Surgical Cytoreduction in Ovarian Cancer

May 1, 2004

I would like to compliment the authorson their comprehensive reviewof cytoreductive surgery forovarian cancer. However, some oftheir interpretation of the literaturewarrants amplification, and some conclusionsmerit presentation of an alternativeperspective.

I would like to compliment the authorson their comprehensive reviewof cytoreductive surgery forovarian cancer. However, some oftheir interpretation of the literaturewarrants amplification, and some conclusionsmerit presentation of an alternativeperspective.Presurgical Tumor Burden
Understandably, "optimal" cytoreductionis more easily accomplishedfor small tumor burdens than largeones. However, as indicated in thereview, ovarian cancer with extensiveintra-abdominal disease is suggestedto have a natural history that isunalterable due to "tumor biology,"even if "optimal" cytoreduction isachieved.[1-4]Unfortunately, the literature correlatingthe extent of intra-abdominaldisease present before cytoreductionwith subsequent survival has flawsthat Drs. McCreath and Chi have notaddressed. As noted in the review,Hoskins et al reported a better mediansurvival for patients cytoreduced to≤ 1 cm of residual disease if the extrapelvicdisease was ≤ 1 cm in largestdimension before cytoreductionthan for patients with extrapelvic disease> 1 cm in largest dimension beforecytoreduction, and concluded thatinnate biologic properties of the disease,as manifested by the extent ofintra-abdominal tumor burden, mayplay a greater role in determiningprognosis than treatment.[2] However,the percentage of patients in eachgroup with excision of all visible diseasewas not reported. All visible diseasewas probably excised in a higherpercentage of those with small-volumedisease before surgery than ofthose with extensive disease to resect.Because excision of all visible diseasehas a more significant influenceon survival than an "optimal" outcomeof ≤ 1 cm residual disease, asreported by numerous investigators,then stratification by any parameterproducing subgroups with dissimilarcytoreductive outcomes cannot produceequivalent survival.[5-8] Hence,the superior survival noted for patientswith small-volume disease beforesurgery probably reflects morecomplete cytoreduction within thatgroup rather than differences in tumorbiology.Our group recently reported a prospectiveinvestigation in 408 patientswith stage IIIC epithelial ovarian cancerfor whom a ranking system wasdeveloped to quantify the extent ofintra-abdominal disease at multiplelocations before cytoreduction.[7]Cytoreduction to a visibly diseasefreeoutcome had a more significantinfluence on survival (P = .001) thanthe extent of metastatic diseasepresent before surgery (P = .05). Although"aggressive" or unfavorabletumor biology, as defined by a diminishedpossibility of significantlyaltering the natural history of the diseaseby treatment, may play a moresignificant role in determining survivalthan the operative outcome forsome patients, the extent of intra-abdominaldisease before surgery doesnot correlate with tumor biology predictablyenough to influence treatmentstrategies.[7]Optimal Cytoreduction
The authors acknowledge a rangeof criteria to define optimal cytoreductionin the literature and indicatethat the Gynecologic Oncology Groupdefines this parameter as ≤ 1 cm ofresidual disease. However, little insightis given as to why specific thresholdsare used to define optimalcytoreduction by different individuals.In all probability, these differentcriteria are used as a result of personalbeliefs about the feasibility ofachieving specific operative outcomesand traditional training, rather thancorrelation of operative outcomes withsurvival.[9]Clearly, a visibly disease-free operativeoutcome is associated with thehighest probability of long-termsurvival or cure, has been shown tobe achievable for the majority of patientswith advanced-stage disease,and should probably be used to defineoptimal cytoreduction in thefuture.[5-8,10] Efforts should bemade to acquire and use all availabletechniques to achieve completecytoreduction primarily, as it isfeasible.[7,10]Neoadjuvant Chemotherapy
The authors note the purpose ofneoadjuvant chemotherapy to be reductionof the extent of intraabdominaldisease before intervalcytoreductive surgery, thus diminishingmorbidity and facilitating "optimal"cytoreduction by reducing theextent of surgery required. They acknowledgethat overall mediansurvival following neoadjuvant chemotherapyand interval surgery doesnot approach the median survivalachieved with primary surgery andadjunctive chemotherapy. Indeed,throughout the cytoreductive literature,patients with advanced epithelialovarian cancer whose macroscopicdisease is completely resected beforechemotherapy, as well as those with≤ 1 cm of residual disease, are reportedto have better median and 5-yearsurvivals than patients with equivalentoperative outcomes after intervalcytoreduction following neoadjuvantchemotherapy.[5-8,11-13]A theoretical disadvantage associatedwith neoadjuvant chemotherapyis the possibility of metastatic diseasedeveloping drug resistance duringexposure to cytotoxic agents.Hence, residual disease after intervalcytoreductive surgery may have anincreased probability of resistance tochemotherapy compared to residualdisease after primary cytoreductivesurgery. Although available data mayjustify neoadjuvant chemotherapy inpatients with absolute contraindicationsto surgery and findings that conclusivelypreclude complete oroptimal cytoreduction, correlation ofspecific radiographic and/or laparoscopicobservations with primarycytoreductive outcomes has undergoneminimal investigation. Given thesignificant variation in both theability to perform specific proceduresdescribed to facilitate cytoreductionand opinion concerning applicabilityof the procedures among gynecologiconcologists, it is possiblethat the probability of complete oroptimal primary cytoreduction ismore significantly influenced by theoperating physician than by any specificradiographic or laparoscopicfinding.[9]In light of the fact that reports ofneoadjuvant chemotherapy and intervalcytoreduction have not duplicatedthe more favorable outcomes ofprimary cytoreductive surgery and adjunctivechemotherapy, the appropriatenessof undertaking a phase III trialcomparing the outcomes of neoadjuvantchemotherapy/interval cytoreductionto those achieved with primarycytoreductive surgery/adjunctive chemotherapyremains questionable. Finally,because patients who undergoboth complete primary and intervalcytoreduction achieve a better survivalthan corresponding patients withsmall-volume (≤ 1-2 cm) visible residualdisease following either strategy,any prospective investigationwithout a visibly disease-free surgicalobjective may not determine themost efficacious treatment strategywith acceptable morbidity.[5-8,11-13]Surgery at Expert Centers
McCreath and Chi summarize thestatus of cytoreductive surgery admirablybut indicate that the extent ofsurgery necessary during cytoreductiveoperations justifies performing theprocedures at "expert centers." Althoughsuch an idealistic recommendationmay be politically correct,suggestions such as this one distractattention from the fundamental issueof the importance of involving a gynecologiconcologist in the care of allwomen with genital cancers, and ovariancancer in particular. Availabledata indicate that the treating physicianis more important to the outcomethan the institution.[5-7,9,10,14] "Privatepractitioners" and "academicians"should cooperate as a team tofacilitate the treatment of all womenwith ovarian cancer by gynecologiconcologists.

Disclosures:

The author has nosignificant financial interest or other relationshipwith the manufacturers of any productsor providers of any service mentioned in thisarticle.

References:

1.

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2.

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10.

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