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Journal of Clinical Oncology, Vol 26, No 19 (July 1), 2008: pp. 3176-3182 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.1258 Nonplatinum Topotecan Combinations Versus Topotecan Alone for Recurrent Ovarian Cancer: Results of a Phase III Study of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group
From the Department of Gynecology, Charité University Medical Center; The Center for Clinical Research, Unfallkrankenhaus; Helios-Klinikum Berlin, Germany; Praxis for Gynecologic Oncology, Berlin; Ernst-Moritz-Arndt University of Greifswald, Greifswald; University of Jena, Jena; Ludwig-Maximilian-Universität of Munich, Munich; Klinikum Ernst-von-Bergmann Potsdam, Potsdam; Practice for Oncology and Hematology, Kronach, Germany; and the University of Innsbruck, Innsbruck, Austria Corresponding author: Jalid Sehouli, MD, Humboldt-University, Department of Gynecology and Obstetrics, Carite/Campus Virchow-Klinikum, Augustenburger Platz 1, Berlin 13353, Germany; e-mail: sehouli{at}aol.com
Purpose The management of recurrent ovarian cancer remains controversial. Single-agent topotecan is an established treatment option, and preliminary evidence suggests improved tumor control by combining topotecan with etoposide or gemcitabine. Patients and Methods Women with relapsed ovarian cancer after primary surgery and platinum-based chemotherapy were randomly assigned to topotecan monotherapy 1.25 mg/m2/d, topotecan 1.0 mg/m2 plus oral etoposide 50 mg/d, or topotecan 0.5 mg/m2/d plus gemcitabine 800 mg/m2 on day 1 and 600 mg/m2 on day 8 every 3 weeks. Patients were stratified for platinum-refractory and platinum-sensitive disease according to a recurrence-free interval of less or more than 12 months, respectively. The primary end point was overall survival. Secondary end points included progression-free survival, objective response rates, toxicity, and quality of life (as measured by the European Organisation for Research and Treatment of Cancer [EORTC] 30-item Quality-of-Life Questionnaire). Results The trial enrolled 502 patients with a mean age of 60.5 years (± 10.2 years), 208 of whom were platinum resistant. Median overall survival was 17.2 months (95% CI, 13.5 to 21.9 months) with topotecan, 17.8 months (95% CI, 13.7 to 20.0 months) with topotecan plus etoposide (log-rank P = .7647), and 15.2 months (95% CI, 11.3 to 20.9 months) with topotecan plus gemcitabine (log-rank P = .2344). Platinum-sensitive patients lived significantly longer than platinum-refractory patients (21.9 v 10.6 months). The median progression-free survival was 7.0, 7.8, and 6.3 months, respectively. Objective response rates were 27.8%, 36.1%, and 31.6%, respectively. Patients under combined treatment were at higher risk of severe thrombocytopenia. Conclusion Nonplatinum topotecan combinations do not provide a survival advantage over topotecan alone in women with relapsed ovarian cancer.
Ovarian cancer ranks third among all estimated new cancer cases of the female reproductive system, and is still associated with a poor survival prognosis.1-3 Radical surgery and chemotherapy with platinum compounds and taxanes are now recognized as the standard of care in the first-line setting.4 Although initial response rates are high, most patients will subsequently encounter recurrent disease. Recurrent ovarian cancer is an incurable condition. Treatment options are less standardized in this difficult situation, and are a matter of ongoing debate.5 The length of the disease-free interval after response to platinum divides patients into groups with different survival prognosis. Platinum-refractory, partially platinum-sensitive, and platinum-sensitive disease have arbitrarily been defined by recurrence after less than 6, 6 to 12, and more than 12 months.6 It is assumed that the application of nonplatinum agents may extend the platinum-free interval, and there is now considerable research interest in developing alternative nonplatinum treatment strategies.7 Topotecan, a topoisomerase-I inhibitor, has extensively been studied in both platinum-resistant and platinum-sensitive relapsed ovarian cancer.8-10 Topotecan demonstrated similar activity to paclitaxel,11 and lacks cross resistance.12 In vitro data suggest marked synergy of topotecan with other cytotoxic drugs.13 The GINECO study group showed encouraging results with a combination of topotecan and etoposide, a topoisomerase II-inhibitor, in 80 patients with prior platinum treatment.14 Gemcitabine, a pyrimidine analog, is another promising candidate to be added to topotecan.15,16 Apart from early clinical reports, none of the mentioned drug doublets have yet been compared with topotecan alone in a controlled trial.17 It is unclear whether the expected higher toxicity of combined chemotherapy pays off in a substantial survival benefit. This multicenter, randomized trial compared the effectiveness of two nonplatinum doublets, topotecan-etoposide and topotecan-gemcitabine, with topotecan monotherapy in women with recurrent ovarian cancer. The primary trial objective was to investigate whether any combination enhances overall survival compared with topotecan monotherapy. We had secondary objectives in determining the progression-free survival, response rates, toxicity, and quality of life with either treatment.
Patients Eligible women were 18 years of age or older and had recurrent epithelial ovarian cancer after radical surgery and first-line platinum-containing chemotherapy. Additional entry criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and normal renal, hepatic, and bone marrow function. Patients with any previous second-line chemotherapy were excluded, as were patients with secondary malignancy or underlying serious, uncontrolled concurrent medical or psychiatric diseases. All patients gave written, informed consent, and the institutional review boards of all participating centers approved the study. An independent monitoring institute was responsible for data control. The principal investigator had full access to all the data in the study and takes responsibility for the accuracy and integrity of the data analysis. The protocol was reviewed and certified by the German Cancer Society (DKG).
Study Design and Treatment At the time of protocol review by the DKG, we had already completed a phase I study on the optimum dose of the topotecan-gemcitabine combination,19 and almost finished a phase II study on safety.20 The institutional review board requested to withhold opening of the topotecan-gemcitabine arm until the final results of the phase II study were available. Thus, the randomization procedure was conducted in two steps. The first 150 patients were randomly assigned to topotecan or topotecan-etoposide in a 1:1 fashion. Thereafter, patients were assigned to topotecan, topotecan-etoposide, or topotecan-gemcitabine in a 1:1:2 ratio. Patients were randomly assigned to receive (1) topotecan 1.25 mg/m2/d on days 1 to 5 as a 30-minute infusion every 3 weeks, (2) topotecan 1.0 mg/m2/d on days 1 to 5 as a 30-minute infusion plus 50 mg of oral etoposide on days 6 to 12 every 3 weeks, or (3) topotecan 0.5 mg/m2/d on days 1 to 5 as a 30-minute infusion plus gemcitabine 800 mg/m2 on day 1 and 600 mg/m2 on day 8 every 3 weeks. Dose escalation of the topotecan compound up to 1 mg/m2 was allowed given good tolerability of the initial dose. All patients received 5-HT3-antagonists intravenously for prophylaxis of nausea and emesis. Patients were required to show leukocyte counts of at least 2 x 109/L and platelet counts of at least 100 x 109/L before continuing individual courses of chemotherapy. The primary use of granulocyte colony-stimulating factor or erythropoietin was not allowed.
Study End Points Progression-free survival was defined as the interval between the first administration of study drugs and the clinical diagnosis of tumor progression, or, if fatal events were not preceded by the diagnosis of tumor progression, death resulting from any cause. Tumor progression was assumed in case of any of the following findings: new or progressive lesions detected by radiologic imaging (eg, computed tomography or magnetic resonance imaging), physical examination, the histologic diagnosis of recurrence. Elevation of CA-125 serum concentration only was not accepted for study enrollment. Response was classified according to the criteria of the WHO and the International Union Against Cancer (UICC).21 Complete response was defined as the complete disappearance of all measurable and assessable disease by physical examination or imaging. Partial response was assumed in case of a 50% reduction in the sums of the product of two perpendicular diameters of the tumor. Stable disease was considered for all patients who had less than partial response but no evidence of progressive disease. Progressive disease was defined by an increase of least 25% in the sums of the product of the lesion or evidence of a new tumor. Overall response included complete and partial response, whereas disease control comprised complete and partial response, and stable disease. Quality of life was assessed by the self-administered European Organisation for Research and Treatment of Cancer (EORTC) 30-item Quality-of-Life questionnaire (QLQ-30)22 before and after the fourth and sixth cycle of chemotherapy. The instrument measures six health-related domains (physical functioning, role functioning, emotional functioning, cognitive functioning, social functioning, and global quality of life), eight symptom scales (that is, fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea), and the financial impact item. Toxicity was graded according to Version 2.0 of the National Cancer Common Toxicity Criteria (available at http://ctep.cancer.gov/reporting/ctc_archive.html). Unexpected adverse events and serious adverse events were reported to the institutional review board and the Federal Agency of Pharmaceutical Products (BfARM) regardless of their relation to study drugs. ECG tracing was performed before each treatment course. Blood samples for monitoring of hematology and blood chemistry were drawn before chemotherapy and once a week.
Statistical Analysis We did not aim at a head-to-head comparison between the combined regimens. Analysis of a difference in overall survival employed the Kaplan-Meier product limit method and log-rank tests, stratified for the platinum-free interval. HRs were derived from univariate Cox regression, stratified for the platinum-free interval as well.
Secondary subgroup analyses were carried out for platinum-sensitive and -resistant patients. All secondary analyses were conducted in an exploratory fashion. Differences in response rates and toxic events were evaluated by exploratory global
Between September 1999 and November 2004, 521 patients were screened, and 502 were considered eligible to participate in the trial. Of these, 178 were randomly assigned to topotecan monotherapy, 177 to topotecan plus etoposide, and 147 to topotecan plus gemcitabine. Ten patients did not receive study treatment, but were included in the intention-to-treat analysis as randomly assigned. The study profile is depicted in Figure 1.
The baseline profile was well balanced for demographic and disease characteristics (Table 1). Most patients (317 of 491; 64.6%) were platinum sensitive, as indicated by a treatment-free interval of more than 12 months.
The median number of chemotherapy cycles applied in the monotherapy, etoposide, and gemcitabine arm was six (range, zero to 26), six (range, zero to 17), and six (range, zero to 10) , respectively. A total of 121 (67.9%), 109 (61.6%), and 77 (52.4%) patients completed at least six cycles of treatment. After a median follow-up of 14 months (range, 1 to 74 months), 129 women were still alive (25.7%; 95% CI, 21.9% to 29.8%). The median overall survival was 16.8 months (95% CI, 14.3 to 18.6 months) and did not differ between the treatment groups (Fig 2). Median overall survival was 17.2 months (95% CI, 13.5 to 21.9 months) with topotecan monotherapy, 17.8 months (95% CI, 13.7 to 20.0 months) with topotecan plus etoposide (log-rank P = .7647), and 15.2 months (95% CI, 11.3 to 20.9 months) with topotecan plus gemcitabine (log-rank P = .2344).
With topotecan monotherapy as the reference, differences in survival times translate to HRs of 1.04 (95% CI, 0.81 to 1.33) for topotecan plus etoposide and 1.18 (95% CI, 0.90 to 1.53) for topotecan plus gemcitabine. Platinum-sensitive patients survived significantly longer than platinum-resistant patients (21.9 [95% CI, 18.5 to 24.6] v 10.6 [95% CI, 9.3 to 11.6] months; log-rank P < .0001). The performance of topotecan monotherapy did not differ between early and late accrual periods (median overall survival, 15.8 [95% CI, 13.5 to 19.8] v 17.2 [95% CI, 13.3 to 19.3] months). Median progression-free survival was 7.1 months (95% CI, 6.3 to 7.7 months). Again, there was no difference between treatment arms (Fig 3). The median progression-free survival with topotecan monotherapy, topotecan plus etoposide, or topotecan plus gemcitabine was 7.0 months (95% CI, 5.5 to 8.3 months), 7.8 months (95% CI, 6.6 to 9.2 months; log-rank P = .2993), and 6.3 months (95% CI, 4.9 to 7.4; log-rank P = .3798). The corresponding HRs were 0.90 (95% CI, 0.72 to 1.12) and 1.11 (95% CI, 0.88 to 1.40), respectively. Platinum sensitivity remained an important predictor of treatment success, with median progression-free survival times of 8.4 (95% CI, 7.6 to 9.2) and 4.5 (95% CI, 3.8 to 5.9) months (log-rank P < .0001).
Objective response could be measured in 350 patients, 111 of whom achieved complete or partial response (31.7%; 95% CI, 36.9 to 36.9%). No significant differences were observed between treatment groups. Results are summarized in Table 2.
All drugs showed distinct toxicity profiles, with the highest incidence of grade 3 and 4 hematotoxicity noted in the topotecan-etoposide arm (Table 3).
Hematologic toxicity caused treatment delays of more than 1 week in 55, 94, and 54 patients assigned to the monotherapy, etoposide, and gemcitabine arm. Nonhematologic toxic events were responsible for treatment delays in 9, 16, and 16 patients, respectively. Supportive care was necessary in 95 (53.4%), 99 (55.9%) and 72 (49.0%) patients randomly assigned to topotecan monotherapy, topotecan-etoposide, and topotecan-gemcitabine. A total of 256 patients were prescribed third-line chemotherapy because of tumor progression, 48 of whom received platinum compounds. Treosulfan (n = 111) and pegylated doxorubicin (n = 56) were the most frequently used nonplatinum agents. Quality of life did not detectably change throughout the study, and did not differ between treatment groups at baseline, after the third cycle, and after completion of the last cycle of chemotherapy (Table 4).
Managing recurrent ovarian cancer remains a clinical challenge. Although the major principle of salvage chemotherapy is to maintain tumor control and health-related quality of life as long as possible with the less toxic drug or drug combination available, both patients and caregivers will seek treatment options that are likely to prolong survival. Previous studies suggested that this goal can be achieved with established chemotherapeutic agents.24-27 The results from this trial refute the thesis that nonplatinum doublets offer any advantage over topotecan monotherapy to women with recurrent ovarian cancer, regardless of their susceptibility to platinum. Survival times, tumor response rates, and quality-of-life measurements were almost identical among study arms. Combined therapy was generally associated with a higher risk of grade 3 and 4 thrombocytopenia. Some aspects of this trial may be of importance for future treatment recommendations. The topotecan-alone arm employed a dose of 1.25 mg/m2 for the 5-days schedule rather than the US Food and Drug Administration–recommended dose of 1.5 mg/m2. The reduced dose is now widely accepted by many opinion leaders and cancer societies because of its broader therapeutic index.28 Interestingly, the observed median overall survival of 17 months compares well to the range of 8 to 14 months reported by other phase III topotecan trials that used the standard dose of 1.5 mg/m2.11,29 This may add some indirect evidence that topotecan exposure can safely be lowered without compromising tumor control, while markedly improving the hematologic toxicity profile.9 One might argue with the treatment options offered in this trial, which did not incorporate a platinum compound, at least for patients with platinum-sensitive disease. Apparently straightforward and persuading, the concept of rechallenging platinum-sensitive patients to a second round of platinum has been primary derived from early uncontrolled studies.30,31 The only published randomized comparison of a platinum-containing triple therapy with paclitaxel alone enrolled only 97 patients and does not allow for firm conclusions about superiority of second-line platinum over nonplatinum treatment in terms of overall survival.33 On the basis of two newer large phase III trials, there is currently consensus in the scientific community as to the gold standard of platinum-based combination chemotherapy for platinum-sensitive patients.26,27,32 Recently, a large study of the Gynecologic Cancer Intergroup (GCIG) compared paclitaxel plus carboplatin to carboplatin plus doxorubicin HCl. This drug has been approved for the treatment of recurrent ovarian cancer, and is a valuable option for platinum-resistant patients. The therapeutic index of topotecan may be improved by a weekly schedule, which is currently under investigation.34 The present data may best be compared with the large GCIG trial of carboplatin plus gemcitabine versus carboplatin monotherapy (Fig 4).25 In that trial, the proportion of patients with a recurrence-free interval more than 12 months (106 of 177; 59.9%) randomly assigned to combined gemcitabine-carboplatin met the distribution of the population studied here. However, compared with the present trial, fewer patients had been pretreated with taxanes (122 of 178; 68.5%), thus forming a group with a better prognosis. Median recurrence-free survival (8.6 months; 95% CI, 7.9 to 9.7 months) was similar to the present estimates. The median overall survival, handled as a secondary outcome in the intergroup trial, was calculated at 18.0 months (95% CI, 16.2 to 20.2 months). In contrast, the incidence of grade 3/4 hematologic toxicity was higher with gemcitabine-carboplatin than with the treatment options investigated in this study.
Although any comparison between both trials must be made with extreme caution, the similar findings underline the need for a randomized trial comparing platinum-based combination with topotecan monotherapy in platinum-sensitive patients. However, it is likely that such a trial will accrue quite slowly, given the widely accepted platinum treatment standard, current prevailing thought of physicians, and compelling trials on targeted therapies. In conclusion, if topotecan is considered for treating recurrent ovarian cancer, monotherapy remains the standard of care. The current large trial provides no evidence that topotecan plus etoposide or topotecan plus gemcitabine improve clinical outcomes compared with topotecan alone, but will increase toxicity.
The author(s) indicated no potential conflicts of interest.
Conception and design: Jalid Sehouli, Guelten Oskay-Oezcelik, Werner Lichtenegger Administrative support: Jalid Sehouli, Dirk Stengel, Guelten Oskay-Oezcelik, Peter Klare, Werner Lichtenegger Provision of study materials or patients: Jalid Sehouli, Guelten Oskay-Oezcelik, Alain G. Zeimet, Harald Sommer, Peter Klare, Martina Stauch, Axel Paulenz, Oumar Camara, Elke Keil, Werner Lichtenegger Collection and assembly of data: Jalid Sehouli, Guelten Oskay-Oezcelik, Alain G. Zeimet, Harald Sommer, Martina Stauch, Axel Paulenz, Oumar Camara, Elke Keil, Werner Lichtenegger Data analysis and interpretation: Jalid Sehouli, Dirk Stengel, Guelten Oskay-Oezcelik, Werner Lichtenegger Manuscript writing: Jalid Sehouli, Dirk Stengel, Guelten Oskay-Oezcelik, Alain G. Zeimet, Harald Sommer, Werner Lichtenegger Final approval of manuscript: Jalid Sehouli, Dirk Stengel, Guelten Oskay-Oezcelik, Alain G. Zeimet, Harald Sommer, Peter Klare, Martina Stauch, Axel Paulenz, Oumar Camara, Elke Keil, Werner Lichtenegger
The following institutions participated in the study: Medizinische Einrichtung der RWTH Aachen, Itertalklinik Aachen, St Franziskus-Hospital, Ahlen, Klinikum St Marien Lehrkrankenhaus, Amberg, Klinikum Aschaffenburg, Kreiskrankenhaus Bautzen, Krankenhaus Belzig, Charite/Campous Virchow-Klinikum, Charité/Campus Benjamin Franklin, Berlin, Charité/Campus Mitte, Berlin, Praxis Dr Kühn, Berlin, Praxis Dr Kindler, Berlin, Praxis Dr Eilers-Lönnecker, Berlin, Praxis Dr Ludwig, Berlin, Gemeinschaftspraxis Dr Herrenberger, Dr Keitel-Wittig, Dr Kirsch, Berlin, Helios Klinikum Berlin—Klinikum Buch, DRK—Kliniken Köpenick, Berlin, Vivantes Humboldt Krankenhaus, Berlin, PARITÁTISCHES Krankenhaus Lichtenberg, Berlin, Vivantes Klinikum im Friedrichshain, Berlin, DRK Kliniken Berlin Westend, Krankenhaus Neukölln, Berlin, Praxis Dr Ruhmland, Berlin, Krankenhaus am Urban, Berlin, Marienhospital Brühl, St Elisabeth Hospital, Bochum, Klinikum Chemnitz, Praxis Dr Walther, Cottbus, Carl-Thiem-Klinikum Cottbus, Praxis Dr Deutschmann, Dresden, Klinikum Duisburg Wedau Kliniken, Praxis Dr Hauch, Erfurth, Gemeinschaftspraxis Ringel, Friedberg, Klinikum der Albert-Ludwig-Universität Freiburg, Kreiskrankenhaus Freudenstadt, Praxis Dr Heinrich, Fürstenwalde, SRH Wald-Klinikum Gera, Ernst-Moritz-Arndt-Universität, Greifwald, Kreiskrankenhaus Groβenhain, Krankenhaus Güstrow, Städtisches Krankenhaus Martha-Maria Halle-Dölau, Allgemeines Krankenhaus Barmbek, Hamburg, Vinzenzkrankenhaus Hannover, St Vincenz-Krankenhaus, Heiligenstadt, Klinikum Hoyerswerda, Städt. Krankenanstalten Idar-Oberstein, Universitätsklinikum Innsbruck, Universitätsfrauenklinik Jena, Städtische Kliniken, Kassel, Praxis Stauch, Kronach, Städtisches Klinikum St Georg, Leipzig Ev. Krankenhaus Ludwigsfelde-Teltow, Praxis DrWierick, Lohsa/Weisskolm, DRK Krankenhaus Luckenwalde, Klinikum der Universität München Innenstadt, St Elisabeth Krankenhaus Mayen, Universitätsklinikum Mannheim, DRK-Krankenhaus Mecklenburg-Strelitz, Krankenhaus Ludmillenstift, Meppen Dietrich-Bonhoeffer-Klinikum Neubrandenburg, Friedrich-Ebert-Krankenhaus Neumünster, Ev. Krankenhaus Oberhausen, St Joseph-Krankenhaus, Postdam, St Marien Krankenhaus, Siegen, St Lukas Klinik Solingen, Hanse-Klinikum Stralsund, Universitätsklinikum des Saarlands, Thüringen-Klinik Georgius Agricola, Saalfeld, Harz-Klinikum Wernigerode-Blankenburg, Praxis Dr Schwarz, Oranienburg, HUMAINE Vogtland Klinikum Plauen, Klinikum Dorothea Christiane Erxleben Quedlinburg, Klinikum der Stadt Ludwigshafen am Rhein, Klinikum Riesa-Groβenhain Krankenhaus Riesa, Universitätsfrauenklinik Rostock, Klinikum Südstadt Rostock, Praxis Dr Dworzanski, Schmiedeberg, Gemeinschaftspraxis Dr Kunstmann/Dr Scheck, Stockelsdorf, Gemeinschaftspraxis Dr Forstbauer and Dr Ziske, Troisdorf, Klinikum Ernst von Bergmann, Potsam, Müritz-Klinikum, Waren, Evangelisches Krankenhaus Wesel, Kliniken des Muldentalkreises Krankenhaus Wurzen, Kreiskrankenhaus Zittau, Kreiskrankenhaus Mittleres Erzgebirge, Zschopau, Gemeinschaftspraxis Leitsmann/Lenk, Zwickau.
We thank all of the patients and families, clinical investigators, and trial facility staff who made this work possible.
Supported by the German Cancer Society (DKG) and the North-Eastern German Society of Gynecological Oncology (NOGGO). Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical Trials repository link available on www.JCO.org.
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Gore ME, Fryatt I, Wiltshaw E, et al: Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds. Gynecol Oncol 36:207-211, 1990[CrossRef][Medline] 31. Markman M, Rothman R, Hakes T, et al: Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 9:389-393, 1991[Abstract] 32. Pfisterer J, Ledermann JA: Management of platinum-sensitive recurrent ovarian cancer. Semin Oncol 33:S12–S16, 2006[CrossRef][Medline] 33. Cantù MG, Buda A, Parma G, et al: Randomized controlled trial of single-agent paclitaxel versus cyclophosphamide, doxorubicin, and cisplatin in patients with recurrent ovarian cancer who responded to first-line platinum-based regimens. J Clin Oncol 20:1232-1237, 2002 34. Sehouli J, Oskay G, Stengel D, et al: Topotecan weekly versus routine 5-day schedule in patients with platinum-resistant ovarian cancer (TOWER): A randomized, two-stage phase-II study of the North-Eastern German Society of Gynaecological Oncology (NOGGO). J Clin Oncol 25:280s, 2007 (suppl; abstr 5526) Submitted November 8, 2007; accepted March 18, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 or Fisher's exact test. Differences in indicators of quality of life were compared by a repeated-measures analysis of variance. All point estimates, differences, and rations are reported with their 95% CIs, where appropriate. 
