Obstetrics & Gynecology:
Efficacy of a Regional Network for Ovarian Cancer Care
van Altena, Anne M. MD, PhD; van den Akker, Petronella A.J.; de Hullu, Joanne A. MD, PhD; Ottevanger, Petronella B. MD, PhD; Aalders, Annet L. MD; Gerritse, Rene MD; Happel, Martin MD; Hoekstra, Marcel P. MD; Janssen, Mark-Jan MD; Samlal, Rahul A.K. MD, PhD; Smeets, Kirsten M.W.H. MD; Snijders, Marc P.M.L. MD, PhD; Vasmel, Maria J. MD; Vollebergh, Jos H.A. MD; Kiemeney, Lambertus A.L.M. PhD; Massuger, Leon F.A.G. MD, PhD
Departments of Obstetrics and Gynecology, Medical Oncology, and Epidemiology, Biostatistics, and Health Technology Assessment and Urology, Radboud University Medical Centre, Nijmegen, the Departments of Obstetrics and Gynecology, Rijnstate Hospital, Arnhem, Streekziekenhuis Koningin Beatrix, Winterswijk, Rijnstate Hospital, Zevenaar, Bernhoven Hospital, Veghel, Maasziekenhuis, Boxmeer, Gelderse Vallei Hospital, Ede, Slingeland Hospital, Doetinchem, Canisius-Wilhelmina Hospital, Nijmegen, Hospital St. Jansdal, Harderwijk, and Bernhoven Hospital, Oss, and the Comprehensive Cancer Centre of the Netherlands, Utrecht, the Netherlands.
Corresponding author: Anne M. van Altena, MD, PhD, Department of Obstetrics & Gynecology, Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands; e-mail: A.vanAltena@obgyn.umcn.nl.
Presented at the European Society of Gynecological Oncology, October 11–14, 2009, Belgrade, Serbia, and at the International Gynecologic Cancer Society, October 2012, 13–16, Vancouver, Canada.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: To study the influence of a regional collaboration in epithelial ovarian cancer care on staging procedures, debulking results, and survival.
METHODS: In an effort to optimize epithelial ovarian cancer treatment, a regional collaboration was introduced in the Netherlands in 2000. Gynecologic oncologists from the university center conducted surgery in community hospitals when ovarian cancer was considered based on the risk of malignancy index or clinical suspicion. The National Cancer Registry registered 1,554 patients with epithelial ovarian cancer diagnosed in 11 participating Dutch hospitals between 1996 and 2010. Surgical procedures were compared during three periods (1996–1999, 2000–2004, and 2005–2009). Log-rank tests compared Kaplan-Meier survival curves of progression-free and overall survival before (1996–2000) and during the start of the collaboration (2001–2005).
RESULTS: Staging was adequate for 139 patients (23.0%) before collaboration, and this proportion increased during the study periods to 32.1% and 62.1% (P<.01), when gynecologic oncologists more often staged cancer in patients (36.7% compared with 54.7% and 80.6%; P<.01). For 1,197 patients with advanced stage disease (stage IIb or greater), the proportion of debulking procedures with an optimal (residual volume less than1 cm) as well as a complete result (no residuals) increased during the 14-year study period from 57.4% to 76.5% (P<.01) and from 24.1% to 43.4% (P<.01), respectively. Survival rates were similar before and during the start of the collaboration. In multivariable analysis, the treatment variables completeness of debulking, chemotherapy, and gynecologic oncologist attendance were independent prognostic factors for overall survival, as were age, stage, and tumor grade.
CONCLUSIONS: After regional collaboration, gynecologic oncologists attended more surgeries and surgical outcomes improved, but progress in survival could not be demonstrated. Regional collaboration improved care for ovarian cancer patients.
LEVEL OF EVIDENCE: II
Epithelial ovarian cancer is the most lethal gynecologic cancer in the developed world, and the prognosis has improved only slightly in recent decades. Changes in chemotherapy regimens achieved progress, but further improvement of survival may be expected from surgical treatment.
A meta-analysis showed that increased cytoreduction is associated with better survival.1 Complete debulking gives the greatest benefit of surgery.2,3 A full staging procedure will upstage approximately 30% of the patients with early stage disease.4,5 It is generally accepted that gynecologic oncologists perform the surgical procedures more adequately than general gynecologists,6,7 which results in better survival.6,8–10 An overview of the European pattern of care in the 1990s showed that substantial numbers of patients with ovarian cancer were treated suboptimally.11 At that time in the Netherlands, general gynecologists treated most patients in the hospital of diagnosis, and still do in many other countries. Initiatives to centralize treatment have been launched in the past 20 years.
Regional collaboration in gynecologic oncology was introduced in 2000, and 11 hospitals participated. The main goal was to improve care by means of consultations with gynecologic oncologists when ovarian cancer was suspected. The 11 hospitals cover a region with 1.7 million inhabitants; approximately 110 patients have epithelial ovarian cancer diagnosed annually. The risk of malignancy index was implemented in 2005 to improve care with standardized risk assessment for pelvic masses.12
The aims of our population-based study were to assess changes that coincide with the introduction of the collaboration and to evaluate the role of the collaboration in care. The attendance of gynecologic oncologists during surgery, staging and debulking results, and survival of patients are all factors that we compared before and after the regional network was introduced.
MATERIALS AND METHODS
The Institutional Board of the National Cancer Registry and all the gynecologic departments involved gave their ethical approval for this retrospective population-based study in the east of the Netherlands. All consecutive patients in this region with epithelial ovarian cancer diagnosed between 1 January 1996 and 1 January 2010 were selected from the Netherlands Cancer Registry. This registry is based on the reports of all newly diagnosed malignancies in the automated nationwide pathology archive and the national registry of hospital discharge diagnoses. Trained medical registrars, using a standard case record form, studied the hospital records of the patients. We compared the surgical results of 1996–1999 (before the collaboration) with those of 2000–2004 (during introduction of the collaboration) and 2005–2009 (full introduction of the collaboration). To allow sufficient follow-up, we studied survival during two calendar periods (1996–2000 and 2001–2005).
The 11 hospitals involved one specialized university center hosting five gynecologic oncologists. These gynecologists completed a fellowship in gynecologic oncology or are registered as gynecologic oncologists by the Dutch Society of Obstetrics and Gynecology (or both). The three teaching hospitals that were involved in the network had two semi-specializing gynecologists and approximately eight general gynecologists each. Semi-specializing gynecologists are not formally trained in oncology, but they treat most of the oncology patients in the larger teaching hospitals. Seven nonteaching general hospitals with four to six general gynecologists collaborated. The maximum radius from the university medical center to the satellite hospitals was approximately 100 km.
From 2005 onward, gynecologists were requested to register the risk of malignancy index parameters for all patients with adnexal masses for the purpose of a prospective observational study of the effectiveness of the risk of malignancy index.12 This index was calculated as the multiplied value of the ultrasound score, menopausal status, and serum CA 125 level, as Tingulstad proposed in 1999.13 In 2008, it was formally introduced as a tool for selecting patients for surgery performed by a gynecologic oncologist. A score of 200 or more on the risk of malignancy index indicated the need for a gynecologic oncologist. If the score was less than 200, the gynecologic oncologist only participated when specifically requested.
In agreement with previous studies, we defined the minimal adequate staging as a total abdominal hysterectomy and bilateral salpingo-oophorectomy, infracolic omentectomy, at least one resected lymph node, and one peritoneal biopsy. As the evidence-based Dutch guideline 2009 states,14 a staging procedure should include resection of at least 10 lymph nodes. We decided to show the results according to our definition as well as the number of lymph nodes. We defined optimal debulking as leaving no residual tumor larger than 1 cm in diameter. Complete debulking constitutes surgery with no macroscopic residual tumor. We analyzed the debulking results for patients with advanced stage disease (stage IIb or higher).
We used the Pearson χ2 and Student t test to compare categorical and continuous characteristics. We used survival techniques to study the time to recurrence or to death. We defined progression-free survival as the interval between the date of diagnosis and the date of tumor recurrence or the date of death, whichever occurred first.
Women with no recurrence were censored at their last follow-up date. We defined recurrence as a clinical examination or radiologic study with evidence of recurrent disease, preferably with pathologic confirmation or an increase of CA 125 greater than or equal to twice the upper normal limit on two occasions at least 1 week apart. We defined overall survival as the time between diagnosis and death or the last follow-up date. The women still living at the last follow-up date, 1 January 2011, were censored.
We calculated the Kaplan-Meier estimates of progression-free and overall survival in the time groups. We also calculated the survival figures for those patients who were treated by a gynecologist (ie, underwent a debulking surgery) because this group may primarily benefit from the collaboration. The log-rank test determined differences in Kaplan-Meier estimates.
Univariable proportional hazards models helped us study the influence of clinicopathologic factors on overall survival. We used a multivariable model to determine the effect of the study period on survival adjusted for other prognostic variables. All P values are two-sided, and we considered the associations significant at P<.05. We used the Statistical Package for Social Sciences version 16.0 for the analyses.
A total of 1,554 patients in the region had epithelial ovarian cancer diagnosed. Table 1 shows their clinicopathologic characteristics. Most of these patients had advanced stage of disease. No International Federation of Gynecology and Obstetrics stage was recorded in the medical records for 107 patients, and the pathology reports or surgical reports (or both) did not clarify the exact stage. Three of the patients were categorized as having early stage disease diagnosed and 98 patients had advanced stage disease diagnosed. The stage remained unclear for six patients who were excluded from the analysis of surgical outcomes.
Table 1 shows the characteristics during the various study periods. During the last period, more serous cancers and fewer adenocarcinomas “not otherwise specified” were diagnosed. The grade was more often unknown in this last period. Patients more often received adequate platinum-based chemotherapy over time (P=.04).
Only patients who needed staging surgery were included in the staging analysis. Staging was not applicable for 1,033 patients because an advanced stage became clear before or during surgery. A total of 362 patients underwent primary staging surgery, and another 91 patients underwent staging surgery secondarily, for example, when initially benign or borderline disease had been expected. The information was lacking for one patient.
The reasons for omitting a staging procedure were recorded in 68 medical records. The main reasons were fertility, another indication for chemotherapy (tumor histology), and poor condition. The proportions of omitted staging surgeries for the three calendar periods were somewhat similar: 15 (3.4%) for the first period; 29 (5.1%) for the second period; and 24 (4.4%) for the third period. A gynecologic oncologist more frequently performed the surgery for patients with a risk of malignancy index more than 200. Gynecologic oncologists were involved in 33.9% of the surgeries during the first period, in 57.5% during the second period, and in 87.5% during the third period. Table 2 shows that gynecologic oncologists performed increasingly more adequate staging procedures and surgeries during the 14-year study period.
A total of 1,197 patients had disease that was International Federation of Gynecology and Obstetrics stage IIb or more, as clinically or surgically determined. Of these patients, 737 (61.6%) underwent primary debulking surgery. Clinical data for three patients were lacking. In 457 women, the primary debulking surgery was cancelled. The decisions about debulking surgery were based on clinical signs, imaging studies, or the patient's refusal. The decision also could be made soon after the surgery started, after inspection of the tumor alone. The main reasons for omitting primary debulking were the clinical condition of the patient (n=126; 27.6%), tumor volume or localization (n=232; 50.8%), patient refusal (n=43; 9.4%), or a combination of these reasons (n=26; 6.2%).
In the group of 457 patients for whom the primary debulking surgery was canceled, 165 patients underwent interval debulking. The tumor volume or localization was the main reason for not performing the primary debulking. A total of 902 patients (75.3%) with advanced stage disease received a primary or interval debulking, and this proportion remained stable over the study period.
The proportion of primary debulking surgeries decreased and the proportion of interval debulking surgeries increased (Table 3). The proportions of optimal and complete debulking increased. The debulking surgeries were increasingly performed by a gynecologic oncologist. The location of the interval debulking changed significantly over the years.
Figure 1 shows the Kaplan-Meier curves of the progression-free and overall survival in the patient groups with diagnoses before and after the collaboration. Survival was not significantly different during the two periods, and survival did not improve significantly for patients who underwent debulking surgery (Fig. 2). Table 4 shows the variables that independently influence overall survival. Younger age, early stage, endometrioid or mucinous histology, lower tumor grade, no residual tumor or residual tumor smaller than 1 cm, attendance of a gynecologic oncologist, and adequate chemotherapy were associated with prolonged survival. The type of hospital was not associated with survival outcome. Using multivariable Cox regression, we determined the following six independent variables: age; stage; tumor grade; completeness of debulking; presence of a gynecologic oncologist; and adequacy of chemotherapy.
This study describes all changes occurring after the regional collaboration for epithelial ovarian cancer started in the Netherlands. One prominent change was the increase in surgeries performed by gynecologic oncologists. Introducing the risk of malignancy index in risk assessment may have contributed to this change. Both the staging and debulking results improved greatly during the collaboration. Several care changes after the collaboration started may have improved the surgery. These changes include multidisciplinary consultation before treatment, using the risk of malignancy index, having gynecologic oncologists attend the surgeries, the organization of care for the patients, and the protocols and guidelines that are being used in the network. Unfortunately, we cannot determine the precise reason for the improvements because of the retrospective design of the study.
Gynecologic oncologists attended the staging surgeries of more than 85% of the patients with a risk of malignancy index more than 200. Most of the remaining 15% were treated in one hospital where the semi-specializing gynecologist operated with a specializing general surgeon. One might question the use of the risk of malignancy index, which may increase the number of surgeries performed by gynecologic oncologists for benign tumors. However, van den Akker et al12 show that the opposite is true. Moreover, a recent study shows that using the risk of malignancy index to centralize care is cost-effective.15
While discussing the adequacy of the staging procedure, we found that more than 70% of the study population did not undergo optimal staging according to the definition of the Dutch evidence-based guideline for epithelial ovarian cancer, which includes at least 10 lymph nodes. The benefit of a staging procedure including 10 lymph nodes has never been proven with respect to survival, but we know that patients with early stage disease with a well-differentiated tumor can be spared chemotherapy.16–18 The role of biopsies of normal peritoneum is still being debated. We chose to present the procedures in the Dutch guideline, which are compatible with the quality indicators defined by the European Organisation for Research and Treatment of Cancer–Gynaecological Cancer Group.19
In a minority of cases, the surgeon outlined the reason for inadequate staging and the majority of reasons were valid. We advocate further research to identify factors that affect compliance with the guideline in daily practice.
In contrast to the circumstances of the staging procedure, the gynecologists were aware of the inadequate procedure for debulking surgery. The reasons for not achieving complete debulking were recorded for most of the patients. Tumor volume and localization were the main reasons; these are well-known factors negatively influencing debulking.20,21
The increase in interval debulking surgeries may have contributed to more complete debulking. Studies of interval debulking surgery and survival are contradictory22,23 because of confounding by indication. We have no data regarding operative morbidity, which might have added interesting information about the differences between primary and interval debulking surgery.
Approximately 25% of all patients with advanced stage disease had no debulking surgery, and this proportion was stable over time. This is consistent with data for the whole Dutch population.24 Apparently, a subgroup of patients is ineligible for surgery mainly because of the volume or localization of the tumor or patient characteristics such as age and comorbidity.
Despite the improvement in clinical care, survival did not improve. There was a nonsignificant difference in overall 5-year survival of 3% (from 36% to 39%). An improvement of 3% overall survival would be compatible with the Dutch nationwide figures for survival,24 in which 5-year relative survival has improved (35% in 1989–1993 compared with 41% in 2004–2009). The lack of a significant difference between groups could be attributable to inadequate study size. A post hoc power analysis determined that at least 3,045 patients per study group would be necessary to show a significant increase of 3% in 5-year survival, based on our observed survival.
The lack of an increase in survival also may be attributed to other factors like the inappropriate chemotherapy treatment. Chemotherapy was inadequate for approximately 30% of the patients. Chemotherapy was not started for 25% of these patients because of their poor clinical condition. The remaining patients, especially during the first study period, never received a platin-containing chemotherapeutic or they never received the adequate number of courses, mainly because of their condition.
Other factors are the increasing number of high-grade tumors in the second study period, and tumor grade is associated with survival in the Cox regression analysis. The increased percentage of serous carcinomas and fewer adenocarcinomas not otherwise specified are probably caused by improved diagnostics and therefore are not considered a real shift.
This population-based study covered 14 years and all surgical aspects of ovarian cancer care, including reasons for omitting procedures. Although there is enough knowledge about adequate surgical procedures, many patients worldwide do not receive the best treatment, partly because of lack of collaboration between institutions and physicians. The results of this study look promising for future collaboration in the field of gynecologic oncology. Regional networks can help in several ways to enhance management.
1. Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002;20:1248–59.
2. du Bois BA, Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d'Investigateurs Nationaux Pour les Etudes des Cancers de l'Ovaire (GINECO). Cancer 2009;115:1234–44.
3. Harter P, Hilpert F, Mahner S, Kommoss S, Heitz F, Pfisterer J, et al.. Prognostic factors for complete debulking in first- and second-line ovarian cancer. Int J Gynecol Cancer 2009;19(Suppl 2):S14–7.
4. Hoskins WJ. Surgical staging and cytoreductive surgery of epithelial ovarian cancer. Cancer 1993;71(Suppl 4):1534–40.
5. Young RC, Decker DG, Wharton JT, Piver MS, Sindelar WF, Edwards BK, et al.. Staging laparotomy in early ovarian cancer. JAMA 1983;250:3072–6.
6. Vernooij F, Heintz P, Witteveen E, van der Graff Y. The outcomes of ovarian cancer treatment are better when provided by gynecologic oncologists and in specialized hospitals: a systematic review. Gynecol Oncol 2007;105:801–812.
7. du Bois BA, 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;112:422–36.
8. du Bois BA, 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;15:183–91.
9. Engelen MJ, Kos HE, Willemse PH, Aalders JG, de Vries EG, Schaapveld M, et al.. Surgery by consultant gynecologic oncologists improves survival in patients with ovarian carcinoma. Cancer 2006;106:589–98.
10. Earle CC, Schrag D, Neville BA, Yabroff KR, Topor M, Fahey A, et al.. Effect of surgeon specialty on processes of care and outcomes for ovarian cancer patients. J Natl Cancer Inst 2006;98:172–80.
11. Verleye L, Vergote I, van der Zee AG. Patterns of care in surgery for ovarian cancer in Europe. Eur J Surg Oncol 2010;36(Suppl 1):S108–14.
12. van den Akker PA, Aalders AL, Snijders MP, Kluivers KB, Samlal RA, Vollebergh JH, et al.. Evaluation of the Risk of Malignancy Index in daily clinical management of adnexal masses. Gynecol Oncol 2010;116:384–8.
13. Tingulstad S, Hagen B, Skjeldestad FE, Halvorsen T, Nustad K, Onsrud M. The risk-of-malignancy index to evaluate potential ovarian cancers in local hospitals. Obstet Gynecol 1999;93:448–52.
15. Geomini PM, Kruitwagen RF, Bremer GL, Massuger L, Mol BW. Should we centralise care for the patient suspected of having ovarian malignancy? Gynecol Oncol 2011;122:95–9.
16. Trimbos JB, Schueler JA, van der BM, Hermans J, van LM, Heintz AP, et al.. Watch and wait after careful surgical treatment and staging in well-differentiated early ovarian cancer. Cancer 1991;67:597–602.
17. Trimbos JB, Vergote I, Bolis G, Vermorken JB, Mangioni C, Madronal C, et al.. Impact of adjuvant chemotherapy and surgical staging in early-stage ovarian carcinoma: European Organisation for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm trial. J Natl Cancer Inst 2003;95:113–25.
18. Winter-Roach B, Hooper L, Kitchener H. Systematic review of adjuvant therapy for early stage (epithelial) ovarian cancer. Int J Gynecol Cancer 2003;13:395–404.
19. Verleye L, Ottevanger PB, van der GW, Reed NS, Vergote I. EORTC-GCG process quality indicators for ovarian cancer surgery. Eur J Cancer 2009;45:517–26.
20. Burghardt E, Girardi F, Lahousen M, Tamussino K, Stettner H. Patterns of pelvic and paraaortic lymph node involvement in ovarian cancer. Gynecol Oncol 1991;40:103–6.
21. Heintz AP, Hacker NF, Berek JS, Rose TP, Munoz AK, Lagasse LD. Cytoreductive surgery in ovarian carcinoma: feasibility and morbidity. Obstet Gynecol 1986;67:783–8.
22. Bristow RE, Chi DS. Platinum-based neoadjuvant chemotherapy and interval surgical cytoreduction for advanced ovarian cancer: a meta-analysis. Gynecol Oncol 2006;103:1070–6.
23. Vergote I, Trope CG, Amant F, Kristensen GB, Ehlen T, Johnson N, et al.. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 2010;363:943–53.
24. van Altena AM, Karim-Kos HE, de VE, Kruitwagen RF, Massuger LF, Kiemeney LA. Trends in therapy and survival of advanced stage epithelial ovarian cancer patients in the Netherlands. Gynecol Oncol 2012;125:649–54.
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