑
Groen JV, Michiels N, van Roessel S, et al. Venous wedge and segment resection during pancreatoduodenectomy for pancreatic cancer: impact on short- and long-term outcomes in a nationwide cohort analysis. Br J Surg 2021;109:96–104.
- 13.↑
Rebelo A, Büdeyri I, Heckler M, et al. Systematic review and meta-analysis of contemporary pancreas surgery with arterial resection. Langenbecks Arch Surg 2020;405:903–919.
- 14.↑
Kuroki N, Ono Y, Sato T, et al. Long-term outcome of patients with postoperative refractory diarrhea after tailored nerve plexus dissection around the major visceral arteries during pancreatoduodenectomy for pancreatic cancer. World J Surg 2022;46:1172–1182.
- 15.↑
Scholten L, Mungroop TH, Haijtink SAL, et al. New-onset diabetes after pancreatoduodenectomy. Surgery 2018;164:6–16.
- 16.↑
Moore JV, Tom S, Scoggins CR, et al. Exocrine pancreatic insufficiency after pancreatectomy for malignancy: systematic review and optimal management recommendations. J Gastrointest Surg 2021;25:2317–2327.
- 17.↑
Yu J, Sun R, Han X, Liu Z. New-onset diabetes mellitus after distal pancreatectomy. J Laparoendosc Adv Surg Tech A 2020;30:1215–1222.
- 18.↑
Scholten L, Stoop TF, Del Chiaro M, et al. Systematic review of functional outcome and quality of life after total pancreatectomy. Br J Surg 2019;106:1735–1746.
- 19.↑
Seelen LWF, van Oosten AF, Brada LJH, et al. Early recurrence after resection of locally advanced pancreatic cancer following induction therapy. Ann Surg 2023;278:118–126.
- 20.↑
Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, et al. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer. J Clin Oncol 2013;31:23–29.
- 21.↑
Mackay TM, Latenstein AEJ, Sprangers MAG, et al. Relationship between quality of life and survival in patients with pancreatic and periampullary cancer. J Natl Compr Canc Netw 2020;18:1354–1363.
- 22.↑
Mackay TM, Dijksterhuis WPM, Latenstein AEJ, et al. The impact of cancer treatment on quality of life in patients with pancreatic and periampullary cancer. HPB (Oxford) 2022;24:443–451.
- 23.↑
Balaban EP, Mangu PB, Khorana AA, et al. Locally advanced, unresectable pancreatic cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2016;34:2654–2668.
- 24.↑
Loehrer PJ, Feng Y, Cardenes H, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol 2011;29:4105–4112.
- 25.↑
Philip PA, Lacy J, Portales F, et al. Nab-paclitaxel plus gemcitabine in patients with locally advanced pancreatic cancer (LAPACT): a multicentre, open-lab phase 2 study. Lancet Gastroenterol Hepatol 2020;5:285–294.
- 26.↑
Witvliet-van Nierop JE, Lochtenberg-Potjes CM, Wierdsma NJ, et al. Assessment of nutritional status, digestion and absorption, and quality of life in patients with locally advanced pancreatic cancer. Gastroenterol Res Pract 2017;2017:6193765.
- 27.↑
Hill CS, Rosati L, Wang H, et al. Multiagent chemotherapy and stereotactic body radiation therapy in patients with unresectable pancreatic adenocarcinoma. Pract Radiat Oncol 2022;12:511–523.
- 28.↑
Hurt CN, Mukherjee S, Bridgewater J, et al. Health-related quality of life in SCALOP, a randomized phase 2 trial comparing chemoradiation therapy regimens in locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2015;93:810–818.
- 29.↑
van der Sijde F, Schafthuizen L, van ’t Land FR, et al. Quality of life of locally advanced pancreatic cancer patients after FOLFIRINOX treatment. Support Care Cancer 2022;30:2407–2415.
- 30.↑
Field W, Rostas JW, Martin RCG. Quality of life assessment for patients undergoing irreversible electroporation (IRE) for treatment of locally advanced pancreatic cancer (LAPC). Am J Surg 2019;218:571–578.
- 31.↑
Rao AD, Sugar EA, Chang DT, et al. Patient-reported outcomes of a multicenter phase 2 study investigating gemcitabine and stereotactic body radiation therapy in locally advanced pancreatic cancer. Pract Radiat Oncol 2016;6:417–424.
- 32.↑
Vornhulz M, Anton S, Eross B, et al. Role of stereotactic body radiation in the enhancement of the quality of life in locally advanced pancreatic adenocarcinoma. Radiat Oncol 2022;17:108.
- 33.↑
Coebergh van den Braak RRJ, van Rijssen LB, van Kleef JJ, et al. Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative. Acta Oncol 2018;57:195–202.
- 34.↑
Walma MS, Brada LJ, Patuleia SIS, et al. Treatment strategies and clinical outcomes in consecutive patients with locally advanced pancreatic cancer: a multicenter prospective cohort. Eur J Surg Oncol 2021;47:699–707.
- 35.↑
Strijker M, Mackay TM, Bonsing BA, et al. Establishing and coordinating a nationwide multidisciplinary study group: lessons learned by the Dutch Pancreatic Cancer Group. Ann Surg 2020;271:e102–104.
- 36.↑
von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. J Clin Epidemiol 2008;61:344–349.
- 37.↑
Dutch Pancreatic Cancer Group. DPCG-definities resectabiliteit pancreascarcinoom. Accessed November 20, 2022. Available at: https://dpcg.nl/wp-content/uploads/2020/04/Criteria_resectabiliteit.pdf
- 38.↑
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365–376.
- 39.↑
Fitzsimmons D, Johnson CD, George S, et al. Development of a disease specific quality of life (QoL) questionnaire module to supplement the EORTC core cancer QoL questionnaire, the QLQ-C30 in patients with pancreatic cancer. Eur J Cancer 1999;35:939–941.
- 40.↑
de Ligt KM, Aaronson NK, Liegl G, et al. Updated normative data for the EORTC QLQ-C30 in the general Dutch population by age and sex: a cross-sectional panel research study. Qual Life Res 2023;32:2477–2487.
- 41.↑
Campbell F, Foulis A, Verbeke C. Dataset for the histopathological reporting of carcinomas of the pancreas, ampulla of Vater and common bile duct. The Royal College of Pathologists; 2010.
- 42.↑
Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg 2009;250:187–196.
- 43.↑
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol 1998;16:139–144.
- 44.↑
Laquente B, Macarulla T, Buges C, et al. Quality of life of patients with metastatic pancreatic adenocarcinoma initiating first-line chemotherapy in routine practice. BMC Palliat Care 2020;19:103.
- 45.↑
van Dijk SM, Heerkens HD, Tseng DSJ, et al. Systematic review on the impact of pancreatoduodenectomy on quality of life in patients with pancreatic cancer. HPB (Oxford) 2018;20:204–215.
- 46.↑
Heerkens HD, van Berkel L, Tseng DSJ, et al. Long-term health-related quality of life after pancreatic resection for malignancy in patients with and without severe postoperative complications. HPB (Oxford) 2018;20:188–195.
- 47.↑
Del Chiaro M, Rangelova E, Segersvärd R, Arnelo U. Are there still indications for total pancreatectomy? Updates Surg 2016;68:257–263.
- 48.↑
Stoop TF, Ateeb Z, Ghorbani P, et al. Impact of endocrine and exocrine insufficiency on quality of life after total pancreatectomy. Ann Surg Oncol 2020;27:587–596.
- 49.↑
Griffioen IPM, Rietjens JAC, Melles M, et al. The bigger picture of shared decision making: a service design perspective using the care path of locally advanced pancreatic cancer as a case. Cancer Med 2021;10:5907–5916.
- 50.↑
van de Water LF, van den Boorn HG, Hoxha F, et al. Informing patients with esophagogastric cancer about treatment outcomes by using a web-based tool and training: development and evaluation study. J Med Internet Res 2021;23:e27824.
- 51.↑
Gilliland TM, Villafane-Ferriol N, Shah KP, et al. Nutritional and metabolic derangements in pancreatic cancer and pancreatic resection. Nutrients 2017;9:243.
- 52.↑
Poulia KA, Antoniadou D, Sarantis P, Karamouzis MV. Pancreatic cancer prognosis, malnutrition risk, and quality of life. Nutrients 2022;14:442.
- 53.↑
Iglesia D, Avci B, Kiriukova M, et al. Pancreatic exocrine insufficiency and pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer. United European Gastroenterol J 2020;8:1115–1125.
- 54.↑
Demirtas H, Schafer JL. On the performance of random-coefficient pattern-mixture models for non-ignorable drop-out. Stat Med 2003;22:2553–2575.
