- Email: [email protected]
Clinical research in epithelial ovarian cancer and patients’ outcome
chapter 3
Annals of Oncology 22 (Supplement 7): vii16–vii19, 2011 doi:10.1093/annonc/mdr421
Clinical research in epithelial ovarian cancer and patients’ outcome J. Rochon1 & A. du Bois2 1
Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg; 2Department of Gynecology and Gynecologic Oncology, Kliniken Essen Mitte (KEM), Essen, Germany
chapter 3
introduction In 1999, the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) Organkommission OVAR, a subcommittee of the German Cancer Society, started a project aiming at improving outcome in ovarian cancer patients. Part of this ongoing project is a German-wide quality assurance programme termed QSOVAR that focuses on the outcomes of patients who are treated at hospitals participating in clinical studies versus non-study hospitals. Extended data on the first cohort (QS-OVAR 2001) have been presented elsewhere [1]. In the next section, we briefly describe the design of this study and present data on a 3year follow-up, which have been partially included in a recent systematic review [2]. We close with a discussion of our findings and their consequences.
patients and methods In phase I of QS-OVAR, all 1123 German gynecology departments were asked for the number of newly diagnosed ovarian cancer patients treated in 2001. In phase II, all responding hospitals were asked to document each newly diagnosed patient in the third quarter of 2001. Follow-up was done 2 and 3 years after the diagnosis of ovarian cancer. Overall survival was the primary endpoint. The secondary endpoint was adherence to treatment guidelines with regard to surgery and chemotherapy. Completeness of surgical staging in early ovarian cancer was defined according to German guidelines and included nine items. Staging was defined as ‘complete’ if none of these nine items was missing and as ‘optimal’ if only one item was missing. Adjuvant platinum-based chemotherapy was considered standard care for patients with early ovarian cancer except those patients with Fe´de´ration Internationale de Gyne´cologie et d’Obste´trique (FIGO) stage IA and highly differentiated tumours. Standard care for patients with
advanced disease included surgery that aimed at maximal tumour debulking. Here, we also differentiated between ‘complete’ surgery without any postoperative macroscopic tumour residual and so-called ‘optimal’ debulking with residuals up to 1 cm maximum diameter. Standard chemotherapy for patients with advanced disease included administration of a platinum–paclitaxel combination. With regard to hospital characteristics, we were primarily interested in study participation, that is, participation in prospective clinical trials conducted by one of the two German cooperative study groups, the AGO Study Group Ovarian Cancer (AGO-OVAR) and Northeastern Society of Gynecologic Oncology (NOGGO). The two study groups organize almost all national and international cooperative clinical trials in Germany in this field. AGO-OVAR is a member group of the Gynecologic Cancer Intergroup (GCIG) and both study groups are members of the European Network of Gynaecologic Oncology Trial Groups (ENGOT). In addition, we evaluated hospital volume because this characteristic is supposedly associated with better outcome in oncology. Hospital volume was categorized as low (1–11 patients/ year), medium (12–23 patients/year) and high (24+ patients/year). In addition, we collected information about patient variables [age, performance status according to Eastern Cooperative Oncology Group (ECOG), comorbidity, and history of second malignancies] and disease variables (FIGO stage, tumour grade, histological subtype, and presence of ascites of >500 ml).
results The analysis was based on 476 patients from 165 hospitals which represents about one-third of patients diagnosed with ovarian cancer in Germany per quarter. About 50% of the 165 hospitals were study hospitals (Table 1). However, only 21% (59 out of 275) patients in study hospitals were enrolled in
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
Downloaded from http://annonc.oxfordjournals.org/ at Northern Arizona University on June 23, 2015
We evaluated the relationship between the outcome of newly diagnosed ovarian cancer patients treated in 1123 German gynecology departments in 2001, and their participation in clinical trials through two German cooperative study groups. In addition, we evaluated other potential factors predicting outcome including hospital volume. The analysis was based on 476 patients from 165 hospitals and 3-year follow-up. Patients treated in study hospitals had a higher chance of receiving treatment according to national guidelines. This included a higher chance of receiving optimal staging in early stage disease and of receiving the recommended combination of surgical debulking and combination chemotherapy in advanced disease. On multivariable Cox model analysis, overall survival was significantly worse in patients treated in non-study hospitals.
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FIGO IIB–IV. Thus, we separately explored the effect of study participation in both strata, and found a survival benefit for patients with advanced ovarian cancer FIGO IIB–IV treated at study hospitals. The median overall survival time was 35 months for patients in study hospitals compared to 25 months for patients in non-study hospitals (Figure 2). Finally, we fitted a multivariable Cox model to assess the effect of participation in clinical trials on survival in patients with FIGO I–IV, taking into account all patient and disease characteristics measured, and also hospital volume (Table 2). This multivariable analysis showed that overall survival was significantly worse in patients treated at non-study hospitals (HR = 1.66, 95% CI: 1.22 to 2.27, P = 0.001).
discussion do healthcare systems that are active in clinical research deliver better outcomes for patients than healthcare systems that are inactive in research? In our study, participation in clinical trials as a quality characteristic of hospitals was associated with improved Table 1. Hospital and patient characteristics
Hospitals (n) 1–11 patients/year (%) 12–23 patients/year (%) 24+ patients/year (%) Patients (n) 65+ years (%) PS ECOG 0/1 (%) Comorbidity (%) Second cancer (%) FIGO IIB-IV (%) Grade 3/4 (%) Serous histology (%) Ascites >500 ml (%) Median follow-up (months)
All
Study hospitals
Non-study hospitals
165 49 32 19 476 46 79 24 14 74 45 69 40 35
80 31 39 30 275 45 79 24 12 80 50 71 40 35
85 66 26 8 201 46 79 25 17 66 39 66 40 35
P-value
<0.001
0.945 0.987 0.663 0.161 0.001 0.017 0.234 0.989 0.940
FIGO, Fe´de´ration Internationale de Gyne´cologie et d’Obste´trique staging; PS ECOG, Eastern Cooperative Oncology Group performance status scale. 100%
80%
Surgery-/Chemo-
60%
Surgery+/Chemo-
40%
20%
OR = 2.17 95% CI [1.47–3.19] P < 0.001
Surgery-/Chemo+
*
Surgery+/Chemo+
* Optimal surgery
0% 275 pts in study hospitals
201 pts in non-study hospitals
Figure 1. Adherence to treatment guidelines with regard to surgery and chemotherapy in ovarian cancer FIGO I–IV according to hospital participation in clinical trials.
doi:10.1093/annonc/mdr421 | vii17
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prospective clinical trials. Hospital-based descriptive analyses showed that participation in clinical studies was associated with higher hospital volume. For example, only 8% of non-study hospitals were high-volume centres compared with 30% of the study hospitals. Patients in study hospitals were generally similar to patients in non-study hospitals, except for imbalances with respect to FIGO stage and grade: Patients in study hospitals had higher FIGO stages and poorer differentiated tumours. Altogether, two-thirds of patients were diagnosed with advanced ovarian cancer FIGO IIB–IV. Second cancers were reported in 14% of patients. The Kaplan-Meier estimate for median follow-up time was 3 years. A total of 199 deaths occurred within this observation period. With respect to the adherence to treatment guidelines, patients with early ovarian cancer had a higher chance of receiving standard care (optimal staging and standard chemotherapy) in study hospitals than patients in non-study hospitals. In particular, patients in study hospitals were more likely to receive optimal staging than patients in non-study hospitals [odds ratio (OR) 2.75, 95% confidence interval (CI): 1.15 to 6.59, P = 0.030]. Overall, 23% of patients with early ovarian cancer had surgical staging with none or maximally one item missing. Seventy-one per cent of patients in study hospitals and 65% of patients in non-study hospitals received standard chemotherapy. In patients with advanced disease, 50% of patients in study hospitals and 38% of patients in non-study hospitals received the combination of optimal debulking with platinum–taxane chemotherapy (OR = 1.68, 95% CI: 1.08 to 2.60, P = 0.027). Further analysis showed differences in surgical outcome between study and non-study hospitals: 46% of patients in non-study hospitals had tumour residuals larger than 1 cm in contrast to 34% of patients in study hospitals. Thus, patients treated at study hospitals had a higher chance of being optimally debulked with a postoperative residual tumour of a maximum diameter of up to 1 cm (OR = 1.63, 95% CI: 1.05 to 2.53, P = 0.032). In patients with advanced disease, we also found statistically significant differences between study and non-study hospitals with regard to the quality of chemotherapy. The proportion of patients receiving the recommended platinum–taxane combination was 70% in study hospitals and 59% in non-study hospitals (P = 0.049). Altogether, about 46% of patients in study hospitals and only 28% of patients in non-study hospitals received treatment according to guidelines. Thus, patients in study hospitals had twice the chance of receiving standard treatment as patients in non-study hospitals (Figure 1). Since better treatment usually improves survival, we investigated the corresponding effect using a multivariable Cox model. As expected, suboptimal treatment was associated with worse survival, even after adjustment for all patient and disease characteristics measured [Hazard Ratio (HR) = 2.70, 95% CI: 1.89 to 3.85, P < 0.001]. Univariate survival analysis in patients with FIGO I–IV showed that treatment at non-study hospitals was associated with a higher risk of death, but this effect was not statistically significant (HR = 1.19, 95% CI: 0.90 to 1.57, P = 0.222). However, patients in study hospitals differed from patients in non-study hospitals, particularly with respect to FIGO stage. In addition, most events occurred in the advanced stages
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Table 2. Multivariable Cox model for overall survival in patients with ovarian cancer in Germany in 2001
Survival probability (%)
100%
75%
Variable 50% Log-rank test: P = 0.006 HR = 1.50 [95% CI: 1.12–2.00]
25% Study hospitals
(N = 219, E = 103)
Non-study hospitals
(N = 133, E = 81)
0% 0
6
12
18
24
30
36
129 63
100 43
43 15
Months No. at risk 219 Study hospitals Non-study hospitals 133
187 109
166 95
149 83
survival in patients with epithelial ovarian cancer. With regard to ovarian cancer, study participation has hardly been investigated outside Germany. One exception is Robinson et al. [3] who also showed a positive effect of study participation but used a very different study design. In other diseases, however, this effect has been discussed for a much longer period of time. A beneficial effect of trial participation on survival has been reported, for example, in patients with multiple myeloma [4] and non-small cell lung cancer [5]. At least four reviews have been published so far but with varying conclusions [6–9]. Braunholtz et al. [6] concluded that randomized controlled trials (RCT) tend to have a beneficial rather than a harmful effect on individual patients. The Emergency Care Research Institute [7] summarized 10 comparisons and concluded that some evidence shows that patients in trials survive longer than similar patients who are not in trials. In contrast, Peppercorn et al. [8] concluded that data are insufficient with regard to the existence of a trial effect. Vist et al. [9] concluded that outcomes of patients participating in a RCT do not differ from those of patients who receive similar treatments and do not participate in a RCT.
what do we precisely mean by a study participation effect and is it an artifact or a measure for improving quality? Evaluating a study participation effect is not a trivial issue. First of all, when evaluating study participation, it is important to note which groups are compared with each other. As suggested by Braunholtz et al. [6], several comparisons are possible. Most studies compare ‘on-study patients’ with ‘off-study patients’; but the definitions of the groups often differ substantially and are biased by study inclusion criteria. In our study, we did not compare ‘on-study patients’ with ‘off-study patients’ but compared all patients treated at hospitals participating in clinical studies with all patients from non-study hospitals. Therefore, the effect of study participation was supposed to cover more than just the participation of some patients in specific clinical trials. In addition, in our study, only 21% of patients treated at study hospitals had actually been enrolled in prospective clinical trials, which included a large GCIG trial for
vii18 | Rochon & du Bois
E
HR
95% CI
P-value
275 201
108 91
1 1.66
Reference 1.22–2.27
0.001
170 150 156
77 52 70
1 1.01 1.14
Reference 0.71–1.46 0.80–1.63
0.940 0.461
259 217
75 124
1 1.67
Reference 1.19–2.33
0.003
374 102
126 73
1 2.55
Reference 1.80–3.60
<0.001
360 116
122 77
1 1.72
Reference 1.25–2.37
0.001
408 68
164 35
1 1.31
Reference 0.90–1.91
0.154
124 352
15 184
1 4.53
Reference 2.62–7.82
<0.001
261 215
89 110
1 1.17
Reference 0.88–1.56
0.285
147 329
47 152
1 1.29
Reference 0.92–1.82
0.142
284 192
88 111
1 1.74
Reference 1.30–2.33
<0.001
N, number of patients; E, number of events; HR, hazard ratio; CI, confidence interval; FIGO, Fe´de´ration Internationale de Gyne´cologie et d’Obste´trique staging; ECOG, Eastern Cooperative Oncology Group performance status scale.
advanced ovarian cancer in 2001. This trial did not show any superiority of the experimental treatment [10]. Furthermore, our study also revealed positive effects for patients with early ovarian cancer at a time when no protocol had been active. Our model rather implied the hypothetical assumption that patients in study hospitals have a better outcome than patients in nonstudy hospitals because hospitals participating in trials accumulate knowledge and develop special infrastructures associated with study participation. Furthermore, trial centres are subject to regular auditing and monitoring and therefore may have a more rigorous external system of quality control. In addition, team members in trial units may not only be interested in studies on ovarian cancer but may also be motivated to keep up with new developments in other medical fields. Taking all this into account, it could well be that even patients who are not actively enrolled in study protocols but treated at hospitals participating in clinical studies could benefit from these hospital characteristics. In this way, study
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Figure 2. Kaplan–Meier survival curves in ovarian cancer FIGO IIB–IV according to hospital participation in clinical trials.
Study participation Yes No Hospital volume High Medium Low Age < 65 years ‡ 65 years Performance status ECOG 0/1 ECOG > 1 Comorbidity None Present Second cancer None Present Stage FIGO I–IIA FIGO IIB–IV Grade G 1/2/unknown G 3/4 Histology Other Serous Ascites £ 500 ml > 500 ml
N
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Volume 22 | Supplement 7 | November 2011
In addition, the comparisons in the current study were adjusted for potentially confounding factors, such as age, stage of disease, and comorbidities. Finally, more patients with advanced disease were treated in study hospitals, which should, if at all, disadvantage these institutions with respect to patients’ outcome as compared to non-study hospitals that more often treated patients with better prognosis. Our study demonstrated the heterogeneity in the treatment patterns of ovarian cancer in Germany and showed the areas needing improvement. Furthermore, we found a beneficial trial participation effect and generated a hypothesis. QS-OVAR 2001 was followed by QS-OVAR 2004 and QS-OVAR 2008. The results of the further analyses of QS-OVAR 2004 and 2008 are expected in 2012.
disclosures The authors have not declared any conflicts of interest.
references 1. du Bois A, Rochon J, Lamparter C, Pfisterer J. Pattern of care and impact of participation in clinical studies on the outcome in ovarian cancer. Int J Gynecol Cancer 2005; 15: 183–191. 2. du Bois A, Rochon J, Pfisterer J, Hoskins WJ. Variations in institutional infrastructure, physician specialization and experience, and outcome in ovarian cancer: a systematic review. Gynecol Oncol 2009; 112(2): 422–436. 3. Robinson WR, Ritter J, Rogers AS et al. Clinical trial participation is associated with improved outcome in women with ovarian cancer. Int J Gynecol Cancer 2009; 19: 124–128. 4. Karjalainen S, Palva I. Do treatment protocols improve end results? A study of survival of patients with multiple myeloma in Finland. Br Med J 1989; 299: 1069–1072. 5. Davis S, Wright PW, Schulman SF et al. Participants in prospective, randomized clinical trials for resected non-small cell lung cancer have improved survival compared with nonparticipants in such trials. Cancer 1985; 56: 1710–1708. 6. Braunholtz DA, Edwards SJ, Lilford RJ. Are randomized clinical trials good for us (in the short term)? Evidence for a ‘trial effect’. J Clin Epidemiol 2001; 54(3): 217–224. 7. ECRI Evidence Report. Patients’ reasons for participation in clinical trials and effect of trial participation on patient outcomes. ECRI Health Technology Assessment Information Service 2002; Vol. 74: Available at: https:// www.ecri.org/Documents/Clinical_Trials_Patient_Guide_Evidence_Report.pdf. 8. Peppercorn JM, Weeks JC, Cook EF, Joffe S. Comparison of outcomes in cancer patients treated within and outside clinical trials: conceptual framework and structured review. Lancet 2004; 363(9405): 263–270. 9. Vist GE, Bryant D, Somerville L et al. Outcomes of patients who participate in randomized controlled trials compared to similar patients receiving similar interventions who do not participate. Cochrane Database Syst Rev 2008 (3): MR000009. 10. Pfisterer J, Weber B, Reuss A et al. Randomized phase III trial of topotecan following carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: A gynecologic cancer intergroup trial of the AGO-OVAR and GINECO. J Natl Cancer Inst 2006; 98(15): 1036–1045.
doi:10.1093/annonc/mdr421 | vii19
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participation of a center but not an individual patient could add to a superior outcome based on receiving better quality of care. This hypothesis is supported by our data indicating that the observed benefit was not limited to patients enrolled in active protocols. Indeed, treatment standards, in particular for surgery, were more strictly implemented in study hospitals than in non-study hospitals. The purpose of our original study was to evaluate the pattern and quality of care for patients with ovarian cancer in Germany in 2001. We showed that German hospitals differ with respect to adhering to treatment guidelines and that the implementation of standards into clinical routine is still not satisfactory, despite some progress. However, QS-OVAR 2001 demonstrated the willingness of German hospitals to participate in quality assurance programs. This fact particularly applies to high-volume centers, which may reflect centralization. On the other hand, a bias toward participation of higher volume hospitals cannot be ruled out. Similarly, results may be biased because not all German hospitals participated in the current study. In phase I, 481 (43%) of the 1123 institutions contacted responded, 38 indicated that they did not treat patients with ovarian cancer. The 165 hospitals participating in phase II may not be a representative sample of all German hospitals. It is reasonable to speculate that hospitals that are willing to participate in quality assurance programs, such as QS-OVAR, are also hospitals that better adhere to treatment guidelines, so that the overall outcome of their patients may be too optimistic. However, this kind of selection bias can be assumed to primarily affect the results of researchinactive institutions because research-active institutions are more willing to be subject to quality assurance. For example, 50% of participating hospitals in QS-OVAR 2001 were research-active (as defined by the membership of AGO-OVAR or NOGGO), whereas only about 25% of all German hospitals fulfill this criterion. Therefore, the observed differences between research-active and research-inactive institutions can be considered a conservative estimate of the true differences that would have been revealed if all institutions had participated in our study. The same may be probably true with respect to the patients included in QS-OVAR 2001. The analysis was based on 34% of 1413 patients diagnosed with ovarian cancer per quarter in Germany. Obviously, data on the two-thirds of patients not included in the present quality assurance study would have been preferable. Unfortunately, national cancer registries are not established in Germany and consequently the data presented here is the most representative data collection available. Nevertheless, the possibility of selection bias as a cause of observed differences between research-active and research-inactive institutions should be taken into account. However, as mentioned above our notion of study participation is less biased than the simple comparison of ‘on-study patients’ with ‘off-study patients’ within institutions.
Annals of Oncology 22 (Supplement 7): vii16–vii19, 2011 doi:10.1093/annonc/mdr421
Clinical research in epithelial ovarian cancer and patients’ outcome J. Rochon1 & A. du Bois2 1
Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg; 2Department of Gynecology and Gynecologic Oncology, Kliniken Essen Mitte (KEM), Essen, Germany
chapter 3
introduction In 1999, the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) Organkommission OVAR, a subcommittee of the German Cancer Society, started a project aiming at improving outcome in ovarian cancer patients. Part of this ongoing project is a German-wide quality assurance programme termed QSOVAR that focuses on the outcomes of patients who are treated at hospitals participating in clinical studies versus non-study hospitals. Extended data on the first cohort (QS-OVAR 2001) have been presented elsewhere [1]. In the next section, we briefly describe the design of this study and present data on a 3year follow-up, which have been partially included in a recent systematic review [2]. We close with a discussion of our findings and their consequences.
patients and methods In phase I of QS-OVAR, all 1123 German gynecology departments were asked for the number of newly diagnosed ovarian cancer patients treated in 2001. In phase II, all responding hospitals were asked to document each newly diagnosed patient in the third quarter of 2001. Follow-up was done 2 and 3 years after the diagnosis of ovarian cancer. Overall survival was the primary endpoint. The secondary endpoint was adherence to treatment guidelines with regard to surgery and chemotherapy. Completeness of surgical staging in early ovarian cancer was defined according to German guidelines and included nine items. Staging was defined as ‘complete’ if none of these nine items was missing and as ‘optimal’ if only one item was missing. Adjuvant platinum-based chemotherapy was considered standard care for patients with early ovarian cancer except those patients with Fe´de´ration Internationale de Gyne´cologie et d’Obste´trique (FIGO) stage IA and highly differentiated tumours. Standard care for patients with
advanced disease included surgery that aimed at maximal tumour debulking. Here, we also differentiated between ‘complete’ surgery without any postoperative macroscopic tumour residual and so-called ‘optimal’ debulking with residuals up to 1 cm maximum diameter. Standard chemotherapy for patients with advanced disease included administration of a platinum–paclitaxel combination. With regard to hospital characteristics, we were primarily interested in study participation, that is, participation in prospective clinical trials conducted by one of the two German cooperative study groups, the AGO Study Group Ovarian Cancer (AGO-OVAR) and Northeastern Society of Gynecologic Oncology (NOGGO). The two study groups organize almost all national and international cooperative clinical trials in Germany in this field. AGO-OVAR is a member group of the Gynecologic Cancer Intergroup (GCIG) and both study groups are members of the European Network of Gynaecologic Oncology Trial Groups (ENGOT). In addition, we evaluated hospital volume because this characteristic is supposedly associated with better outcome in oncology. Hospital volume was categorized as low (1–11 patients/ year), medium (12–23 patients/year) and high (24+ patients/year). In addition, we collected information about patient variables [age, performance status according to Eastern Cooperative Oncology Group (ECOG), comorbidity, and history of second malignancies] and disease variables (FIGO stage, tumour grade, histological subtype, and presence of ascites of >500 ml).
results The analysis was based on 476 patients from 165 hospitals which represents about one-third of patients diagnosed with ovarian cancer in Germany per quarter. About 50% of the 165 hospitals were study hospitals (Table 1). However, only 21% (59 out of 275) patients in study hospitals were enrolled in
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
Downloaded from http://annonc.oxfordjournals.org/ at Northern Arizona University on June 23, 2015
We evaluated the relationship between the outcome of newly diagnosed ovarian cancer patients treated in 1123 German gynecology departments in 2001, and their participation in clinical trials through two German cooperative study groups. In addition, we evaluated other potential factors predicting outcome including hospital volume. The analysis was based on 476 patients from 165 hospitals and 3-year follow-up. Patients treated in study hospitals had a higher chance of receiving treatment according to national guidelines. This included a higher chance of receiving optimal staging in early stage disease and of receiving the recommended combination of surgical debulking and combination chemotherapy in advanced disease. On multivariable Cox model analysis, overall survival was significantly worse in patients treated in non-study hospitals.
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Volume 22 | Supplement 7 | November 2011
FIGO IIB–IV. Thus, we separately explored the effect of study participation in both strata, and found a survival benefit for patients with advanced ovarian cancer FIGO IIB–IV treated at study hospitals. The median overall survival time was 35 months for patients in study hospitals compared to 25 months for patients in non-study hospitals (Figure 2). Finally, we fitted a multivariable Cox model to assess the effect of participation in clinical trials on survival in patients with FIGO I–IV, taking into account all patient and disease characteristics measured, and also hospital volume (Table 2). This multivariable analysis showed that overall survival was significantly worse in patients treated at non-study hospitals (HR = 1.66, 95% CI: 1.22 to 2.27, P = 0.001).
discussion do healthcare systems that are active in clinical research deliver better outcomes for patients than healthcare systems that are inactive in research? In our study, participation in clinical trials as a quality characteristic of hospitals was associated with improved Table 1. Hospital and patient characteristics
Hospitals (n) 1–11 patients/year (%) 12–23 patients/year (%) 24+ patients/year (%) Patients (n) 65+ years (%) PS ECOG 0/1 (%) Comorbidity (%) Second cancer (%) FIGO IIB-IV (%) Grade 3/4 (%) Serous histology (%) Ascites >500 ml (%) Median follow-up (months)
All
Study hospitals
Non-study hospitals
165 49 32 19 476 46 79 24 14 74 45 69 40 35
80 31 39 30 275 45 79 24 12 80 50 71 40 35
85 66 26 8 201 46 79 25 17 66 39 66 40 35
P-value
<0.001
0.945 0.987 0.663 0.161 0.001 0.017 0.234 0.989 0.940
FIGO, Fe´de´ration Internationale de Gyne´cologie et d’Obste´trique staging; PS ECOG, Eastern Cooperative Oncology Group performance status scale. 100%
80%
Surgery-/Chemo-
60%
Surgery+/Chemo-
40%
20%
OR = 2.17 95% CI [1.47–3.19] P < 0.001
Surgery-/Chemo+
*
Surgery+/Chemo+
* Optimal surgery
0% 275 pts in study hospitals
201 pts in non-study hospitals
Figure 1. Adherence to treatment guidelines with regard to surgery and chemotherapy in ovarian cancer FIGO I–IV according to hospital participation in clinical trials.
doi:10.1093/annonc/mdr421 | vii17
Downloaded from http://annonc.oxfordjournals.org/ at Northern Arizona University on June 23, 2015
prospective clinical trials. Hospital-based descriptive analyses showed that participation in clinical studies was associated with higher hospital volume. For example, only 8% of non-study hospitals were high-volume centres compared with 30% of the study hospitals. Patients in study hospitals were generally similar to patients in non-study hospitals, except for imbalances with respect to FIGO stage and grade: Patients in study hospitals had higher FIGO stages and poorer differentiated tumours. Altogether, two-thirds of patients were diagnosed with advanced ovarian cancer FIGO IIB–IV. Second cancers were reported in 14% of patients. The Kaplan-Meier estimate for median follow-up time was 3 years. A total of 199 deaths occurred within this observation period. With respect to the adherence to treatment guidelines, patients with early ovarian cancer had a higher chance of receiving standard care (optimal staging and standard chemotherapy) in study hospitals than patients in non-study hospitals. In particular, patients in study hospitals were more likely to receive optimal staging than patients in non-study hospitals [odds ratio (OR) 2.75, 95% confidence interval (CI): 1.15 to 6.59, P = 0.030]. Overall, 23% of patients with early ovarian cancer had surgical staging with none or maximally one item missing. Seventy-one per cent of patients in study hospitals and 65% of patients in non-study hospitals received standard chemotherapy. In patients with advanced disease, 50% of patients in study hospitals and 38% of patients in non-study hospitals received the combination of optimal debulking with platinum–taxane chemotherapy (OR = 1.68, 95% CI: 1.08 to 2.60, P = 0.027). Further analysis showed differences in surgical outcome between study and non-study hospitals: 46% of patients in non-study hospitals had tumour residuals larger than 1 cm in contrast to 34% of patients in study hospitals. Thus, patients treated at study hospitals had a higher chance of being optimally debulked with a postoperative residual tumour of a maximum diameter of up to 1 cm (OR = 1.63, 95% CI: 1.05 to 2.53, P = 0.032). In patients with advanced disease, we also found statistically significant differences between study and non-study hospitals with regard to the quality of chemotherapy. The proportion of patients receiving the recommended platinum–taxane combination was 70% in study hospitals and 59% in non-study hospitals (P = 0.049). Altogether, about 46% of patients in study hospitals and only 28% of patients in non-study hospitals received treatment according to guidelines. Thus, patients in study hospitals had twice the chance of receiving standard treatment as patients in non-study hospitals (Figure 1). Since better treatment usually improves survival, we investigated the corresponding effect using a multivariable Cox model. As expected, suboptimal treatment was associated with worse survival, even after adjustment for all patient and disease characteristics measured [Hazard Ratio (HR) = 2.70, 95% CI: 1.89 to 3.85, P < 0.001]. Univariate survival analysis in patients with FIGO I–IV showed that treatment at non-study hospitals was associated with a higher risk of death, but this effect was not statistically significant (HR = 1.19, 95% CI: 0.90 to 1.57, P = 0.222). However, patients in study hospitals differed from patients in non-study hospitals, particularly with respect to FIGO stage. In addition, most events occurred in the advanced stages
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Table 2. Multivariable Cox model for overall survival in patients with ovarian cancer in Germany in 2001
Survival probability (%)
100%
75%
Variable 50% Log-rank test: P = 0.006 HR = 1.50 [95% CI: 1.12–2.00]
25% Study hospitals
(N = 219, E = 103)
Non-study hospitals
(N = 133, E = 81)
0% 0
6
12
18
24
30
36
129 63
100 43
43 15
Months No. at risk 219 Study hospitals Non-study hospitals 133
187 109
166 95
149 83
survival in patients with epithelial ovarian cancer. With regard to ovarian cancer, study participation has hardly been investigated outside Germany. One exception is Robinson et al. [3] who also showed a positive effect of study participation but used a very different study design. In other diseases, however, this effect has been discussed for a much longer period of time. A beneficial effect of trial participation on survival has been reported, for example, in patients with multiple myeloma [4] and non-small cell lung cancer [5]. At least four reviews have been published so far but with varying conclusions [6–9]. Braunholtz et al. [6] concluded that randomized controlled trials (RCT) tend to have a beneficial rather than a harmful effect on individual patients. The Emergency Care Research Institute [7] summarized 10 comparisons and concluded that some evidence shows that patients in trials survive longer than similar patients who are not in trials. In contrast, Peppercorn et al. [8] concluded that data are insufficient with regard to the existence of a trial effect. Vist et al. [9] concluded that outcomes of patients participating in a RCT do not differ from those of patients who receive similar treatments and do not participate in a RCT.
what do we precisely mean by a study participation effect and is it an artifact or a measure for improving quality? Evaluating a study participation effect is not a trivial issue. First of all, when evaluating study participation, it is important to note which groups are compared with each other. As suggested by Braunholtz et al. [6], several comparisons are possible. Most studies compare ‘on-study patients’ with ‘off-study patients’; but the definitions of the groups often differ substantially and are biased by study inclusion criteria. In our study, we did not compare ‘on-study patients’ with ‘off-study patients’ but compared all patients treated at hospitals participating in clinical studies with all patients from non-study hospitals. Therefore, the effect of study participation was supposed to cover more than just the participation of some patients in specific clinical trials. In addition, in our study, only 21% of patients treated at study hospitals had actually been enrolled in prospective clinical trials, which included a large GCIG trial for
vii18 | Rochon & du Bois
E
HR
95% CI
P-value
275 201
108 91
1 1.66
Reference 1.22–2.27
0.001
170 150 156
77 52 70
1 1.01 1.14
Reference 0.71–1.46 0.80–1.63
0.940 0.461
259 217
75 124
1 1.67
Reference 1.19–2.33
0.003
374 102
126 73
1 2.55
Reference 1.80–3.60
<0.001
360 116
122 77
1 1.72
Reference 1.25–2.37
0.001
408 68
164 35
1 1.31
Reference 0.90–1.91
0.154
124 352
15 184
1 4.53
Reference 2.62–7.82
<0.001
261 215
89 110
1 1.17
Reference 0.88–1.56
0.285
147 329
47 152
1 1.29
Reference 0.92–1.82
0.142
284 192
88 111
1 1.74
Reference 1.30–2.33
<0.001
N, number of patients; E, number of events; HR, hazard ratio; CI, confidence interval; FIGO, Fe´de´ration Internationale de Gyne´cologie et d’Obste´trique staging; ECOG, Eastern Cooperative Oncology Group performance status scale.
advanced ovarian cancer in 2001. This trial did not show any superiority of the experimental treatment [10]. Furthermore, our study also revealed positive effects for patients with early ovarian cancer at a time when no protocol had been active. Our model rather implied the hypothetical assumption that patients in study hospitals have a better outcome than patients in nonstudy hospitals because hospitals participating in trials accumulate knowledge and develop special infrastructures associated with study participation. Furthermore, trial centres are subject to regular auditing and monitoring and therefore may have a more rigorous external system of quality control. In addition, team members in trial units may not only be interested in studies on ovarian cancer but may also be motivated to keep up with new developments in other medical fields. Taking all this into account, it could well be that even patients who are not actively enrolled in study protocols but treated at hospitals participating in clinical studies could benefit from these hospital characteristics. In this way, study
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Figure 2. Kaplan–Meier survival curves in ovarian cancer FIGO IIB–IV according to hospital participation in clinical trials.
Study participation Yes No Hospital volume High Medium Low Age < 65 years ‡ 65 years Performance status ECOG 0/1 ECOG > 1 Comorbidity None Present Second cancer None Present Stage FIGO I–IIA FIGO IIB–IV Grade G 1/2/unknown G 3/4 Histology Other Serous Ascites £ 500 ml > 500 ml
N
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In addition, the comparisons in the current study were adjusted for potentially confounding factors, such as age, stage of disease, and comorbidities. Finally, more patients with advanced disease were treated in study hospitals, which should, if at all, disadvantage these institutions with respect to patients’ outcome as compared to non-study hospitals that more often treated patients with better prognosis. Our study demonstrated the heterogeneity in the treatment patterns of ovarian cancer in Germany and showed the areas needing improvement. Furthermore, we found a beneficial trial participation effect and generated a hypothesis. QS-OVAR 2001 was followed by QS-OVAR 2004 and QS-OVAR 2008. The results of the further analyses of QS-OVAR 2004 and 2008 are expected in 2012.
disclosures The authors have not declared any conflicts of interest.
references 1. du Bois A, Rochon J, Lamparter C, Pfisterer J. Pattern of care and impact of participation in clinical studies on the outcome in ovarian cancer. Int J Gynecol Cancer 2005; 15: 183–191. 2. du Bois A, Rochon J, Pfisterer J, Hoskins WJ. Variations in institutional infrastructure, physician specialization and experience, and outcome in ovarian cancer: a systematic review. Gynecol Oncol 2009; 112(2): 422–436. 3. Robinson WR, Ritter J, Rogers AS et al. Clinical trial participation is associated with improved outcome in women with ovarian cancer. Int J Gynecol Cancer 2009; 19: 124–128. 4. Karjalainen S, Palva I. Do treatment protocols improve end results? A study of survival of patients with multiple myeloma in Finland. Br Med J 1989; 299: 1069–1072. 5. Davis S, Wright PW, Schulman SF et al. Participants in prospective, randomized clinical trials for resected non-small cell lung cancer have improved survival compared with nonparticipants in such trials. Cancer 1985; 56: 1710–1708. 6. Braunholtz DA, Edwards SJ, Lilford RJ. Are randomized clinical trials good for us (in the short term)? Evidence for a ‘trial effect’. J Clin Epidemiol 2001; 54(3): 217–224. 7. ECRI Evidence Report. Patients’ reasons for participation in clinical trials and effect of trial participation on patient outcomes. ECRI Health Technology Assessment Information Service 2002; Vol. 74: Available at: https:// www.ecri.org/Documents/Clinical_Trials_Patient_Guide_Evidence_Report.pdf. 8. Peppercorn JM, Weeks JC, Cook EF, Joffe S. Comparison of outcomes in cancer patients treated within and outside clinical trials: conceptual framework and structured review. Lancet 2004; 363(9405): 263–270. 9. Vist GE, Bryant D, Somerville L et al. Outcomes of patients who participate in randomized controlled trials compared to similar patients receiving similar interventions who do not participate. Cochrane Database Syst Rev 2008 (3): MR000009. 10. Pfisterer J, Weber B, Reuss A et al. Randomized phase III trial of topotecan following carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: A gynecologic cancer intergroup trial of the AGO-OVAR and GINECO. J Natl Cancer Inst 2006; 98(15): 1036–1045.
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participation of a center but not an individual patient could add to a superior outcome based on receiving better quality of care. This hypothesis is supported by our data indicating that the observed benefit was not limited to patients enrolled in active protocols. Indeed, treatment standards, in particular for surgery, were more strictly implemented in study hospitals than in non-study hospitals. The purpose of our original study was to evaluate the pattern and quality of care for patients with ovarian cancer in Germany in 2001. We showed that German hospitals differ with respect to adhering to treatment guidelines and that the implementation of standards into clinical routine is still not satisfactory, despite some progress. However, QS-OVAR 2001 demonstrated the willingness of German hospitals to participate in quality assurance programs. This fact particularly applies to high-volume centers, which may reflect centralization. On the other hand, a bias toward participation of higher volume hospitals cannot be ruled out. Similarly, results may be biased because not all German hospitals participated in the current study. In phase I, 481 (43%) of the 1123 institutions contacted responded, 38 indicated that they did not treat patients with ovarian cancer. The 165 hospitals participating in phase II may not be a representative sample of all German hospitals. It is reasonable to speculate that hospitals that are willing to participate in quality assurance programs, such as QS-OVAR, are also hospitals that better adhere to treatment guidelines, so that the overall outcome of their patients may be too optimistic. However, this kind of selection bias can be assumed to primarily affect the results of researchinactive institutions because research-active institutions are more willing to be subject to quality assurance. For example, 50% of participating hospitals in QS-OVAR 2001 were research-active (as defined by the membership of AGO-OVAR or NOGGO), whereas only about 25% of all German hospitals fulfill this criterion. Therefore, the observed differences between research-active and research-inactive institutions can be considered a conservative estimate of the true differences that would have been revealed if all institutions had participated in our study. The same may be probably true with respect to the patients included in QS-OVAR 2001. The analysis was based on 34% of 1413 patients diagnosed with ovarian cancer per quarter in Germany. Obviously, data on the two-thirds of patients not included in the present quality assurance study would have been preferable. Unfortunately, national cancer registries are not established in Germany and consequently the data presented here is the most representative data collection available. Nevertheless, the possibility of selection bias as a cause of observed differences between research-active and research-inactive institutions should be taken into account. However, as mentioned above our notion of study participation is less biased than the simple comparison of ‘on-study patients’ with ‘off-study patients’ within institutions.