Gynecologic Oncology 116 (2010) 483–488

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Gynecologic Oncology

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Video-assisted thoracic surgery (VATS) evaluation of pleural effusions in patientswith newly diagnosed advanced ovarian carcinoma can influence the primarymanagement choice for these patients☆

John P. Diaz a, Nadeem R. Abu-Rustum a, Yukio Sonoda a, Robert J. Downey b, Bernard J. Park b,Raja M. Flores b, Kaity Chang a, Mario M. Leitao Jr. a, Richard R. Barakat a, Dennis S. Chi a,⁎a Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USAb Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center New York, NY, USA

☆ This work was presented as an oral plenary atWomen's Cancer by the Society of Gynecologic Oncolog⁎ Corresponding author. Fax: +1 212 717 3214.

E-mail address: gynbreast@mskcc.org (D.S. Chi).

0090-8258/$ – see front matter © 2009 Elsevier Inc. Adoi:10.1016/j.ygyno.2009.09.047

a b s t r a c t

a r t i c l e i n f o

Article history:

Received 3 August 2009Available online 28 November 2009

Keywords:VATSAdvanced ovarian carcinomaThracoscopyPleural disease

Objectives. To assess the utility of thoracoscopy in defining the extent of intrathoracic disease and survivaloutcomes in patients with moderate to large pleural effusions at the time of diagnosis of advanced ovariancarcinoma.

Methods. We reviewed the records of all patients with untreated advanced ovarian carcinoma andmoderate to large pleural effusions who underwent video-assisted thoracoscopic surgery (VATS) ourinstitution between 6/01 and 10/08. Demographic, clinicopathologic and outcome data were collected for allpatients with a final diagnosis of ovarian carcinoma.

Results. Forty-two patients met eligibility criteria, with a median age of 58 years; median CA-125 level of

1747 U/mL; and medium serum albumin of 3.9 g/dl. VATS was performed for right-sided effusions in 30patients (71%). Macroscopic pleural disease was found in 29 patients (69%). Of the 11 patients with negativecytology, macroscopic pleural disease was found in 4 (36%). Intrathoracic cytoreductive surgery wasperformed in 6 (33%) of the 18 patients with intrathoracic disease N1 cm. After VATS, 29/42 (69%) patientsunderwent attempted primary abdominal surgical debulking. Thirteen patients (31%) received neoadjuvantchemotherapy. Twelve (92%) of these patients underwent interval cytoreductive surgery. Patients who weredirected after VATS to neoadjuvant chemotherapy instead of primary surgical cytoreduction had a 2-year PFSrate of 22% compared to 42% for the primary cytoreductive group (P=0.36).

Conclusions. Overall,managementwas altered basedonVATSfindings in43%of cases. Further investigation isneeded to define the prognostic significance of VATS evaluation of the burden of pleural disease.

© 2009 Elsevier Inc. All rights reserved.

Introduction

Ovarian cancer affects 1 in 70 women and is the second mostcommon gynecologic malignancy in the United States. Most womenpresent with advanced-stage disease, and ovarian cancer remains themost lethal gynecologic malignancy with 15,310 deaths expected in2008 [1]. Fallopian tube and primary peritoneal cancer are lesscommon but are histologically similar to ovarian cancer and areapproached using the same treatment strategies.

Primary surgical debulking is a fundamental component of ovariancancer treatment in patients with advanced-stage disease at initialpresentation. The definition of optimal debulking has ranged fromcomplete gross resection to b2 cm. The current accepted standard foran optimal debulking surgery is no residual lesion N1 cm. Retrospec-

the 2009 Annual Meeting onists.

ll rights reserved.

tive series have consistently demonstrated that optimal vs. subopti-mal debulking is associated with improved overall survival regardlessof the definition used for optimal debulking [2–10].

Several authors have also reported survival benefit in patients withstate IV disease when optimal cytoreduction can be achieved[3,11–18]. It is estimated that more than one-third of patients withstage IV ovarian carcinoma present with pleural effusions [18,19].Many patients with malignant pleural effusions are evaluated withcomputed tomography scan (CT) to determine whether bulkythoracic disease precludes an attempt at abdominal surgical cytor-eduction. It is unclearwhether an accurate assessment of intrathoracicdisease and extent of diaphragmatic pleural involvement can bemadefrom radiographic studies alone. The presence of macroscopicintrathoracic disease may alter patient management, particularly ifunresected N1–2 cm intrathoracic tumor deposits would leave thepatient with suboptimal residual disease at the conclusion of maximalintra-abdominal cytoreduction.

We have previously reported our experience performing VATS inpatientswith suspected advanced ovarianmalignancies andmoderate

484 J.P. Diaz et al. / Gynecologic Oncology 116 (2010) 483–488

to large pleural effusions [20]. We found that 65% of patients withsuspected advanced ovarian cancer and moderate to large pleuraleffusions had intrathoracic diseased identified on VATS, with themajority (11/15, 73%) having disease N1 cm in diameter. The objectiveof the current study is to assess the utility of thoracoscopy in definingthe extent of intrathoracic disease and a possible association withsurvival outcomes in patients withmoderate to large pleural effusionsat the time of diagnosis of advanced ovarian carcinoma.

Methods

After obtaining approval from our institutional Institution ReviewBoard, the prospectively maintained Virginia K. Pierce GynecologyDatabase at our institution was queried to identify all patients withsuspected advanced ovarian cancer who underwent VATS for theevaluation moderate to large pleural effusions between 6.1.2001 and10.31.2008. Patients undergoing VATS for previously treated diseaseor who were found to have a malignancy other than ovariancarcinoma were excluded from this analysis. All patients includedwere eligible for an attempt at abdominal cytoreductive surgery basedon the findings at the time of VATS. This study is an update of ourpreviously published experience [20,21].

Our institutional practice has been to consider VATS in any patientwith a pleural effusion occupying one third or more of the pleuralcavity on upright chest radiograph (Fig. 1). VATS was performed bymembers of the Thoracic Service using techniques previouslydescribed [20]. Patients with cytologically or pathologically confirmedpleural disease underwent talc pleurodesis either intraoperatively orpostoperatively to prevent recurrent effusions. Patients with optimalintrathoracic disease underwent further abdominal surgery on thesame day or at a later date, at the discretion of the attendinggynecologic oncology surgeon. Those patients with suboptimalintrathoracic disease received neoadjuvant chemotherapy withcarboplatin and paclitaxel.

Electronic medical records were reviewed to abstract patientdemographics, surgical findings, site of metastatic disease, extent ofsurgery, amount of residual disease, histology, tumor grade, chemo-therapy treatment, additional surgical procedures, and follow-updata. Optimal surgical debulking was defined as residual disease of

Fig. 1. Treatment paradigm for the management of women with suspected

less than 1 cm in maximal tumor diameter at the completion ofsurgery.

All patients were included in the survival analysis. Progression-free survival (PFS) was defined as the time in months from the date ofVATS to diagnosis of recurrence based on tissue biopsy, death, ordoubling of CA-125 nadir for patients with persistent disease at thecompletion of surgery. Overall survival (OS) was determined from thetime of VATS to the time of a known cancer-related death or at lastfollow up. PFS and OS were estimated using Kaplan–Meier estimatesand compared with the log-rank test where indicated. Median countswere analyzed using the Mann-Whitney-U test. Dichotomous group-ings were analyzed using the chi-square and Fisher's exact test asappropriate. Statistical significance was defined as Pb0.05. Statisticalanalysis was performed using SPSS version 15.0 (Chicago, IL).

Results

Forty-six patients were identified who underwent video-assistedthoracoscopic surgery (VATS) for moderate to large pleural effusionswith suspected advanced ovarian cancer. Four patients were excludedfrom this analysis. Three had a non-ovarian primary: appendiceal,lymphoma, and endometrial. One patient had known liver metastasisandwas not considered a candidate for primary cytoreductive surgeryat the time of VATS. This left 42 evaluable patients for the currentanalysis including 17 patients which have previously reported [20].The primary surgeon in all 42 VATS procedures was an attendingthoracic surgical oncologist. Supplementary Table 1 lists patient andtumor characteristics at the time of VATS. Table 1 summarizes thecharacteristics of those patients who were triaged to primaryabdominal cytoreductive surgery compared to those who receivedneoadjuvant chemotherapy.

VATS revealed macroscopic disease in 29/42 patients (69%) withnodules N1 cm in 18/29 (62%) or forty-three percent of the entirecohort, summarized in Supplementary Table 2. Pleural cytology wasperformed preoperatively or at the time of the VATS procedure in 38/42 patients. The pleural cytologywas positive for malignant cells in 27(64%), negative in 11 (26%), and not performed in 4 (10%) patients(Table 2). The 4 patients which did not have pleural cytologyperformed had intrathoracic disease N1 cm. Of the 27 patients with

advanced ovarian carcinoma and moderate to large pleural effusions.

Table 3Findings at the time of VATS divided by triage.

Characteristics Primary cytoreductivesurgeryN=29

NeoadjuvantchemotherapyN=13

P

Malignant cells, N (%)Yes 19 (66) 12 (92) NSNo 10 (34) 1 (8)

Pleural effusion side, N (%)Right 19 (66) 11 (84) NS

Table 1Demographics and surgical findings after triage for VATS.

Characteristics PrimarycytoreductivesurgeryN=29

NeoadjuvantchemotherapyN=13

P

Age (years)Median (range) 56 (41–78) 60 (44–81) NS

Race or ethnic group, N (%) NSWhite 25 (86) 11 (85)Asian 2 (7) 1 (7)Black 0 (0) 1 (7)Hispanic 1 (3) 0 (0)Other 1 (3) 0 (0)

Histology, N (%) NSSerous 28 (97) 11 (85)Endometrioid 1 (3) 0 (0)Mucinous 0 (0) 1 (7)Mixed 0 (0) 1 (7)

Tumor grade, N (%) NSWell differentiated 1 (3) 0 (0)Moderately differentiated 1 (3) 0 (0)Poorly differentiated 27 (93) 13 (100)

Preoperative serumCA-125 (U/ml)Median (range)

2,127 (202–20,888) 567 (237–5042) 0.007

Preoperative albumin (g/dl) NSMedian (range) 3.9 (2.3–4.4) 3.9 (3.0–4.6)

Preoperative platelets (K/μl) NSMedian (range) 369 (242–909) 452 (214–750)

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positive pleural cytology, 12 (44%) had gross disease N1 cm, 9 (33%)had disease b1 cm, and 6 (22%) had no gross disease. Among the 11patients with negative cytology, 4/11 (36%) had macroscopic disease,2/4 had measurable disease N1 cm (Table 3).

Management after VATS is detailed in Fig. 2. In the 29 patients withmacroscopic disease, primary abdominal surgical debulking wasperformed in 17 (58%),while 12 (41%)went on to receive neoadjuvantchemotherapy. Of the 18 patients with intrathoracic tumor N1 cm, 12(67%) went on to receive neoadjuvant chemotherapy. Six patientsunderwent intrathoracic cytoreduction through a VATS approach bythe attending Thoracic surgeon. No patient underwent a thoracotomy.The VATS intrathoracic cytoreductive surgery was followed byabdominal cytoreductive surgery in all 6 patients, and was resectedto optimal residual disease after surgical interventions. Of the 11patientswith intrathoracic disease b1 cm, all underwent an abdominalcytoreductive procedure. Optimal debulking surgery was achieved in8 (72%) patients. Thirteen of the forty-two (31%) patients whounderwent a VATS procedure were found to have no evidence ofintrathoracic disease. Twelve of 13 (92%) underwent primarycytoreductive surgery. Optimal debulking was achieved in 10 (83%)of these patients. One patient received neoadjuvant chemotherapydespite a negative VATS due to a pulmonary embolus detected aftertheir VATS procedure but prior to attempted abdominal cytoreductivesurgery planned for a later date.

Overall, 29/42 patients (69%) underwent attempted primaryabdominal cytoreductive surgery after VATS with optimal cytoreduc-

Table 2Findings at VATS and pleural cytology (N=42).

Cytologypositive

Cytologynegative

Cytology notperformed

N (%) N (%) N (%)

Macroscopic disease 21 (78) 4 (36) 4 (100)N1 cm 12 (44) 2 (18) 4 (100)b1 cm 9 (33) 2 (17) 0 (0)

No evidence of disease 6 (22) 7 (64) 0 (0)Totals 27 (64) 11 (26) 4 (10)

tion achieved in 23/29 (79%) patients. Thirteen (31%) receivedneoadjuvant chemotherapy following their VATS procedure. Twelveof the thirteen (92%) patients underwent interval debulking surgerywith an interval cytoreduction to b1 cm residual disease achieved in12/13 (92%). Of these 12 patients a complete gross resection wasattained in 8 patients. The one patient who did not proceed to intervaldebulking surgery progressed during her initial course of chemother-apy and ultimately succumbed to her disease. No patient hasdeveloped thoracic port-site recurrences to date. VATS alteredprimary management in 18/42 (43%) of patients with 12 subse-quently undergoing neo-adjuvant chemotherapy and 6 undergoingintrathoracic followed by abdominal cytoreduction.

The median follow up for the entire cohort was 29.0 months(range 1-70 months). The median progression-free survival was 15.0months (95% CI: 12.2–17.8). The 2-year progression-free survival ratefor the group who underwent primary cytoreductive surgery was 42%compared to 22% for the neoadjuvant group (P=0.36) (Fig. 3). Themedian overall-survival for the entire cohort was 39.0 months (95%CI: 29.1–48.8). The median overall survival rate for the group whounderwent primary cytoreductive surgery was 40 months (95% CI:25.1–54.9) compared to 34 months (95% CI: 20.6–47.4) for theneoadjuvant group (P=0.33) (Fig. 4).

Discussion

Approximately 10% of patients who present with advanced stageovarian carcinoma will be stage IV [22]. The benefits of debulking inpatients with malignant pleural effusions compared with other stageIV disease criteria have been evaluated with mixed results. Goodmanet al. [23] described the role of cytoreductive surgery in themanagement of stage IV disease. In their initial series evaluatingprimary and interval debulking in 35 patients with stage IV disease,they reported no difference in survival among patients who hadoptimal intra-abdominal cytoreduction. Several authors have dem-onstrated improved survival in association with optimal primarydebulking since this first report (Supplementary Table 3). Thereported rate of optimal primary debulking ranges from 27% to 78%among the subgroup of patients classified as having stage IV diseasebased on malignant pleural effusions alone [11–14,16–18]. Bristow etal. reported a median survival of 38.4 months in optimally debulkedpatients (b1 cm) compared to 10.3 months for patients suboptimallydebulked (P=0.0004). This study of 84 patients with stage IV diseaseincluded 32 (38%) with malignant pleural effusions. There was no

Left 7 (24) 1 (8)Bilateral 2 (7) 1 (8)

Pleural fluid evacuated, (mL)Median (range) 1000 (0–3000) 1600 (0–2500) NS

Macroscopic disease, N (%)Yes 17 (59) 12 (92) NSNo 12 (41) 1 (8)

Intrathoracic disease size,N (%)b1 cm 11 (38) 1 (8) b0.001N1 cm 6 (21) 12 (92)

Cytology, N (%)Positive 15 (52) 12 (92) NSNegative 10 (35) 1 (8)

Fig. 2.Management of patients after VATS procedure. VATS altered primarymanagement in 18/42 (42%) patients with 12 subsequently undergoing neo-adjuvant chemotherapy and6 undergoing intrathoracic followed by abdominal cytoreduction.

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difference in median survival comparing patients with pleuraleffusion and other stage IV criteria. Munkarah et al. [15] reportedtheir experience with 108 women with stage IV ovarian carcinoma,using a definition of optimal debulking as b2 cm. The median survivalof the optimally debulked patients was 25 months compared to15months for the suboptimally debulked patients (Pb0.02). Howeverin patients with pleural effusion only as their criteria for stage IVdisease, they found no difference in survival between the optimallydebulked patients (25months) compared to suboptimal (23 months).In contrast, in a smaller cohort of 23 patients with stage IV disease,Brunisholz and colleagues [12] found that the 9 patients with pleuraleffusions had reduced survival compared to patients with other sitesof distant metastasis.

Patients with malignant pleural effusions who are optimallycytoreduced have been reported to have decreased survival whencompared to optimally cytoreduced patients who have diseaseconfined to the abdomen. In a previous study from our institution,Eitan et al. [24] reported a median survival of 58 months for optimally

Fig. 3. Progression-free survival. Themedian progression-free survival was 15.0months.The 2-year progression-free survival rate for the group who underwent primarycytoreductive surgery was 42% compared to 22% for the neoadjuvant group, P=0.36.

cytoreduced stage IIIC compared to 30 months for optimallycytoreduced patients with stage IV based solely on malignanteffusions (P=0.0016). The poorer prognosis likely reflects the moreaggressive and advanced nature of disease, which extends extraper-itoneally. These results also raise the question of whether undetectedbulky residual intrathoracic disease contributes to this difference.

In our present study, 64% of patientswithmoderate to large pleuraleffusions had macroscopic intrathoracic disease. Of the 27 patientswith positive cytology, 21 (78%) had evidence of macroscopic disease.Thirty-six percent of the patients with negative cytology had evidenceof macroscopic disease at the time of VATS. In patients with moderateto large pleural effusions, pleural cytology may not be a reliableindicator of the presence of intrathoracic disease. Fifty-seven percentof patientswithmacroscopic intrathoracic disease had nodules greaterthan 1 cm. The large volume intrathoracic disease theoretically mighthave negated the beneficial effects of the abdominal surgicaldebulking. Therefore VATS is an important diagnostic procedure that

Fig. 4. Overall survival. The medi.an overall survival for the entire cohort was39.0 months. The median overall survival for the group who underwent primarycytoreductive surgery was 40 months compared to 34 months for the neoadjuvantgroup, P=0.33.

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can identify appropriate candidates for consideration of intrathoraciccytoreductive surgery or neoadjuvant chemotherapy.

VATS has multiple applications in patients with moderate to largepleural effusions with suspected advanced ovarian carcinoma. VATS isan effective technique for performing pleurodesis. VATS may furtherhelp to triage appropriate cases for intrathoracic debulking as moreaggressive intraabdominal surgical techniques are being consideredwith the goal of obtaining an optimal cytoreductive outcome.Numerous studies have demonstrated that extensive surgery utilizingradical upper abdominal surgery is often required to obtain an optimalcytoreduction [4,25–28]. Many consider intraabdominal diaphrag-matic disease as a limiting factor in obtaining an optimal cytoreduction[29]. Superficial diaphragmatic studding can be easily managed withablation or diaphragmatic peritonectomy.More extensive diseasemayrequire the use of full thickness resection [11,30]. VATS may betterevaluate the extent of full thickness, bulky diaphragmatic disease, andassist the surgeon in planning the appropriate intrathoracic surgicalapproach. VATS also facilitates the ability to perform intrathoraciccytoreductive surgery. Eisenkop [31] reported the outcomes of 30patients who underwent thoracoscopy either by a transdiaphragmaticapproach at laparotomy or through the chest wall prior to a planedabdominal procedure. In this series, 33% underwent pleural implantablation and/or tumor excision, influencing the final cytoreductiveoutcome. Six patients underwent intrathoracic cytoreductive surgeryin our series. All six were rendered optimal in the thoracic cavity andproceeded to undergo an optimal intraabdominal cytoreductivesurgery. This may prove to be a vital tool in increasing the number ofstage IV patients who achieve an optimal cytoreduction at primarysurgery and more accurately reflect a true optimal state.

The small sample size of this current series is insufficient toaddress survival outcomes after VATS based on primary cytoreductivesurgery vs. neoadjuvant chemotherapy. There was no overall survivaldifference between the two groups. However, when reviewing theprogression-free survival analysis there was an improved survival inthose patients who underwent a VATS procedure and proceeded to anattempt at primary abdominal cytoreduction compared to thosepatients who received neoadjuvant chemotherapy. This differencewas not statistically significant. The finding of N1 cm of unresectableintrathoracic disease at the time of VATS may prove to be an indicatorof poor prognosis. These patients who would have otherwiseundergone attempt at abdominal cytoreductive surgery were appro-priately triaged to neoadjuvant chemotherapy. Overall the findings atVATS altered the primary management in 18/42 (43%) of patients.Thirteen (31%) of these patients avoided a potentially morbidabdominal cytoreductive procedure that would have left N1 cm ofintrathoracic disease behind. The morbidity of aggressive cytoreduc-tive surgery in advanced ovarian carcinoma is well documented[4,25]. The potential benefit from this procedure may be negated withresidual disease N1 cm remaining in the intrathoracic cavity.

This study is limited by the small sample size and the biasesinherent to a retrospective review. These data demonstrate that the69% of patients with moderate to large pleural effusion had grossintrathoracic disease identified at VATS. Additionally the findings atVATS altered the management of 43% of these patients. VATS shouldbe considered in management algorithm for patients with suspectedadvanced ovarian carcinoma and pleural effusions. Larger studies areneeded to confirm our findings and determine what role intrathoraciccytoreduction may have in this patient population.

Conflict of interest/disclosure statementThe authors have no conflicts of interest to disclose.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.ygyno.2009.09.047.

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