NEOADJUVANT CHEMOTHERAPY FOR THE TREATMENT OF ADVANCED STAGE OVARIAN CANCER

ABSTRACT

Multiple studies throughout the world have demonstrated in small series that survival is not negatively impacted in the management of ovarian cancer when neoadjuvant chemotherapy followed by aggressive cytoreductive surgery is employed. Indeed, a trial from Yale University suggests that progression-free survival may actually be improved. All the trials to date have reported that the benefits of neoadjuvant chemotherapy appear to be related primarily to the surgery. The surgery is easier as less aggressive surgery can more readily accomplish maximum cytoreduction, blood loss and operating time are significantly reduced and intensive care unit stays and overall hospital stays are significantly reduced when neoadjuvant chemotherapy is employed in the management of advanced stage ovarian cancer. We must await the results of an EORTC study to see whether a large prospective randomized trial can substantiate the results of retrospective and small prospective studies. Neoadjuvant chemotherapy is a viable consideration for any patient with findings consistent with an advanced stage ovarian cancer who fulfills diagnostic imaging criteria for non-cytoreducibility. INTRODUCTION

Ovarian cancer is the major pelvic reproductive organ cancer health hazard to women in the world. The American Cancer Society estimates, 25,580 women will be develop ovarian

cancer and 16,090 will die from this disease.1

The reason for this high mortality is that

approximately 70% of all epithelial ovarian cancers are not diagnosed until the disease is advanced. There are currently no circulating tumor markers or diagnostic imaging tests available that are routinely accurate for the early detection of ovarian cancer2 The conventional management of epithelial ovarian cancers, which represent approximately 90% of all ovarian cancers seen, is aggressive cytoreductive surgery followed by platinum-taxane combination chemotherapy.2 The role of cytoreductive surgery is not based on prospective randomized trials. It is based on retrospective reviews from numerous institutions. The standard chemotherapy used throughout the world is carboplatin and paclitaxel. This

treatment usually produces objective responses in approximately 80% of all women who have not been previously treated with chemotherapy for an ovarian cancer.3 Neoadjuvant chemotherapy was originally introduced at Yale in 1979 for patients whose medical condition did not permit them to undergo aggressive cytoreductive surgery. 3-5 Neoadjuvant chemotherapy for advanced stage ovarian cancer was subsequently introduced for patients who appeared not to be surgically cytoreducible based on diagnostic imaging standards.6

DIAGNOSIS AND MANAGEMENT OF OVARIAN CANCER

Diagnosis and management of ovarian cancer is one of the greatest challenges in oncology. approximately,half of ovarian carcinoma patients die

from the disease making it the leading cause of gynecologic cancer-related death in most industrialized countries 1. Although approach and knowledge of epithelial ovarian cancer has changed in the past 25 years, the overall survival has not been affected as approximately 65% to70% of all cases continue to be diagnosed with stage III or stage IV disease. Surgical reduction of tumor bulk has become the preferred first step in the management of advanced epithelial ovarian cancer
2.

Observations that the

excision of large tumor masses could provide palliation and a modest extension of life have been recorded for more than 50 years Approximately 70% of patients present with advanced ovarian cancer, when optimal debulking can not be obtained, and therefore gain little benefit from surgery. On the other hand, patients who are severely compromised medically carry an unwarranted risk to surgery.5 Neoadjuvant chemotherapy (NACT) has been proposed as a novel therapeutic approach to a variety of solid tumors when the disease is not amenable to surgical resection at the time of diagnosis or the patient is unfit for aggressive debulking surgery
5.

NACT has now been recognized as a

6,7.

useful modality for the treatment of various advanced cancers

In cases

with advanced ovarian carcinomas, platinum based chemotherapy regimens have been found to produce higher response rates and in some studies have produced a statistically significant survival advantages compared with drug regimens without platinum
8,9.

Thus the two treatment options available for treating patients with advanced ovarian tumor are either a primary surgical cytoreduction or to start with chemotherapy hoping or down staging the tumor and then go ahead with surgery.8

SURGICAL MANAGEMENT OF OVARIAN CANCER

In 1935, Lynch reported a landmark paper in the management of ovarian cancer. 9 He observed that ovarian cancer appeared to be familial, that most of the patients alive at 5 years either had borderline malignant potential tumors or had well differentiated cancers of the ovary and that one third of the women alive at 5 years were alive with disease. The latter invariably died 7-8 years following the original diagnosis.10 In 1940, Pemberton introduced the idea of an omentectomy as part of the initial management of ovarian cancer. 10 In 1968, Munnell reported his aggressive surgical approach to the management of ovarian cancer which included resection of the sigmoid colon when the disease apparently was confined to the pelvis. 11 However, it was Griffiths retrospective study that demonstrated that when women were operated on with advanced stage ovarian cancer and residual disease >1.5 cm in maximum diameter were left in the abdominal cavity, these patients almost invariably were dead in 2 years. 12 When patients were operated on and were found to have intraabdominal carcinomatosis but only miliary seedings, i.e. tumor implants <1.5 cm in maximum diameter, in the upper abdomen, such patients had a 5 year survival of approximately 20%. Griffiths then demonstrated, in a third group of patients, when large volume disease was present in the upper abdomen and he was able to surgically cytoreduce the cancer such that at the end of the operation the residual disease was

<1.5 cm in maximum diameter, these patients had a prolonged survival with 20% alive at 5 years. It was this retrospective review by Griffiths that established the concept of aggressive surgery followed by aggressive chemotherapy as the ideal way to manage advanced stage ovarian cancer.12 The clinical basis of aggressive cytoreductive surgery in the initial management of ovarian cancer is the significantly improved survival gained by those patients in whom optimal cytoreductive surgery was accomplished
12,13.

The presence of residual disease after surgery is one of the most

adverse prognostic factors for survival. Therefore, although the definition of optimal cytoreduction has been modified over the last two decades, it is generally agreed that every attempt should be made to surgically resect as much disease as safely possible 14 The value of debulking after induction chemotherapy has been largely debated in the last decades. Recently several investigators introduced the concept of interval debulking surgery meaning a surgical procedure with debulking intent foreword and followed by cytoreductive chemotherapy
14,15.

Based on the GOG 152 data,

interval debulking surgery does not seem to be indicated in patients who underwent primarily a maximal surgical effort by a gynecological oncologist
15.

In a population of patients with advanced ovarian carcinomawho deemed unresectable by surgical exploration, neoadjuvant chemotherapy helped to select patients for feasible and relatively less aggressive interval 5

debulking. Patients who did not respond or progressed under chemotherapy were spared surgery
16.

An issue of importance is which criteria should be used to define the respectability of the tumor and consequently the selection of which patients might benefit from NACT approach. Imaging (computed tomography scan) based criteria have been developed by different authors
17,18

Nelson et al showed that the predictive value of a positivetest (CT scan demonstrating non respectability) was only 67%. Bristow et al developed a predictive index that was able to correctly predict surgical outcome (optimal < 1 cm versus suboptimal residual disease status) The specificity or the ability to identify patients undergoing optimal debulking was 80%.It allows for making a histological diagnosis and objectively documents the extent of the disease. At the same time it identifies patients who can be optimally debulked, thus not denying the possible benefit of such a procedure. The issue of port site implantation in this patient group can probably be addressed by proper technique (Closure of the peritoneum and excision of trocar port site at the definitive surgery) and immediate (< 1 week) start of chemotherapy Initiation of chemotherapy was significantly delayed in the laparotom than the laparoscopy group. Chemotherapy was platinum based. 17 The value of neoadjuvant chemotherapy is to obtain optimum cytoreduction by means of less aggressive surgery. debulking surgery in NACT group was less aggressive than in the conventional group with less 6

blood loss rates, shorter intensive care stay and shorter postoperative hospitalization. There was no significant difference between perioperative morbidity and mortality in the two patient groups.The overall survival was not improved. In an analysis by Surwit et al, the median survival of 29 patients who underwent primary chemotherapy was 22 months, which the author said was similar to that of patients who undergo primary surgery The patients receiving NACT were significantly older and had a poor performance status but still obtained a similar survival.

NEOADJUVANT CHEMOTHERAPY

Neoadjuvant chemotherapy was originally introduced for patients who presented with advanced stage ovarian cancer and were medically disabled.3-5 Over the ensuing decade a reasonable experience was obtained suggesting that patients who were medically unable to tolerate aggressive cytoreductive surgery at the time of their initial presentation, but who received chemotherapy and then were able to undergo cytoreductive surgery, had a survival that was quite similar to those patients who initially had large volume disease present in the upper abdomen or Stage IV disease. A decade later, neoadjuvant chemotherapy followed by

aggressive surgery was introduced for patients who were not medically compromised but who, by CT scan criteria, appeared to have disease that was not surgically cytoreducible. 6 Basically,

patients with disease >2 cm in diameter in the upper abdomen that involved coating the diaphragm and was confluence with implants in the liver serosa, omentum replaced by tumor with the tumor in the omentum reaching the hilum of the spleen, porta hepatis metastases, enlarged (>2 cm) suprarenal para-aortic lymph nodes and disease in the thorax were indications to recommend neoadjuvant chemotherapy as these preoperative CT findings were usually associated with extensive upper abdominal metastases that could not be optimally cytoreduced. Our criteria for selecting patients for neoadjuvant chemotherapy also required cytology or histology specimens consistent with ovarian cancer to be present before chemotherapy is initiated. We have found that performing cytology and cell block analysis on ascites fluid could routinely give us findings consistent with a non-mucinous epithelial ovarian cancer.13

Neoadjuvant chemotherapy for the treatment of advanced stage ovarian cancer as employed means that the chemotherapy is administered before any surgery is performed. Cytologic material or biopsies can be obtained using diagnostic imaging to direct the biopsy. Patients who receive neoadjuvant chemotherapy are ultimately recommended to undergo standard cytoreductive surgery. Neoadjuvant chemotherapy must be distinguished from interval debulking surgery. The latter is performed when suboptimal cytoreduction is done as the initial operation. In general patients receive 3 cycles of chemotherapy following suboptimal surgical cytoreduction then undergo interval debulking surgery. Data has been presented suggesting that those patients who have been suboptimally cytoreduced, have 3 cycles of platinum-based chemotherapy and then are optimally cytoreduced, do better than those patients who do not undergo interval cytoreductive surgery.14 However, data suggests that interval cytoreduction does not improve the results of initial suboptimal cytoreduction. 15 Patients who are being

operated for ovarian cancer should be operated by physicians trained to do aggressive cytoreductive surgery. Conventional treatment is aggressive cytoreductive surgery followed by aggressive chemotherapy. Neoadjuvant chemotherapy for the management of ovarian cancer reverses the treatment techniques used in conventional treatment. The major concern about neoadjuvant chemotherapy in the management in advanced stage ovarian cancer has been an issue of survival. There are now multiple studies which suggest that the survival of patients treated with neoadjuvant chemotherapy is similar to that of patients who undergo conventional treatment.16-18 There appears to be no compromise in overall survival. However, to achieve survival comparable to that of women who undergo conventional treatment, it is necessary that optimal cytoreductive surgery is performed following completion of the neoadjuvant chemotherapy. If one delays the time from completing the chemotherapy to the time of performing the surgery, it has been our anecdotal experience that resistant disease develops that is not responsive to conventional chemotherapy.
5

Despite controversies in the definition of optimal cytoreduction, all investigators agree that patients who fail to undergo optimal debulking at the first attempt have a much poorer prognosis.5 Not only the volume of residual disease, but also the initial metastatic tumour load is of prognostic significance. Even though aggressive surgery is important in the treatment of ovarian cancer, tumour biology also co-determines the success of surgery as is shown by several observers.6-8 Advanced stage at presentation and biology of the tumour co-determine the abysmal 5-year survival figures of about only 25% in these patients.7

The primary aim was not to debate on the role of primary surgery, which remains the gold standard of care, but to establish better resectability (and the equivalent overall survival) with use of NACT in advanced ovarian cancer. An approach that provides equivalent survival with better (lesser) treatment related morbidity should ideally be the treatment of choice NACT followed by interval debulking surgery has been proposed as an alternative approach for the initial management of bulky ovarian cancer, aiming at the improvement of surgical efficacy and patients quality of life. The interest in NACT in advanced ovarian cancer grew out of observation of good overall response rate using platinum and taxane based chemotherapy in sub optimally cytoreduced patient. Published literature consists

predominantly of retrospective observations and it appears that NACT followed by interval cytoreduction improves the prognosis and quality of life in selected groups of patients.9-28 It is significant to note that these studies have been limited to patients bearing medical conditions that precluded an immediate surgical intervention. Out of the studies quoted here only 2 have compared the use of NACT as the primary against the use of chemotherapy after an initial unsuccessful surgical attempt (in which case the

chemotherapy is better termed as induction chemotherapy). Our study, although retrospective in nature, includes patients who could have been eligible candidates for surgery upfront but received NACT due to refusal for surgery or treating oncologists assessment. Taken together these studies have shown that use of NACT followed by interval debulking reduces 10

perioperative morbidity 29-30 in terms of significant reduction in estimated blood loss, duration of postoperative intensive care unit stay and overall hospitalization, does not worsen the prognosis, and more importantly improves the quality of life.9 Feasibility of NACT in advanced ovarian cancer. Not only is this approach safe in terms of treatment related morbidity but also, more importantly, it does not adversely affect the survival (overall or disease free)7 The argument in favour of NACT is multifactorial. First, given the advanced stage at diagnosis , patients are usually nutritionally depleted and in poor general condition. Following NACT, patients performance status is improved prior to surgery, owing to the reduction in tumour volume, ascites and pleural effusion. With the disease under control and relief of distressing symptoms of abdominal distension and discomfort, nutritional improvement ensues resulting in improved perioperative outcome as also the need for a less extensive surgery due to reduced tumour bulk. Finally, surgical cytoreduction may be improved, which in turn leads to a better prognosis and survival. An additional advantage of NACT is that it allows the in vivo assessment of tumour chemo sensitivity, which permits the clinician to choose

appropriate therapeutic options. A systematic review of neoadjuvant chemotherapy and interval cytoreduction in which conclude that the survival outcome achievable with initial chemotherapy is inferior to successful 11

upfront cytoreductive surgery and also that survival outcome was inversely proportional to an increasing number of preoperative chemotherapy cycles with each additional cycle associated with a 4.1 month reduction in median survival time. However whether the two groups are really comparable is a matter of debate. Most patients taken for neoadjuvant chemotherapy have a poorer general condition, more volume disease and possibly poorer tumour biology and hence one would expect a poorer result in this group. A true comparison would be made if all the inoperable patients (by whatever criteria used) 10

NEOADJUVANT CHEMOTHERAPY FOLLOWING SURGICAL ASSESSMENT FOR OPERABILITY

Neoadjuvant chemotherapy treated with single agent Platinum based combination chemotherapy prior to undergoing cytoreductive surgery . Demonstrated combination chemotherapy provided more complete responses and more dramatic drops in Ca 125 values than single agent Platinum therapy.10 Th post operative course was substantially better in patient who received adjuvant chemotherapy under their diection than in woman who had undergone primary surgical cytoreduction followed by Platinum based chemotherapy. Intra operative complications and post operative complication were substantially less, as was the duration of intensive care unit and hospital stays. NACT followed by surgery offered patient the same overall survival as that achieved when sub optimal cytoreduction is performed at the first operation and than interval cytoreduction surgery is performed. An improvement quality of life as compared with that of women undergoing primary cytoreduction. 15 The patient who were optimally cytoreduced 12

following neo adjuvant chemotherapy had a statistically improved survival compared who had non debulked tumours. The median overall survival was 22 months. Vergote et all reported that patient with stage IV disease, patient with total metastatic load greater than 1000grams, uncountable plaque-shaped peritoneal metastases and or a poor performance status are the best candidates for neoadjuvant chemotherapy.15

SELECTION OF PATIENT WHOP MIGHT BENEFIT FROM THE NEOADJUVANT CHEMOTHERAPY ROUTE

Patient who benefit most from neoadjuvant chemotherapy for the treatment of advance stage ovarian cancer are those in whom optimal cytoreductive surgery cannot be performed. Imaging with CT scan prformed prior to primary staging and cytoreduction. The CT criteria suggested that the inability to performed optimal cytoreduction was based mainly on the presence of bulky disease in the upper abdomen or in the pleural cavity and identify patient who could not be optimally cytoreduced included the omentum being replace by tumour and the tumour extending to the spleen, disease greater than 2cm in diameter in the mesentery of the small bowel, on the liver serosa or in its parenchyma, the CT scan finding are usually ascociated with more disease being found at the surgery that frequently result in suboptimal cytoreductive surgery. In addition the finding of pericardial lympnodes and pulmonary and pulmonal nodules are also ascociated with a poo prognosis and are likely to be ascociated with sub optimal cytoreductive surgery .16 Ca 125 levels as a means of determining who might benefit from surgical cytoreduction as the initial steps in the management of these patient as compared to those who might benefit

13

from neoadjuvant chemotherapy. Ca 125 value less than 500U/ml were highly likely to be optimally cytoreduced. Combining Ca 15 findings with CT scan finding can help to establish parameters for selecting patient with apparent advance stage ovarian cancer who might benefit from the neoadjuvant route 14

THE ROLE OF CYTOLOGY IN PRE TREATMENT DIAGNOSIS

The role of cytology in pre treatment evaluation of women with clinical findings consistent with ovarian cancer who are being considered for neoadjuvant chemotherapy. Approximately 70% of epithelial ovarian cancers (EOC), the most common form of ovarian cancers, are not diagnosed until the disease has involved the upper abdomen or spread beyond the abdominal cavity 1 A lack of early warning signals and a lack of sensitive, clinically available diagnostic tests to detect early stage disease results in most women not being diagnosed until the cancer is in an advanced stage, and cure is frequently elusive 1,17. Neoadjuvant chemotherapy is now gaining popularity as a means of improving the physical and emotional trauma associated with initial ovarian cancer treatment
914

. The

subjective improvement in the sense of well-being when patients are given chemotherapy first is well recognized compared to when aggressive cytoreductive surgery is the first step in the treatment regimen
1114.

Concern has been raised about the reliability of using cytology to

diagnose ovarian cancer. The pathologist is not required to confirm the diagnosis of ovarian cancer based on cytologic material. It would be ideal if the pathologist or cytologist could exclude the possibility

14

of ovarian primary or definitely confirm the ovarian primary. However, the reality is the opposite simply because of the limitations of cytology.6 The malignant features included clusters and single pleomorphic tumor cells with high nuclear-to-cytoplasm ratios. There were no particular features distinguishing the malignant cells originating from ovarian cancers from those arising from nongynecologic organs. It is well known that the cytologic diagnosis of ovarian cancer is difficult
[16].

However, the clinical setting

presented, does not seek a definitive pathologic diagnosis but rather to gain additional support for the clinical impression derived from the physical examination, serology studies, and diagnostic imaging findings. Based on this particular pinpoint clinical management related question, i.e., compatible or noncompatible with ovarian primary, we summarized the following cytologic features to lead us to the conclusion that a cytologic specimen is compatible with an ovarian primary. Ovarian adenocarcinomas are characterized by a predominance of Smaller, less cohesive cancer cell clusters and papillae with irregular outlines and many single cells. The tumor cells are typically pleomorphic and appear syncytial with indistinct cell borders. The tumor cell cytoplasm is usually abundant and vacuolated
[16].

Malignant cells with the above

features are compatible with serous carcinoma, particularly when papillary architecture and/or psammoma bodies can be identified.13 The findings of the surgical specimen histologic evaluations obtained after neoadjuvant chemotherapy was completed are presented and compared to the pretreatment cytology

CA125 REGRESSION DURING NEOADJUVANT CHEMOTHERAPY

15

Serum CA125 is the representative tumor marker of ovarian cancer. The regression of CA125 has been studied for the evaluation of chemotherapeutic effect and furthermore as a prognostic indicator However, analyses on CA125 regression rates reported often included the surgical debulking effect or clear cell carcinoma and mucinous adenocarcinoma putative to be cisplatin resistant tumors
11,12.

The prognostic factors of advanced ovarian cancer include the

amount of residual tumor after surgery, performance status, histological grade, histological type, and age
13,14.

Although tumor reduction measured by diagnostic imaging is the most common

method of evaluating the anticancer effect of chemotherapy, this effect does not always reflect the prognosis.Generally, when CA125 level is used to evaluate the therapeutic effect of chemotherapy, either the absolute value of CA125 level at the completion of chemotherapy or the time of 50% reduction of CA125 level, or the half-time, is used. Makar et al. [1] reported that decline of CA125 level to below 65 U/ml or a reduction of greater than 50% of the prechemotherapy level 4 weeks after the second cycle of chemotherapy is an independent prognostic factor for survival. Sevelda et al.
[2]

reported that patients with CA125 level greater

than 35 U/ml after two cycles had a relative risk for mortality of 3.1 after a median follow-up of 24 months. Redman et al. [3] also reported a good 12-month prognosis in patients with CA125 levels lower than 35 U/ml after two cycles. However, the subjects in Redmans study had a mean prechemotherapy CA 135 level of 321 U/ml. For cases with high CA125 level before chemotherapy, although a good regression of CA125 is achieved by the chemotherapy, some cases may not reach normalization of CA125 after two or three cycles. These cases will then be evaluated as nonresponsive if the absolute CA125 level is used as the criterion of evaluation, which may pose a problem in the prediction of prognosis. Frasci et al.
4

used the days until

normalization of CA125 level as the evaluation standard. They recommended a standard period

16

of 30 days, but the problem is that many cases of advanced cancers do not reach normalization within 30 days. In recent years, NAC has been tried for the treatment of advanced ovarian cancers However, the risks of recurrence and death remain high even in cases that respond to NAC and cytoreductive surgery is possible.12 CA125 regression rate, it is possible to stratify TIIIc or M1 ovarian serous adenocarcinoma cases into those with a good prognosis of survival and those with poor prognosis. The chemotherapy regimen is platinumbased chemotherapy. Recently, CA125 regression has been reported as a reliable biological tool for the paclitaxel/platinum-based chemotherapy, which is currently the standard therapy. The responders with regression coefficients of CA125 levels greater than _0.039 are predicted to have a good prognosis following surgery after NAC. In these patients, radical curative surgeries are chosen actively, and if consolidation chemotherapy is to be conducted after radical surgery, the same regimen used in NAC in which efficacy has been proved should be employed. In nonresponders with regression coefficients less than _0.039, even curative surgery is conducted, there is a high risk of death from recurrence within 3 years. In these cases, a new second-line regimen should be used for postoperative chemotherapy, or decision of an alternate option of less invasive palliative surgery may also be arrived. In any case, decision of chemotherapy regimen or surgical modality should be made considering the maximum benefits for the quality of life of the patient. 17

CURRENT STATUS OF NEOADJUVANT CHEMOTHERAPY

Neoadjuvant chemotherapy plays a strong role in women with advanced stage ovarian cancer that is not surgically cytoreducible. 3,5,16 Other institutions are now using laparoscopy to assess surgical cytoreducibility.16,17 One report suggests that all patients with Stage III disease, not just those that are non-cytoreducible, may be treated with neoadjuvant chemotherapy followed by surgery without compromising their survival. 16 Currently reports on neoadjuvant chemotherapy for the treatment of advanced stage ovarian cancer are either retrospective or limited in patient numbers. The European Organization for the Research and Treatment of Cancer (EORTC) study is now randomizing 742 women between neoadjuvant chemotherapy (platinum and taxane) for 3 cycles followed by aggressive cytoreductive surgery followed by 3 more cycles of chemotherapy vs. conventional treatment, i.e. aggressive cytoreduction followed by 6 cycle of the combination of platinum and paclitaxel. The results of that trial will be extremely helpful in sorting out a role for neoadjuvant chemotherapy in the management of advanced stage ovarian cancer..In seeking ways to identify which women with apparent advanced ovarian cancer based on physical examinations, computerized tomography scans, and cytology and/or biopsy evaluation may or may not benefit from neoadjuvant chemotherapy. Surprisingly, women with the most aggressive cancers did not express the highest levels of CA 125, at least based on an arbitrary but high cutoff value of 2000 U/ml. High serum CA 125 values may reflect the presence of excessive ascites or pleural effusions causing peritoneal or pleural irritation as opposed to being true measures of volume of cancer. Two recent studies suggest that ascites is a poor prognostic factor for women who have advanced ovarian cancer
[10,

18

11].

Women with Stage IIIC disease and ascites in our study were treated in a conventional

fashion had a statistically reduced survival compared with those without ascites Neoadjuvant chemotherapy appears to be effective in women who have advanced ovarian cancer that by CT criteria cannot be optimally cytoreduced
7.

Subjective improvements in sense

of well-being, quality of life, tolerance of chemotherapy, and cost/benefit ratios From study demonstrates that women treated with neoadjuvant chemotherapy have the same overall survival as women treated in a conventional fashion with aggressive cytoreductive surgery followed by the platinum-based chemotherapy despite the neoadjuvant group being significantly older and having a poorer performance status.

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REFERENCES

1. Jemal A, Tiwari RD, Murray T, et al. Cancer Statistics 2004. Cancer Journal for Clinicians 2004; 54:8-29. 2. Ozols RF, Rubin SC, Thomas G, Robboy S. Epithelial ovarian cancer. In Principles and Practice of Gynecologic Oncology, Second Edition, Edited by W.J. Hoskins, C. A. Perez and R.C. Young. Lippincott-Raven Publishers, Philadelphia, 1997 pp 919-986. 3. Chambers JT, Chambers SK, Voynick IM, Schwartz PE. Neoadjuvant chemotherapy in stage X ovarian carcinoma. Gynecologic Oncology 1990; 37:327-331. 4. Schwartz PE, Chambers JT, Makuch R. Neoadjuvant chemotherapy for advanced ovarian cancer. Gynecologic Oncology 1994; 55:33-37. 5. Schwartz PE, Rutherford TJ, Chambers JT, et al. Neoadjuvant chemotherapy for advanced ovarian cancer: long-term survival. Gynecologic Oncology 1999; 72:93-99. 6. Nelson BE, Rosenfield AT, Schwartz PE. Preoperative abdominopelvic computed tomography prediction of optimal cytoreduction in epithelial ovarian carcinoma. Journal of Clinical Oncology 1993; 11:166-172.

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7. McDowell E. Three cases of extirpation of diseased ovaries. Eclectic Repertory Analyt Rev 1817; 7:242. 8. Tait L. The Pathology and Treatment of Disease of the Ovaries. New York, William Wood & Co, 4th Edition, 1983, p 253. 9. Lynch F. A clinical review of 110 cases of ovarian cancer. American Journal of Obstetrics and Gynecology 1936; 32:753-772. 10. Pemberton FA. Carcinoma of the ovary. American Journal of Obstetrics and Gynecology 1941; 40:751-760. 11. Munnell EW. The changing prognosis and treatment in cancer of the ovary. A report of 235 patients with primary ovarian carcinoma 1952-1961. American Journal of Obstetrics and Gynecology 1968; 100:790-805. 12. Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian cancer. Monographs National Cancer Institute 1975; 45:101-104. 13. Schwartz PE, Zheng W. Neoadjuvant chemotherapy for advanced ovarian cancer: The role of cytology in pretreatment diagnosis. Gynecol Oncol 2003; 90:644-650. 14. van der Burg ME, van Lent M, Buyse M, et al. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer. New England Journal of Medicine 1995; 332:629-634. 15. Neijt JP, ten Bokkel Huinink WW, van der Burg ME, et al. Randomized trial comparing two combination chemotherapy regimens (CHAP-5 v CP) in advanced ovarian carcinoma. Journal of Clinical Oncology 1987; 5:1157-1168.

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16. Surwit E, Childers J, Atlas I, et al. Neoadjuvant chemotherapy for advanced ovarian cancer. International Journal of Gynecologic Cancer 1996; 6:356-366. 17. Vergote I, DeWever I, Tjalma W, et al. Neoadjuvant chemotherapy or primary debulking surgery in advanced ovarian carcinoma: a retrospective analysis of 285 patients. Gynecologic Oncology 1998; 71:431-436.

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