Support Care Cancer DOI 10.1007/s00520-014-2223-2
ORIGINAL ARTICLE
Symptoms from treatment with sunitinib or sorafenib: a multicenter explorative cohort study to explore the influence of patient-reported outcomes on therapy decisions J. J. Koldenhof & P. O. Witteveen & R. de Vos & M. Walraven & C. N. Tillier & H. M. W. Verheul & S. C. C. M. Teunissen
Received: 15 May 2013 / Accepted: 20 March 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Optimal long-lasting treatment with sunitinib and sorafenib is limited by dose modifications (DMs) due to adverse events (AEs). These AEs may be underrecognized and their influence on health-related quality of life (HRQL) underestimated. Improved insight into the relationship between AEs and therapy decisions is needed. To improve decision making around managing symptoms and reduce DMs, this study was set up to explore the influence of patient-reported symptoms on therapy decisions. Methods In this multicenter cohort study, patient characteristics, reasons for and different forms of used dose modifications, and AEs were prospectively obtained from cancer patients on sunitinib/sorafenib treatment. Used instruments to get insight into AEs were the patient-scored Utrecht Symptom Diary (USD) and the professional-scored Common Terminology Criteria for AEs version 3.0. Results Median total treatment duration in 42 patients was 16 weeks. Median time till dose modification was 10 weeks. DMs occurred mostly due to multiple mild AEs. By using the J. J. Koldenhof (*) : P. O. Witteveen : M. Walraven : S. C. C. M. Teunissen Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands e-mail:
[email protected] R. de Vos Amsterdam School of Health Professions, Academic Medical Center, Amsterdam, The Netherlands C. N. Tillier Department of Medical Oncology, The Netherlands Cancer Institute– Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands H. M. W. Verheul Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
USD, a higher prevalence of most AEs was found compared to the literature. Sixty percent of the patients experienced a decreased HRQL due to multiple AEs. Conclusions Because severe AEs due to sunitinib/sorafenib treatment seldom occur, it is more important to focus on treating and preventing multiple mild AEs with higher impact on HRQL, when trying to avoid dose modifications. Using patient self-reported measurement methods helps to early recognize symptoms and to differentiate among symptom intensities. This systematic approach might help to achieve the optimal dosing, which might improve PFS and OS. Keywords Advanced cancer . Dose modifications . Patient-reported outcome . Sorafenib . Sunitinib . Symptom intensity
Introduction Anti-angiogenic agents inhibit tumor angiogenesis, which is essential for tumor growth and metastasis [1]. These agents are more likely to stabilize tumor growth than to achieve tumor regression [2, 3]. Well-responding patients will be treated during a long period, which needs tolerance for treatment and a predictable, treatable profile of adverse events (AEs) [2]. Optimal treatment is limited by the need of dose modifications which might cause a decreasing progressionfree survival (PFS) and overall survival (OS), although there is limited prospective data on the relationship between dose intensity and effectiveness [4]. When the oral angiogenic inhibitors sunitinib and sorafenib became widely available, treatment options changed for chemotherapy-resistant tumors like renal cell cancer (RCC), hepatocellular carcinoma (HCC), gastrointestinal stromal
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tumors (GIST), and pancreatic neuroendocrine tumors (pNET) [3, 5–9]. Besides AEs, patients experience disease-related complaints, which together can be summarized as symptoms. Symptoms, particularly when more than one event occurs at the same time and if not managed effectively, influence healthrelated quality of life (HRQL) [1] and therefore are a threat for the quality of treatment. In the literature, dose discontinuation because of AEs occurred in about 27 % of HCC patients on sorafenib [7]. Dose discontinuation occurred in 19 % and dose reduction in 42 % of GIST patients on sunitinib [6]; in RCC patients, those occurred in 8–24 % and 13–49 %, respectively [3, 8–12]. Dose reductions were not only based on grade 3 AEs but also due to multiple grade 1/2 AEs, although these AEs were treated optimally [3, 6, 7, 10–13]. In clinical trials, symptom severity from a professional point of view is graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 3.0 (CTCAE3.0), a descriptive terminology which can be utilized for AE reporting [14]. Although most studies are focused on measurement of symptom frequency and severity, a systematic measurement of symptom burden is not available. Symptom burden is experienced differently in each patient, so self-report is the most reliable indicator of symptom presence and intensity especially in the vulnerable group of patients receiving sunitinib or sorafenib [15]. This Dutch study was set up to explore the influence of patient-reported symptoms on therapy decisions in patients on sunitinib or sorafenib treatment.
Patients and methods Patients Incurable cancer patients (≥18 years of age), treated with monotherapy sunitinib or sorafenib at the outpatient clinic of the Department of Medical Oncology (MO) of the University Medical Center Utrecht (UMCU) or VU University Medical Center (VUMC). Inclusion started in December 2007 and was closed in April 2010. Methods The primary objective was to get to explore the influence of patient-reported outcomes on therapy decisions. Endpoints for the primary objective were (i) duration of initial dose in weeks, (ii) frequency of dose modification, and (iii) description of used dose modifications and their frequencies, all separated out by agent and disease. The secondary objective was to determine symptoms. Endpoints for the secondary objective were (i) symptom prevalence, (ii) symptom severity, (iii) frequency of measured
symptoms that cause dose modification, and (iv) prevalence of reestablishment of the initial dose. Definitions and measurements Symptoms, burden, and severity In this study, disease-related complaints and/or toxicities due to treatment have been summarized as symptoms. The definition of “other” symptoms is any single symptom that could not be classified as hand-foot skin reaction (HFSR), diarrhea, laboratory abnormalities, and multiple AEs. The presence of more than one symptom at the same time is considered as multiple symptoms. Symptom prevalence and severity from a professional point of view was obtained from the CTCAE registration in the medical records. The most frequently used self-assessment tool for symptom severity is the Edmonton Symptom Assessment Scale (ESAS), a nine-item monitoring tool focused on advanced cancer patients without active treatment. Therefore, the ESAS was translated in the Dutch patient-reported Utrecht Symptom Diary (USD). The adapted tool consists of 11 numerical rating scales (0–10) related to the most prevalent symptoms in advanced cancer patients: pain, fatigue, nausea, sleeping problems, dyspnea, dry mouth, constipation, dysphagia, confusion, anxiety, and depressed mood [16–22]. Because there were no specific patient-reported outcome tools available for TT AEs, we developed two specific versions of the USD to measure symptom prevalence and burden in patients on sunitinib or sorafenib treatment: a USD sunitinib and a USD sorafenib. These two USDs were based on all AEs and generic disease-related complaints with a prevalence ≥10 % and all grade 3–4 AEs as mentioned in both investigator’s brochures of the oral agents, sunitinib and sorafenib [23, 24]. Besides, experienced symptoms could be added by patients themselves. Patients score all symptoms weekly without help and, as in the ESAS, on a 0–10 numeric scale (0 = no burden; 10 = unbearable burden). As de Boer et al. have shown that a single item to measure reduced HRQL is valid and reliable, our patients scored the influence of symptom burden on HRQL by answering the question “To what extent do these symptoms influence your quality of life?” on a single-item 0–7 numeric scale with 0 = no influence and 7 = complete influence in a negative way [25]. Dose The initial dose is defined as the recommended dose, which for sunitinib is 50 mg once daily, on a 4 weeks on/2 weeks (1 cycle) off treatment schedule. Sunitinib is registered as the
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first-line treatment for locally advanced/metastatic RCC (mRCC) and the second-line treatment for inoperable GIST. For inoperable pNET, a dosing of 37.5 mg once a day is recommended. The recommended dose of sorafenib, registered as the firstline treatment for inoperable HCC and the second-line treatment for mRCC, is 400 mg bid continue (1 cycle = 4 weeks). Therapy decisions were obtained from the medical records and defined as every dose modification, decided by the medical oncologist, in agreement with the patient, and lasting longer than 1 day. Dose modifications, in the form of dose interruption, reduction, or discontinuation, due to AEs were performed when the optimal treatment of AEs failed.
Table 1 Baseline patient characteristics, total treatment duration, and time until dose modification Variable
Sunitinib N=26
Sorafenib N=16
All patients N=42
Male sex, N (%)
17 (61)
11 (39)
28 (67)
Age, mean years (min–max)
62 (42–78)
66 (53–82)
64 (42–82)
Primary diagnosis, N (%) mRCC
24 (75)
8 (25)
32 (76)
HCC
–
8 (50)
8 (19)
Child Pugh A
–
5 (63)
Child Pugh unknown
–
3 (37)
GIST
1 (100)
0
1 (2)
Othera
1 (100)
0
1 (2)
None
21 (70)
9 (30)
30 (71)
1
4 (40)
6 (60)
10 (24)
2
1 (50)
1 (50)
2 (5)
18 (4–66)
16 (1–144)
16 (1–144)
mRCCb
18 (4–107)
43 (1–144)
19 (1–144)
HCC
–
13 (2–27)
13 (2–27)
GISTb
47
–
47
Othera
10
–
10
11 (2–59)
6 (0–22)
10 (0–59)
mRCC
10 (2–59)
2 (0–17)
9 (0–59)
Systemic prior treatment, N (%)
Ethical approval Because the USD is a standard tool in daily practice of the Department of Medical Oncology in the UMCU, approval of the Medical Ethics Committee was not requested.
TTD, median weeks (min–max)
Statistical analysis
TUDM, median weeks (min–max)
Descriptive statistics of patient characteristics, reasons for and different forms of used dose modification(s), and symptoms (severity and burden) were performed. To analyze total treatment duration (TTD), time until dose modification (TUDM), and reasons for and different forms of used dose modifications, patients were categorized by treatment (sunitinib/sorafenib) and tumor type (mRCC/HCC). The χ2 (Fisher’s exact test) and t tests were used to compare variables among groups. The adjusted Wald statistics and the Bonett and Price method were used to compute the 95 % confidence interval (CI) for differences in proportions and medians [26, 27]. TTD and TTUM were evaluated by using the Kaplan-Meier curves. Differences between groups were tested by using the log-rank test. A two-tailed p value
