Long-Term Effects of Two Formats of Cognitive Behavioral Therapy for Insomnia Comorbid with Breast Cancer

Transcription

1 pii: sp INSOMNIA Long-Term Effects of Two Formats of Cognitive Behavioral Therapy for Insomnia Comorbid with Breast Cancer Josée Savard, PhD 1,2,3 ; Hans Ivers, PhD 1,2,3 ; Marie-Hélène Savard, PhD 2,3 ; Charles M. Morin, PhD 1 1 School of Psychology, Université Laval; 2 CHU de Québec-Université Laval Research Center; 3 Université Laval Cancer Research Center, Québec, Québec, Canada Study Objectives: The goal of this randomized controlled trial, conducted in breast cancer patients, was to assess the long-term efficacy of a video-based cognitive behavioral therapy for insomnia (VCBT-I), as compared to a professionally administered intervention (PCBT-I) and to a no-treatment group (CTL). An earlier report revealed that, at posttreatment, VCBT-I patients showed significantly greater sleep improvements than CTL, but that PCBT-I produced superior effects than VCBT-I on some sleep and secondary outcomes. In this report, long-term effects are compared. Methods: Two hundred forty-two women with breast cancer and with insomnia symptoms or using hypnotic medications participated to this three-arm randomized controlled trial: (1) PCBT-I (n = 81); (2) VCBT-I (n = 80); or (3) no treatment (CTL; n = 81) group. PCBT-I was composed of six weekly, individual sessions of approximately 50 min, whereas VCBT-I comprised a 60-min animated video and six booklets. Results: Study measures (sleep and secondary variables) were administered at pretreatment and posttreatment, and at a 3-, 6-, and 12-mo follow-up. Treatment gains were well sustained at follow-up in both PCBT-I and VCBT-I. As at posttreatment, the remission rate of insomnia at follow-up was greater in PCBT-I than in VCBT-I, which was greater than in CTL. Conclusions: Although face-to-face therapy remains the optimal format to efficaciously administer CBT for insomnia in cancer patients, a minimal intervention, such as the video-based intervention tested in this study, produces significant and sustainable treatment effects. Clinical Trial Registration: ClinicalTrials.gov identifier NCT Keywords: cognitive behavioral therapy, insomnia, long-term effects, minimal intervention, self-help Citation: Savard J, Ivers H, Savard MH, Morin CM. Long-term effects of two formats of cognitive behavioral therapy for insomnia comorbid with breast cancer. SLEEP 2016;39(4): Significance Self-administered forms of cognitive behavioral therapy for insomnia (CBT-I) are increasingly recommended to increase patients accessibility to this treatment. However, it is important to compare their long-term efficacy to that of a professionally-administered CBT-I (PCBT-I), which constitutes the standard delivery format. This study suggests that a video-based CBT-I (VCBT-I) provides a most valuable alternative. It could be used as a stand-alone treatment in settings where resources for administering CBT-I are lacking. However, given that many VCBT-I patients were still symptomatic following treatment, minimal interventions should ideally be used as part of a stepped care model in which low-intensity interventions are followed by more intensive forms of treatment (e.g., group or individual sessions) when needed. Clinical trials are needed to assess the utility of a stepped care approach to administer CBT-I. INTRODUCTION Insomnia affects 30% to 60% of cancer patients and its prevalence is highest in women with breast cancer. 1 3 If left untreated, insomnia is very likely to become chronic, 2 which is associated with an array of detrimental consequences for the individual 4 and societal costs that considerably exceed those of an effective insomnia treatment. 5 Cognitive behavioral therapy (CBT), the treatment of choice for insomnia, 6 has proven efficacious among cancer patients in its standard format (i.e., face-to-face sessions) However, the accessibility of CBT for insomnia (CBT-I) in routine cancer care is very limited, mostly because of the time and costs associated with the treatment sessions, as well as the lack of trained health care professionals. Thus, most patients currently do not receive any treatment for insomnia or are prescribed hypnotic medications only, 16 which may lead to several risks and side effects. 6,17 19 Self-administered CBT-I constitutes a promising, more accessible, alternative treatment delivery format. Various minimal formats (e.g., bibliotherapy, web-based intervention) have been found to improve sleep in primary insomnia and insomnia comorbid with psychological disorders. 20,21 In the context of cancer, small scale studies confirmed the feasibility and provided some preliminary evidence supporting the efficacy of a video-based 22 and a web-based 23 CBT-I. Our research group recently published short-term results (pretreatment versus posttreatment) of a randomized controlled trial (RCT) of 242 women treated for breast cancer comparing the efficacy of a video-based CBT-I (VCBT-I) to that of a professionally administered CBT-I (PCBT-I) and a control condition (CTL). 24 Results indicated that, although treatment effects were larger in PCBT-I for several variables, VCBT-I produced significantly greater sleep improvements than CTL. However, the long-term effect of these two treatment formats needs to be compared. One of the advantages of CBT-I over hypnotic medications is its well-established capacity to produce sustainable improvements, but it is unknown whether this is also true when CBT-I is self-administered. This report compares the long-term effects of PCBT-I and VCBT-I, up to a 12-mo follow-up, as well as their remission and relapse rates. We hypothesized that therapeutic gains would be well sustained in both PCBT-I and VCBT-I. Despite this specific goal, all five time points had to be included in the statistical analyses. To avoid overlap with our prior report, 24 pretreatment versus posttreatment effects are not presented. With only a few exceptions, these findings were identical to those already reported. METHODS More details on the methodology are provided elsewhere. 24 SLEEP, Vol. 39, No. 4, CBT for Insomnia in Breast Cancer Savard et al.

2 Participants Inclusion/Exclusion Criteria Inclusion criteria: (a) radiation therapy for a nonmetastatic breast cancer within the past 18 mo; (b) insomnia symptoms as defined by a score 8 on the Insomnia Severity Index (ISI) 25 or utilization of a psychotropic medication as a sleep aid 2 nights in the past 2 w; (c) between 18 and 75 y old; and (d) able to readily read and understand French. Exclusion criteria: (a) severe cognitive impairments (e.g., diagnosis of Parkinson disease) or a score 23 on the Mini-Mental State Examination 26 (MMSE); (b) severe psychiatric disorder as assessed using the Structured Clinical Interview for DSM-IV (SCID 27 ; e.g., severe major depression) or self-reported by the patient (e.g., bipolar disorder); (c) diagnosis of a sleep disorder other than insomnia (e.g., obstructive sleep apnea); (d) nightshift work in the past 3 mo or in the next 18 mo; (e) received psychotherapy specifically for insomnia; and (f) severe visual, hearing, or language defects. Because we wanted to maximize the generalization of the findings, we only excluded patients who had a psychiatric disorder that could interfere with the insomnia treatment or for whom an insomnia treatment was not the most appropriate intervention at that time. The only severe psychiatric disorder that was excluded on the basis of the SCID was a severe major depressive disorder as determined using the DSM-IV severity specifiers (i.e., presence of most of the criteria symptoms and clear-cut, observable disability). Patients with a less severe major depression could therefore be included. Because the SCID evaluates only a minority of psychological disorders, patients were also asked at recruitment whether they had already received a diagnosis of a severe psychological disorder and we gave the examples of bipolar disorder, schizophrenia, or other psychoses. Patients with such disorders were excluded. Besides, as we wanted to reproduce as much as possible what could be done in in a clinical setting, no polysomnographic recording was performed. Hence, we asked patients whether they had already received a diagnosis of a sleep disorder other than insomnia such as sleep apnea and periodic limb movements. If so, they were excluded. Recruitment Based on a priori power analyses, we aimed at recruiting 240 women. The participants were recruited between April 2008 and October 2011 and approached at the radio-oncology department of L Hôtel-Dieu de Québec (CHU de Québec-Université Laval), during their radiation therapy (often on their last treatment week). Eligible and consenting patients were asked to read and sign the informed consent form and were invited to a clinical interview. Patients with no insomnia symptoms at that time but otherwise eligible for the study and those with insomnia symptoms but not willing to participate in the study at that time (e.g., timing not good for them or desire to see if insomnia would remit by itself) were asked to participate in a phone screening procedure, using the ISI, administered every 2 to 4 mo until 18 mo postradiation therapy. Patients who had or in whom insomnia symptoms had developed or reported using hypnotics at that time were then invited to a clinical interview. This study was approved by the research ethics committee of CHU de Québec-Université Laval. Overall, 1,817 patients were approached at the clinic, among whom 819 were eligible and had insomnia symptoms (or were using hypnotic medications) and 182 accepted to participate (Figure 1). An additional 78 patients were recruited from the phone screening procedure, for a total of 260 (overall participation rate: 20%). Of these, 18 were excluded following the clinical interview, leaving 242 participants who were randomized in the study. Participants Characteristics At pretreatment, no patient was receiving chemotherapy and 4.5% of them were still receiving radiation therapy. The average ISI score was 14.3 and hypnotic medications were used by 18% of the sample (i.e., at least once per week in the past month; Table 1). No between-group differences were found at baseline on any demographic or medical variable. However, the CTL group reported a significantly lower sleep efficiency (SE; P = 0.02) and a greater total wake time (TWT; P = 0.008) on the sleep diary as compared to the other two groups. In addition, a larger proportion of participants met the diagnostic criteria for an insomnia syndrome in the CTL than in the VCBT-I group (P = 0.01). Dropouts Sixty-three participants dropped out of the study, 20 in the PCBT-I, 31 in the VCBT-I, and 12 in the CTL group. Thirtyeight participants dropped out following randomization, 8 participants after the posttreatment assessment, 6 participants after the 3-month follow-up, and 11 participants after the 6-month follow-up. Reasons for quitting were: exceeded the allocated time for the completion of measures (n = 20; 4 in PCBT-I, 12 in VCBT-I, and 4 in CTL); study judged too burdensome (n = 14; 4 in PCBT-I, 8 in VCBT-I, and 2 in CTL); lack of interest (n = 7; 4 in PCBT-I, 1 in VCBT-I, and 2 in CTL); no longer had a subjective sleep complaint (n = 7; 3 in PCBT-I, 3 in VCBT-I, and 1 in CTL); refusal to pursue completion of sleep diary (n = 4; 1 in PCBT-I and 3 in CTL); worsening of the physical condition/death (n = 6; 3 in PCBT-I, and 3 in VCBT-I); dissatisfied with the treatment (n = 3; 1 in PCBT-I and 2 in VCBT-I); the wish to stop thinking about cancer (n = 1; in CTL) or no reason provided (n = 1; in VCBT). Comparisons between Completers and Noncompleters. Comparisons between completers (n = 176; 72.7%) and participants with incomplete data (n = 66; 27.3%) were performed on demographic, medical, and main outcome variables at baseline. Noncompleters were more likely: (a) to be in the VCBT-I (36.3%) or PCBT-I (30.9%) conditions compared to the CTL condition (14.8%), χ 2 (2) = 10.12, P < 0.001; (b) to have a high school or lower education (38.0% versus 20.8%), χ 2 (2) = 8.88, P = 0.01; (c) to have a psychological disorder (any type; 32.6% versus 21.2%,P = 0.05), an anxiety disorder (48.5% versus 34.0%, P = 0.04) or a mood disorder (15.2% versus 5.1%, P = 0.01); (d) to report using an antidepressant (34.9% versus 22.2%; P = 0.04); and (e) to have a higher baseline ISI score (mean = 15.5 versus 13.8; t(238) = 2.78, P = 0.006). SLEEP, Vol. 39, No. 4, CBT for Insomnia in Breast Cancer Savard et al.

3 Solicited (n = 1,817) Eligible (n = 1,646) Excluded (n = 171) Not meeting inclusion criteria (n = 135) Declined to participate (n = 36) With Insomnia ISI 8 or Rx 2 nights within 2 week (n = 819) Declined RCT and screening (n = 369) Phone screening (n = 796) Declined RCT but accepted screening (n = 268) Accepted screening (n = 528) Without Insomnia ISI < 8 and Rx < 2 nights within 2 week (n = 827) Declined screening (n = 299) Accepted RCT (n = 182) Accepted RCT (n = 78) Total (n = 260) (16%) Excluded at clinical interview (n = 18) Randomized (n = 242) Professionally-administered CBT-I (n = 81) Video-based CBT-I (n = 80) Control (n = 81) Posttreatment Drop-out (n = 11) Posttreatment Drop-out (n = 23) Analyzed (n = 80) Posttreatment Drop-out (n = 4) 3-month follow-up Drop-out (n = 3) 3-month follow-up Drop-out (n = 2) Analyzed (n = 80) 3-month follow-up Drop-out (n = 3) 6-month follow-up Drop-out (n = 2) 6-month follow-up Drop-out (n = 1) Analyzed (n = 80) 6-month follow-up Drop-out (n = 3) 12-month follow-up Drop-out (n = 4) 12-month follow-up Drop-out (n = 5) Analyzed (n = 80) 12-month follow-up Drop-out (n = 2) Figure 1 Participants flow chart. CBT-I, cognitive behavioral therapy for insomnia; ISI, Insomnia Severity Index; RCT, randomized controlled trial; Rx, hypnotic medication. SLEEP, Vol. 39, No. 4, CBT for Insomnia in Breast Cancer Savard et al.

4 Table 1 Participants characteristics at baseline. Variable PCBT-I (n = 81) VCBT-I (n = 80) CTL (n = 81) Total (n = 242) Statistic (F or χ 2 ) Age, y, mean (SD) 52.6 (8.9) 55.3 (8.7) 55.4 (8.8) 54.4 (8.8) 2.63, P = 0.07 Income, $, mean (SD) (32 831) (29 687) (31 505) (31 378) 0.56, P = 0.57 Education, % (n) 5.58, P = 0.23 High school or lower 30.0 (24) 37.2 (29) 32.5 (26) 33.2 (79) Junior college 21.3 (17) 26.9 (21) 33.8 (27) 27.3 (65) University 48.8 (39) 35.9 (28) 33.8 (27) 39.5 (94) Marital status, % (n) 5.68, P = 0.46 Married/cohabiting 63.0 (51) 65.8 (52) 63.0 (51) 63.9 (154) Divorced 19.8 (16) 13.9 (11) 21.0 (17) 18.3 (44) Single 14.8 (12) 16.5 (13) 8.6 (7) 13.3 (32) Widow 2.5 (2) 3.8 (3) 7.4 (6) 4.6 (11) Occupation, % (n) 1.50, P = 0.96 Full or part time 23.5 (19) 24.1 (19) 23.5 (19) 23.7 (57) Sick leave 43.2 (35) 38.0 (30) 43.2 (35) 41.5 (100) Retired 22.2 (18) 27.9 (22) 25.9 (21) 25.3 (61) Other 11.1 (9) 10.1 (8) 7.4 (6) 9.5 (23) Menopausal status, % (n) 4.56, P = 0.34 Premenopause 9.9 (8) 5.0 (4) 7.5 (6) 7.5 (18) Perimenopause 33.3 (27) 23.8 (19) 33.8 (27) 30.3 (73) Postmenopause 56.8 (46) 71.3 (57) 58.8 (47) 62.2 (150) Comorbidity, % (n) Medical (any chronic disease) 71.6 (58) 79.8 (63) 79.0 (64) 76.8 (185) 1.83, P = 0.40 Psychiatric disorder (any) 55.6 (45) 53.8 (43) 50.6 (41) 53.3 (129) 0.41, P = 0.82 Anxiety 40.7 (33) 35.0 (28) 38.3 (31) 38.0 (92) 0.57, P = 0.75 Mood 6.2 (5) 8.8 (7) 8.6 (7) 7.9 (19) 0.47, P = 0.79 Substance 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 0.00, P = 0.99 Adjustment 24.7 (20) 20.0 (16) 13.6 (11) 19.4 (47) 3.22, P = 0.20 Antidepressant medication Users, % (n) 27.2 (22) 22.5 (18) 27.2 (22) 25.6 (62) 0.61, P = 0.74 Frequency, weekly, mean (SD) 7.8 (3.0) 6.6 (2.7) 8.6 (3.7) 7.7 (3.2) 1.94, P = 0.15 Anxiolytic medication Users, % (n) 29.6 (24) 32.5 (26) 33.3 (27) 31.8 (77) 0.28, P = 0.87 Frequency, weekly, mean (SD) 4.6 (2.6) 3.4 (2.8) 5.5 (3.6) 4.5 (3.0) 3.15, P = 0.05 Hypnotic medication Users, % (n) 21.0 (17) 17.5 (14) 14.8 (12) 17.8 (43) 1.06, P = 0.59 Frequency, weekly, mean (SD) 4.6 (2.4) 4.2 (2.0) 4.9 (2.4) 4.6 (2.2) 0.28, P = 0.75 Cancer stage, % (n) 6.19, P = (7) 11.3 (9) 17.3 (14) 12.4 (30) I 37.0 (30) 40.0 (32) 34.6 (28) 37.2 (90) II 38.3 (31) 26.3 (21) 29.6 (24) 31.4 (76) III 11.1 (9) 16.3 (13) 14.8 (12) 14.1 (34) Unknown 4.9 (4) 6.3 (5) 3.7 (3) 5.0 (12) Cancer duration, mo, mean (SD) 11.2 (12.1) 9.7 (5.6) 8.8 (3.9) 9.9 (8.0) 1.97, P = 0.14 Mastectomy type, % (n) 5.22, P = 0.07 Partial 88.6 (70) 78.5 (62) 90.1 (73) 85.8 (205) Total 11.4 (9) 21.5 (17) 9.9 (8) 14.2 (34) Current radiotherapy, % (n) 4.7 (3) 4.4 (3) 4.4 (3) 4.5 (9) 0.01, P = 0.99 Chemotherapy, % (n) 59.3 (48) 55.0 (44) 51.9 (42) 55.4 (134) 0.91, P = 0.64 Type of chemotherapy (n = 112/134), % (n) 4.38, P = 0.82 FEC (7) 13.2 (5) 19.4 (7) 17.0 (19) FEC-D 52.6 (20) 44.7 (17) 41.7 (15) 46.4 (52) TC 13.2 (5) 18.4 (7) 8.3 (3) 13.4 (15) AC/AC-T 10.5 (4) 13.2 (5) 19.4 (7) 14.3 (16) Other 5.3 (2) 10.5 (4) 11.1 (4) 8.9 (10) Hormone therapy, % (n) 76.5 (62) 68.8 (55) 75.3 (61) 73.6 (178) 1.45, P = 0.48 Type of hormone therapy (n = 167/178), % (n)* Tamoxifen 70.2 (40) 50.0 (27) 51.8 (29) 57.5 (96) 5.74, P = 0.06 Anastrozole 28.1 (16) 44.4 (24) 41.1 (23) 37.7 (63) 3.57, P = 0.17 Exemestane 1.8 (1) 1.9 (1) 5.4 (3) 3.0 (5) not valid Letrozole 14.0 (8) 18.5 (10) 17.9 (10) 16.8 (28) 0.47, P = 0.79 Trastuzumab (n = 232), % (n) 14.3 (11) 13.0 (10) 5.1 (4) 10.8 (25) 3.97, P = 0.14 Bevacizumab (n = 231), % (n) 4.0 (3) 0.0 (0) 2.5 (2) 2.2 (5) not valid Insomnia syndrome, % (n) 72.8 (59) a,b 62.5 (50) b 80.2 (65) a 71.9 (174) 6.33, P = 0.04 Insomnia duration, mo, mean (SD) 93.4 (151.0) 90.7 (142.4) (154.5) 98.9 (149.5) 0.50, P = 0.61 ISI score, mean (SD) 14.0 (4.3) 14.5 (4.4) 14.2 (4.4) 14.3 (4.4) 0.26, P = 0.77 Total wake time, min, mean (SD) (50.5) b (46.9) b (72.9) a (57.9) 4.89, P = Total sleep time, min, mean (SD) (63.1) (56.4) (75.2) (65.4) 0.84, P = 0.43 Sleep efficiency, %, mean (SD) 79.8 (9.4) b 79.3 (8.7) b 75.6 (12.5) a 78.2 (10.3) 3.88, P = 0.02 All participants received radiation therapy. *Only for HTX users; more than one type possible. FEC-100, 5-fluorouracil, epirubicin and cyclophosphamide; FEC-D, 5-fluorouracil, epirubicin and cyclophosphamide plus docetaxel; TC, taxol and carboplatin; AC/AC-T, adriamicide and cyclophosphamide/adriamicide and cyclophosphamide plus taxol. Means followed by different superscript letters are significantly different according to post hoc comparisons. SLEEP, Vol. 39, No. 4, CBT for Insomnia in Breast Cancer Savard et al.

5 Study Design and Randomization This study was a three-arm RCT with an allocation ratio of 1:1:1: (1) professionally administered CBT-I (PCBT-I; n = 81); (2) video-based CBT-I (VCBT-I; n = 80); and (3) control group (CTL; no CBT-I; n = 81). Participants were assessed at pretreatment and posttreatment, as well as at 3-, 6-, and 12-mo follow-ups. The randomization sequence was prepared by a biostatistician and the allocation sequence was concealed in opaque, sealed envelopes, numbered in advance and opened sequentially. All research personnel were blind to the group allocation sequence. Procedure Pretreatment Assessment Patients completed at home a battery of self-report scales and a 2-w daily sleep diary. A clinical interview (90 min) at the research center was then scheduled within 2 w. The interviewer first completed any missing data on the questionnaires with the patients and then administered the MMSE, the SCID, and the Insomnia Interview Schedule 18 (IIS). After their eligibility was confirmed, participants were informed of their group assignment. Intervention Phase CBT-I was of a duration of 6 w and combined behavioral, cognitive, and educational strategies. 11,12,18 As in primary insomnia, the intervention focuses on factors that are believed to maintain the insomnia over time, that is, maladaptive sleep behaviors and dysfunctional cognitions about sleep. Participants of the two CBT-I groups received the same series of six booklets (13 21 pages), with a different theme each week. PCBT-I: These patients received six weekly, individual treatment sessions of approximately 50 min. CBT-I sessions were administered by licensed psychologists and PhD students in clinical psychology with significant experience. Overall, 18.4% of the treatment sessions were assessed by a psychologist to ascertain treatment integrity. Seventy-four participants (91.4%) received all six treatment sessions. Adherence data were available for 70 completers: 100%, 94%, and 100% reported that they at least moderately put into practice the behavioral, cognitive, and sleep hygiene recommendations, respectively. These rates decreased to 97%, 65%, and 93%, respectively, when using a more stringent criterion (rating of a lot or extremely on the scale). VCBT-I: These participants received a self-help treatment package composed of a 60-min video (DVD format) and six booklets. 22 More details about the video-based intervention can be found elsewhere. 22 Each week, participants had to first watch a video segment (5 to 20 min each) and then read a booklet. They were informed that they could call a licensed psychologist to get further explanation on the treatment strategies proposed, but only seven participants (8.8%) did. Adherence data were available on the 54 completers: 100% reported to have read the six booklets and 89.8% watched all six video segments. In addition, 96%, 81%, and 94% reported that they at least moderately put into practice the behavioral, cognitive, and sleep hygiene recommendations, respectively, whereas these rates decreased to 59%, 54% and 74%, respectively, when using at least a lot as the criterion. Control Group (CTL): These participants did not receive CBT-I. A complimentary package of VCBT-I material (booklets and video) was offered to them when the 12-mo follow-up was completed; 60 participants who were still in the study at that time accepted and thus were mailed the treatment material. Posttreatment and Follow-up Assessments At each time point, participants completed the same self-report scales, another 2 w of sleep diary, and another phone interview to supply any missing data and administer the IIS. Interviewers were blind for the treatment condition in order to minimize the performance bias. Participants received 40$ CDN for each time point completed. Measures All French Canadian versions of measures used have been empirically validated or developed by the authors of the original version. Main Outcome Measures Insomnia Severity Index 18,28 : This is a seven-item questionnaire evaluating insomnia severity. A score of 8 or greater is used to detect clinically significant insomnia, whereas a score of 15 or greater indicates the possible presence of an insomnia disorder. 25 The ISI was validated in cancer patients. 25 Daily Sleep Diary: To provide subjective estimates of sleep onset latency (SOL), wake after sleep onset (WASO), early morning awakenings (EMA), TWT, total sleep time (TST), SE (ratio of TST on time spent in bed) and usage of hypnotic medications. Insomnia Interview Schedule (IIS) 18 : A semistructured interview to diagnose the presence of an insomnia syndrome defined as follows: subjective complaint of sleep difficulties, SOL or WASO greater than 30 min, 3 nights/w, duration 1 mo, associated with impaired daytime functioning or marked distress OR using a hypnotic medication 3 nights/w for 1 mo. Secondary Dependent Variables Multidimensional Fatigue Inventory (MFI) 29 : The French Canadian version of the MFI 30 contains 15 items (rated on a scale from 0 to 4). The average individual score of fatigue was used in this study. Hospital Anxiety and Depression Scale (HADS) 31,32 : A 14- item questionnaire rated on a scale from 0 to 3 and divided into two subscales: depression (HADS-D: seven items) and anxiety (HADS-A: seven items). European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) 33 : Only the global Quality of Life score (item 13) was used for the purpose of this study. Dysfunctional Beliefs and Attitudes about Sleep Scale Abbreviated version (DBAS-16) 34 : DBAS-16 is composed of 16 items assessing to what extent the person endorses erroneous beliefs about sleep (e.g., unrealistic sleep expectations) on an 11-point Likert scale ranging from 0 (strongly disagree) to 10 (strongly agree). SLEEP, Vol. 39, No. 4, CBT for Insomnia in Breast Cancer Savard et al.

6 Statistical Analyses All data were double-entered and missing or aberrant data were verified for maximal integrity. Analyses for the main hypotheses were performed using an intent-to-treat approach. No data imputation was performed. Demographics, healthrelated data, psychiatric diagnoses, medication use, cancer characteristics and treatments were investigated as potential covariates. 35 No variable was found to meet our criterion (i.e., correlations > 0.30 with main outcomes); hence, no covariate was included in the models. To investigate changes on study variables within and between conditions, 3 (Groups) 5 (Time: 5 assessments) splitplot linear (for continuous outcomes) and generalized (for binary outcomes) mixed model analyses were completed to test Group, Time, and Interaction effects (decomposed using simple effects when significant). Effect sizes (Cohen d) were computed as the ratio of raw change and the root mean square error (RMSE) of the model. All analyses were performed with SAS (SAS Institute, Cary, NC) using a standard twotailed 5% alpha level. Simple effects and post hoc comparisons used a Bonferroni-like corrected alpha level computed with the simultaneous test procedure (i.e., addition of the main effects + interaction alpha levels divided by the number of simple effects tested). 37 RESULTS Figure 2 Between-groups differences at each time point. ISI, Insomnia Severity Index; Pre, pretreatment; Post, posttreatment; FU3, 3-mo followup; FU6, 6-mo follow-up; FU12, 12-mo follow-up; PCBT-I, professionally administered cognitive behavioral therapy for insomnia; VCBT-I, videobased cognitive behavioral therapy for insomnia; CTL, control group; TWT, total wake time; SE, sleep efficiency; IIS, Insomnia Interview Schedule. Treatment Effects on Sleep Measures A significant overall Group Time (3 5) interaction was found on the ISI total score, F(8,741) = 5.49, P < 0.001, and on all variables derived from the sleep diary, except TST (P = 0.24). Comparisons between the posttreatment and the follow-up phase indicated non-significant changes on ISI scores, SOL, WASO, TWT, and SE in PCBT-I, and on ISI scores, SOL, EMA, TWT, TST, and SE in VCBT-I (Table 2). However, a significant increase of EMA (+4.1 min) and of TST (+11.7 min) in PCBT-I and a significant increase of WASO in VCBT-I (+3.5 min) were found. CTL participants significantly improved on all sleep variables. Findings also revealed a nonsignificant reduction in the proportion of users of hypnotic medications in the PCBT-I group, a significant reduction in the VCBT-I group, and a significant increase in the CTL group. Overall, effect sizes of time effects from posttreatment to the follow-up phase showed a small worsening of sleep in PCBT-I and VCBT-I groups (mean Cohen d = 0.10 for both conditions), whereas the CTL group exhibited a moderate improvement (mean Cohen d = 0.48). Of note, although the mean ISI scores and SE values fell clearly within the nonclinical range (ISI < 8; SE > 85%) at posttreatment and throughout follow-up in PCBT-I, they were slightly below or over that threshold in VCBT-I (Figure 2). Treatment Effects on Secondary Variables Significant overall Group Time (3 5) interactions were found on all secondary variables, except depression (P = 0.17; Table 3). Time effects comparing posttreatment and the followup phase revealed nonsignificant changes for PCBT-I on anxiety, depression, fatigue, and quality of life and for VCBT-I SLEEP, Vol. 39, No. 4, CBT for Insomnia in Breast Cancer Savard et al.

7 Table 2 Mean scores, adjusted for baseline values, obtained on sleep diary variables by each group at all assessments and effects obtained. Variable Time PCBT-I VCBT-I CTL F ISI Pre (df = 741) Post FU FU FU Post-FU change (d ) 0.3 NS a (0.07) 0.3 NS a ( 0.08) 2.0*** b ( 0.48) 5.76, P = SOL (min) WASO (min) EMA (min) TWT (min) TST (min) SE (%) Hypnotic medications users (%) (df = 753) Pre Post FU FU FU Post-FU change (d ) 0.0 NS a (0.00) 1.3 NS a (0.09) 5.6*** b ( 0.39) 4.81, P = Pre Post FU FU FU Post-FU change (d ) 0.8 NS a (0.05) 3.5* a (0.20) 8.1*** b ( 0.47) 8.69, P < Pre Post FU FU FU Post-FU change (d ) 4.1** a (0.22) 1.1 NS a,b (0.06) 5.6** b ( 0.30) 4.39, P = 0.01 Pre Post FU FU FU Post-FU change (d ) 4.9 NS a (0.16) 5.6 NS a (0.18) 18.9*** b ( 0.61) 12.08, P < Pre Post FU FU FU Post-FU change (d ) 11.7** (0.27) 0.8 NS (0.02) 13.7* (0.32) 1.99, P = 0.14 Pre Post FU FU FU Post-FU change (d ) 0.6 NS a ( 0.10) 0.8 NS a ( 0.13) 3.4*** b (0.60) 9.71, P < Pre Post FU FU FU Post-FU change (OR) 4.2 NS a (0.58) 6.4* a (0.61) 6.6* b (1.57) 5.37, P = Means followed by superscript letters are significantly different according to post hoc comparisons. F test is Condition Time interaction (group differences between change scores). *P < 0.05, **P < 0.01, ***P < Cohen d = 0.20 = small effect; d = 0.50 = moderate effect; d = 0.80 = large effect. FU, followup; ISI, Insomnia Severity Index; SOL, sleep onset latency; WASO, wake after sleep onset; EMA, early morning awakening; TWT, total wake time; TST, total sleep time; SE, sleep efficiency; OR, odds ratio. on depression and DBAS scores. A significant improvement was found in VCBT-I on anxiety, fatigue, and quality of life, whereas DBAS scores significantly increased in PCBT-I and decreased in CTL. Overall, effect sizes from posttreatment to the follow-up phase showed symptom worsening of a small magnitude in PCBT-I (mean Cohen d = 0.14), whereas VCBT-I SLEEP, Vol. 39, No. 4, CBT for Insomnia in Breast Cancer Savard et al.

8 Table 3 Mean scores, adjusted for baseline values, obtained on secondary variables by each group at all assessments and effects obtained. Variable Time PCBT-I VCBT-I CTL F HADS-A Pre (df = 742) Post FU FU FU Post-FU change (d ) 0.0 NS (0.02) 0.9* ( 0.35) 0.1 NS ( 0.05) 1.62, P = 0.20 HADS-D (df = 742) MFI (df = 740) EORTC-QOL (df = 742) DBAS-16 (df = 739) Pre Post Pre-post change (d ) 1.9*** a ( 0.80) 0.8* b ( 0.34) 0.5 NS b ( 0.20) 5.10, P = FU FU FU Post-FU change (d ) 0.3 NS (0.12) 0.4 NS ( 0.18) 0.1 NS ( 0.03) 1.32, P = 0.27 Pre Post FU FU FU Post-FU change (d ) 0.1 NS a (0.15) 0.2** b ( 0.33) 0.1 NS a,b ( 0.10) 3.96, P = 0.02 Pre Post FU FU FU Post-FU change (d ) 2.3 NS a ( 0.15) 3.8* b (0.24) 2.6 NS a ( 0.17) 3.72, P = 0.02 Pre Post FU FU FU Post-FU change (d ) 0.3** a (0.28) 0.2 NS a (0.22) 0.4*** b ( 0.35) 9.31, P < Means followed by superscript letters are significantly different according to post hoc comparisons. F test is Condition Time interaction (group differences between change scores). *P < 0.05, **P < 0.01, ***P < Cohen d = 0.20 = small effect; d = 0.50 = moderate effect; d = 0.80 = large effect. FU, followup; HADS-A, anxiety subscale of the Hospital Anxiety and Depression Scale; HADS-D, depression subscale of the Hospital Anxiety and Depression Scale; MFI, Multidimensional Fatigue Inventory; EORTC-QOL, European Organization for Research and Treatment of Cancer Quality of Life (global item); DBAS-16, Dysfunctional Beliefs about Sleep scale Abbreviated. and CTL exhibited a small improvement (mean Cohen d = 0.18 and 0.07, respectively). Remission Rates by Group Two criteria of insomnia remission were used: (a) ISI score < 8; and (b) not meeting the insomnia syndrome criteria according to the IIS. Remission rates between conditions were compared after adjusting for baseline ISI raw scores. For ISI-defined remission, only a main group effect was found, F(2,198) = 12.87, P < At posttreatment, the ISI remission rate was significantly greater in PCBT-I (70%), as compared to both VCBT-I (45%) and CTL (27%), F(2,539) = 12.78, P < At the 3- and 6-mo follow-ups, remission rates were still significantly greater in PCBT-I (64% and 73%, respectively) when compared to VCBT-I (56% and 52%) and CTL (37% and 39%), but these differences were no longer significant at the 12-mo evaluation (PCBT-I = 67%, VCBT-I = 59%, CTL = 48%; P = 0.10). For the IIS-defined remission, again, only a significant group main effect was observed, F(2,198) = 6.59, P < At posttreatment, and at the 3- and 6-mo follow-ups, PCBT-I exhibited a significantly higher rate (77%, 79%, and 82%, respectively) compared to CTL (49%, 50%, and 56%, respectively), whereas remission rates in VCBT-I (68%, 61%, 69%) were not different from the other two conditions. No significant differences were found at the 12-mo follow-up (PCBT-I = 75%, VCBT-I = 70%, CTL = 64%, P = 0.34). Relapses Rates by Group Relapse was defined as meeting one remission criterion at posttreatment but failing to meet the same criterion at one of the follow-ups. The analyses adjusted for baseline ISI raw scores. With regard to the ISI criterion, no significant main betweengroups effect was found when relapse rates were tested at each follow-up assessment, F(2,87) = 0.63, P = However, when investigating any relapse occurring during the entire follow-up period, participants in the CTL condition were 2.6 times more SLEEP, Vol. 39, No. 4, CBT for Insomnia in Breast Cancer Savard et al.

9 likely (odds ratio = 2.57) to experience at least one relapse (66.7%), compared to treated participants (PCBT-I: 47.8%; VCBT-I: 41.7%), t(87) = 1.77, P = Analyses on the IIS showed no significant main between-groups difference when relapse was tested at each follow-up assessment (P = 0.60), nor when it was investigated for the entire follow-up period (P = 0.77). DISCUSSION This study aimed at comparing long-term effects of a videobased CBT-I to that of a face-to-face intervention and to a no-treatment control group for treating insomnia symptoms in breast cancer patients. Our earlier report, 24 focusing on pretreatment versus posttreatment comparisons, revealed that the video-based intervention produced greater treatment effects at posttreatment than the control condition on most sleep variables (ISI, SOL, WASO, TWT, SE, and dysfunctional beliefs about sleep). In addition, larger effects in PCBT-I, as compared to VCBT-I, were found on the ISI total score and most secondary variables (depression, fatigue, dysfunctional beliefs about sleep). This superiority of PCBT-I over VCBT-I was discussed in depth in our earlier article. 24 Briefly, this larger effect on some sleep and secondary variables could be attributable to the professional guidance provided in PCBT-I, which could help patients use the strategies they learned in order to cope not only with insomnia but also with the related symptomatology (e.g., anxiety symptoms). Follow-up data generally indicated a very good sustainment of these treatment gains, up to 12 mo after, in both PCBT-I and VCBT-I conditions, whereas CTL patients generally improved. Thus, self-administered CBT-I appears to produce sustainable sleep improvements in this population. Results also indicated greater insomnia remission rates in PCBT-I than VCBT-I, who obtained larger remission rates than CTL, at 3- and 6-mo follow-ups. These group differences vanished at the 12-mo evaluation. Only a few variables significantly deteriorated following CBT-I, that is, WASO (+3.5 min) in VCBT-I and EMA (+4.1 min) and DBAS scores (+0.3) in PCBT-I. However, all of these changes were of a small magnitude (Cohen d = 0.20, 0.22, and 0.28, respectively). A slight deterioration of sleep is not surprising given that, typically, patients who receive CBT-I tend to loosen up on the application of some treatment strategies (e.g., increased time in bed) in the long term. 38 The lack of between-groups differences at the 12-mo followup is mostly attributable to the significant improvement of control participants at that time, which could be due to a natural remission phenomenon. Natural remission of insomnia has been found to occur in 45.8% of cancer patients. 2 The mean insomnia duration of 112 mo reported by CTL patients at baseline appears to contradict this explanation. However, insomnia is known to have a wax and wane evolution characterized by several remissions and relapses. 2,39,40 When asked about the duration of their insomnia, it is possible that our participants identified the moment when insomnia first occurred rather than the onset of their last episode. Hence, the improvement found in control patients could represent a natural remission of their most recent episode. Other factors that may have contributed to these sleep improvements in CTL individuals at follow-up are their increased use of hypnotic medications (from 14.5% of the patients at posttreatment to 21.1% at follow-up) and the simple fact of completing questionnaires and sleep diary on several occasions. In summary, these follow-up results suggest that, although face-to-face sessions remain the best format for administering CBT-I efficaciously, a low-intensity CBT-I, such as the videobased intervention tested in this study, appears to provide a most valuable alternative in settings where resources for administering this treatment are lacking and in the community. In such cases, our video-based intervention, and perhaps other forms of minimal CBT-I (e.g., Internet-based programs), could be used as a stand-alone treatment. Indeed, our remission rates indicate that a minimal CBT-I is sufficient to fully treat an important proportion of patients (45% and 68% depending on the criterion), an effect that is largely sustained over time. However, given that many VCBT-I patients were still symptomatic following treatment, minimal interventions should ideally be used as part of a stepped care model in which low-intensity interventions are followed by more intensive forms of treatment (e.g., group or individual sessions) when needed. 41 Appropriate entry-level treatments of stepped care models are interventions that allow a significant proportion of patients to become symptom free, 42,43 a criterion that is clearly met by our videobased intervention. This study is characterized by many strengths including the use of a large sample size, recruited directly at the clinic, and few exclusion criteria, thus increasing the generalization of the findings. The assessment of treatment integrity and the 1-y follow-up are other strengths. However, the findings generalization is limited by the inclusion of women with breast cancer only. It is therefore unknown whether the same pattern of results would be found in patients with other types of cancer or individuals with no medical comorbidity. The relatively low participation rate also limits the external validity. This is mainly due to the large number of eligible patients (n = 514) who declined participation because they thought they did not have insomnia severe enough to warrant treatment despite reporting clinical insomnia symptoms. The differential dropout rate obtained across groups (13.6% in PCBT-I versus 28.8% in VCBT-I) is another limitation. Although this may have overestimated the efficacy of VCBT-I (given that noncompleters tended to be less educated and have more psychiatric comorbidity), it probably indicates more that a self-administered intervention is not a suitable treatment format for everybody, which again calls for using minimal interventions as part of stepped-care models. REFERENCES 1. Savard J, Villa J, Ivers H, Simard S, Morin CM. 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10 4. Savard J, Savard MH. Insomnia and cancer: prevalence, nature, and nonpharmacologic treatment. Sleep Med Clin 2013;8: Daley M, Morin CM, LeBlanc M, Gregoire JP, Savard J. The economic burden of insomnia: direct and indirect costs for individuals with insomnia syndrome, insomnia symptoms, and good sleepers. Sleep 2009;32: National Institutes of Health. National Institutes of Health Stateof-the-Science Conference Statement on Manifestations and Management of Chronic Insomnia in Adults, June 13-15, Sleep 2005;28: Berger AM, Kuhn BR, Farr LA, et al. Behavioral therapy intervention trial to improve sleep quality and cancer-related fatigue. Psychooncology 2009;18: Davidson JR, Waisberg JL, Brundage MD, MacLean AW. Nonpharmacologic group treatment of insomnia: a preliminary study with cancer survivors. Psychooncology 2001;10: Epstein DR, Dirksen SR. Randomized trial of a cognitive-behavioral intervention for insomnia in breast cancer survivors. 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11 ACKNOWLEDGMENTS The authors sincerely thank the patients for their participation in this study and Fred Sengmueller for revising the manuscript. We also acknowledge the contribution of the following persons for their involvement in the recruitment, assessment and treatment of the study participants: Virginie Audet-Croteau, Emmanuelle Bastille-Denis, Marie-Solange Bernatchez, Rosée Bruneau- Bhérer, Genevieve Dionne, Aude Caplette-Gingras, Lucie Casault, Joanne Castonguay, Caroline Desautels, Anne-Josée Guimond, Stéphanie Hamel, Catherine Marcotte, Louis-Philippe Marion, Joanie Mercier, Mylène Ross- Plourde, Véronique Roy, Sophie Ruel, Eugénie Simard, Valérie Tremblay, Claudia Trudel-Fitzgerald, and Julie Villa. DISCLOSURE STATEMENT This was not an industry supported study. This research was funded by the Canadian Breast Cancer Research Alliance (grant #017738) and a research scientist award from the Fonds de la recherche en santé du Québec to the first author. Dr. Morin is on the advisory board of Merck and Valeant and has received research support from Novartis. The other authors have indicated no financial conflicts of interest. This study was conducted at the CHU de Québec-Université Laval Research Center, Québec, Québec, Canada. SUBMISSION & CORRESPONDENCE INFORMATION Submitted for publication July, 2015 Submitted in final revised form October, 2015 Accepted for publication November, 2015 Address correspondence to Josée Savard, PhD, Laval University Research Center, 11 Côte du Palais, Québec, Québec, Canada, G1R 2J6; Tel: (418) ; Fax: (418) ; josee.savard@psy.ulaval.ca SLEEP, Vol. 39, No. 4, CBT for Insomnia in Breast Cancer Savard et al.