Perioperative Morbidity and the Rush to Chemotherapy

Abstract

Since the seminal study published by Griffiths 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, especially in those patients with the greatest amount of tumor preoperatively (tumors 3 cm and those patients with 4 involved axillary nodes). A more modern study, however, showed no effect of interval between surgery and adjuvant chemotherapy in patients treated with fluorouracil, doxorubicin, and cyclophosphamide chemotherapy for breast cancer. 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 ( 2 cm). In this trial, the interval between surgery and the initiation of adjuvant chemotherapy was predictive of survival in a multivariate analysis. Other factors predictive of survival were younger age, non–clear-cell histology, and lower-volume residual disease after debulking surgery. With the hazard ratio set at 1.0 for a 1-week interval between surgery and chemotherapy, hazard ratios for 2, 3, 4, 5, and 6 weeks were 1.2, 1.4, 1.5, 1.7, and 1.8, respectively. Time interval to initiation of chemotherapy was also the least powerful predictor of survival. Finally, the study did not explore reasons for the delays in initiation of chemotherapy in some patients, and one might therefore wonder if patients with more extensive surgery or nutritional deprivation had more postoperative complications, slower recovery of bowel function, and subsequent recovery to an acceptable performance status to allow patients to proceed with chemotherapy. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 4 FEBRUARY 1 2005