Role of laparoscopy in predicting optimal cytoreduction (RT 1 cm) in patients with advanced ovarian cancer

Giovanni Scambia, Anna Fagotti, Francesco Fanfani.

Department of Obstetrics and Gynecology Catholic University of Sacred Hearth Rome, Italy 

Objective. To study whether laparoscopy can be considered as adequate and reliable as standard laparotomy in predicting optimal cytoreduction (RT < 1 cm) in patients with advanced ovarian cancer.

Material and Methods. From March to November 2003, 95 patients with suspected advanced ovarian or peritoneal cancer have been studied. Thirtyone cases were excluded due to an anesthesiological class of risk ASA III–IV (51.6%) or for the presence of a large size mass reaching the xiphoid (48.4%), impeding laparoscopy. Sixty-four patients completed the study. All patients were submitted to preoperative clinico-radiological work-up and then to both laparoscopy and standard longitudinal laparotomy, sequentially. Some specific preoperatively defined parameters were analyzed during each procedure in order to obtain the most thorough evaluation on the possibility to get an optimal cytoreduction.

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Results.The overall accuracy rate of laparoscopy in assessing optimal cytoreduction was 90%. The negative predictive value (NPV) of the clinical–radiologic evaluation corresponded to 73%, whereas in no case was the judgment of unresectable disease obtained by laparoscopy changed by the laparotomic approach (NPV 100%). On the contrary, an optimal debulking was achievable in 34 of 39 cases (87%) selected as completely resectable by explorative laparoscopy.

Conclusion. Laparoscopy can be considered super imposable to standard longitudinal laparotomy in identifying not optimally resectable advanced ovarian cancer patients.

Introduction
The standard care for advanced epithelial ovarian cancer (Ozols 2000) is currently a primary cytoreduction followed by platinum-taxanes based chemotherapy. Among the prognostic factors one of the most important is the complete excision of all visible disease. Moreover many patients are often considered unresectable when an optimal residual tumor would not be achievable with acceptable morbidity. Less traumatic surgical approaches as minilaparotomy and gasless and CO2 laparoscopy represent an accurate and reliable mechanism for predicting whether optimal surgery can be achieved with a minimal stress for the patient. Moreover, many parameters associated with the possibility of cytoreducion can be easly assessable by laparoscopy and minilaparotomy. At least, the surgeon may be more comfortable with a direct visualization of the cancer spread. Bristow et al, (2000) previously identified a “Predictive Index Model” based on 25 pre-operative CT radiographic features, which was highly accurate in recognizing patients with advanced epithelial ovarian carcinoma unlikely to undergo optimal primary cytoreductive surgery but this method did not solve the issue of an histological diagnosis. The aim of this study was to investigate whether laparoscopy and/or minilaparotomy can be considered an adequate but less invasive alternative to standard laparotomy to predict optimal cytoreduction in advanced ovarian cancer patients.

PATIENTS AND METHODS
Study Design
Between March and November 2003, 95 patients with a suspected advanced ovarian or peritoneal cancer were enrolled in this study at the Division of Gynecologic Oncology of the Catholic University of Rome. All eligible patients were counseled concerning the design and the scope of the study and they signed a written informed consent to submit to all the procedures described and to use their data prospectively. Of the 95 patients, 31 cases (34%) were excluded from surgery during the combined pre-operative surgical (a large size mass) and anaesthesiological evaluation (ASA III or IV). The remaining 64 patients were evaluated with complete physical and gynecological examination, abdomino-pelvic MRI or CT-scan, pelvic and abdominal ultrasonography, chest X-ray and assessment of Ca125 serum levels.


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The major clinical criteria for inoperability have been considered presence of large-volume ascites, elevated preoperative Ca125 serum levels and infiltration of the pelvic sidewall. Moreover, a GOG performance status > 2 was also judged as a negative predictive factor for cytoreduction. Both ultrasound and radiological procedures were performed to evaluate the possibility to have an optimal cytoreduction to a residual tumor less than 1 cm. The instrumental criteria used to predict the surgical outcome of the patients were the radiographic features designed by Bristow et al. in 2000. Therefore, a clinical and instrumental judgment of possible optimal cytoreduction was completed before each patient entered in the operating room. All patients were submitted to two sequential surgical approaches, laparoscopy and classical standard longitudinal laparotomy. In 45 cases, between LPS and standard laparotomy, minilaparotomy was also performed. During each approach, patients were evaluated for optimal debulking investigating frozen pelvis, omental cake, diaphragmatic or peritoneal extensive carcinomatosis, tumor diffusion to the small and large curvature of the stomach, large and/or small bowel mesentery disease, spleen and/or liver metastases, bulky lymph nodes. At the end of each surgical approach the judgment of a possible optimal cytoreduction was stated according to the criteria previously described. In the case of negative result, standard surgery (including total abdominal hysterectomy with bilateral salpingo-oophorectomy, appendectomy, total infragastric omentectomy, peritonectomy limited to pelvis, paracolic gutters, anterolateral diaphragmatic areas, bowel resection limited to the rectosigmoid, and removal of bulky lymphnodes to the infrarenal paraaortic level) was completed to a minimal residual disease less than 1 cm,. In the other case, surgery was abandoned for a neo-adjuvant treatment followed by an interval debulking surgery (IDS).

Peri-operative
Care Bowel preparation, antithrombotic prophylaxis, and short-term antibiotic prophylaxis were performed . Two to three units of autologue blood were stored preoperatively. Operative time has been calculated from the skin incision to the end of each surgical procedure. Operative complications have been defined as bowel, bladder, uretheral or vascular injuries and estimated blood loss (EBL) exceeding 500 ml. They have been reported only when regarding the diagnostic/explorative phase of the operation, divided for each type of approach.

Surgical Technique
As a choice, we carry on open-laparoscopy in all suspicious advanced ovarian/peritoneal cancer cases. With the patient under general anesthesia in a supine position, a 1,5-2 cm skin incision is made, usually in the per umbilical region (above or below the umbilicus, according to the extension and the position of the mass or the presence of previous scar on the abdomen). The subcutaneous fat is opened, the abdominal fascia is exposed for approximately 2-3 cm and then incised by cold-knife. The parietal peritoneum is smoothly dissected by blunt scissors and the peritoneal cavity is opened. In the presence of large volume ascites, it is firstly drained by open suction. At this point, a primary exploration of the abdominal cavity by the finger is performed in order to identify any possible adherence or obstacle to the introduction of the trocar (Autosuture Blunt-tip trocar, 10 mm. Tyco, Healthcare, Gosport, UK) and thus to avoid any possible injury to the nearest organs. After the introduction of the trocar and the optics (10mm, 30°), pneumoperitoneum is induced and one or two ancillary 5-mm trocars are inserted in the iliac fossae bilaterally or where it is possible. A careful complete abdominal and pelvic inspection is carried out, in order to compare the clinical and instrumental situation with the a direct view and to identify any possible cause of non-optimal cytoreduction.

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All peritoneal surfaces and the gutters are closely examined and the liver is evaluated by rotating the laparoscope 360° through the umbilical port using grasping forceps as retractors. The small bowel loops and mesentere are evaluated by carefully folding back the various intestinal segments. The pelvis is explored after the bowel loops are retracted in the upper abdomen when possible. At the end of laparoscopy the abdomen is deflated with trocars in place and the site of trocars are irrigated with 5% povidine-iodine and peritoneal trocar sites (10 to 12 mm trocars) are closed.

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In 45 patients, after laparoscopy, minilaparotomy, a 7-9 cm per umbilical midline longitudinal skin incision is performed and the same evaluation is carried out. Finally, the incision is extended from the supra umbilical region to the pubis and the final decision to optimally cytoreduce the patient is taken.

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Results
All patients were submitted to the clinical and instrumental evaluation. However, only 64 of 95 patients (67.3%) completed the second step of the study. The major reasons for exclusion were i) an anaesthesiological class of risk (ASA) III-IV, which was observed in 16 out of 31 cases (51.6%) and ii) the presence of a large mass estimated > 20 cm or reaching the xifoidal apophasis, occupying all the abdominal cavity and/or infiltrating the abdominal wall, which was observed in 11 cases (35.5%). Other minor reasons for exclusion were 2 large umbilical hernias and 1 emergency surgery for an ipovolemic shock. Moreover, one patient with the diagnosis of a small pelvic recurrence was completely managed by laparoscopy and she did not enter in the study.
The clinico-pathological characteristics of the 64 patients entered in the study are listed in Table I.

Mean age was 57.4 years (SD ± 12.7). Mean Ca125 serum levels were 790 U/ml (SD ±1680). Ascitis was found in 20 patients (31,3%). In 42 patients (65,6%) a serous hystotipe was histologically diagnosed, whereas a G3 grade was identified in 43 cases (167,2%). All patients were pre-operatively evaluated for tumor resectability: an optimal cytoreduction was considered achievable in 38 of 64 patients (59.4%), the tumor was judged unresectable in 11 cases (17.2%), while the pre-operative evaluation was considered unsatisfactory in 15 cases (23.4%). After the pre-operative evaluation, all the patients were submitted to two sequential surgical approaches, laparoscopy and standard laparotomy. Moreover, a minilaparotomic incision was performed in 45 cases after laparoscopy and before laparotomy.
However, three cases (4.7%) could not be evaluated by laparoscopy for the presence of multiple and tenacious adherences hindering the access of the abdominal and pelvic cavity.
For obtaining the most accurate evaluation on the possibility to get an optimal cytoreduction, some specific pre-operatively defined parameters were analyzed during each surgical procedure.

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Table 2 shows the number of cases in which each parameter could be observed by laparoscopy and laparotomy. As expected, the number of not valuable cases in the laparoscopic group was higher than in the laparotomic one, for any parameter investigated. The most common reason for this difference was the presence of extensive and dense and vascularized tumor adhesions hindering the exploration of specific anatomical sites (i.e. frozen pelvis). Some specific conditions, as the presence of peritoneal (24 of 24), diaphragmatic carcinosis (17 of 17) and mesentery disease (13 of 13 evaluable) were entirely valuated by laparoscopy. On the contrary, the state of lymph nodes (59 of 64), the stomach infiltration (19 of 64) and the presence of a diaphragmatic carcinosis (10 of 64) resulted as the less accurate parameters investigated by laparoscopy.

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Accuracy, positive-predictive value (PPV: probability of cancer involvement assessed by laparoscopy) and negative- predictive value ( NPV: probability of absence of cancer assessed by laparoscopy ) for each specific parameter and for each specific approach had been evaluated (Table 3). As expected, with the exclusion of lymph nodes status, accuracy values are quite high in the group of valuable cases ranging from 84 to 100%.

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Finally, a comparison on the surgical outcome estimation according to clinico-instrumental, laparoscopic and combined clinico-instrumental and laparoscopic versus laparotomic evaluation was performed (Table 4). In no case the judgment of unresectable by laparoscopy was changed by the laparotomic approach (NPV 100%); the PPV of laparoscopy and of the pre-operative clinical-instrumental evaluation were super imposable (87% and 87%). Moreover, the combination of the clinical-instrumental and laparoscopic evaluation did not improve neither the positive- nor the negative predictive rate.

Discussion
To date, laparoscopy has been suggested and widely accepted as the standard approach for the surgical treatment of benign and suspicious adnexal masses (Manolitsas 2001; Canis 2002) and even for the staging and treatment of early ovarian cancer (Pomel 1995; Vergote 2001). On the contrary, only scanty data exist on the use of laparoscopy in advanced ovarian cancer, to stage the disease and to assess the chance of optimal cytoreductive surgery. Vergote et al. (1998) firstly reported a large series of cases in which open laparoscopy was carried on for evaluating the management of patients with advanced ovarian cancer.

However, no studies until now have demonstrated that the laparoscopic approach completely fits the standards of an explorative laparotomy in predicting the surgical outcome of these patients, in terms of optimal debulking. Although laparoscopy is easy to apply and advantageous in terms of postoperative recovery, technical limits due to the absence of a direct tactile evaluation by palpation and the presence of fixed masses and carcinomatous adhesions hindering the visualization of certain anatomical spaces make the routine use of this procedure still undergoing evaluation.

In this study we compared the power of laparoscopy to explorative standard laparotomy in predicting optimal cytoreduction in the same group of advanced ovarian cancer patients. The accuracy rate of laparoscopy in predicting the laparotomic status of parameters which are the main causes of unresectability by laparotomy ranged from 80 to 100%. Laparoscopy correctly identified all cases with peritoneal and/or diaphragmatic carcinomatosis and/or mesentery disease (PPV=100%, 82% and 100%, respectively), resulting in an overall judgment of unresectabilty (NPV) of 100%. The opposite value of NPV represents a very important clinical measure that is the rate ofinappropriate unexploration or the ratio of patients thought to have unresectable disease but who will in fact undergo optimal surgery if operated upon.
This measure corresponds to the false negative rate and here is zero, since in no case the laparoscopic decision was changed by laparotomy.
On the contrary, an optimal debulking was achievable in 34 of 39 cases (87%) selected as completely resectable by explorative laparoscopy. Thus the rate of unnecessary exploration or the ratio of patients thought to have resectable disease but who actually will be left with a suboptimal residuum is 13%. This measure is the inverse of PPV and corresponds to the false positive rate. The main cause for exclusion (4 of 5, 80%) was the presence of bulky para-aortic lymph nodes, deeply infiltrating the aortic and/or the caval wall. The laparoscopic lymphnodal evaluation was missing in the largest part of patients (92%) because of technical limits due to the absence of a direct tactile evaluation by palpation, thus suggesting it can not represent a goal in the laparoscopic staging of advanced ovarian cancer. In the remaining case, a residual disease larger than 1 cm was left deep in the rectum, in order to avoid the risk of a definitive colostomy in a young woman. In this context, the accuracy rate of laparoscopy in predicting number and site of bowel resection has been quite disappointing, corresponding to 84%. However, the extension of carcinomatous adhesions and the presence of fixed masses or large omental cake can easily justify this result. Among widely available, less traumatic and more precise techniques to predict surgical outcome in advanced ovarian cancer patients, CT has been reported to have an accuracy rate of 70-90% (Kawamoto 1999; Forstner 1995; Nelson 1993).
In a recent paper from Bristow et al (2000) the combination of clinical and instrumental parameters can provide a very accurate score to identify patients unlikely to undergo primary cytoreductive surgery.
In the present study, laparoscopy shows a higher NPV compared to the clinical-instrumental evaluation (100% versus 87%) whereas the PPV is super imposable between the two techniques. As a consequence, those patients considered resectable by the preoperative clinico-instrumental assessment would not probably benefit of a second, time-loosing and expensive technique as laparoscopy, which actually seems not to add any further information regarding the surgical outcome of the patients.
On the contrary, those cases judged unresectable by clinico-instrumental evaluation could really benefit of a laparoscopic approach that can confirm the predicted surgical outcome and provide an histological diagnosis by a less traumatic access.
However, in this context, the elevated number of not valuable cases by laparoscopy should be emphasized. Among 64 cases enrolled in the study, the presence of multiple and tenacious adherences hindered the access to the abdominal and pelvic cavity in 3 patients (4.7%), whereas no definitive conclusions on the possibility of optimal cytoreduction cold be drawn in 10 cases (15.6%). Moreover, 34% of the patients were considered not eligible for medical or surgical conditions at the time of diagnosis. It is possible that future wider inclusion criteria in the anaesthesiologic area, and a larger confidence by the surgeon could make this percentage diminish. Finally, the occurrence of port-site metastases has raised significant concern about the use of laparoscopic surgery for procedures associated with malignant disease.
The actual incidence of port-site metastases is not known ; however estimates range from 0 to 1.2 % (Wexner 1995) that is comparable to the incidence of implantation metastases observed after conventional open surgery.
A recent paper by Abu-Rustum (2003) has demonstrated that Co2 pneumoperitoneum does not affect overall survival of women with persistent metastatic ovarian cancer. Although only some recommendations were carried out in our study as we did never observe trocar metastases in our patients. Conclusions  Laparoscopy can be considered super imposable to standard longitudinal laparotomy in identifying not optimally resectable AOC patients. Patients considered resectable by preoperative clinical–radiological assessment would probably not benefit of a second, time-loosing, and expensive technique such as laparoscopy.
Cases judged unresectable by clinical–radiological evaluation could really benefit from a laparoscopic approach that can improve the predicted surgical outcome and provide a histological diagnosis by a less traumatic access.

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