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08.07.2020 | Original Research | Ausgabe 8/2020 Open Access

Advances in Therapy 8/2020

Patient Burden and Real-World Management of Chemotherapy-Induced Myelosuppression: Results from an Online Survey of Patients with Solid Tumors

Zeitschrift:
Advances in Therapy > Ausgabe 8/2020
Autoren:
Robert S. Epstein, Matti S. Aapro, Upal K. Basu Roy, Tehseen Salimi, JoAnn Krenitsky, Megan L. Leone-Perkins, Cynthia Girman, Courtney Schlusser, Jeffrey Crawford
Wichtige Hinweise

Digital Features

To view digital features for this article go to https://​doi.​org/​10.​6084/​m9.​figshare.​12488759.
Key Summary Points
Why carry out this study?
The side effects of chemotherapy, including myelosuppression, remain a major source of concern for both patients and health care providers.
The consequences of chemotherapy-induced myelosuppression (CIM) include anemia, thrombocytopenia, and neutropenia, all of which can cause severe complications, and limit the ability of patients to receive chemotherapy on time and at standard-of-care doses.
Prior research has documented patients’ perceptions of the side effects of chemotherapy; however, research into the real-world impact of CIM on patients’ lives is limited, and the ‘patient voice’ on CIM, and how it is currently managed, is lacking.
What was learned from the study?
Despite the current availability and use of various supportive care interventions, CIM places a substantial burden on patients with advanced solid tumors, impacting many aspects of their daily lives.
This survey provides valuable insights into patients’ perspectives on the impact and management of CIM, and suggests that methods to prevent or proactively manage CIM could improve the quality of life of patients receiving chemotherapy.

Introduction

Myelosuppression is an important treatment-related toxicity among patients with cancer [ 13], and occurs when the actively dividing hematopoietic stem and progenitor cells (HSPCs) in the bone marrow, which give rise to blood cell lineages, are damaged by cytotoxic chemotherapy. Chemotherapy-induced myelosuppression (CIM) commonly manifests as anemia, neutropenia, thrombocytopenia, and/or lymphopenia [ 1, 46], and often results in an increased risk of life-threatening infections, shortness of breath, fatigue, and, potentially, excess bleeding. CIM is currently managed with chemotherapy dose reductions and delays, in addition to rescue interventions that stimulate or mobilize white cells (growth factors, such as granulocyte colony-stimulating factors [G-CSFs]); replenish red blood cells (RBCs) and platelets (transfusions); or stimulate RBC precursors (growth factors, such as erythropoiesis-stimulating agents [ESAs]) [ 4, 79]. Despite the use of these interventions, however, clinically significant CIM continues to be a major acute toxicity of cytotoxic chemotherapy, possibly because currently available interventions are administered reactively, i.e., after HSPCs have been damaged by chemotherapy. The wide application of chemotherapy dose reductions and/or delays can also reduce the dose intensity of the chemotherapy and, potentially, its intended antitumor efficacy [ 3, 911].
CIM is particularly relevant for patients with small cell lung cancer (SCLC), breast cancer, and colorectal cancer (CRC), for which chemotherapy, alone, or in combination with immune checkpoint inhibitors, remains a cornerstone of treatment [ 1216]. A systematic literature review to assess the real-world effectiveness and tolerability of treatments for SCLC, for example, showed that hematologic toxicities were the most commonly reported adverse events (AEs); neutropenia was reported in approximately two-thirds of patients receiving first-line chemotherapy, and almost three-quarters of patients receiving second-line chemotherapy [ 17].
Research into patients’ perceptions of the side effects of chemotherapy, including those associated with CIM, has been well documented, particularly with regard to symptoms of fatigue and effects on family [ 1822]. Overall, these studies suggest that patients’ concerns extend beyond physical symptoms to include non-physical concerns over daily routines, emotional well-being, and relationships [ 19, 2123]. By comparison, much less is known about how the management of CIM-associated side effects impacts patients. One survey of 15,785 adult cancer patients assessed the burden of time associated with medical visits for the management of chemotherapy-induced anemia (CIA) and neutropenia on patients and caregivers, and found that each visit involved approximately 2 h for the patient and over 1 h for caregivers [ 24]. Likewise, several surveys conducted to determine the impact of blood transfusions on patients with CIA have concluded that the time spent travelling to medical facilities, along with blood testing and the procedure itself, presents a considerable burden to patients [ 2426]. While these studies highlight the logistic burden associated with CIM, there remains a need for more research into the broader impact that CIM and its management has on patients’ lives, and to raise awareness among patients regarding the contribution of CIM to the overall toxicities associated with chemotherapy.
The purpose of the current study was to capture the perceptions, experiences, and challenges that patients encounter when diagnosed with myelosuppression as part of chemotherapy treatment for advanced solid tumors. Here, we describe patients’ perspectives on the management of CIM among those with breast, lung, and colorectal cancers, and the overall impact that myelosuppression has on patients’ lives.

Methods

Study Objectives and Format

The objectives of the study were to understand what treatments were administered for CIM and the challenges that patients encountered in receiving these; determine from a patient perspective whether CIM impacted dose/frequency of chemotherapy; gain insights into which member of the care team paid most attention to symptoms associated with CIM; and to capture the “patient voice” in how CIM impacted their life.
The study was conducted in accordance with the Declaration of Helsinki, and electronic consent was obtained from all participants prior to study entry. The study was reviewed by the Sterling institutional review board (IRB), and granted exemption status according to Department of Health and Human Services research criteria, signifying that full IRB review was not required.

Survey Population

Participants were identified from an online US panel of patients with a wide range of health conditions, including cancer. The target sample size was 300 participants living with breast cancer, lung cancer, or CRC, with a target ratio of 120:90:90 per cancer type, respectively. Male and female participants aged 18 years or more were included if they had received chemotherapy treatment within the past 12 months, and had experienced at least one episode of myelosuppression in the past year, encompassing the following: required blood transfusion; required G-CSF or granulocyte macrophage colony-stimulating factor (GM-CSF); required platelet transfusion; had a serious infection such as pneumonia or sepsis after receiving chemotherapy treatment; required ESAs to increase RBC count; or diagnosed with myelosuppression but with no treatment intervention.

Research Instrument Development

The survey was designed, as per the study objectives, considering a review of published literature, and the draft questions were reviewed by experts for scientific content and question design. Questions, including screening and demographic questions, as well as core survey content, were presented sequentially in several formats, which included a choice of one response from a defined list of possible statements; questions that asked the participant to choose multiple responses (e.g., Select all that apply); dichotomous questions (Yes/No); and statements where the participant was asked to indicate their agreement using a Likert scale (e.g., 1 = Strongly disagree, 2 = Disagree, 3 = Neutral/not sure, 4 = Agree, 5 = Strongly agree). Lay definitions of key terms were provided (upon cursor selection) to aid response selection (Table  1). Participants were also asked to provide verbatim responses to a single open-ended question about how the side effects from myelosuppression impacted their lives.
Table 1
Lay definitions of key terms
Term
Explanation
Anemia
Fewer/less red blood cells, which sometimes causes you to be tired
Lymphocytes
Types of white blood cells that work to fight illness and disease
Lymphopenia
Fewer/less lymphocytes, which sometimes increases your risk of infection
Myelosuppression
A decrease in bone marrow activity that results in the reduced production of blood cells. Myelosuppression is a common side effect of chemotherapy
Neutropenia
Fewer/less white blood cells, which sometimes increases your risk of infection
Platelets
Tiny blood cells that help your body form clots to stop bleeding
Thrombocytopenia
Fewer/less platelets, which sometimes increases your risk of bleeding

Data Analysis

Data were aggregated to ensure anonymity and key findings summarized using descriptive statistics. Chi-square tests were used to calculate p values (MS Excel).

Results

A total of 2908 participants started the survey, of whom 2496 were disqualified, most commonly for not having received chemotherapy in the previous 12 months ( n = 1269) or for not having lung, breast, or colorectal cancer ( n = 334). A further 111 participants only partially completed the survey and were excluded from the analysis. The full survey was completed by 301 participants between November 11, 2019 and December 8, 2019. Of these, 291 (97%) recalled being told by their health care provider (HCP) that they had at least one episode of myelosuppression, and 10 (3%) recalled receiving treatment associated with myelosuppression.
Sixty percent of the participants were female, most (80%) were under 60 years of age, and 60% were working (Table  2). Fifty-one percent of the participants had breast cancer, 33% had lung cancer (of whom 46% had SCLC), and 16% had CRC. Seventy-five percent of participants had been diagnosed with cancer within the previous 3 years. All participants self-identified as having experienced some form of myelosuppression (anemia, neutropenia, thrombocytopenia, lymphopenia) in the past year. Self-reported comorbidities included diabetes (30%), depression (28%), and hypertension (23%).
Table 2
Participant baseline demographics, clinical characteristics, and myelosuppression
 
Breast cancer
Lung cancer
Colorectal cancer
Total
Patients, n
153
100
48
301
Gender, n (%)
 Male
21 (14)
67 (67)
32 (67)
120 (40)
 Female
132 (86)
33 (33)
15 (31)
180 (60)
 Other
0
0
1 (2)
1 (< 1)
Age group, years, n (%)
 18–59
134 (88)
75 (75)
32 (67)
241 (80)
 ≥ 60
19 (12)
25 (25)
16 (33)
60 (20)
Currently working (full or part time), n (%)
92 (60)
65 (65)
24 (50)
181 (60)
Years since cancer diagnosis, n (%)
 < 1
37 (24)
19 (19)
11 (23)
67 (22)
 1–3
75 (49)
53 (53)
29 (60)
157 (52)
 ≥ 4
40 (26)
28 (28)
8 (17)
76 (25)
 Not answered
1 (1)
0 (0)
0 (0)
1 (< 1)
Myelosuppression, n (%) a
 Anemia
103 (67)
51 (51)
30 (63)
184 (61)
 Neutropenia
80 (52)
61 (61)
37 (77)
178 (59)
 Lymphopenia
56 (37)
32 (32)
24 (50)
112 (37)
 Thrombocytopenia
47 (31)
36 (36)
18 (38)
101 (34)
aParticipants could select more than one option
Most participants reported that they had been diagnosed with anemia (61%) or neutropenia (59%), while fewer participants reported a doctor’s diagnosis of lymphopenia (37%) or thrombocytopenia (34%; Table  2). Approximately one-third of participants reported receiving either G(M)-CSF, ESAs, or RBC transfusions (37%, 36%, and 35%, respectively); platelet transfusions were reported by 22% of participants; and 21% reported no treatment (Fig.  1). Illustrative comments in response to the open-ended question included:
I handled the side effects of myelosuppression pretty well during the chemotherapy. The thing that bothered me the most was the [pegfilgrastim] and I hated being injected. I had terrible bone pain after each shot.
[Myelosuppression] affected me greatly. I felt the side effects daily. My immune system was affected, and I had to get shots to increase my [blood] counts.
In total, 64% of participants recalled chemotherapy dose delays, reductions, discontinuations, and/or changes due to myelosuppression (Fig.  2).
Myelosuppression was most frequently managed by an oncologist, and most participants thought that their oncologist was aware of their side effects and treated them quickly (Table  3); however, 29% of participants felt that their side effects were not treated, and 30% felt that their oncologist did not understand how uncomfortable they were as a result of myelosuppression side effects. Results were similar across the three tumor types (Table  3).
Table 3
Side effect management by oncologists, as reported by participants
Statement a
Breast ( n = 153)
Lung ( n = 100)
CRC ( n = 48)
Total ( N = 301)
Oncologist warned me to expect side effects from chemotherapy, %
75
76
77
76
Oncologist did not treat my side effects from myelosuppression, %
29
29
29
29
Oncologist treated my side effects quickly, %
73
74
69
73
Oncologist did not understand how uncomfortable I was from the side effects I experienced, %
33
28
25
30
aParticipants selected 4 (Agree) or 5 (Strongly agree) on a 1–5 scale
Most participants (88%) considered myelosuppression to have a moderate or major overall impact on life (Table  4). Participant-reported impact of myelosuppression was significantly higher among participants aged below 50 years compared with those aged at least 50 years ( p = 0.01); however, no significant differences were observed when participants were stratified by gender, employment status, cancer type, or comorbidities (depression, diabetes, hypertension).
Table 4
Relationship of demographics and clinical characteristics to perceived overall impact of myelosuppressi
 
Patients, n
Minor impact, n (%)
Moderate impact, n (%)
Major impact, n (%)
p value
All patients
301
36 (12)
146 (48.5)
119 (39.5)
Age
 < 50 years
191
15 (8)
98 (51)
78 (41)
0.01
 ≥ 50 years
110
21 (19)
48 (44)
41 (37)
 
Gender
 Male
120
19 (16)
61 (51)
40 (33)
0.26
 Female
180
17 (9)
84 (47)
79 (44)
 
Working status
 Working
181
19 (11)
93 (51)
69 (38)
0.40
 Not working
120
17 (14)
53 (44)
50 (42)
 
Cancer type
 Breast
153
15 (10)
75 (49)
63 (41)
0.59
 Lung
100
13 (13)
46 (46)
41 (41)
 
 Colorectal
48
8 (17)
25 (52)
15 (31)
 
Comorbidities
 Depression
  Yes
85
6 (7)
46 (54)
33 (39)
0.20
  No
216
30 (14)
100 (46)
86 (40)
 
 Diabetes
  Yes
91
8 (9)
46 (51)
37 (41)
0.54
  No
210
28 (13)
100 (48)
82 (39)
 
 Hypertension
  Yes
69
9 (13)
33 (48)
27 (39)
0.95
  No
232
27 (12)
113 (49)
92 (40)
 
Some illustrative verbatim responses regarding the impact of myelosuppression side effects included the following:
Did not get out as much, not able to work, always feeling tired. Had to take preventative measures to guard against diseases and germs.
It has made everyday life more difficult in all areas.
I had to severely curtail my social activities so I was not exposed to germs. I avoided family holiday activities [and] had some depression because of lack of social interaction and concern over potential infection.

Discussion

Studies seeking to gain insight into patients’ perspectives on the burden of CIM are important, as hematologic side effects can have a substantial negative impact on patients’ quality of life and may contribute to suboptimal treatment outcomes [ 1, 4, 6, 19]. Many studies have sought to understand patients’ perceptions of the symptoms associated with CIM, but few studies have been designed to better understand patients’ perspectives on the overall impact of CIM and how it is managed in daily practice.
In the current survey, anemia and neutropenia were reported most commonly (61% and 59% of participants, respectively), whereas thrombocytopenia and lymphopenia were relatively less common (34–37% of participants). The actual rates of myelosuppression reported in the survey are higher than would be expected in an all-comer population, given that we focused only on participants with a diagnosis of myelosuppression and/or treatment for myelosuppression. In a study of electronic medical records from 339 evaluable patients diagnosed with SCLC, for example, real-world rates of chemotherapy-induced neutropenia, anemia, and thrombocytopenia were 45%, 41%, and 25%, respectively [ 27]. The finding that anemia and neutropenia were more common than thrombocytopenia is consistent with the prescribing information for a range of myelosuppressive chemotherapy treatments, although many report neutropenia as being more common than anemia [ 3]. It is possible that the relatively broad inclusion criteria in this online survey may have led to overestimation of the incidence of CIA, since participants with anemia resulting from the cancer itself or other underlying causes would also have been included.
In line with the finding that most participants were diagnosed with anemia or neutropenia, G(M)-CSF, ESAs, and RBC transfusions were described as the most common supportive care interventions, each being reported in approximately one-third of participants. Retrospective studies of supportive care use among US patients with solid tumors or lymphoma have shown that 35–55% of patients receive prophylaxis with myeloid growth factors [ 28, 29]; however, far fewer patients receive ESAs [ 27, 30]. The low utilization of ESAs in the USA may partly reflect the US Food and Drug Administration’s decision in 2007 to restrict ESA use to patients with a hemoglobin (Hb) level of less than 10 g/dL owing to concerns over rapid tumor progression and shortened overall survival with ESAs at Hb  greater than 12 g/dL [ 31]. Similarly, there has been a shift toward a more restrictive policy on transfusions for CIA in recent years, with guidelines supporting a Hb threshold of less than 7 g/dL for most patients [ 32]. Despite these recommendations, the findings of the current study, along with previous reports on patterns of supportive care use in patients on chemotherapy, suggest that, in general, interventions such as growth factors and transfusions are commonly used. Indeed, only 21% of survey participants in the current study reported receiving no treatment. This finding is notable, as the supportive care interventions themselves can present additional risks, such as bone pain with G(M)-CSF; thrombotic events with ESAs; and transfusion reactions and infections with RBC and platelet transfusions; as well as being a burden to patients [ 7, 8, 2426, 33].
Approximately two-thirds of survey participants experienced an issue with continuing on their current chemotherapy regimen due to myelosuppression, reflecting the substantial impact of hematologic side effects on standard-of-care treatment schedules and doses. This is in line with findings from studies in patients with advanced non-small cell lung cancer and breast cancer. In these studies, chemotherapy was delayed by at least 1 week in approximately one-third of patients, and approximately 40% of patients had a relative dose intensity of less than 85% [ 9, 34]. Such dose modifications are clinically relevant, as maintaining appropriate dose intensity is important in both the curative setting and in treatment with palliative intent [ 3]. For this reason, the development of equally effective chemotherapy regimens that carry less long-term risks has been an important focus of research. The frequent, uninterrupted administration of low-dose (metronomic) chemotherapy, for example, is thought to result in sustained, low blood levels of chemotherapy, with fewer side effects, and a reduced need for supportive therapies [ 35]. However, although alternative dosing strategies may be useful to reduce CIM, they should be limited to situations where dose reductions are not expected to compromise long-term outcomes.
Participants reported that myelosuppression was most frequently managed by an oncologist, as opposed to a nurse, physician assistant, or other HCP. This differs to other areas of supportive care, such as the management of nausea and vomiting, where oncology nurses are often better placed to manage side effects, as they have more frequent contact with individual patients and offer a holistic approach to care [ 36, 37]. Nevertheless, most participants had confidence in their oncologist to be aware of and treat side effects, although some perceived that their oncologists did not understand the impact that side effects had on their lives. A previous study examining patients’ perceptions of the physician–patient relationship and communication about AEs also found that most patients reported having a good relationship with their physician, and that they had extensive discussions about what side effects might occur. However, those discussions did not always provide patients with sufficient understanding or adequately equip patients to cope with the AEs [ 38]. Overall, the results are encouraging, but suggest that there is a need for improved communication between patients and their treating physician, both in terms of improving patients’ understanding of potential side effects and in listening to their perspectives on how these events affect everyday life. Indeed, improved patient–physician communication would help foster shared decision-making, especially when critical decisions regarding treatment discontinuation or treatment changes must be made.
It is notable that most participants, particularly younger participants, felt that myelosuppression side effects had a moderate-to-major life impact, despite the fact that most perceived their symptoms to be expected and treated quickly. In particular, in their verbatim responses, many participants described a substantial negative impact on their ability to carry out daily tasks, due to fatigue and concerns about infection. This is especially pertinent in light of the COVID-19 pandemic that occurred following the completion of this survey, which is likely to further exacerbate the impact of myelosuppression on patients’ lives by creating an additional burden to health care systems and by heightening fears that a weakened immune system will put oncology patients at risk of severe complications from the virus [ 39, 40].
One limitation of this study is that the use of an online patient database to engage participants may have created bias in favor of reflecting the preferences of participants with more familiarity with online technologies, or who were healthier than the average oncology patient. In principle, patients with worse disease characteristics, requiring aggressive treatment for cancer and/or CIM may not have been interested or able to participate in the survey. The study is also based solely on patient self-report, and the extent to which patients can accurately recall this type of information is not known. Thus, these findings should be considered alongside findings from other patient populations and using other methods, such as prospective observation, patient diaries, and/or interviews within clinical settings, to confirm and extend the findings. On the other hand, a key strength of using an online platform is that participants may be more willing to share information than in a face-to-face interview, and may be less likely to be directed toward a socially desirable response. Additionally, the use of verbatim responses provides important information on aspects of the patient burden of CIM that would not otherwise be captured in a closed response questionnaire.

Conclusion

Despite the use of chemotherapy dose reductions and delays, G(M)-CSF, ESA injections, and blood transfusions to address CIM, the findings of this survey suggest that the real-world impact of myelosuppression on patients is substantial, with almost all participants reporting a moderate or major impact on their lives. The data highlight that there is an unmet need to prevent or proactively manage CIM to improve patients’ quality of life and to improve communication between HCPs and their patients.

Acknowledgements

We give special thanks to the patients who participated in the survey, and to Dr Upal K Basu Roy from the LUNGevity Foundation (lung cancer advocacy community) for his involvement and authorship.

Funding

Sponsorship for this study, the Rapid Service and Open Access Fees were funded by G1 Therapeutics, Inc. (Research Triangle Park, NC, USA).

Medical Writing and Editorial Assistance

Medical writing assistance in the preparation of this article was provided by Fiona Scott, contracted by Alligent Europe (Envision Pharma Group). Plain language writing support was provided by Lauri Arnstein, Envision Pharma Group. Support for all assistance was funded by G1 Therapeutics, Inc.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Prior Presentation

Data from this study have been previously published, in part, as a poster presentation at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 2020 virtual conference, May 18–20, and as an electronic abstract at the American Society of Clinical Oncology (ASCO) 2020 annual meeting (virtual format), May 29–31.

Disclosures

Robert S. Epstein is a consultant for G1 Therapeutics, Inc. and serves on the board for Proteus Digital, Fate Therapeutics, Illumina, Veracyte, and Decipher Biosciences. Matti S. Aapro has served as a consultant for Amgen, Bristol Myers Squibb, Daiichi Sankyo, Fresenius Kabi, G1 Therapeutics, Inc., Genomic Health, Helsinn Healthcare, Merck KGaK, Merck, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz, Tesaro, and Vifor Pharma; is on the Speakers’ Bureau for Accord Research, Amgen, Biocon, Dr Reed, Genomic Health, Helsinn Healthcare, Mundipharma, Novartis, Pierre Fabre, Pfizer, Roche, Sandoz, Taiho Pharmaceutical, Tesaro, and Vifor Pharma; and has received research funding from Helsinn Healthcare, Novartis, Pierre Fabre, and Sandoz. Upal K. Basu Roy has received research funding from Astra Zeneca, Bristol Myers Squibb Foundation, and Merck unrelated to this project. Tehseen Salimi was a paid employee of G1 Therapeutics, Inc., at the time of study completion and manuscript preparation, and is currently a paid employee of Taiho Oncology, Inc. JoAnn Krenitsky is a consultant for G1 Therapeutics, Inc. Megan L. Leone-Perkins is a paid consultant for HealthiVibe, a division of Corrona LLC. Cynthia Girman is a consultant for G1 Therapeutics, Inc., and Epstein Health, LLC. Courtney Schlusser is a consultant for G1 Therapeutics, Inc., and Epstein Health, LLC. Jeffrey Crawford has served as an advisor to Amgen, Coherus, G1 Therapeutics, Inc., and Pfizer.

Compliance with Ethics Guidelines

The study was conducted in accordance with the Declaration of Helsinki, and electronic consent was obtained from all participants prior to study entry. The study was reviewed by the Sterling IRB, and granted exemption status according to Department of Health and Human Services research criteria, signifying that full IRB review was not required.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creativecommons.​org/​licenses/​by-nc/​4.​0/​.

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