Background
Patient-reported outcome measures (PROMs) are used increasingly in clinical practice to assess patients’ quality of life (QoL). Addressing QoL is important for patients with a short life expectancy, such as those with pancreatic and periampullary carcinoma, which has a median overall survival of 4 to 6 months.1 Different types of treatment that may improve survival in patients with pancreatic cancer may also impact QoL. Pancreatic resection has been found to be associated with a temporary deterioration in QoL, which usually returns to baseline values after 3 to 6 months.2,3 Moreover, chemotherapy has been found to improve QoL in randomized studies in the adjuvant and palliative setting.4,5
QoL may also be used to predict survival. Previous studies with other types of cancer (eg, breast, lung, esophageal, liver) consistently found a correlation between QoL and survival.6–11 Previous studies combined patients with different types of cancer, including a limited number (∼6%) of those with pancreatic cancer.9,10 Most of the data were acquired from randomized trials that included patients who were relatively fit. Only 1 case series of 55 patients with advanced pancreatic cancer suggested a prognostic relationship between the physical functioning scale scores of the EORTC Quality of Life Questionnaire-Core 30 (QLQ-C30) and survival.12
In the Netherlands, the Dutch Pancreatic Cancer Project (PACAP) was established in 2013. This is a multicenter cohort of patients with pancreatic and periampullary carcinoma for whom clinical data and PROMs are collected.13 We used this cohort to investigate the relationship between QoL and survival in daily clinical practice. The aim of this study was to examine which domains of QoL are predictive of survival in patients with pancreatic and periampullary cancer.
Methods
Study Design
This is a post hoc analysis of a prospective multicenter cohort of PROMs in patients with pancreatic and periampullary cancer. Currently, 48 centers in the Netherlands participate in the PACAP PROMs. Clinical data were included from the nationwide population-based Netherlands Cancer Registry (NCR). Both registries are incorporated within PACAP.13 Patients provided written informed consent for participation and linkage of their data between the registries. This study was designed in accordance with the STROBE guidelines.14
Study Population
Adult patients (aged ≥18 years) diagnosed with pancreatic and periampullary cancer in January 2015 through February 2018 who were registered in the NCR and participated in PACAP PROMs were included. Patients were excluded if they completed the baseline questionnaire after start of cancer treatment (n=143 of the total cohort).
Data Collection
The NCR data include patient, tumor, and treatment characteristics, such as date of diagnosis, age at diagnosis, sex, body mass index, comorbidities, ECOG performance status, pathologic diagnosis, tumor location, tumor stage (according to AJCC, 7th edition), tumor size, tumor differentiation grade, date of initial treatment, type of pancreatic resection, margin status (microscopically radical [R0] and irradical resection [R1]), (neo)adjuvant/palliative chemo(radio)therapy, biliary drainage, and survival data.15 PROMs at baseline and 3-month follow-up were used. Baseline measurement was defined as a measurement between the date of diagnosis and the start of first cancer treatment (eg, chemo[radio]therapy, resection, or local ablative therapy). Overall survival was defined as time between date of diagnosis and date of death.
QoL Assessment
The QoL data include data derived from the Happiness,16 EORTC QoL Questionnaire-Core 30 (QLQ-C30),17 and EORTC QLQ-PAN2618 questionnaires.19,20 The Happiness questionnaire consists of 4 items, including satisfaction with one’s life as a whole, happiness today, happiness during the last month, and the level at which one feels they currently stand on a scale from worst to best possible life. All items use a scale of 0 (worst) to 10 (best).16
The cancer-specific EORTC QLQ-C30 questionnaire encompasses global health status, 5 functioning scales (ie, physical, role, emotional, cognitive, and social functioning) and 8 symptom scales/items (ie, fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea), and financial difficulties. The pancreatic-specific EORTC QLQ-PAN26 questionnaire includes 9 disease- and treatment-related symptoms (pain, eating-related items, cachexia, hepatic symptoms, side effects, altered bowel habit, ascites, indigestion, and flatulence) and 5 emotional domains specific to pancreatic cancer (body image, healthcare satisfaction, sexuality, fear of future health, and ability to plan future). The items of the EORTC questionnaires use 4 response categories, which after linear transformation, form a scale ranging from 0 to 100. A higher score on the functional and global scales indicate better QoL, whereas for problems and symptoms, higher scores indicate poorer QoL. In addition, a summary score was obtained from the EORTC QLQ-C30 questionnaire21 based on the mean of all scale and item scores with the exclusion of global QoL and financial impact, and after reversing the scores of the symptom scales.
The relationship between baseline and delta QoL (between baseline and 3-month follow-up) and survival was assessed using the scales/items from the 3 questionnaires. Secondary analyses addressed the relationship between QoL and survival for patients undergoing pancreatic resection and those not undergoing pancreatic resection (with or without metastases).
Statistical Analysis
Descriptive statistics were used to analyze baseline, tumor, and treatment characteristics and QoL scores. These data were reported as proportions for binary or categorical variables, and as mean (SD) or as median with interquartile range (IQR) for continuous variables as appropriate. Missing data from clinical variables (0.9%–13.7%) were imputed by multiple imputation using predictive mean matching in which 20 dummy sets were created. Primary and secondary analyses were performed with baseline and delta QoL (3-month follow-up minus baseline) scores. Survival analyses were performed using Cox regression models. QoL variables with P<.20 in univariable analysis were selected for inclusion in multivariable analysis with backward stepwise selection and reported as hazard ratios (HRs) with corresponding 95% confidence intervals. Analyses were adjusted for patient, tumor, and treatment characteristics and other known predictors for survival. Delta analyses were additionally adjusted for baseline scores. The covariates are presented in the footnotes of the tables. The prognostic value of baseline QoL predictors was assessed using Nagelkerke R2 (ie, explained variance) in univariable analysis, multivariable analysis with adjustment for clinical variables (ie, sex, age, body mass index, ECOG performance status, tumor topography, tumor stage, and type of chemotherapy), and multivariable analysis with adjustment clinical variables and other predictive QoL items from the same questionnaire. An increase in explained variance in analyses with adjustment for clinical variables of 5% was considered clinically relevant. These analyses were performed according to the previously described method for estimation of R2 after multiple imputation.22 The survival analyses were repeated for the resected and nonresected subgroups. Two-sided P<.05 were considered statistically significant after adjustment for multiple testing using the Benjamini-Hochberg procedure.
Results
Population
For baseline analyses, 376 patients were included. After exclusion of 143 patient who completed the baseline questionnaire after treatment initiation, 233 patients remained. Similarly, for delta analyses, 256 patients were included, and after exclusion of 108 patients, 148 patients remained. Overall response rate to the questionnaires during the study period was 60%. Most patients were diagnosed with pancreatic adenocarcinoma (n=194; 83.3%) and had stage III (n=77; 33.0%) or IV (n=61; 26.2%) disease. Overall, 141 patients (60.5%) received chemotherapy. Of all patients, 103 (44.2%) underwent a pancreatic resection and 130 (55.8%) did not. During the study period, 159 patients (68.2%) of the cohort died. Median follow-up of patients was 13.1 months (IQR 7.4–17.5). Median overall survival was 13.6 months (95% CI, 11.6–15.6) for the total cohort, 20.7 months (95% CI, 14.9–26.5) for patients after resection, and 9.3 months (95% CI, 7.7–11.2) for patients without resection. Table 1 provides an overview of patient, tumor, and treatment characteristics. Most QoL scores changed over time; Table 2 provides QoL scores for all items and Figure 1 presents a radar chart of the EORTC QLQ-C30 and QLQ-PAN26 scores.
Patient Characteristics
Median Quality of Life Scores
Baseline and 3-month QoL scores for the total cohort based on the (A, B) EORTC QLQ-C30 ([A] summary and functioning scoresa; [B] symptom scoresb) and (C) EORTC-PAN26 (symptom scoresb) questionnaire items.
Abbreviations: QLQ-C30, Quality of Life Questionnaire-Core 30; QLQ-PAN26, Quality of Life Questionnaire, pancreatic cancer module 26; QoL, quality of life.
aHigher scores represent better QoL.
bHigher scores represent worse QoL.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 10; 10.6004/jnccn.2020.7579
Baseline and 3-month QoL scores for the total cohort based on the (A, B) EORTC QLQ-C30 ([A] summary and functioning scoresa; [B] symptom scoresb) and (C) EORTC-PAN26 (symptom scoresb) questionnaire items.
Abbreviations: QLQ-C30, Quality of Life Questionnaire-Core 30; QLQ-PAN26, Quality of Life Questionnaire, pancreatic cancer module 26; QoL, quality of life.
aHigher scores represent better QoL.
bHigher scores represent worse QoL.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 10; 10.6004/jnccn.2020.7579
Baseline and 3-month QoL scores for the total cohort based on the (A, B) EORTC QLQ-C30 ([A] summary and functioning scoresa; [B] symptom scoresb) and (C) EORTC-PAN26 (symptom scoresb) questionnaire items.
Abbreviations: QLQ-C30, Quality of Life Questionnaire-Core 30; QLQ-PAN26, Quality of Life Questionnaire, pancreatic cancer module 26; QoL, quality of life.
aHigher scores represent better QoL.
bHigher scores represent worse QoL.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 10; 10.6004/jnccn.2020.7579
Baseline QoL and Survival
For the total cohort, independent baseline QoL predictors based on multivariable analyses for reduced survival were overall happiness today (HR per step on 0–10 scale, 0.92; 95% CI, 0.84–0.92; P=.035), role functioning (HR per step on 0–100 scale, 0.99; 95% CI, 0.99–1.00; P=.007), diarrhea (HR per step on 0–100 scale, 1.01; 95% CI, 1.00–1.01; P=.018), pancreatic pain (HR per step on 0–100 scale, 1.01; 95% CI, 1.00–1.02; P=.009), and body image (HR per step on 0–100 scale, 1.01; 95% CI, 1.00–1.01; P=.035) (Table 3).
Univariable and Multivariable Analysis of Relationship Between Baseline QoL Scores and Overall Mortality
For patients who had undergone resection, no independent baseline QoL score predicted survival (supplemental eTable 1; available with this article at JNCCN.org).
For patients without resection, lower overall satisfaction with life, lower physical and cognitive functioning, and higher QLQ-C30 summary, fatigue, (pancreatic) pain, constipation, diarrhea, and body image scores were independent predictors for reduced survival in multivariable analysis (Table 4).
Univariable and Multivariable Analysis of Relationship Between Baseline QoL Scores and Overall Mortality of Patients Without Resection
Delta QoL and Survival
For the total cohort in multivariable analysis, the only independent predictor for reduced survival was more constipation at 3 months compared with baseline (HR per step on 0–100 scale, 1.02; 95% CI, 1.01–1.03; P=.006; supplemental eTable 2). For patients with or without resection, no independent delta QoL score predicted survival (supplemental eTables 3 and 4).
The small HRs from baseline and delta multivariable analyses from the EORTC QLQ-C30 and QLQ-PAN26 scales (eg, HR, 1.02) represent the risk of mortality per 1 point change in score on a 0–100 scale (eg, from 66–67). This HR of 1.02 corresponds to a HR of 1.22 per 10 points change in score (eg, from 66–76; HR, 1.02^10=1.22).
Explained Variance Baseline Without Resection
Together, the clinical variables (ie, sex, age, body mass index, ECOG, tumor topography, tumor stage, and type of chemotherapy) in this subgroup model explained 20% of the outcome variance (blue bars, Figure 2). Figure 2 shows what percentage of the outcome is explained additionally by the various independent QoL predictors individually (orange bars). When for example the item physical functioning was added, 32% of variance of the outcome was explained (12% increase by adding this to the model; blue plus orange bar for physical functioning). All baseline QoL items except diarrhea accounted for >5% of the additional explained variance and were therefore considered to be of additional prognostic value. A similar effect was seen after adding the other QoL items from the same questionnaire to the model (gray bars, Figure 2).
Additional prognostic value of independent baseline QoL predictors for overall mortality of patients without resection for pancreatic and periampullary adenocarcinoma expressed as Nagelkerke R2. Blue bars: clinical variables include sex, age, body mass index, ECOG performance status, tumor topography, tumor stage, and type of chemotherapy. Orange bars: additional explained variance of the QoL item. Gray bars: additional explained variance of the other QoL items from the same questionnaire.
Abbreviations: QLQ-C30, Quality of Life Questionnaire-Core 30; QLQ-PAN26, Quality of Life Questionnaire, pancreatic cancer module 26; QoL, quality of life.
aItem one (ie, satisfaction with one’s life as a whole) from the Happiness questionnaire. In gray, not adjusted for other QoL items from the Happiness questionnaire.
bFrom the EORTC QLQ-C30 questionnaire. In gray, adjusted for the other predictive QoL items from the EORTC QLQ-C30 questionnaire (ie, summary score, physical functioning, cognitive functioning, fatigue, pain, constipation, diarrhea).
cFrom the EORTC QLQ-PAN26 questionnaire. In gray, adjusted for the other predictive QoL items from the EORTC QLQ-PAN26 questionnaire (ie, pancreatic pain, body image).
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 10; 10.6004/jnccn.2020.7579
Additional prognostic value of independent baseline QoL predictors for overall mortality of patients without resection for pancreatic and periampullary adenocarcinoma expressed as Nagelkerke R2. Blue bars: clinical variables include sex, age, body mass index, ECOG performance status, tumor topography, tumor stage, and type of chemotherapy. Orange bars: additional explained variance of the QoL item. Gray bars: additional explained variance of the other QoL items from the same questionnaire.
Abbreviations: QLQ-C30, Quality of Life Questionnaire-Core 30; QLQ-PAN26, Quality of Life Questionnaire, pancreatic cancer module 26; QoL, quality of life.
aItem one (ie, satisfaction with one’s life as a whole) from the Happiness questionnaire. In gray, not adjusted for other QoL items from the Happiness questionnaire.
bFrom the EORTC QLQ-C30 questionnaire. In gray, adjusted for the other predictive QoL items from the EORTC QLQ-C30 questionnaire (ie, summary score, physical functioning, cognitive functioning, fatigue, pain, constipation, diarrhea).
cFrom the EORTC QLQ-PAN26 questionnaire. In gray, adjusted for the other predictive QoL items from the EORTC QLQ-PAN26 questionnaire (ie, pancreatic pain, body image).
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 10; 10.6004/jnccn.2020.7579
Additional prognostic value of independent baseline QoL predictors for overall mortality of patients without resection for pancreatic and periampullary adenocarcinoma expressed as Nagelkerke R2. Blue bars: clinical variables include sex, age, body mass index, ECOG performance status, tumor topography, tumor stage, and type of chemotherapy. Orange bars: additional explained variance of the QoL item. Gray bars: additional explained variance of the other QoL items from the same questionnaire.
Abbreviations: QLQ-C30, Quality of Life Questionnaire-Core 30; QLQ-PAN26, Quality of Life Questionnaire, pancreatic cancer module 26; QoL, quality of life.
aItem one (ie, satisfaction with one’s life as a whole) from the Happiness questionnaire. In gray, not adjusted for other QoL items from the Happiness questionnaire.
bFrom the EORTC QLQ-C30 questionnaire. In gray, adjusted for the other predictive QoL items from the EORTC QLQ-C30 questionnaire (ie, summary score, physical functioning, cognitive functioning, fatigue, pain, constipation, diarrhea).
cFrom the EORTC QLQ-PAN26 questionnaire. In gray, adjusted for the other predictive QoL items from the EORTC QLQ-PAN26 questionnaire (ie, pancreatic pain, body image).
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 10; 10.6004/jnccn.2020.7579
Discussion
This multicenter study including patients with pancreatic and periampullary cancer in daily clinical practice showed that several QoL domains measured at baseline and follow-up predict survival, even when adjusting for well-known clinical prognostic parameters such as ECOG performance status.15 Because QoL questionnaires measure patients’ perspective on their functioning and symptoms, they may provide a more sensitive and comprehensive picture of patients’ health status that may be missed by traditional clinical measures (eg, tumor stage or performance status).6,23
We found lower happiness, a worse body image, and a lower summary score to predict reduced survival of patients with pancreatic and periampullary cancer. With the Happiness questionnaire, happiness is measured as life satisfaction, hedonic level of affect, and contentment.16 Taking this into account, the happiness items could cover more QoL aspects than for example the global health status item only, and therefore come forth as predictor, whereas global health status does not. Previous studies found that satisfaction with life among patients with cancer is correlated with clinical (eg, times of admission, surgical treatment, postoperative complications, length of hospital stay), psychosocial (eg, depressive symptoms, stress, social support, self-esteem), and sociodemographic (eg, marital status, occupation) factors.24–26 Several of these factors have been associated with survival, such as postoperative complications, depressive symptoms, and marital status.27–29 This could also be a reason why life satisfaction or happiness is associated with survival in our population. In addition, it was suggested that socioeconomic status (eg, marital status, occupation) of patients with cancer is a survival predictor.23 Unfortunately, because socioeconomic status is not registered accurately in the NCR, we could not investigate this in more detail.
Body image is often negatively influenced in patients with cancer by physical changes caused by the disease or treatment, such as after surgery for breast or colorectal cancer (eg, mastectomy, colostomy).30,31 Specifically for patients with pancreatic and periampullary cancer, body image may be affected by the occurrence of cachexia.32 The incidence of cachexia in patients with pancreatic cancer is high, cachexia-related complications occur often, and cachexia has been associated with reduced survival.33–35 Apart from obstructive jaundice, which often is the presenting symptom among patients with pancreatic and periampullary cancer, other mechanisms leading to cachexia are still not completely clear and evaluation of this multifactorial syndrome is not straightforward.35 For this reason, this easy-to-measure QoL item—body image— could be representative of cachexia, which is an important prognostic factor for patients with cancer, especially in combination with other factors of cachexia (eg, weight loss, anorexia).
The summary score combines 13 of the 15 EORTC QLQ-C30 scales and was among other things developed to reduce the risk of type I errors caused by multiple testing. The score was found to have equal or superior known-groups validity and responsiveness to change over time compared with the separate scales.21 Although many of these individual scales were shown to have predictive value in other cancers,7,23,36,37 this was not yet the case for patients with pancreatic and periampullary cancer, nor for the relatively new summary score. This score uses the information of the individual scales, while maintaining a broad QoL scope. In addition, it is measured with a widely implemented and validated questionnaire. Therefore, through comparison of data from other pancreatic or periampullary cancer populations, it can be investigated whether this item is not only efficient (ie, single vs multiple testing) but also effective for measuring a predictive relation to survival (ie, robust single higher order factor model).21
We found that baseline QoL scores were specifically predictive of survival for the subgroup of patients who did not undergo pancreatic resection. In contrast, baseline scores were not predictors of mortality in the resected subgroup. This might be because of the longer survival times after resection and thus other factors that may come into play in the course time that could also influence survival. In other patient groups, for example patients with colorectal cancer, baseline QoL has been associated with survival after resection.38 However, the disease course in patients with pancreatic cancer is fairly different from that of other cancer types, for instance regarding morbidities, treatment, disease recurrence, and survival. Of the baseline symptoms that we found to be predictive of survival among patients who did not undergo a resection, diarrhea as a symptom deserves special attention. Diarrhea can be treatment-related or a symptom of exocrine pancreatic insufficiency, which occurs in up to 92% in patients with unresectable pancreatic or periampullary tumors within 6 months from diagnosis.39 Unfortunately, often only a small proportion of patients in the palliative setting receive pancreatic enzyme replacement therapy.40 Recent studies have suggested that this therapy may independently improve survival.41 Therefore, this is an important and potentially modifiable risk factor that can be identified through PROMs.
For delta QoL, we found that constipation was predictive of mortality for the total cohort. Some studies, for example those in patients with lung and esophageal cancer, have shown that deterioration of QoL scores was predictive of shorter survival times,37,42 whereas delta scores for patients with head and neck cancer were not related to survival.43 It may be hypothesized that the patients with more constipation were those with progressive disease and more pain, and therefore received more opioids, leading to obstipation. Unfortunately, due to a limited number of events in the subgroups of our dataset, we could not test this hypothesis and could only adjust for a limited number of confounding factors.
Our results have important implications for daily practice and research. In the explained variance analysis (Nagelkerke R2), we found that the QoL items were of additional prognostic value on top of the clinical variables. Given the prognostic value of QoL parameters, these parameters may be used during shared decision-making regarding disease management and treatment in the (outpatient) clinic. Ideally, patients should complete questionnaires before meeting their clinician so that QoL can be discussed during the subsequent appointment. The summary score could easily be used for evaluation of overall QoL, because it is one seemingly valid score compared with the 15 individual scale scores. When specific symptoms are present, such as diarrhea, these could be addressed immediately. Predictive QoL parameters may be added to prediction models for survival,44,45 in addition to patient, tumor, and treatment characteristics, to improve their predictive outcome. Finally, QoL parameters may be considered as a stratification factor in clinical trials and should be included in the core set of mandatory baseline measurements.15,20
Some limitations of our study should be considered. First, median overall survival of our cohort is relatively high compared with other population-based studies.46–48 Although the NCR covers all patients with cancer in the Netherlands, selection bias has probably occurred in the PROMs registry. Almost half of this study population underwent resection, whereas usually this is approximately 20% in the Netherlands.47 Second, almost 60% of patients without surgery received chemotherapy, whereas this is approximately 30% in an unselected subgroup.47 Presumably, fit patients are more willing to participate in QoL questionnaire studies, or clinicians are more likely to include fit patients. Third, approximately 40% of patients were excluded because baseline questionnaires were not completed before treatment initiation. Fourth, although the association model remained stable, due to limitations in the sample size, multiple testing and some statistical uncertainty were introduced. To reduce this, the Benjamini-Hochberg procedure was used. Fifth, adjustment for chemotherapy duration or change of treatment was not feasible in delta subgroup analyses, because the number of patients and nonevents (ie, nondeath) decreased in the subgroups compared with the total cohort. Future studies with a larger sample size are needed to investigate this newly found relationship between QoL and survival more clearly.
Conclusions
In daily clinical practice for patients with pancreatic and periampullary carcinoma, QoL is related to survival regardless of patient, tumor, and treatment characteristics. Overall happiness (Happiness), summary score (EORTC QLQ-C30), and several functioning and symptom scale item scores (EORTC QLQ-C30 and QLQ-PAN26) were predictive of survival. Baseline QoL scores were of prognostic value for patients without resection, whereas delta QoL scores were predictive for the total cohort. Given their additional prognostic value, PROMs may be used for different reasons in the clinical setting (ie, shared decision-making, disease management/treatment, clinical prediction models, or stratification in trials).
Acknowledgments
The authors thank the registration team of the Netherlands Cancer Registry for their dedicated data collection, and Mariska Prins and Joyce Pijpers for the coordination of the Patient Reported Outcome Measure registry.
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