Neoadjuvant Chemotherapy for Ovarian Cancer
Neoadjuvant Chemotherapy for Ovarian Cancer
Few would question the statement
that the role of surgery in the
management of epithelial ovarian
cancer is unique in solid tumor
It is currently "standard practice"
for physicians confronted with a patient
with a "solid tumor" to search
for evidence of spread of the malignancy
beyond the local area of involvement
before undertaking an aggressive
attempt to produce a "surgical cure."
For example, while a female patient
shown to have multiple peritoneal implants
from a documented stomach
cancer may still have the primary cancer
removed in a reasonable effort to
prevent, treat, or avoid bleeding, perforation,
or pain, there should be no
realistic expectation that the metastatic
disease can be resected in an attempt
to "cure" the malignancy.
Yet, if this same patient presented
with an advanced ovarian cancer, and
similar surgical findings in the peritoneal
cavity, every reasonable effort
would be made to remove all visible
tumor deposits, as "standard management,"
prior to the initiation of chemotherapy.[
1] Thus, in addition to
the common use of surgical exploration
to define the extent of disease,
and to "cure" the small percentage of
patients with an apparently localized
cancer, aggressive surgery is considered
to play a central role in optimizing
survival in the large majority
of women with advanced ovarian
The justifications-both extensive
retrospective and far more limited prospective
data-for what might reasonably
be considered a most unusual
management paradigm for a "solid tumor"
are nicely outlined in the review
by Vergote and his colleagues. This
body of evidence can be very briefly
summarized as follows: Patients with
advanced ovarian cancer who initiate
chemotherapy with the smallest possible
residual tumor volume (preferably
no gross residual disease) experience
the greatest opportunity for prolonged
survival and possible "cure."
Unfortunately, despite the conclusiveness
of this observation, it currently
remains unknown if patients
who initiate cytotoxic therapy with
less (or no) gross disease live longer
because they underwent successful
surgical cytoreduction, or if they live
longer because of currently poorly
characterized but favorable biologic
characteristics of their disease process.
Stated slightly differently, are
the biologic features of a particular
ovarian malignancy that permit or prevent
removal of macroscopic cancer
(eg, absence or presence of diffuse
peritoneal carcinomatosis, or extensive
lymph node involvement) the
same factors that define a tumor's
inherent chemosensitivity or propensity
to develop "acquired" drug resistance?
If biology is the major factor,
"successful surgical cytoreduction"
can appropriately be viewed merely
as a "clinical indicator of that favorable
biology," rather than as the reason
for the favorable outcome.
Aggressive Surgical Approach
Finally, it is possible, or perhaps even likely, that both biology and surgical skill are critically important issues in defining the success of subsequently administered chemotherapy, and in determining an individualpatient's ultimate survival. In fact, a reasonable argument can be advanced that an aggressive surgical management philosophy will become even more clinically relevant in the future as increasingly effective chemotherapeutic agents are developed. At least conceptually, it will be critically important that all viable malignant cells are exposed to the concentrations of these drugs required to achieve the desired cytotoxic or cytostatic effect. An example of the favorable impact of a successful attempt at removing all or most gross residual disease in women with advanced ovarian cancer is the survival advantage associated with cisplatin-based intraperitoneal chemotherapy.[2-4] Existing evidence supports the conclusion that the ovarian cancer patient most likely to benefit from regional treatment is one with the smallest possible residual volume when treatment is initiated (eg, a maximum tumor diameter < 1 cm). Neoadjuvant Chemotherapy
In those individuals who are unable to undergo primary surgical cytoreduction, either due to extensive intra- or extra-abdominal disease, or where comorbid medical conditions would argue against employing this strategy, the concept of neoadjuvant chemotherapy has been advanced by a number of investigators over the past decade (references included in the Vergote review). Researchers have used a variety of methods to determine whether a patient is a candidate for such an approach, including physical and radiographic findings (eg, extensive carcinomatosis), or an initial laparoscopic assessment to determine resectability of the cancer. As discussed by Vergote, the results of an important European/Canadian prospective phase III randomized trial may provide (a) critical supportfor the statement that the ultimate survival outcome in advanced ovarian cancer is equivalent if chemotherapy follows, or precedes, an attempt at maximal surgical cytoreduction; or (b) the first proof that primary cytoreductive surgery before the administration of cytotoxic chemotherapy is a crucial factor in optimizing the chances for the most favorable outcome in this malignancy. Conclusions
For the present, however, it is reasonable to conclude, as have Vergote and his colleagues, that if a patient with advanced ovarian cancer is able to undergo an attempt at complete tumor removal performed by an appropriately skilled surgeon, this should be the preferred management option. Additional justification for this statement comes from the knowledge that cytoreductive procedures performed in ovarian cancer patients by experiencedgynecologic cancer surgeons currently are associated with highly acceptable risks of both short- and long-term morbidity, and very low mortality. Conversely, it is also legitimate to offer patients the realistic hope for a satisfactory outcome if chemotherapy (platinum/taxane-based) is the initial treatment approach, following histologic confirmation of a malignancy consistent with either ovarian or primary peritoneal cancer. Depending on the extent and rapidity of response, as well as the patient's overall medical status, it may be reasonable to consider an interval surgical cytoreductive procedure (following three to fours courses of chemotherapy), or to complete the treatment program without additional surgery. For a specific individual undergoing treatment, optimal management will depend on particular clinical circumstances and patient choice.
2. Alberts DS, Liu PY, Hannigan EV, et al: Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 335:1950-1955, 1996.
3. Markman M, Bundy BN, Alberts DS, et al: Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in smallvolume stage III ovarian carcinoma: An Intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 19:1001-1007, 2001.
4. Armstrong DK, Bundy BN, Baergen R, et al: Randomized phase III study of intravenous paclitaxel and cisplatin versus intravenous paclitaxel, intraperitoneal cisplatin and intraperitoneal paclitaxel in optimal stage III epithelial ovarian cancer: A Gynecologic Oncology Group trial (abstract 803). Proc Am Soc Clin Oncol 21:201a, 2002.