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Surgical Cytoreduction in Ovarian Cancer

Surgical Cytoreduction in Ovarian Cancer

I would like to compliment the authors on their comprehensive review of cytoreductive surgery for ovarian cancer. However, some of their interpretation of the literature warrants amplification, and some conclusions merit presentation of an alternative perspective. Presurgical Tumor Burden
Understandably, "optimal" cytoreduction is more easily accomplished for small tumor burdens than large ones. However, as indicated in the review, ovarian cancer with extensive intra-abdominal disease is suggested to have a natural history that is unalterable due to "tumor biology," even if "optimal" cytoreduction is achieved.[1-4] Unfortunately, the literature correlating the extent of intra-abdominal disease present before cytoreduction with subsequent survival has flaws that Drs. McCreath and Chi have not addressed. As noted in the review, Hoskins et al reported a better median survival for patients cytoreduced to ≤ 1 cm of residual disease if the extrapelvic disease was ≤ 1 cm in largest dimension before cytoreduction than for patients with extrapelvic disease > 1 cm in largest dimension before cytoreduction, and concluded that innate biologic properties of the disease, as manifested by the extent of intra-abdominal tumor burden, may play a greater role in determining prognosis than treatment.[2] However, the percentage of patients in each group with excision of all visible disease was not reported. All visible disease was probably excised in a higher percentage of those with small-volume disease before surgery than of those with extensive disease to resect. Because excision of all visible disease has a more significant influence on survival than an "optimal" outcome of ≤ 1 cm residual disease, as reported by numerous investigators, then stratification by any parameter producing subgroups with dissimilar cytoreductive outcomes cannot produce equivalent survival.[5-8] Hence, the superior survival noted for patients with small-volume disease before surgery probably reflects more complete cytoreduction within that group rather than differences in tumor biology. Our group recently reported a prospective investigation in 408 patients with stage IIIC epithelial ovarian cancer for whom a ranking system was developed to quantify the extent of intra-abdominal disease at multiple locations before cytoreduction.[7] Cytoreduction to a visibly diseasefree outcome had a more significant influence on survival (P = .001) than the extent of metastatic disease present before surgery (P = .05). Although "aggressive" or unfavorable tumor biology, as defined by a diminished possibility of significantly altering the natural history of the disease by treatment, may play a more significant role in determining survival than the operative outcome for some patients, the extent of intra-abdominal disease before surgery does not correlate with tumor biology predictably enough to influence treatment strategies.[7] Optimal Cytoreduction
The authors acknowledge a range of criteria to define optimal cytoreduction in the literature and indicate that the Gynecologic Oncology Group defines this parameter as ≤ 1 cm of residual disease. However, little insight is given as to why specific thresholds are used to define optimal cytoreduction by different individuals. In all probability, these different criteria are used as a result of personal beliefs about the feasibility of achieving specific operative outcomes and traditional training, rather than correlation of operative outcomes with survival.[9] Clearly, a visibly disease-free operative outcome is associated with the highest probability of long-term survival or cure, has been shown to be achievable for the majority of patients with advanced-stage disease, and should probably be used to define optimal cytoreduction in the future.[5-8,10] Efforts should be made to acquire and use all available techniques to achieve complete cytoreduction primarily, as it is feasible.[7,10] Neoadjuvant Chemotherapy
The authors note the purpose of neoadjuvant chemotherapy to be reduction of the extent of intraabdominal disease before interval cytoreductive surgery, thus diminishing morbidity and facilitating "optimal" cytoreduction by reducing the extent of surgery required. They acknowledge that overall median survival following neoadjuvant chemotherapy and interval surgery does not approach the median survival achieved with primary surgery and adjunctive chemotherapy. Indeed, throughout the cytoreductive literature, patients with advanced epithelial ovarian cancer whose macroscopic disease is completely resected before chemotherapy, as well as those with ≤ 1 cm of residual disease, are reported to have better median and 5-year survivals than patients with equivalent operative outcomes after interval cytoreduction following neoadjuvant chemotherapy.[5-8,11-13] A theoretical disadvantage associated with neoadjuvant chemotherapy is the possibility of metastatic disease developing drug resistance during exposure to cytotoxic agents. Hence, residual disease after interval cytoreductive surgery may have an increased probability of resistance to chemotherapy compared to residual disease after primary cytoreductive surgery. Although available data may justify neoadjuvant chemotherapy in patients with absolute contraindications to surgery and findings that conclusively preclude complete or optimal cytoreduction, correlation of specific radiographic and/or laparoscopic observations with primary cytoreductive outcomes has undergone minimal investigation. Given the significant variation in both the ability to perform specific procedures described to facilitate cytoreduction and opinion concerning applicability of the procedures among gynecologic oncologists, it is possible that the probability of complete or optimal primary cytoreduction is more significantly influenced by the operating physician than by any specific radiographic or laparoscopic finding.[9] In light of the fact that reports of neoadjuvant chemotherapy and interval cytoreduction have not duplicated the more favorable outcomes of primary cytoreductive surgery and adjunctive chemotherapy, the appropriateness of undertaking a phase III trial comparing the outcomes of neoadjuvant chemotherapy/interval cytoreduction to those achieved with primary cytoreductive surgery/adjunctive chemotherapy remains questionable. Finally, because patients who undergo both complete primary and interval cytoreduction achieve a better survival than corresponding patients with small-volume (≤ 1-2 cm) visible residual disease following either strategy, any prospective investigation without a visibly disease-free surgical objective may not determine the most efficacious treatment strategy with acceptable morbidity.[5-8,11-13] Surgery at Expert Centers
McCreath and Chi summarize the status of cytoreductive surgery admirably but indicate that the extent of surgery necessary during cytoreductive operations justifies performing the procedures at "expert centers." Although such an idealistic recommendation may be politically correct, suggestions such as this one distract attention from the fundamental issue of the importance of involving a gynecologic oncologist in the care of all women with genital cancers, and ovarian cancer in particular. Available data indicate that the treating physician is more important to the outcome than the institution.[5-7,9,10,14] "Private practitioners" and "academicians" should cooperate as a team to facilitate the treatment of all women with ovarian cancer by gynecologic oncologists.

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. Covens AL: A critique of surgical cytoreduction in advanced ovarian cancer. Gynecol Oncol 78:269-274, 2000.
2. Hoskins WJ, Bundy BN, Thigpen JT, et al: The influence of cytoreductive surgery on recurrence- free interval and survival in small-volume stage III epithelial ovarian cancer: A Gynecologic Oncology Group study. Gynecol Oncol 47:159-166, 1992.
3. Potter ME, Partridge EE, Hatch KD, et al: Primary surgical therapy for ovarian cancer: How much and when. Gynecol Oncol 40:195-200, 1991.
4. Jaeger W, Ackermann S, Kessler H, et al: The effect of bowel resection on survival in advanced epithelial ovarian cancer. Gynecol Oncol 83:286-291, 2001.
5. Naik R, Nordin A, Cross PA, et al: Complete cytoreduction: Is epithelial ovarian cancer confined to the pelvis biologically different from bulky abdominal disease? Gynecol Oncol 78:176-180, 2000.
6. Le T, Krepart GV, Lotocki RJ, et al: Does debulking surgery improve survival in biologically aggressive ovarian cancer? Gynecol Oncol 67:208-214, 1997.
7. 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.
8. 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.
9. Eisenkop SM, Spirtos NM: What are the current surgical objectives, strategies, and technical capabilities of gynecologic oncologists treating advanced epithelial ovarian cancer? Gynecol Oncol 82:489-497, 2001.
10. Eisenkop SM, Friedman RL, Wang HT: Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: A prospective study. Gynecol Oncol 69:103-108, 1998.
11. Schwartz PE, Thomas JR, Chambers JT, et al: Neoadjuvant chemotherapy for advanced ovarian cancer: Long-term survival. Gynecol Oncol 72:93-99, 1999.
12. Kuhn W, Rutke S, Spathe K, et al: Neoadjuvant chemotherapy followed by tumor debulking prolongs survival for patients with poor prognosis International Federation of Gynecology and Obstetrics stage IIIC ovarian carcinoma. Cancer 92:2585-2591, 2001.
13. Mazzeo F, Berliere M, Kerger J, et al: Neoadjuvant chemotherapy followed by surgery and chemotherapy in patients with primarily unresectable, advanced-stage ovarian cancer. Gynecol Oncol 90:163-169, 2003.
14. 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.
 
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