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Surgical Cytoreduction in Ovarian Cancer

Surgical Cytoreduction in Ovarian Cancer

Tumor resection without expectation of complete excision violates the traditional tenets of surgical oncology. The concept of operability carries the implication of complete tumor excision with a margin of normal tissue. This classic view was challenged by Griffith's landmark 1975 paper showing an improved survival with surgical cytoreduction-a technique that cut across tumor and rarely attained negative margins.[1] He showed in 70 patients that survival time was inversely proportional to the size of the residual tumor after surgery. Cytoreductive Surgery
Drs. McCreath and Chi comprehensively survey the current literature on cytoreductive surgery in ovarian cancer.[2] They look at three main groups of patients: (1) those who received primary cytoreductive surgery followed by chemotherapy, (2) those who were first treated with chemotherapy and then followed by interval cytoreductive surgery, and (3) those who experienced a recurrence of ovarian cancer and underwent secondary cytoreductive surgery. The authors conclude that numerous retrospective analyses have established primary cytoreductive surgery as the standard of care for advanced ovarian cancer. Optimal cytoreductive surgery increases survival, but interval cytoreductive surgery does not lead to as lasting a diseasefree interval and survival as does upfront primary surgery. Secondary cytoreductive surgery has a role in the management of patients with platinum- sensitive disease. Several theoretical justifications support cytoreduction of tumor volume. There are host factors: Removing tumor might remove immunosuppression, tumor masses may deplete the host metabolically and interfere with bowel function, and large tumor masses have poor vascularity at the tumor's center, resulting in compromised drug delivery.[3] The firstorder kinetics concept of tumor biology suggests that a rapid exponential decrease in tumor size by excision permits elimination of the residuum by adjuvant therapy.[4] Theoretically, enhancement of chemosensitivity may occur by removing masses with a low growth fraction.[5] Finally, the famous Goldie-Coldman hypothesis posits that the greater the number of cells present, the greater the chance of developing subgroups of tumor clones that are resistant to chemotherapy.[6] Survival Dilemmas
Epithelial ovarian cancers constitute a heterogeneous group with striking variations in response to therapy. Well-established standard prognostic risk factors include grade, stage, age, and extent of surgical cytoreduction. However, we have all been mystified by patients who are long-term survivors and sometimes are even cured. There is nothing different about the phenotype of their cancer from that of patients who die in 18 months. Although the overall 5-year survival in advanced ovarian cancer has not changed much in the past decade, it is the subset of usually young women who, with aggressive surgical and chemotherapeutic management, survive to 5 years even with disease. The debate on surgical cytoreduction will never completely disappear because the mixed nature of patients, tumors, and surgeons will prevent a clean comparison of optimally cytoreduced and suboptimally cytoreduced patients. Several key issues fuel the debate. First, the level of training of the surgeon clearly affects the survival of patients.[7,8] This is not happy information for places where the medical or social structure encourages patients to stay locally for their care. Although chemotherapy has been tremendously effective, ovarian cancer remains a surgically managed disease at primary presentation. It is common to see recurrences in areas where previous surgery inadequately resected the disease. This occurs even in women who have gone into a clinical and radiologic remission and thus reinforces the need for upfront surgical resection. Tumor biology and how it affects both the actual surgical effort and the response to chemotherapy has been hotly discussed. That is, are those with more indolent cancers easier to cytoreduce than those with more aggressive disease?[9,10] Chemotherapy Considerations
In clinical practice, adjuvant chemotherapy is chosen for the sicker and older patients. There is the theoretical concern that neoadjuvant chemotherapy may select for chemotherapy-resistant tumor cell clones. Women with advanced ovarian cancer present with multiple organ system stresses. Ascites and malnutrition cause "third spacing" and prerenal failure, and these patients frequently have varying degrees of intestinal obstruction.[11] These significant medical and surgical problems need to be corrected before chemotherapy can be effectively and safely administered. When these problems are inadequately addressed, the likelihood of failed therapy with multiple organ system failure and sepsis is higher. Patients who have been surgically cytoreduced become much more resilient and are able to tolerate full-dose chemotherapy.[12] Conclusions
We continue to search for different molecular and genetic paradigms in which to understand differences in the behavior of epithelial ovarian cancer. Meanwhile, expert surgical management remains the mainstay of primary therapy for the disease.

Disclosures

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References

1. Griffiths CT: Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. Natl Cancer Inst Monogr 42:101-104, 1975.
2. McCreath WA, Chi DS: Surgical cytoreduction in ovarian cancer. Oncology 18:645-653, 2004.
3. Edmonson AH, Fleming TR, Decker DG, et al: Different chemotherapeutic sensitivities and host factors affecting prognosis in advanced ovarian carcinoma vs minimal residual disease. Cancer Treat Rep 63:241-247, 1979.
4. Mayo JG, Laster WR Jr, Andrews CM, et al: Success and failure in the treatment of solid tumors. III. “Cure” of metastatic Lewis lung carcinoma with methyl-CCNU (NSC-95441) and surgery-chemotherapy. Cancer Chemother Rep 56:183-195, 1972.
5. Le T, Krepart GV, Lotocki RJ, et al: Does debulking surgery improve survival in biologically aggressive ovarian carcinoma? Gynecol Oncol 67:208-214, 1997.
6. Goldie JH, Coldman AJ: A mathematical model for relating the drug sensitivity of tumours to their spontaneous mutation rate. Cancer Treat Rep 63:1727-1733, 1979.
7. Eisenkop SM, Spirtos NM, Montag TW, et al: The impact of subspecialty training on the management of advanced ovarian cancer. Gynecol Oncol 47:203-209, 1992.
8. Bristow RE, Tomacruz RS, Armstrong DK, et al: Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: A meta-analysis. J Clin Oncol 20:1248-1259, 2002.
9. Eisenkop SM, Spirtos NM, Friedman RL, et al: Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with advanced ovarian cancer: A prospective study. Gynecol Oncol 90:390-396, 2003.
10. Eisenkop SM, Spirtos NM: Procedures required to accomplish complete cytoreduction of ovarian cancer: Is there a correlation with “biological aggressiveness” and survival? Gynecol Oncol 82:435-441, 2001.
11. Castaldo TW, Petrilli ES, Ballon SC, et al: Intestinal operations in patients with ovarian carcinoma. Am J Obstet Gynecol 139:80-84, 1981.
12. Blythe JG, Wahl TP: Debulking surgery: Does it increase the quality of survival? Gynecol Oncol 14:396-408, 1982.
 
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