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Please note this is a comparison between Version 1 by Arya Mariam Roy and Version 3 by Lindsay Dong.
Neuroendocrine tumors (NETs) are a group of heterogenous neoplasms arising from the diffuse neuroendocrine system. Several therapies have been added to the treatment landscape that have improved long-term outcomes. Despite therapeutic advancements, the symptom burden of the disease remains high, impacting health-related quality of life (HRQoL).
- health-related quality of life
- neuroendocrine tumor
1. Introduction
Neuroendocrine tumors (NETs) are a group of heterogeneous malignancies that originate from neuroendocrine cells. Most well-differentiated NETs have an indolent course [1][2]. Multiple new treatments have been approved in recent years, primarily based on the evidence of inhibition of tumor growth and delay of disease progression [3][4][5][6][7][8]. Nevertheless, the symptomatic burden of disease remains high. A recent global survey of patients with NETs, conducted in more than 12 countries, demonstrated the considerable impact of NETs on symptoms, work, activities of daily living, and healthcare resource use [9]. NETs are associated with a wide range of symptoms from excess hormone production to tumor burden, which affect quality of life. The most commonly reported symptoms are fatigue, diarrhea, and flushing [1]. Clinical trials for new treatment options generally focus on disease progression and toxicity rather than quality of life. Moreover, treatment decisions are often based on patient comorbidities and the toxicity profile of the drugs, rather than taking patient preference or symptoms into consideration. Decision-making aimed only at improving overall survival with newer drugs may not achieve a desired symptom control goal or quality of life.
Patient-reported outcomes should play a pivotal role in selecting treatment options in NET, as symptoms can be debilitating. In recent years, health-related quality of life (HRQoL) measurements have gained increasing relevance in clinical trials. There are many available validated tools for evaluating HRQoL, but no clear consensus on the optimal tool for use in trials or clinical practice [10].
2. Health-Related Quality of Life (HRQoL) in Neuroendocrine Tumors
Currently approved therapies that are commonly utilized in NET patients include octreotide, lanreotide, everolimus, sunitinib, telotristat, and peptide receptor radionuclide therapy (PRRT) [4][7][11][12][13]. Pivotal randomized phase III trials using these agents evaluated patient quality-of-life while on active treatment or the control arm, utilizing validated HRQoL questionnaires.
1. Introduction
Neuroendocrine tumors (NETs) are a group of heterogeneous malignancies that originate from neuroendocrine cells. Most well-differentiated NETs have an indolent course [1,2]. Multiple new treatments have been approved in recent years, primarily based on the evidence of inhibition of tumor growth and delay of disease progression [3,4,5,6,7,8]. Nevertheless, the symptomatic burden of disease remains high. A recent global survey of patients with NETs, conducted in more than 12 countries, demonstrated the considerable impact of NETs on symptoms, work, activities of daily living, and healthcare resource use [9]. NETs are associated with a wide range of symptoms from excess hormone production to tumor burden, which affect quality of life. The most commonly reported symptoms are fatigue, diarrhea, and flushing [1]. Clinical trials for new treatment options generally focus on disease progression and toxicity rather than quality of life. Moreover, treatment decisions are often based on patient comorbidities and the toxicity profile of the drugs, rather than taking patient preference or symptoms into consideration. Decision-making aimed only at improving overall survival with newer drugs may not achieve a desired symptom control goal or quality of life.
Patient-reported outcomes should play a pivotal role in selecting treatment options in NET, as symptoms can be debilitating. In recent years, health-related quality of life (HRQoL) measurements have gained increasing relevance in clinical trials. There are many available validated tools for evaluating HRQoL, but no clear consensus on the optimal tool for use in trials or clinical practice [10].
2. Health-Related Quality of Life (HRQoL) in Neuroendocrine Tumors
Currently approved therapies that are commonly utilized in NET patients include octreotide, lanreotide, everolimus, sunitinib, telotristat, and peptide receptor radionuclide therapy (PRRT) [4,7,13,65,80]. Pivotal randomized phase III trials using these agents evaluated patient quality-of-life while on active treatment or the control arm, utilizing validated HRQoL questionnaires. The study tools used, and results, are summarized in
Table 1 summarized the health-related quality of life in phase III neuroendocrine tumor patients.
2 and detailed below.
Table 12. Health-related quality of life in phase III neuroendocrine tumor patients.
Health-related quality of life in phase III neuroendocrine tumor studies.
| Clinical Trial | HRQoL Tool Used | Patient Population Studied | HRQoL in Comparison to Control Arm |
|---|
| Octreotide vs. Placebo (PROMID) [11] | Octreotide vs. Placebo (PROMID) [13] | EORTC QLQ-C30 | GI and unknown primary NETs | At 6-month follow up mark, no statistically significant difference from baseline was observed between two arms. |
| Lanreotide vs. Placebo (CLARINET) [4] | EORTC QLQ-C30, EORTC QLQ-GI.NET21 | GI, pancreatic NETs, and unknown primary | No statistically significant difference in the change from baseline to post treatment QoL scores between the two arms. | |
| Everolimus vs. Placebo (RADIANT 4) [13][14] | Everolimus vs. Placebo (RADIANT 4) [17,80] | FACT-G | GI and lung NETs | The median time to definitive deterioration in FACT-G score was similar between both arms with no significant difference between both arms. |
| Sunitinib vs. Placebo [ | ||||
| Carcinoid syndrome with diarrhea | ||||
| Durable responders had QoL improvements in EORTC QLQ-C30 global health status, nausea and vomiting, pain, diarrhea, and EORTC QLQ-GI.NET21 gastrointestinal symptoms than non-durable responders both over the DBPT and OLE period *. |
* Durable response defined as a BM frequency reduction of >/30% from baseline for >/50% of the time Abbreviations: NET = neuroendocrine tumor, GI = gastrointestinal, HRQoL = health-related quality of life, EORTC QLQ-30 = European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire, EORTC QLQ GI.NET21 = NET specific EORTC QoL questionnaire, FACT-G = Functional Assessment of Cancer Therapy-General, PRRT = peptide receptor radionuclide therapy, DBTP = double blind treatment period, OLE = open label extension.
HRQoL is a particularly important consideration for patients with NETs, who can develop both tumor- and hormone-related symptoms during their disease course [9]. The common symptoms affecting the HRQoL of NET patients are listed in
Table 2. Patients with relatively slow-growing tumors may be prescribed local and systemic treatments for prolonged periods lasting a decade or more, and many hope to remain functional throughout their journey. Further, although the incidence of NET in patients 65 years or above is highest, it is also diagnosed in younger adults, whose health goals may be different [2].
3. Patients with relatively slow-growing tumors may be prescribed local and systemic treatments for prolonged periods lasting a decade or more, and many hope to remain functional throughout their journey. Further, although the incidence of NET in patients 65 years or above is highest, it is also diagnosed in younger adults, whose health goals may be different [2].
Table 23.
Common symptoms affecting HRQoL of NET patients.
| Hormone-related symptoms | Diarrhea, flushing, fatigue, loss of appetite, dyspnea, palpitation, loss of weight | |||
| Tumor burden-related symptoms | Abdominal pain, abdominal distension, ascites, jaundice, compression of adjacent organs | |||
| 6 | ||||
| ] | ||||
| [ | ||||
| 15] | Sunitinib vs. Placebo [6,15] | EORTC QLQ-C30 | Pancreatic NETs | Over the first 10 cycles, no differences were observed in the global HRQoL, physical, emotional, cognitive, role, social functioning, or symptom scales except for diarrhea. Statistically significant worsening of diarrhea in the sunitinib arm with a difference of 21.4 points between the two arms was observed. |
| PRRT vs. Octreotide (NETTER 1) [7] | EORTC QLQ-C30, QLQ-GI.NET21 | Midgut NETs | Time to QoL deterioration was statistically longer in the PRRT arm for multiple domains including global health, role functioning, physical functioning, disease-related worries, body image, diarrhea, pain and fatigue. | |
| Telotristat vs. Placebo (TELESTAR) [3][16] | Telotristat vs. Placebo (TELESTAR) [3,81] | EORTC QLQ-C30 EORTC QLQ-GI.NET21 |
HRQoL studies assessing locoregional modalities of surgery or interventional radiology (IR) procedures are limited by size, absence of a formal HRQoL analysis, and/or lack of prospective analysis. Therefore, a definitive impact of these procedures in the HRQoL of NET patients is largely unknown. There are multiple studies on the effect of surgeries and IR techniques for treating hepatic metastasis such as embolization, radiofrequency ablation, and cryoablation in patients with NET [17][18][19][20][21][25,26,44,46,55].
Validated tools and uniform definitions are key for assessing HRQoL and allowing comparison between studies of approved therapy options to aid treatment selection. There is a wide variety of tools and patient surveys for assessing HRQoL of cancer patients [10] in trials and in clinical practice. As summarized here, all the key phase 3 studies in NET patients used validated tools to assess HRQoL. Most of the studies used the EORTC QLQ-C30 questionnaire, which is a general oncology questionnaire. As fatigue and diarrhea are common in NET patients at the baseline, some trials used FACIT-fatigue and FACIT-D scoring while some studies used QLQ-GI.NET21, which is a NET-specific questionnaire. Cross-study comparisons will be easier with uniform adoption of HRQoL tools for future use, and facilitate treatment-choice discussions in clinical practice. One limitation, even with these validated tools, is reliance on recall when patients and caregivers fill out the HRQoL. A majority are done during office visits, and do not always have journals to track changes in the HRQoL events between visits. Besides journals to assist in recall, the availability of mobile phone applications, which can collect real-time data, may increase patient compliance and confidence in data capture from self-reporting [22][85].
While using a global score and a prior definition for improved QoL are important, there are also some limitations with looking only at overall scores. In the multiple practice-changing clinical trials leading to the approvals of octreotide LAR, lanreotide auto gel, everolimus, and sunitinib, no decline of QoL global scores was seen compared to the control arms, suggesting that therapy did not worsen the quality of life [4][6][11][14]. However, the trial examining sunitinib versus placebo in pancreatic NETs showed that, despite no change in QoL in all aspects, the diarrhea scores reflected that sunitinib worsened this quality measure. In addition, in a retrospective analysis of the PROMID trial, Rinke et al. observed a significantly longer time to deterioration in quality of life in the octreotide LAR group compared to the placebo in clinically relevant NET symptoms such as fatigue, diarrhea, pain, and insomnia, suggesting maintained or improved HRQoL with octreotide LAR [23]. Similarly, everolimus was also associated with more diarrhea and fatigue than the placebo group [13]. The NETTER-1 trial was the only research to have favorably impacted decline in HRQoL compared to control in key domains including global health, physical functioning, role functioning, fatigue, pain, and diarrhea, providing more granular insight on the impact of therapy on life. Therapy discussions should include these outcomes along with discussion of survival benefits [24]. Health-related quality of life should be integrated into tailoring treatment selection in neuroendocrine cancer patients as patient-reported outcomes are a key element of shared decision-making and patient-centered care. In NET patients, the impact on QoL of all currently approved therapies compared to their control arms has been studied using well-validated tools, and should be provided to patients during their pretherapy counseling along with toxicity information. Toxicity assessment of specific treatments should not be a surrogate measure for quality of life of patients, and careful assessment of global QoL scores, as well as individual symptom scores, may provide key insights into the impact of the disease on quality of life and functioning. Real-life studies on the impact of therapy, where most of the care delivery occurs, and HRQoL studies during periods between active treatment need to be conducted to identify the true impact of therapy choices on patients living with NETs.While using a global score and a prior definition for improved QoL are important, there are also some limitations with looking only at overall scores. In the multiple practice-changing clinical trials leading to the approvals of octreotide LAR, lanreotide auto gel, everolimus, and sunitinib, no decline of QoL global scores was seen compared to the control arms, suggesting that therapy did not worsen the quality of life [4,6,13,17]. However, the trial examining sunitinib versus placebo in pancreatic NETs showed that, despite no change in QoL in all aspects, the diarrhea scores reflected that sunitinib worsened this quality measure. In addition, in a retrospective analysis of the PROMID trial, Rinke et al. observed a significantly longer time to deterioration in quality of life in the octreotide LAR group compared to the placebo in clinically relevant NET symptoms such as fatigue, diarrhea, pain, and insomnia, suggesting maintained or improved HRQoL with octreotide LAR [82]. Similarly, everolimus was also associated with more diarrhea and fatigue than the placebo group [80].
The NETTER-1 trial was the only study to have favorably impacted decline in HRQoL compared to control in key domains including global health, physical functioning, role functioning, fatigue, pain, and diarrhea, providing more granular insight on the impact of therapy on life. Therapy discussions should include these outcomes along with discussion of survival benefits [18].
Health-related quality of life should be integrated into tailoring treatment selection in neuroendocrine cancer patients as patient-reported outcomes are a key element of shared decision-making and patient-centered care. In NET patients, the impact on QoL of all currently approved therapies compared to their control arms has been studied using well-validated tools, and should be provided to patients during their pretherapy counseling along with toxicity information. Toxicity assessment of specific treatments should not be a surrogate measure for quality of life of patients, and careful assessment of global QoL scores, as well as individual symptom scores, may provide key insights into the impact of the disease on quality of life and functioning. Real-life studies on the impact of therapy, where most of the care delivery occurs, and HRQoL studies during periods between active treatment need to be conducted to identify the true impact of therapy choices on patients living with NETs.