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Originally published as JCO Early Release 10.1200/JCO.2005.09.922 on December 21 2004 © 2005 American Society of Clinical Oncology.
Perioperative Morbidity and the Rush to ChemotherapyWeinberg Cancer Institute, Franklin Square Hospital Center, Baltimore, MD Since the seminal study published by Griffiths1 over 30 years ago, it has been customary in the treatment of ovarian cancer to begin with a major surgical procedure that is designed both to stage the patient and to remove as much tumor bulk as possible. Some form of adjuvant chemotherapy then follows debulking surgery, except in patients with low-risk stage I disease. The study by Griffiths suggested that patients who underwent major tumor debulking had outcomes similar to patients who presented with low tumor bulk, and had outcomes significantly better than their counterparts, who presented with large volume tumor and did not, or could not, undergo debulking. It remains controversial as to whether the ability to debulk tumor, with its associated outcome improvement, is due to differential tumor biology or to differential surgical skill. More recently, neoadjuvant chemotherapy has been used based on the finding that it remains possible to perform major surgery following preoperative chemotherapy without any apparent increase in operative or postoperative morbidity. To date, no randomized trial has reported outcomes comparing adjuvant and neoadjuvant approaches. Debulking surgery typically includes total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, sampling of pelvic and para-aortic nodes, and major bowel resections with primary anastomosis or creation of an ostomy. Typical postoperative complications include development of deep venous thrombosis and embolic events, delays in return of bowel function, anastomotic leaks, and poor wound healing, particularly in those patients who are nutritionally deprived, which is common in advanced disease due to protein and calorie malnutrition and large-volume ascites containing non-nutritional proteins.
Gynecologic and medical oncologists have typically initiated chemotherapy as soon as feasible after postoperative recovery, and it is not uncommon for patients to have the first cycle of chemotherapy before discharge following debulking surgery. Some protocols even exclude patients who have chemotherapy initiated more than 4 to 6 weeks after debulking surgery. This rush to administer cytotoxic therapy is based on tumor growth and tumor kinetic models suggesting tumor kill is logarithmic and chemotherapy is most effective when tumor burden is low and tumor cells are in a synchronized growth phase. Additionally, randomized studies performed over 35 years ago, in which a single dose of thiotepa or a placebo was administered intraoperatively into the axillary vein of women undergoing modified radical mastectomy for breast cancer, demonstrated superior recurrence-free and overall survival for the treated group,2 especially in those patients with the greatest amount of tumor preoperatively (tumors
In ovarian cancer, one randomized trial explored the value of adding doxorubicin to the cisplatin and cyclophosphamide doublet in ovarian cancer patients (n = 349) who had undergone surgical debulking to an optimal volume ( A more recent publication from Flynn et al5 merged data from four studies of platinum (n = 472) combined with either cyclophosphamide or a taxane, and used univariate and multivariate analyses to evaluate the impact of interval between surgery and adjuvant chemotherapy on progression-free survival. Patients were divided into only two groups: those having chemotherapy within the first 3 weeks (n = 232) or those treated later (n = 240). There were significantly more patients with bulky residual disease in the short interval group (P = .006). There was no statistically significant difference in the two groups, although the trend was in favor of patients in whom chemotherapy was delayed until after the third week (hazard ratio = 0.84; P = .14). Other factors in the multivariate model included volume of residual disease, stage, and performance status; none of these were significant. One could surmise that patients left with bulky disease were started on chemotherapy earlier, in an attempt to chemically reduce the tumor burden, and that their poorer progression-free survival was simply a reflection of prognosis related to postoperative tumor volume. In a study published in this issue of the Journal of Clinical Oncology, Gaducci et al6 once again retrospectively examined, in a multicenter trial using modern taxane-based chemotherapy, the effect of interval between surgery and chemotherapy on both response and survival. Most clinical complete responders underwent second-look surgery. The patient population was typical for advanced ovarian cancer, with 44% having optimal debulking and 56% suboptimal debulking. Intervals between surgery and chemotherapy were divided into quartiles (< 11, 11-21, 22 to 31, and > 31 days). In contradistinction to the study by Flynn et al, 5 there was no trend by interval, debulking status, or other known prognostic variables. Attainment of complete response was related to residual disease and ascites, but not interval. Survival was related to residual disease, stage, and ascites, but not to interval, age, histologic grade, or histologic type. Thus, it becomes very difficult to justify a rush to chemotherapy in the name of improved outcome. Patients often need time to recover bowel function, heal anastomoses, reverse protein and calorie malnutrition, and psychologically accept their diagnosis and need for subsequent cytotoxic therapy. There are no publications in ovarian cancer dealing with the interval between surgery and chemotherapy and its association with perioperative morbidity or mortality. In a recently completed international trial of five different cytotoxic regimens in advanced ovarian cancer, overall perioperative morbidity and mortality were uncommon and unrelated to the cytotoxic regimen used. What was noted, however, was significant perioperative morbidity and mortality in elderly patients and in patients who underwent major bowel resections with chemotherapy initiated during the immediate perioperative period (unpublished data). The paper presented in this volume of the Journal of Clinical Oncology, although weakened somewhat by its retrospective nature, should give us all reason to believe that it is not necessary to initiate adjuvant chemotherapy before the patient has fully recovered from her operative intervention. In the unfit patient, the elderly patient, and the patient who had major bowel resection and primary anastomosis, delaying the onset of chemotherapy will have significantly less impact on outcome, it would seem, than tumor-specific biologic factors over which the clinician has no control. Waiting to initiate adjuvant therapy, which is under physician control, seems to be prudent based on these data. This is frequently known as clinical judgment. Good clinical judgment may even improve tolerance to chemotherapy, improve quality of life while undergoing therapy, and avoid additional admissions for febrile neutropenia or anastomotic leaks, while not negatively affecting response or survival. In practice, surgeons and medical oncologists are implored to temper their enthusiasm to rush to adjuvant chemotherapy, and clinical trials should not be designed to jeopardize a patient's entry if there is delayed recovery from debulking surgery. Author's Disclosures of Potential Conflicts of Interest The following author or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: William P. McGuire III, Amgen, Unither Pharmaceuticals. Honoraria: William P. McGuire III, Amgen, GlaxoSmithKline. Research Funding: William P. McGuire III, GlaxoSmithKline. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration form and the "Disclosures of Potential Conflicts" of Interest section of Information for Contributors found in the front of every issue. 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. Fisher B, Slack N, Katrych D, et al: Ten year follow-up results of patients with carcinoma of the breast in a co-operative clinical trial evaluating surgical adjuvant chemotherapy. Surg Gynecol Obstet 140:528-534, 1975[Medline] 3. Buzdar AU, Smith TL, Powell KC, et al: Effect of timing of initiation of adjuvant chemotherapy on disease-free survival in breast cancer. Breast Cancer Res Treat 2:163-169, 1982[CrossRef][Medline] 4. Omura GA, Bundy BN, Berek JA, et al: Randomized trial of cyclophosphamide plus cisplatin with or without doxorubicin in ovarian carcinoma: A Gynecologic Oncology Group study. J Clin Oncol 7:457-465, 1989[Abstract] 5. Flynn PM, Paul J, Cruickshank DJ, et al: Does the interval from primary surgery to chemotherapy influence progression-free survival in ovarian cancer? Gynecol Oncol 86:354-357, 2002[CrossRef][Medline]
6. Gaducci A, Sartori E, Landoni F, et al: Relationship between time interval from primary surgery to the start of taxane/platinum based chemotherapy and clinical outcome of 313 patients with advanced epithelial ovarian cancer; results of a multicenter retrospective Italian study. J Clin Oncol 23:751-758, 2005
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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3 cm and those patients with 
2 cm). In this trial, the interval between surgery and the initiation of adjuvant chemotherapy was predictive of survival in a multivariate analysis.
