10.1245/s10434-006-9273-8
Annals of Surgical Oncology 14:1136-1142 (2007)
© 2007 Society of Surgical Oncology
Secondary Cytoreductive Surgery in Patients with Platinum-Sensitive Recurrent Ovarian Cancer
Pierluigi Benedetti Panici, MD1,
Antonio De Vivo, MD1,
Filippo Bellati, MD1,
Natalina Manci, MD1,
Giorgia Perniola, MD1,
Stefano Basile, MD1,
Ludovico Muzii, MD2 and
Roberto Angioli, MD2
1 Department of Obstetrics and Gynecology, University of Rome "La Sapienza," Viale del Policlinico, 155, 00161 Rome, Italy
2 Department of Obstetrics and Gynecology, University Campus Bio-Medico of Rome, Via Longoni, 83, 00100 Rome, Italy
Correspondence: Address correspondence and reprint requests to: Pierluigi Benedetti Panici, MD, E-mail: pierluigi.benedettipanici{at}uniroma1.it
 |
ABSTRACT
|
|---|
Background: Secondary surgical cytoreduction (SCR) represents a promising therapeutic strategy for patients affected by ovarian cancer disease recurrence. The aim of this prospective observational trial was to analyze the role of SCR in patients with platinum-sensitive ovarian cancer.
Methods: Patients with platinum-sensitive ovarian cancer underwent SCR by a single surgical team. Clinical and oncologic data were prospectively recorded. A total of 47 patients underwent SCR from 1999 to 2003.
Results: The mean operating time was 210 minutes, and mean blood loss was 500 mL. The most frequent surgical procedures carried out were splenectomy, lymphadenectomy, bowel resection, and extensive peritonectomy. Optimal cytoreduction was achieved in 41 patients. Thirty-seven patients had no visible tumor at the end of SCR. Overall median survival was 49 months. Patients who achieved optimal residual disease had a median survival of 61 months, whereas patients who had residual disease >1 cm had a median survival of 19 months.
Conclusions: Positive CA-125 (cancer antigen 125) was identified as a negative prognostic factor at multivariate analysis. After careful selection, optimal cytoreduction can be achieved in most patients who are subjected to SCR with acceptable morbidity. Residual tumor and CA-125 represent the most important prognostic factors.
Key Words: Recurrent ovarian cancer • Secondary cytoreduction • Platinum sensitive • Prognostic factors
|
INTRODUCTION
|
|---|
Ovarian cancer is the fourth cause of cancer-related death in women. More than 25,000 new cases are diagnosed each year in the United States alone,1 and approximately 70% of these are found in an advanced stage.2,3 Cytoreductive surgery represents a fundamental component of primary treatment.4 Several studies have shown that optimal debulking is associated with better outcomes in terms of chemotherapy response and survival.4–7 The rate of complete pathological responses to chemotherapy decreases from 50% to 20% according to optimal or suboptimal surgery,4,8,9 and most patients in the latter group develop recurrent disease even after a second look finds nothing.10,11 Although secondary surgical cytoreduction (SCR) is technically feasible in a large proportion of patients, its role remains controversial.12 Several retrospective studies and a few prospective analyses have suggested that achievement of optimal residual tumor (RT) at SCR may offer a marked survival advantage to patients affected by disease recurrence.12,13 But to date, to our knowledge, no randomized clinical trial comparing SCR to traditional treatment with second-line chemotherapy has been carried out. Such trials might be difficult to be perform for ethical reasons, and because it is difficult to accrue enough patients. Because of the paucity of data in the literature, physicians are required to carefully tailor treatment strategies on the bases of patients’ characteristics and prognostic factors.
The aim of this prospective observational study was to analyze the role of SCR in patients with platinum-sensitive ovarian cancer who underwent surgery for recurrent disease.
|
MATERIALS AND METHODS
|
|---|
Between 1998 and 2003, patients referred to our institution with a diagnosis of recurrent ovarian cancer were evaluated for possible SCR. Patients were considered amenable to secondary surgery when they met the following criteria: (1) pathology-reviewed and -confirmed invasive epithelial ovarian cancer; (2) completion of primary surgery and platinum-based chemotherapy with a clinically complete response; (3) disease-free interval (DFI) from the end of first-line chemotherapy of >6 months; (4) increasing CA-125 (cancer antigen 125) level (>35 U/mL) and/or radiographic and physical findings suggestive of disease recurrence; (5) absence of radiologically documented unresectable abdominal or nonabdominal metastases or of nonresectable carcinosis; (6) Eastern Cooperative Oncology Group performance status <4; (7) absence of medical contradictions to an extensive surgical procedure; (8) absence of synchronous tumors at other sites (breast, colon, uterus); (9) provision of informed consent. Before SCR, all patients signed an informed consent form. Diagnostic laparoscopy to verify operability was performed in all patients. The surgical goal was to achieve no visible tumor.
Histological typing and grading of the primary surgery were reviewed with World Health Organization criteria, and surgical stage was assigned by using the classification system of the International Federation of Gynecology and Obstetrics.14 Before surgery, all patients were evaluated with preoperative imaging studies (computed tomographic scan or magnetic resonance imaging) of the chest, abdomen, and pelvis, and in selected cases, a positron emission tomography scan was performed. Routine preoperative preparation included the following: (1) 500 mg of paromomycin three times a day and 1.2 g of erythromycin three times a day; (2) thromboprophylaxis with low-molecular-weight heparin, .3 mL of calcium nadroparin provided subcutaneously 1 hour before surgery; and (3) antibiotic prophylaxis with 2 g of cefoxitin provided intravenously at anesthesia induction. In addition, compression stockings were used during and after surgery, and respiratory rehabilitation was carried out with a respiratory exerciser.
DFI was defined as the interval between the end of adjuvant chemotherapy and the clinical diagnosis of disease recurrence. Tumor cytoreduction was defined as optimal if the greatest dimension of the largest RT measured <1 cm and suboptimal if RT measured between 1 and 2 cm. Surgical morbidity was defined as any adverse event occurring within 30 postoperative days. Surgical mortality was defined as death occurring within 30 postoperative days or before leaving the hospital. Survival data was calculated from the date of surgery for recurrence to the date of death or last follow-up. A review of the literature was conducted to compare outcomes with published reports.
Statistical analysis was performed by Kaplan-Meier test and by log rank test to estimate the survival distribution and to analyze the equality of survival group curves. The Cox proportional hazard regression model was used for quantifying the relation between survival and covariates, and the 
2 test was used to evaluate the influence of covariates on surgical outcome at SCR. Statistical significance was set at P < .05.
|
RESULTS
|
|---|
Eighty-one patients were evaluated for SCR: 23 patients (28.4%) with instrumental signs of multiple hepatic or pulmonary recurrences were unsuitable for surgical treatment and underwent chemotherapy, and 11 patients (13.6%) had disease that was defined as not operable at diagnostic laparoscopy for nonresectable carcinosis. Here, we report the results obtained in the remaining 47 patients (58%). The median age at secondary surgery was 52 years (range, 27–71 years). Forty-one patients (87.2%) underwent primary cytoreduction followed by adjuvant platinum-based chemotherapy, whereas the remaining six patients (12.8%) received neoadjuvant chemotherapy before debulking surgery. Histology was serous in 32 cases (68.1%), mucinous in 3 (6.4%), endometrioid in 5 (10.6%), clear cell in 3 (6.4%), and undifferentiated in 4 (8.5%) cases. Tumor stage was I, II, III, and IV in 8 (17%), 4 (8.5%), 33 (70.2%), and 2 (4.2%) patients, respectively. At primary surgery, RT was 
1 cm in 43 patients (91.5%) and >1 cm in four patients (8.5%); in particular, 37 of 43 patients with optimal debulking (RT 1) had no visible tumor at the end of surgery. Fourteen (29.8%) of 47 patients underwent lymphadenectomy (9 pelvic and 5 both pelvic and aortic). The median DFI was 15 months (range, 7–138 months): 16 patients (34%) experienced tumor recurrence between 7 and 12 months, 16 (34%) between 13 and 24 months, and 15 (32%) by >25 months. The recurrence after initial treatment was suspected in four cases by an increasing CA-125 level without radiological findings of recurrence, in 28 cases by an increasing CA-125 level and a positive radiological imaging, and in 11 patients by negative CA-125 and positive imaging. In four cases with negative CA-125 and negative radiological imaging, the recurrence was suspected on the basis of clinical examination.
At SCR, the recurrent tumor was confined to one site in 28 patients (59.6%), to two sites in 14 patients (29.8%), and to three sites in 5 patients (10.6%). The spleen was involved in 17 cases (36.2%), pelvic or aortic lymph nodes in 22 cases (46.8%), inguinal lymph nodes in 2 cases (4.2%), large bowel in 9 cases (19.1%), small bowel in 3 cases (6.4%), peritoneum in 5 cases (10.6%), liver in 4 cases (8.5%), diaphragm in 4 cases (8.5%), pancreas in 2 cases (4.2%), and gastrocolic ligament, vaginal vault, and bladder in 1 case each (2.1%). Retroperitoneal lymph nodes metastases were located in the aortic region in nine cases, in the pelvic region in seven cases, and in both regions concurrently in three cases. Four aortic and one pelvic lymph node metastases occurred in patients who had previously been subjected to pelvic lymphadenectomy during primary surgery. Five patients with aortic, five patients with pelvic, and all three patients with pelvic and aortic lymph node metastases had not previously undergone lymphadenectomy. In a single case, a pelvic lymph node recurrence occurred in a patient who had previously been subjected to extensive pelvic and aortic lymphadenectomy.
Results of SCR were as follows: no visible disease in 37 patients (78.7%), <1 cm in 4 patients (8.5%), between 1 and 2 cm in 4 patients (8.5%), and >2 cm in the remaining 2 patients (4.9%) (Table 1
). In particular, RT < 1 cm was obtained in all patients with a solitary lesion and in 13 (68.4%) of 19 patients with multiple lesions. No visible residual disease was obtained in 26 (92.8%) of 28 single lesions and in 11 (57.9%) of 19 multiple lesions. Nine patients received chemotherapy before undergoing SCR. Surgical procedures carried out were bowel resection in 10 patients, retroperitoneal lymphadenectomy in 22 cases, splenectomy in 17 patients, peritonectomy or laser ablation in 10 cases, partial pancreatectomy in 2 patients, liver resection in 2 patients, inguinal lymph node dissections in 2 patients, and vaginectomy and partial bladder resection in 1 patient each. No postoperative deaths occurred (Table 1). The median number of postoperative days was 5 (range, 3–38 days). The median estimated blood loss was 500 mL (range, 50–2500 mL), and the median operative time was 210 minutes (range, 40–350 minutes).
The median survival from SCR was 49 months (Fig. 1). Log rank analysis revealed that RT at SCR and CA-125 levels at recurrence influenced the prognosis, whereas DFI, use of chemotherapy before secondary surgery, number of sites involved (single or multiple), kind of treatment at primary surgery (interval debulking surgery or primary cytoreduction), RT at first surgery, histology, stage, tumor grade, and site of recurrence did not influence survival (Table 2). Considering RT at SCR, patients with RT 1 cm had an overall median survival of 61 months, whereas those with RT > 1 at SCR had a median overall survival of 19 months (P = .02). This difference was even stronger when comparing median overall survival of cases who achieved no residual visible disease with patients with macroscopic residual disease (P = .01).
Received for publication July 14, 2006.
Accepted for publication October 18, 2006.
TOP
ABSTRACT
INTRODUCTION
