NEOADJUVANT CHEMOTHERAPY SHOULD BE ROUTINELY CONSIDERED

FOR THE TREATMENT OF ADVANCED STAGE OVARIAN CANCER

Peter E. Schwartz, MD
Department of Obstetrics and Gynecology
Yale University School of Medicine
333 Cedar Street FMB 316
New Haven, CT 06520
Phone: 203-785-4014
Fax: 203-785-4135
E-mail: peter.schwartz@yale.edu

Schwartz, PE
SUMMARY

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.

Schwartz, PE
INTRODUCTION

Ovarian cancer is the major pelvic reproductive organ cancer health hazard to American women.
The American Cancer Society estimates this year, 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 cancer.

The conventional management of epithelial ovarian cancers, which represent approximately 90%
of all ovarian cancers seen in the United States, 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 United States 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.

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 by us for patients
who appeared not to be surgically cytoreducible based on diagnostic imaging standards.6

SURGICAL MANAGEMENT OF OVARIAN CANCER

Schwartz, PE

In 1809 McDowell successfully removed a diseased ovary and the patient survived.7 This
Kentucky frontier physician did 13 ovariotomy operations. Eight women survived the surgery.
McDowells initial experience was the first time that a diseased intraabdominal organ was
successfully removed and the patient lived. Nevertheless, it took almost another half century
before the routine removal of diseased ovaries became an accepted surgical practice. The
diseased ovaries removed were invariably thought preoperatively, to be benign. Tate introduced
the concept of an exploratory laparotomy in 1879 as he believed that benign ovarian tumors
might be mistaken for ovarian cancer.8 It was the dogma of that era that one never operated on
ovarian cancer because the surgery did little good and it had no impact on the ultimate survival
of the patient. By the beginning of the 1900s surgeons were routinely operating on women
thought to have ovarian cancer in an effort to removed the diseased organ.

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. 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

Schwartz, PE
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

NEOADJUVANT CHEMOTHERAPY

Neoadjuvant chemotherapy was originally introduced by us for patients who presented with
advanced stage ovarian cancer and were medically disabled.3-5 Over the ensuing decade a
reasonable experience was obtained at the Yale-New Haven Hospital 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

Schwartz, PE
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 in
this presentation 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

Schwartz, PE
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.

CURRENT STATUS OF NEOADJUVANT CHEMOTHERAPY

Reports from Yale-New Haven Hospital and many other sites would strongly suggest that
neoadjuvant chemotherapy plays a strong role in women with advanced stage ovarian cancer that
is not surgically cytoreducible.3,5,16-18 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

Schwartz, PE
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.

Schwartz, PE
REFERENCES

1. Jemal A, Tiwari RD, Murray T, et al. Cancer Statistics 2004. Cancer Journal for
Clinicians 2004; 54:8-29.
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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.
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.

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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
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Monographs National Cancer Institute 1975; 45:101-104.
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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.
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.
18. Ansquer Y, Leblanc E, Clough K, et al. Neoadjuvant chemotherapy for unresectable
ovarian carcinoma. Cancer 2001; 91:2329-2334.

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