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© 2003 American Society for Clinical Oncology Docetaxel and Doxorubicin Compared With Doxorubicin and Cyclophosphamide as First-Line Chemotherapy for Metastatic Breast Cancer: Results of a Randomized, Multicenter, Phase III Trial
From the University of California at Los Angeles, CA; University of Pretoria, Pretoria, and Sandton Oncology Centre, Johannesburg, South Africa; Hospital de San Isidro, Buenos Aires, Argentina; Szt Margit Hospital, Budapest, and County Hospital, Gyor, Hungary; Hospital Clinico San Carlos, Madrid, Spain; City Hospital Trust, Nottingham, and Western General Hospital, Edinburgh, United Kingdom; Oncology Center, Warsaw, and Oncology Center, Poznan, Poland; Waikato Hospital, Hamilton, New Zealand; and Aventis Pharma, Antony, and Institut Curie, Paris, France. Address reprint requests to Jean-Marc Nabholtz, MD, University of California, Los Angeles, Peter Ueberroth Building Suite 3360B, Los Angeles, CA 90095-7077; email: jmnabholtz{at}hotmail.com.
Purpose: This randomized, multicenter, phase III study compared doxorubicin and docetaxel (AT) with doxorubicin and cyclophosphamide (AC) as first-line chemotherapy (CT) in metastatic breast cancer (MBC). Patients and Methods: Patients (n = 429) were randomly assigned to receive doxorubicin 50 mg/m2 plus docetaxel 75 mg/m2 (n = 214) or doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 (n = 215) on day 1, every 3 weeks for up to eight cycles. Results: Time to progression (TTP; primary end point) and time to treatment failure (TTF) were significantly longer with AT than AC (median TTP, 37.3 v 31.9 weeks; log-rank P = .014; median TTF, 25.6 v 23.7 weeks; log-rank P = .048). The overall response rate (ORR) was significantly greater for patients taking AT (59%, with 10% complete response [CR], 49% partial response [PR]) than for those taking AC (47%, with 7% CR, 39% PR) (P = .009). The ORR was also higher with AT in patients with visceral involvement (58% v 41%; liver, 62% v 42%; lung, 58% v 35%), three or more organs involved (59% v 40%), or prior adjuvant CT (53% v 41%). Overall survival (OS) was comparable in both arms. Grade 3/4 neutropenia was frequent in both groups, although febrile neutropenia and infections were more frequent for patients taking AT (respectively, 33% v 10%, P < .001; 8% v 2%, P = .01). Severe nonhematologic toxicity was infrequent in both groups, including grade 3/4 cardiac events (AT, 3%; AC, 4%). Conclusion: AT significantly improves TTP and ORR compared with AC in patients with MBC, but there is no difference in OS. AT represents a valid option for the treatment of MBC.
IN METASTATIC BREAST cancer (MBC), combination chemotherapy produces increased response rates (RR) and time to progression (TTP) compared with monotherapy.1 The incorporation of anthracyclines further improves RRs and TTP beyond those obtained with non–anthracycline-containing combinations.2–4 However, it is unclear whether these improvements produce enhanced survival compared with sequential use of single agents. Indeed, front-line use of anthracycline-containing polychemotherapy yields long-term survival in a small minority of patients (2%).2 The development of more effective regimens is required. Docetaxel was introduced for the treatment of advanced breast cancer in the 1990s. Phase II monotherapy trials, most using 100 mg/m2 every 3 weeks, reported RRs from 30% to 60% in untreated and anthracycline-resistant patients.5–10 Randomized studies subsequently compared single-agent docetaxel with various regimens after anthracycline failure, including mitomycin and vinblastine, methotrexate and fluorouracil (FU), and vinorelbine and continuous-infusion FU.11–13 In the two largest trials,11,12 docetaxel significantly increased RRs and TTP and improved survival compared with mitomycin and vinblastine. In another trial comparing docetaxel with doxorubicin in patients who experienced treatment failure with cyclophosphamide-, methotrexate-, and FU-containing chemotherapy, docetaxel produced superior RRs and TTP, although the latter was not statistically significant.14 These data established docetaxel as one of the most active agents against advanced breast cancer. The activity of docetaxel and the anthracyclines, and the lack of complete cross-resistance between them, provided a rationale to develop these drugs in combination.15 In phase I and II trials, two regimens were defined: 50 mg/m2 of doxorubicin plus 75 mg/m2 of docetaxel (AT),16 or 60 mg/m2 each of doxorubicin and docetaxel.17 The AT regimen has also been used with cyclophosphamide (50/75/500 mg/m2).18 In a phase I/II study, AT (50/75 mg/m2) produced an RR of 81% and TTP of 46 weeks.19 Slightly lower RRs (57% to 66%) were observed in phase II studies that used 60/60 mg/m2.17,20 The feasibility and toxicity of the AT-based combinations were acceptable. This study compared the efficacy and safety of AT (50/75 mg/m2) with doxorubicin and cyclophosphamide (AC; 60/600 mg/m2) in 429 patients with untreated MBC.
Patient Population Women with histologically or cytologically proven metastatic, progressive breast cancer who met the following eligibility criteria were included in the study: 18 to 75 years of age; measurable and/or assessable disease; Karnofsky performance status  60%; WBC count 4,000 cells/µL; hemoglobin 10.0 g/dL; platelets 100,000 cells/µL; serum creatinine  1.5 mg/dL; total bilirubin less than the upper limit of normal (ULN), AST and ALT less than 2.5 x ULN, alkaline phosphatase 5 x ULN; and normal cardiac function confirmed by left ventricular ejection fraction (LVEF). Patients who had received adjuvant or neoadjuvant non–anthracycline-containing chemotherapy were eligible. Prior hormonal therapy for metastatic disease was permitted if there was objective evidence of disease progression, but concurrent hormonal treatment was not allowed. Prior radiotherapy was allowed if it did not involve a site used to assess response and 4 weeks had elapsed since treatment involving 20% of the bone marrow.
Exclusion criteria included the following: previous chemotherapy for metastatic disease; pregnancy or lactation; blastic bone metastases, lymphangitic carcinomatosis, ascites, or pleural effusion as only manifestation of metastatic disease; brain or leptomeningeal involvement; preexisting neurotoxicity Patients were recruited from 58 centers in Europe, South Africa, South America, Australia, and Canada. The study was performed in accordance with the Declaration of Helsinki (Somerset West Amendment) and informed consent was obtained according to local regulatory requirements.
Study Design The primary objective was to compare TTP; secondary objectives were to compare overall RRs (ORRs), times to treatment failure (TTF), toxicity, survival, and quality of life (QoL).
Treatment Premedication for AT included 8 mg of dexamethasone orally 12, 3, and 1 hour(s) before docetaxel, and 12, 24, and 36 hours after infusion. Antiemetics were used at the investigator’s discretion. Primary prophylactic antibiotics or granulocyte colony-stimulating factor (G-CSF) were not permitted. Prophylactic G-CSF was advised if neutropenic complications occurred in a previous cycle, followed by dose reduction if another episode occurred. Febrile neutropenia was fever (above 38°C) with grade 4 neutropenia requiring intravenous antibiotics and/or hospitalization, without documented infection. Chemotherapy was given for a maximum of eight cycles. If no response occurred, further treatment was at the investigator’s discretion. After treatment discontinuation or study completion, no antitumor therapy was permitted until tumor progression was documented or the investigator determined that treatment was necessary. Dose reduction (75 to 60 mg/m2 docetaxel or 50 to 40 mg/m2 doxorubicin with AT, and 60 to 50 mg/m2 doxorubicin with AC) and/or treatment delay or discontinuation were planned for severe toxicities except alopecia and anemia.
Assessments
All lesions (measurable and assessable) were evaluated after cycles 3, 6, and 8 or at study treatment discontinuation, and then every 2 months until disease progression or death. Response was classified according to World Health Organization criteria. All responses had to be confirmed by another evaluation Weekly blood counts were performed. Measurement of LVEF was performed after cycles 3, 6, and 8 and as clinically indicated. Patients discontinued treatment in the event of an LVEF decline more than 10% from baseline and less than the lower limit of normal (LLN). Adverse events were assessed on day 1 before therapy and graded according to National Cancer Institute common toxicity criteria or as mild, moderate, or severe (Coding Symbols for Thesaurus of Adverse Reaction Terms classification) if National Cancer Institute common toxicity criteria were not appropriate. QoL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30, a 30-item core questionnaire, and the QLQ-BR23 module, with 16 items applicable to MBC.21,22 These were completed by patients within 3 days before first infusion, then before every alternate cycle and at each visit during follow-up until progression.
Statistical Methodology and Analysis The intention-to-treat (ITT) population included all randomly assigned patients. Patients who received two treatment cycles with at least one tumor assessment were assessable for response, as were patients removed from the study before two treatment cycles for progressive disease. Analyses of ORR, TTP, and TTF were performed on the assessable and ITT populations. TTP was the primary end point and was calculated from date of randomization to date of first progression. The Kaplan-Meier method was used to analyze TTP, and the groups were compared using the two-sided log-rank test.
The ORR was a secondary end point. A Multivariate analyses were performed on TTP using a Cox proportional hazards model and on ORR using a logistic regression model that incorporated prospectively defined variables. This model permitted analysis of treatment effect adjusting for age, performance status, time from diagnosis to randomization, number of organs involved, visceral involvement, bone involvement, liver involvement, previous hormonal therapy, number of hormonal therapies for advanced disease, adjuvant chemotherapy, relapse within 12 months from end of adjuvant chemotherapy, and baseline QoL score using EORTC Quality of Life Questionnaire C30. TTF was calculated from date of randomization until date of progression, death (any cause), withdrawal owing to adverse event, patient refusal, loss to follow-up, or further anticancer therapy before documented progression (whichever occurred first). The Kaplan-Meier method was used to analyze TTF and the two-sided log-rank test was used to compare the groups.
Safety analyses were performed on all treated patients; adverse events were compared using the Overall survival was analyzed using the Kaplan-Meier method, and the survival curves were compared using the two-sided log-rank test. This study was not powered to detect survival differences.
Patients Of 429 patients randomized (AT, 214 patients; AC, 215 patients), 213 patients in the AT group and 210 patients in the AC group received treatment. Median follow-up was 49 months. Baseline characteristics were well balanced, and major negative prognostic factors were similar in both groups (Table 1  ).
Exposure to Study Medication Both groups received a high median number of cycles per patient (AT, eight cycles; AC, seven cycles); the median relative dose-intensity was 0.96 on both arms. The median cumulative dose of doxorubicin was 378 mg/m2 for patients taking AT and 420 mg/m2 for patients taking AC; the median cumulative dose of docetaxel for patients taking AT was 552 mg/m2. Overall, 118 patients taking AT (55.4%) and 100 patients taking AC (47.6%) received the maximum number of cycles. Reasons for treatment discontinuation included disease progression (AT, 21.0%; AC, 31.6%), adverse events (AT, 14.0%; AC, 13.0%), withdrawn consent (AT, 7.5%; AC, 7.0%), and other reasons (AT, 6.1%; AC, 6.5%). The adverse event that resulted most frequently in discontinuation was asymptomatic LVEF decline (AT, 4%; AC, 8%). Other reasons were primarily investigator decisions to discontinue treatment after six cycles if maximum benefit had been reached.
Efficacy
TTP was analyzed after a median follow-up period of 18 months and was significantly longer in patients treated with AT (median, 37.3 weeks [95% CI, 33.4 to 42.1 weeks] v 31.9 weeks [95% CI, 27.4 to 36.0 weeks]; log-rank P = .014) (Fig 1
The TTF was significantly longer in the AT group (median, 25.6 weeks [95% CI 22.3 to 28.0 weeks] v 23.7 weeks [95% CI 20.6 to 26.0 weeks]; log-rank P = .048; Fig 2 ). In fully assessable patients, TTF was also significantly longer for patients taking AT (median, 27.6 weeks [95% CI, 25.1 to 31.7 weeks] v 24.4 weeks [95% CI, 21.4 to 26.4 weeks]; P = .007).
ORR in the ITT analysis was significantly higher with AT than with AC (59% v 47%; P = .009). For the 191 patients treated with AT who were fully assessable, the ORR was 65%; for the 199 fully assessable patients taking AC, the ORR was 50% (P = .004) (Table 2 ). Fewer patients taking AT experienced progressive disease as best response (AT, 10%; AC, 15%). The AT combination produced a higher RR in all poor-prognosis subgroups (Table 3). When prospectively defined prognostic factors (visceral involvement, number of organs involved, and previous adjuvant therapy) were adjusted for, logistic regression analysis confirmed a significant treatment effect (odds ratio AT/AC 1.7; 95% CI 1.2 to 2.5; P = .007).
Survival analysis was performed at 49 months of median follow-up, when 79% of patients (322 of 429 patients) had died. Of the 322 deaths, 165 of 214 patients (77%) were in the AT group and 176 of 215 patients (82%) were in the AC group. Survival did not differ between the groups (log-rank P = .26; Fig 3 ). Median survival was 22.5 months in the AT group (95% CI, 19.0 to 26.4 months) and 21.7 months in the AC group (95% CI, 19.8 to 25.2 months).
Approximately 60% of patients received additional chemotherapy. In the AC group, 29% of patients (62 of 215 patients) received docetaxel as additional treatment, compared with 6% (13 of 214) in the AT group (Table 4 ).
Safety The incidence of toxic deaths was low. One patient in the AT arm died from congestive heart failure (CHF) on study. Four patients in the AC arm died, one from infection and three from CHF.
Hematologic adverse events were the most frequent toxicity (Table 5
Nonhematologic adverse events are listed in Table 6 . The incidence of grade 3/4 gastrointestinal toxicities was similar except for diarrhea, which occurred more frequently with AT (8% v 1%). No grade 3/4 neurosensory adverse events occurred; severe asthenia was more frequent with AT (9% v 2%). Docetaxel-specific toxicities (severe fluid retention and nail disorders) occurred in fewer than 1% of patients; one patient discontinued AT because of edema.
CHF occurred in 3% of patients (six of 213) receiving AT and 4% (eight of 210) receiving AC (Table 7 ). One hundred eighty patients who received AT and 176 who received AC were assessable for LVEF analysis. An LVEF decrease of 20 points (13% v 6%; P = .03) and 30 points (6% v 1%; P = .01) from baseline occurred more frequently with AC. Among the patients assessable by LVEF (180 patients in the AT group and 176 patients in the AC group), 18% (32 patients in each group) experienced a decrease of LVEF greater than 10% and below the LLN. The cumulative dose of doxorubicin was more than 360 mg/m2 in 54% of patients receiving AT and in 64% receiving AC.
QoL Overall compliance was high (> 70%) through cycle 6. After cycle 6, overall compliance decreased and was quite low in follow-up (< 30%), but the rates in the groups were comparable. The cumulative proportion of missing scores at each cycle was similar in the groups except at cycle 8, where there were more missing data in the AC group.
The baseline Global Health Status/QoL score was comparable for the groups and remained constant throughout the study (Fig 4
This is the first reported phase III trial in MBC comparing AT with a standard anthracycline-containing regimen (AC). We noted improved RRs and increased TTP with AT, although no difference in overall survival was observed. RRs were superior with AT in poor-prognosis patients; this improved RR may be relevant in those with rapidly progressive visceral metastases, for whom effective short-term control of the disease is important, or in neoadjuvant treatment, where tumor reduction is the primary objective. The improvement in median TTP was modest but statistically significant. The TTP curves clearly separate by 15 weeks, and at any time point there was a 32% higher risk of progression for patients taking AC, suggesting that evaluation of median TTP does not completely reflect the potential benefit of AT. These results are consistent with other trials that compared anthracycline and taxane with a standard anthracycline-based regimen. Preliminary data from the only other trial incorporating docetaxel suggest that the combination of docetaxel, doxorubicin, and cyclophosphamide yields higher response rates (54% v 43%) than FU, doxorubicin, and cyclophosphamide (FAC).23 Four phase III studies have combined paclitaxel with either doxorubicin or epirubicin as front-line therapy for MBC.24–27 Trials conducted by the EORTC and in Germany reported superior response rates (although not statistically significant) with paclitaxel and doxorubicin or epirubicin (EP), but no improvement in TTP or survival, when compared with AC or epirubicin and cyclophosphamide.24,25 In the United Kingdom, a study involving 705 patients compared epirubicin and cyclophosphamide with EP; best response rates (67% v 56%) were significantly improved in the EP group, although median progression-free and overall survival did not differ.26 In contrast, Jassem et al27 observed increased response rates (68% v 55%), TTP (8.3 v 6.2 months), and survival (23.3 v 18.3 months) when comparing AP with FAC in 267 patients with advanced breast cancer. This trial is the only study using paclitaxel and anthracycline in which TTP and survival were superior. One potential explanation for the discrepancy in survival results between the current trial and that performed by Jassem et al may be differences in use of second-line therapy. In our study, approximately 60% of patients in each treatment group received additional chemotherapy, including 40% in the AC group and 12% in the AT group who received a taxane (29% and 6% received docetaxel, respectively). Thus there was a high rate of cross-over to docetaxel in the AC group, which could mask any survival benefit of AT. This is especially relevant because docetaxel administered as second-line chemotherapy may prolong survival in patients with MBC who have experienced disease progression with anthracycline treatment.11 In the Jassem trial, 24% of patients in the control FAC arm received a subsequent taxane, including only 14% of patients treated with docetaxel. Both groups in our trial compare favorably in terms of response rates and TTP with single-agent chemotherapy in phase III trials.11,28,29 The observation that anthracycline and taxane combinations yield higher response rates and increased TTP compared with anthracycline or taxane monotherapy was confirmed by the American Intergroup.29 In this study, 739 patients were randomized to paclitaxel, doxorubicin, or both. ORR and TTP were higher in the group receiving combination therapy, but median survival was equivalent. Given the palliative nature of therapy in MBC, delaying disease progression seems to be a reasonable goal. The TTP curves in our study show that more patients on the AT regimen remained progression-free at any time point. The AT regimen was generally well tolerated. In both arms, the principal toxicity was myelosuppression. There was a significantly higher incidence of febrile neutropenia in the AT treatment arm (33% v 10% of patients), although no deaths from sepsis occurred, and the incidence of grade 3/4 infections was low. Nevertheless, patient education, adequate monitoring, and cytokine prophylaxis, at least after an episode of febrile neutropenia, are advisable when using AT. We followed these guidelines and were able to maintain a high median relative dose-intensity and deliver a high median number of cycles of AT. Severe nonhematologic toxicities were infrequent and similar in both treatment groups, except that severe diarrhea and asthenia occurred more frequently with AT. Despite a high cumulative dose of docetaxel (median, 552 mg/m2), severe docetaxel-specific toxicities (such as fluid retention and nail changes) were uncommon and effectively managed. There was no significant difference in cardiac toxicity between the groups. Four percent of patients receiving AT discontinued therapy because of cardiac toxicity, compared with 8% receiving AC. The incidence of CHF (AT, 3%; AC, 4%) was no higher than expected with the use of anthracyclines alone.4,30 These data confirm the lack of a pharmacokinetic interaction between docetaxel and doxorubicin31,32 and suggest that docetaxel does not enhance doxorubicin cardiotoxicity. In conclusion, this phase III study demonstrates that AT is superior to AC in terms of RRs and TTP and at least as effective regarding overall survival. This may be important for patients with rapidly progressive visceral disease. Given its manageable short-term side-effect profile and lack of significant long-term toxicity, the AT combination represents a valid choice for first-line therapy for MBC. In addition, these data provide a compelling rationale for continued development of anthracycline and docetaxel combinations in the adjuvant setting.
We thank the following investigators in the TAX306 Study Group who participated in the trial but who did not contribute to the development of the manuscript: S.J. Allan, T. Al-Tweigeri, I. Alvarez Lopez, A. Anelli, L. Balbiani, P. Barrett-Lee, E. Biondi, C. Blajman, R. Chacon, F. Coppola, M.A. Costa, R. Delva, R. Epelbaum, L. Fein, V. Fosser, M. Freue, F. Gaion, E. Galligioni, C. Garbino, H. Gervasio, C. Graiff, A. Howell, S. Jovtis, O. Keller, J. Martinez, B. Massuti, E. Mickiewicz, A. Murad, M. O’Brien, B. Ojeda, I. Oliver, K. Pittman, L. Provencher, C.A. Ruiz, G. Schwartsmann, R. Snyder, T. Tirona, V. Trillet-Lenoir, I. Tusquets, N. Vigler, A. Viola, E. Walpole, and E. Whipp.
Supported by Aventis Pharma, Antony, France.
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11. Nabholtz JM, Senn HJ, Bezwoda WR, et al: Prospective randomized trial of docetaxel versus mitomycin C plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. J Clin Oncol 17:1413–1424, 1999 12. Sjöström J, Blomqvist C, Mouridsen H, et al: Docetaxel compared with sequential methotrexate and 5-fluorouracil in patients with advanced breast cancer after anthracycline failure: A randomized phase III study with crossover on progression by the Scandinavian Breast Group. Eur J Cancer 35:1194–1201, 1999[CrossRef][Medline] 13. Bonneterre J, Monnier A, Roche H, et al: Taxotere versus 5-fluorouracil + navelbine in patients with metastatic breast cancer as 2nd line chemotherapy. Breast Cancer Res Treat 50:261, 1997 (abstr 564)[CrossRef]
14. Chan S, Friedrichs K, Noel D, et al: Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol 17:2341–2354, 1999
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18. Nabholtz JM, Mackey JR, Smylie M, et al: Phase II study of docetaxel, doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer. J Clin Oncol 19:314–321, 2001
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21. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365–376, 1993 22. Osoba D, Zee B, Pater J, et al: Psychometric properties and responsiveness of the EORTC Quality of Life Questionnaire (QLQ-C30) in patients with breast, ovarian and lung cancer. Qual Life Res 3:353–364, 1994[CrossRef][Medline] 23. Nabholtz J, Paterson A, Dirix L, et al: A phase III randomized trial comparing docetaxel (T), doxorubicin (A) and cyclophosphamide (C) to FAC as first line chemotherapy (CT) for patients (pts) with metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 20:22a, 2001 (abstr 83)
24. Biganzoli L, Cufer T, Bruning P, et al: Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organization for Research and Treatment of Cancer 10961 multicenter phase III trial. J Clin Oncol 20:3114–3121, 2002 25. Luck HJ, Thomssen C, Untch M, et al: Multicentric phase III study in first line treatment of advanced metastatic breast cancer (ABC): epirubicin/paclitaxel (ET) vs epirubicin/cyclophosphamide (EC): A study of the AGO Breast Cancer Group. Proc Am Soc Clin Oncol 19:73a, 2000 (abstr 280) 26. Carmichael J: UKCCR trial of epirubicin and cyclophosphamide (EC) vs. epirubicin and Taxol (ET) in the first line treatment of women with metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 20:22a, 2001 (abstr 84) 27. Jassem J, Pienowski T, Plzanka A, et al: Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: Final results of a randomized phase III multicenter trial. J Clin Oncol 9:1707–1715, 2001
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30. Zambetti M, Moliterni A, Materazzo C, et al: Long-term cardiac sequelae in operable breast cancer patients given adjuvant chemotherapy with or without doxorubicin and breast irradiation. J Clin Oncol 19:37–43, 2001 31. Schuller JA, Czeika M, Kletzl H, et al: Doxorubicin and Taxotere: A pharmacokinetic study of the combination in advanced breast cancer. Proc Am Soc Clin Oncol 17:205a, 1998 (abstr 790) 32. Bellot R, Robert J, Dieras V, et al: Taxotere does not change the pharmacokinetic profile of doxorubicin and doxorubicinol. Proc Am Soc Clin Oncol 17:221a, 1998 (abstr 853) Submitted April 3, 2002; accepted September 13, 2002. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
2 test was used to compare the two groups, and 95% confidence intervals (CIs) were calculated. 
