Upper abdominal cytoreduction and thoracoscopy for advanced epithelial ovarian cancer: unanswered questions and the impact on treatment

Authors


Dr A Fleury, Johns Hopkins Medical Institutions, 600 N. Wolfe Street, Phipps 281, Baltimore, MD 21287, USA. Email aimeefleury@yahoo.com

Abstract

Please cite this paper as: Fleury A, Kushnir C, Giuntoli R, Spirtos N. Upper abdominal cytoreduction and thoracoscopy for advanced epithelial ovarian cancer: unanswered questions and the impact on treatment. BJOG 2012;119:202–206.

Gynaecological oncologists, by conducting Phase II and III chemotherapy trials, have sought to improve survival in women with epithelial ovarian cancer. The greatest impact on survival has been the use of intraperitoneal chemotherapy in women who have had all visible disease removed. No change in drug regimen has had an impact on survival equivalent to that associated with complete cytoreduction or the use of intraperitoneal chemotherapy. Interestingly, these two treatment modalities (complete cytoreduction and intraperitoneal chemotherapy) have not been universally adopted. Most often it is the inability to achieve optimal cytoreduction in the upper abdomen that defines the limit of the cytoreductive effort, and ultimately the integration of intraperitoneal chemotherapy. The importance of identifying disease outside the abdominal cavity, along with achieving complete cytoreduction, is paramount, if the use of intraperitoneal chemotherapy is to be logically integrated in treatment algorithms for women with advanced-stage epithelial ovarian cancer. This report summarises pertinent literature on upper abdominal cytoreduction, discusses surgical techniques and introduces new data on women with epithelial ovarian cancer undergoing thoracoscopy, suggesting consideration of its incorporation into the surgical management of advanced epithelial ovarian cancer.

Introduction

Ovarian cancer is the most lethal of all gynaecological cancers.1–5 Survival is related to stage at diagnosis and the amount of residual disease. Over the last two decades the definition of optimal cytoreduction has changed from residual disease of <2 cm to <1 cm of residual disease. Today, most would define optimal cytoreduction as ‘no visible residual disease’. Gynecologic Oncology Group trials published over the last decade demonstrate improved overall survival and progression-free interval in women with optimal cytoreduction (complete or incomplete) and the use of intraperitoneal chemotherapy. 6–8 Even in women with stage IV disease, benefit is accrued in those undergoing optimal cytoreduction.9 Despite most women being diagnosed with advanced-stage disease from which they die, optimal cytoreduction of all visible disease before adjuvant chemotherapy is associated with maximum survival; increases in 5-year, and even 10-year, survival when compared with women left with visible disease measuring 5–10 mm and even more so when compared with those left with residual disease measuring more than >1 cm have been repeatedly demonstrated in the literature. The women in this last group benefit little from surgery, except for the palliative relief of specific symptoms.8

In the 25 years since 1985, the gynaecological oncology community has sought to improve survival in women with advanced-stage epithelial ovarian cancer by conducting prospective phase II and III chemotherapy studies. As new drugs have been introduced and standards have changed, two facts have been largely ignored. First is the overwhelming level 1 evidence that improved overall survival is associated with intraperitoneal chemotherapy and second, the impact of complete cytoreduction.7,10,11 No change in the drugs accepted as part of the standard of care has had the impact on overall survival associated with the introduction of intraperitoneal chemotherapy following complete cytoreduction. Inexpicably, gynaecological oncologists have not wholly embraced this treatment modality. Similarly, the adoption of complete cytoreduction as the primary surgical endpoint has been slow. Combined with complete cytoreduction, the use of intraperitoneal chemotherapy has been associated with the longest median survival in women with stage III epithelial ovarian cancer reported by the Gynecologic Oncology Group.7,8,12 Vergote et al.,11 writing on behalf of the European Organization for Research and Treatment of Cancer—Gynaecological Cancer Group and the NCIC Clinical Trials Group, compared primary cytoreductive surgery with interval cytoreduction following neoadjuvant chemotherapy and identified complete cytoreduction as the factor associated with the best overall survival whether achieved primarily or in the interval setting. The authors concluded that this should be the primary surgical goal in women with advanced-stage epithelial ovarian cancer.

In part, the slow adoption of treating women with intraperitoneal chemotherapy has been attributed to the increased toxicity associated with its use as well as catheter complications.12 Additionally the ideal number of cycles of intraperitoneal chemotherapy necessary to provide the reported survival benefits has not been enumerated and recent literature confirming the presence of intrathoracic disease in as many as 40% of women with presumed stage III disease logically calls for an explanation as to how the proposed therapeutic advantages of intraperitoneal chemotherapy would affect disease in the thorax.13,14

Issues surrounding the inability of gynaecological oncologists to attain complete cytoreduction most often centre on the inability to achieve this endpoint in the upper abdomen. Both the lack of training during and after fellowship and the lack of substantial prospective evidence demonstrating benefit for each individual procedure necessary to achieve complete cytoreduction in the upper abdomen have been cited as reasons that some surgeons abandon efforts to resect upper abdominal disease.15 This report will summarise literature pertaining to upper abdominal cytoreduction, specifically disease above the diaphragm. We will also present first-time reported data on 75 women with stage III epithelial ovarian cancer undergoing thoracoscopy as part of a primary cytoreductive effort and reasons to consider incorporating this technique into the surgical management of advanced-stage epithelial ovarian cancer.

Disease above the diaphragm presents a challenging and controversial issue. In 2007, Spirtos et al.14 reported data from the Women’s Cancer Center at the European Society of Gynaecologic Oncology on 57 women undergoing transdiaphragmatic thoracoscopy during surgery for apparent stage IIIC epithelial ovarian cancer with negative chest radiographs or computed tomography scans. Twenty-three (40%) were found to have disease involving either the parietal or visceral pleurae. All with pleural disease had involvement of the diaphragm peritoneum and over 90% of the women had positive retroperitoneal lymph nodes. Most of the disease (88%) found above the diaphragm was small (<1 cm) and could be ablated or resected.14

Terauchi et al.13 performed a prospective study evaluating transdiaphragmatic thoracoscopic-assisted pleural biopsy and intrathoracic washings for advanced ovarian cancer with diaphragmatic metastases. Ten women with stage IIIC ovarian cancer with prominent diaphragmatic lesions were eligible for transdiaphragmatic thoracoscopy, then biopsy of pleural lesions thought to be metastases, and pleural washings and were enrolled. Three of the ten women (30%) had metastatic lesions and positive cytology in the thoracic cavity. Two women had positive biopsy results (20%). Two additional women had positive cytology. A total of seven out of the ten (70%) were up-staged to stage IV.13

Following the National Cancer Institute’s Clinical announcement confirming the survival advantage associated with intraperitoneal chemotherapy in women with advanced-stage ovarian epithelial cancer it became even more important to identify those women with extra-abdominal disease and to better understand the extent of suboptimal pleural disease because it makes little sense to subject women to the toxicity associated with intraperitoneal chemotherapy without having a reasonable expectation of benefiting from such an approach. The physicians at the Women’s Cancer Center of Nevada continued to perform subdiaphragmatic thoracoscopy of the right thorax, and to accumulate data that were added to those of the women presented at the European Society of Gynaecological Oncology in 2007. This data set was collected from 1 January 2004 until 31 December 2010. Seventy-five women with presumed stage III ovarian cancer with negative radiological evaluation of the chest underwent primary cytoreductive surgery with the intent to identify and remove all visible disease. Patient and disease characteristics are similar to most reports of women with advanced ovarian cancer undergoing primary surgery (Table 1). Extensive surgery involving the gastrointestinal and urogenital tracts was required to achieve complete cytroreduction. Over 90% (68/75) of the women required resection of diaphragmatic disease to achieve complete cytorection (Table 2). Of the 27 (36%) women with involvement of the pleura, only three had disease that would result in the woman being left with residual disease of >1 cm. Two women had multiple (>1 cm) visceral pleural metastases and one was found to have tumour involving the entire parietal pleura. All 75 women underwent aortic and pelvic lymphadenectomy with resection of the gonadal vessels. Notably, 25 of the 27 (92.6%) women with disease identified in the right thorax had positive retroperitoneal lymph nodes. Overall 55 (73.3%) of the 75 women had metastatic disease identified in the lymph nodes with macroscopic disease identified in lymph nodes above the inferior mesenteric artery in 46 (61.3%) of the women. Given the high percentage of women requiring thoracentesis to drain postoperative pleural effusions (69.3%; 52 of 75), we now routinely place a chest tube at the time of thoracoscopy. Additionally subdiaphragmatic and pelvic drains are also placed (Figure 1 and see Supplementary material, Figures S1–S4).

Table 1.   Patient characteristics (n = 75)
 Positive thoracoscopyNegative thoracoscopy
  1. GOG, Gynecologic Oncology Group.

n (%)27 (36.0)48 (64.0)
Median (range) age, years60.5 (29–75)63 (39–76)
GOG Performance Status (0,1)100%100%
Location of largest disease
Diaphragm2/27 (7.4%)1/48 (2.1%)
Omentum7/27 (25.9%) 10/48 (20.8%)
Pelvis15/27 (55.6%) 37/48 (77.1%)
Lymph nodes2/27 (7.4%)1/48 (2.1%)
Mesentery2/27 (7.4%)1/48 (2.1%)
Table 2.   Surgical procedures
Procedure performedPositive thoracoscopyNegative thoracoscopy
Modified posterior exenteration19/27 (70.4%)38/48 (79.2%)
Aortic and pelvic lymphadenectomy27/27 (100%)48/48 (100%)
Splenectomy4/27 (14.8%)8/48 (16.7%)
Omentectomy27/27 (100%)48/48 (100%)
Distal pancreatectomy1/27 (3.7%)1/48 (2.1%)
Cholecystectomy1/27 (3.7%)1/48 (2.1%)
Large bowel resection2/27 (7.4%)6/48 (12.5%)
Small bowel resection5/27 (18.5%)4/48 (8.3%)
Partial gastrectomy0/27 (0%)2/48 (4.2%)
Partial cystectomy1/27 (3.7%)1/48 (2.1%)
Nephrectomy0/27 (0%)1/48 (2.1%)
Liver resection1/27 (3.7%)1/48 (2.1%)
Diaphragm stripping25/27 (92.6%)43/48 (89.6%)
Full-thickness diaphragm resection12/27 (44.4%)3/48 (6.3%)
Peritoneal resection26/27 (96.3%)45/48 (93.8%)
No residual disease22/27 (81.5%)43/48 (89.6%)
Residual disease <1 cm3/27 (11.1%)2/48 (4.2%)
Residual disease >1 cm2/27 (7.4%)3/48 (6.3%)
Figure 1.

 Pleural nodule; approximately 40% in Stage IIIC ovarian cancer.

Undertaking surgical resection to this extent carries with it associated morbidity and mortality requiring careful patient selection and counselling. For a more detailed discussion on operative technique and sites of special concern, please see the appendix (see Supplementary material, Appendix S1). The anaesthesiologist and critical-care specialists are important and necessary parts of the team effort required to undertake such procedures. It is our practice to begin transfusion of both red blood cells and fresh frozen plasma as soon as coeliotomy is performed and widespread resectable disease is identified. Since beginning this practice we have essentially eliminated the development of significant intraoperative disseminated intravascular coagulopathy. If epidural anaesthesia is to be considered then the associated venous dilatation requires a significant effort to maintain intravascular volume and the issue of the perioperative use of low-molecular-weight heparin must be addressed. The associated sympathetic block results in constriction of the bowel, which may make the use of stapling devices more challenging. For these reasons it is our preference to avoid epidural or spinal anaesthesia as an adjunct to general anaesthesia and prefer no nitrous oxide be used because its accumulation in the gastrointestinal tract can make exposure problematic and closure of the abdominal wall difficult after a long surgical procedure. In an attempt to minimise postoperative complications, all women undergoing modified posterior exenteration and low rectal anastomosis had either a diverting ileostomy or colostomy. Despite taking these preventative measures, three enteric fistulae developed. Two were associated with breakdown of staple lines and one woman developed a duodenal leak following a Billroth II procedure. The majority of the hospital re-admissions were associated with the development of intra-abdominal abscesses, partial small bowel obstruction or dehydration secondary to copious output from an ileostomy (Table 3).

Table 3.   Morbidity and mortality
ComplicationPositive thoracoscopyNegative thoracoscopy
Pneumonia1/27 (3.7%)1/48 (2.1%)
Gastrointestinal fistula1/27 (3.7%)2/48 (4.2%)
Pancreatic leak0/27 (0%)1/48 (2.1%)
Chylous ascites0/27 (0%)1/48 (2.1%)
Urinary tract fistula0/27 (0%)1/48 (2.1%)
Pulmonary embolism1/27 (3.7%)1/48 (2.1%)
Pleural effusion requiring drainage19/27 (70.4%)33/48 (68.8%)
Abscess3/27 (11.1%)4/48 (8.3%)
Re-admission3/27 (11.1%)5/48 (10.4%)
Postoperative death1/27 (3.7%)2/48 (4.2%)

Median operative time was 252 minutes (180–320 minutes). Median hospital stay was 11 days (5–62 days). It was impossible to accurately estimate blood loss because of the amount of ascites present and the use of large amounts of saline and water for hydrodissection during surgery. The median number of units of packed red blood cells and fresh frozen plasma transfused was 7 units (range 1–16 units) and 6 units fresh frozen plasma (1–14 units). The median amount of fluid resuscitation was 9500 ml crystalloid and blood products (range 4000–14 500 ml).

Postoperative deaths resulted from sepsis, as the result of an anastomotic leak; a pulmonary embolism; and a perforated trachea associated with the replacement of an endotracheal tube in anticipation of performing a bronchoscopy (Table 3).

Evaluation of the thoracic cavity can be accomplished either transdiaphragmatically or transthoracically with video assistance, neither of which is technically challenging but may require the assistance of a cardiovascular surgical team for surgeons unfamiliar with these techniques. Multiple authors have reported on the use of these techniques in women with pleural effusions and when suboptimal disease is identified instead of undertaking a primary cytoreductive effort, neoadjuvant chemotherapy can be initiated with the intent of performing an interval debulking procedure in those women responding to chemotherapy.16–19 Many of the same authors have reported success undertaking primary cytoreduction of thoracic disease before undertaking laparotomy with the intent to resect all visible disease.16–20 Although controversial and not fully understood, the role of intrathoracic evaluation and cytoreductive surgery does provide one more method to ensure that unnecessary intra-abdominal cytoreductive surgery is not undertaken in women who otherwise would remain with suboptimal residual disease. This apparently can be performed with minimal morbidity and may have a positive effect on survival.

Conclusions

Epithelial ovarian cancer is most commonly diagnosed in advanced stages. The prognostic value of complete cytoreduction has been reported and confirmed in several publications.6,21,22 Similarly intraperitoneal chemotherapy is associated with improved overall survival in women with small-volume residual disease (<1 cm) and, as with cytoreductive surgery, carries with it increased morbidity. It is therefore mandatory to do all that is necessary to identify disease that cannot be resected before undertaking a maximal cytoreductive effort for disease that will not benefit from the use of intraperitoneal chemotherapy. Using the surgical approach described allows both of these goals to be met, thereby maximising the potential benefit to women with advanced-stage epithelial ovarian cancer.

Disclosure of interests

The authors disclose that NMS is on the Speakers’ Bureau for Olympus and Ethicon.

Contribution to authorship

ACF and CLK conceived and designed the study, performed the study, analysed the data and wrote the paper. RLG conceived and designed the study and contributed materials to the study and NMS conceived and designed the study, performed the study, analysed the data, contributed materials to the study and wrote the paper.

Details of ethics approval

The study was submitted to the institutional review boards at participating hospitals and deemed exempt on the basis of using existing data, de-identified by the investigator.

Funding

The authors received no funding from any source for this manuscript.

Acknowledgements

None.

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