New Look on an Old Debate: Neoadjuvant Chemotherapy for Ovarian Cancer
Abstract & Commentary
by Ronald Coleman, MD, Associate Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman reports no financial relationship to this field of study.
Synopsis: Neoadjuvant chemotherapy lessens surgical morbidity in advanced ovarian cancer and leads to improved survival in stage IV disease.
Source: Hou JY, et al. Gynecol Oncol. (2007), doi:10.1016/j.ygyno.2006.11.025.
Neoadjuvant Chemotherapy (NACT) for ovarian cancer refers specifically to the administration of cytotoxic therapy ahead of a planned surgical resection usually for primary therapy. Traditionally, the approach has been principally reserved for medically infirmed patients or those in whom the tumor burden precludes an adequate cytoreductive effort. However, observations of reduced operative morbidity have encouraged some investigators to use the strategy in selected patients. Hou and colleagues reviewed their experience with NACT over a seven-year period, focusing on perioperative morbidity and survival compared to women approached by conventional surgery followed by chemotherapy, and in cohorts of women treated before and after introduction of a taxane-platinum combination. Overall, 172 patients were identified; approximately 37% of these patients were given NACT (median 6 cycles) before a debulking attempt. Compared to women undergoing primary debulking surgery (PDS), women getting NACT before surgery had significantly shorter operations, less blood loss, fewer transfusions and shorter hospitalizations. In addition, they were less likely to need radical surgical procedures to make them "optimal" and achieved this milestone significantly more often. Survival between to two therapy styles was nearly identical (PFSNACT: 16 mos vs PFSPDS: 14 mos; OSNACT: 46 mos vs OSPDS: 47 mos); however, significantly better PFS and OS was observed among stage IV patients. Patients achieving "optimal" status defined as less than 1 cm residuum had similar outcomes for both survival endpoints. Taxane based combinations outperformed non-taxane combination for both cohorts. The authors concluded that NACT is associated with superior operative endpoints without diminution in survival and should be prospectively studied.
Commentary
There are few more controversial topics in the discussion of primary ovarian cancer management than NACT vs primary surgical resection. A prior report by this group a few years ago (demonstrating similar general results) initiated a firestorm of letters to the editor claiming "foul-play" and cautioned that the approach could ("in fact") hurt patients by denying them appropriate care.1,2 There was also the intimation that the approach (NACT) is being increasingly performed due to declining surgical skills in some gynecologic oncologists.
Since that time, reports of expanding radical surgical procedures to more women documented that the concept of aggressive primary surgery is important to outcome and as such would support the concept of redefining the "optimal" endpoint as no visible residual (see "Outcome of cytoreductive surgery in primary ovarian cancer: what is 'optimal'?" in OB/GYN Clinical Alert, January 2007). However, current reports consistently highlight the reduction in operative morbidity, and despite the obvious negative selection bias of sicker and more advanced disease patients, similar survival.
The foundation for these observations lies in the clinical aspect of chemo-sensitive tumor. Chemo-naïve ovarian cancer, even large volume disease, for the most part, has a significant probability of response to taxane and platinum-based therapy. The responses can be dramatic.3 However, critics suggest the exposure of large volume tumor to active therapy may heighten chemo-resistant clones due to the mixed and large population of such cells in a bulky tumor nodule. In this setting, NACT only perpetuates a select population of resistant cells which should reduce survivorship. Contemporary reports such as the current paper suggest otherwise and do provide some basis for randomized evaluation. Fortunately, some information will be available following the report of the EORTC 55971 trial.
Many questions remain in optimal NACT delivery. For instance, how many cycles should be given ahead of surgery? There is some evidence more (6 or more) has a detrimental effect on survival. In whom is it most appropriate? The significant selection bias has limited this approach to sick and advanced stage (extra-abdominal) disease patients. Would less sick patients also benefit to the same degree? How do you select patients unable to undergo optimal primary surgery? Imaging is of some help but clearly imperfect as are the cadre of biomarkers. Finally, patients with bulky intraperitoneal disease are probably not good candidates for intraperitoneal chemotherapy in the neoadjuvant setting. Would denying, delaying or restricting use of this modality, which has been demonstrated in Phase III clinical trials to be beneficial to survival, be detrimental in the long run? Further work will help to elucidate optimal patients for this approach as has been done for patients with colorectal and breast cancer.
References
- Eisenkop SM. LTE-commenting on "Neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy in patients with primarily unresectable, advanced-stage ovarian cancer." (90:163-169). Gynecol Oncol. 92:1017-8; author reply 1018-9, 2004.
- Eisenkop SM. Commenting on centralizing surgery for gynecologic oncology: a strategy assuring better quality treatment? (89:4-8) by Karsten Munstedt, et al. Gynecol Oncol. 94:605-606; author reply 606-607, 2004.
- Loizzi V, et al. Neoadjuvant chemotherapy in advanced ovarian cancer: a case-control study. Int J Gynecol Cancer. 2005;15:217-223.
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