Departments of 1 Surgery, 2 Biostatistics, 3 Medical Oncology and 4 Pathology, Institut Gustave Roussy, Villejuif, France
Received 11 March 2002; revised 3 June 2002; accepted 8 July 2002
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Abstract |
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To study the results of interval debulking surgery (IDS) in patients treated for unresectable advanced stage ovarian cancer compared with primary debulking surgery (PDS) followed by chemotherapy.
Patients and methods:
An exposednon-exposed study including a group of 34 patients who underwent an IDS and were matched to an historic control group of 34 patients treated with PDS.
Results:
Optimal cytoreductive surgery was achieved in 94% (32 out of 34) of patients in both groups. The rates of post-operative morbidity, blood transfusion and median length of hospitalisation were significantly reduced in the study (IDS) group, but survival did not differ in both groups.
Conclusions:
IDS in patients with advanced stage ovarian cancer offers the same chance of survival as PDS, but it is better tolerated.
Key words: induction chemotherapy, interval debulking surgery, ovarian cancer, unresectable tumour
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Introduction |
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Several non-randomized studies have discussed the benefit of induction chemotherapy in such patients [918]. Two series were randomized and studied a group of patients with bulky residual tumour at the end of primary surgery treated by chemotherapy alone compared with another group of patients who underwent chemotherapy followed by debulking surgery [19, 20]. In the literature, however, no randomized study compared the PDS with interval debulking surgery (IDS). In the present paper we reported a comparative study (exposednon-exposed type) of 34 patients treated with induction chemotherapy followed by debulking surgery.
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Patients and methods |
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Study group
The 34 patients were classified as unresectable during an initial surgical procedure if an optimal cytoreduction was not possible using standard surgery (total hysterectomy with bilateral salpingo-oophorectomy + omentectomy + pelvic and para-aortic lymphadenectomy with or without resection of the recto-sigmoid if necessary), or was feasible but only by using extensive surgery (resection of more than two segments of the digestive tract, and/or spleno-pancreatectomy). Several sites were biopsied. At the end of this initial surgical exploration, residual disease was >2 cm. In none of these patients was standard surgery attempted. This surgical procedure was followed by platinum-based chemotherapy before performing IDS. IDS was attempted after three to four courses of chemotherapy and was followed by chemotherapy.
Control group
This study group was matched to a historic control group selected in a collection of 152 patients treated at our institution between 1985 to 1993 for advanced stage disease with PDS, followed by curative platinum-based chemotherapy and reported previously [2]. These study and control groups were matched according to FIGO (International Federation of Gynecology and Obstetrics, 1987 classification) stage, tumour grade and patient age at diagnosis (±5 years) (Table 1). Characteristics of debulking surgery and survival of patients were compared. The Wilcoxon rank test was used to compare continuous variables. The 2 test was used to compare proportions and a P value <0.05 value was considered significant. Survival curves were compared using a log-rank test.
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Results |
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Study group
In the study (IDS) group, the initial surgical procedure was performed by laparoscopy (in eight patients) or laparotomy (in 26 patients). During this initial surgery, the procedures performed were: ovarian or peritoneal biopsies in 15 patients, salpingo-oophorectomy in 21 patients and hysterectomy with bilateral salpingo-oophorectomy in 10 patients. None of these patients had postoperative morbidity. One of these patients, treated using a laparoscopic approach, developed a trocar site metastasis. Details about the induction chemotherapy are given in Table 1. The median delay between the initial surgical procedure and the first course of chemotherapy was 20 days (range 640 days).
IDS was performed using a midline incision including: hysterectomy (20 patients), salpingo-oophorectomy (11 patients), appendicectomy (10 patients), bowel resection (six patients) with three enterostomies (two of them permanent), splenopancreatectomy in one patient, splenectomy in one patient and large peritonectomies. Twenty-two patients underwent lymphadenectomies (18 pelvic and para-aortic lymphadenectomies).
Optimal cytoreductive surgery (residual disease 2 cm) was achieved in 32 patients. At the end of IDS, 22 (65%) patients had no macroscopic residual disease. Histological examination of the surgical specimens revealed the persistence of residual disease in 31 (91%) patients, but with large areas of tumour necrosis in 13 (38%). Eleven of the 22 (50%) patients who underwent lymphadenectomy had positive para-aortic nodes (with positive pelvic nodes in nine patients). The median number of pelvic and para-aortic positive lymph nodes were two and five, respectively (range 110). Postoperative complications were observed in four (12%) patients: abdominal abscesses (two patients), deep venous thrombosis (one) and a recto-vaginal fistula (one). The median delay between IDS and the next course of chemotherapy was 23 days (range 1466 days).
Control group
In the control (PDS) group, the surgical procedures included a hysterectomy + bilateral salpingo-oophorectomy + omentectomy for all patients with a bowel resection in 24 patients. Eighteen patients developed postoperative complications: bleeding (eight patients), anastomotic leakage (seven patients), abscess (four patients) and peritonitis (one patient). Permanent enterostomy was carried out in eight patients. Optimal cytoreductive surgery (residual disease 2 cm) was achieved in 32 patients. At the end of IDS, 10 (29%) patients had no macroscopic residual disease. The median delay between the PDS and the first course of chemotherapy was 23 days (range 1467 days). All patients received platinum-based chemotherapy. Details about the first-line chemotherapy regimen are given in Table 1.
When we compare the two groups, the rate of bowel resection, permanent enterostomy, blood transfusion, postoperative complications and Intensive Care Unit stay related to the debulking surgery are significantly lower in the study (IDS) group (Table 2). The median length of hospitalisation following debulking surgery is significantly shortened in the study (IDS) group (Table 2). Median survival times were not different (26 months in the study group compared with 22 months in the control group, not significant). The overall and disease-free survival rates at 2 years (95% confidence interval) in the study and control groups were not statistically different (Figures 1 and 2).
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Discussion |
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Our results raise several questions and comments. The first one concerns the criteria used to select patients for induction chemotherapy and patients for PDS. Our data do not imply that all patients with peritoneal disease should have induction chemotherapy. In fact, when PDS is feasible and permits a minimal residual tumour with an acceptable morbidity to be obtained, it should be performed in patients with stage II up to IIIC disease with minor carcinomatosis. Induction chemotherapy should be performed in the case of patients with massive unresectable peritoneal involvement (involvement of hepatic pedicle and/or mesentery and/or para-aortic involvement above the level of the left renal vessels and/or involvement of the diaphragmatic muscle) or in the case of patients for whom surgical resection is feasible but with multiple bowel resection or extensive surgery (involvement of at least two segments of the digestive tract, and/or involvement of the splenic hilus and pancreas) and therefore with a high risk of postoperative morbidity.
In some teams, the selection of unresectable tumours is performed using preoperative abdominopelvic computed tomography (CT) [14, 15], but the surgical procedure is better than a CT scan for confirmation of the diagnosis and evaluation of operability [9]. Such initial surgery is also helpful in evaluating the effect of chemotherapy by comparing the tumour mass at the interval debulking with that at the initial surgery. In the present series, this initial surgery was performed mainly by laparotomy, but since 2 years ago we have been using laparoscopy. Laparoscopic procedure substantially reduces the delay between the initial surgery and the first course of chemotherapy (410 days). The main risk of this approach is the occurrence of metastatic seeding on the trocar site [23, 24]. This risk may be reduced when the peritoneum is closed following laparoscopy [25].
In conclusion, IDS in patients with unresectable advanced stage ovarian cancer seems to offer the same chance of survival as PDS, but with a reduction of morbidity and hospital stay, and improvement in the quality of life of patients. Those preliminary results should be confirmed by a randomized study being conducted by the EORTC (European Organisation for Research and Treatment of Cancer) group, but results of this study are not expected for several years.
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Footnotes |
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References |
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