Interval Cytoreduction Surgery

Interval cytoreductive surgery was popularized in Europe in nonrandomized trials, which suggested that women who underwent initial surgery but were suboptimally cytoreduced should receive three cycles of chemotherapy, and if they responded to the chemotherapy, they should then be optimally surgically cytoreduced.[20-23] Patients who responded to chemotherapy and were then optimally cytoreduced to 1 cm or less residual disease had a prolonged survival compared to those who either could not be optimally cytoreduced at the interval cytoreductive surgery or had not undergone interval cytoreductive surgery. Patients who were reoperated on and had less than 1 cm disease on entry into the abdominal cavity did not appear to benefit from the second operation. However, the overall survival with this approach was not as good as the survival for patients who were optimally cytoreduced to ≤ 1 cm macroscopic disease at the initial surgery.[21]

Figure 3: Residual Disease and Survival in Patients With Ovarian Cancer—Influence of residual disease after cytoreductive surgery for recurrence on overall survival. CI = confidence interval; HR = hazard ratio; OS = overall survival; RD = residual disease after surgery for recurrence. Reprinted, with permission, from Harter P et al.[28]

EORTC Trial

A prospective randomized trial published in 1995 by the European Organization for the Research and Treatment of Cancer (EORTC) demonstrated an increase in both progression-free survival and overall survival for patients who were initially suboptimally cytoreduced to > 1 cm macroscopic residual disease but were then given three cycles of platinum-based chemotherapy and, if they responded, underwent interval cytoreduction to ≤ 1 cm residual disease.[24] Those who underwent interval cytoreduction received three additional cycles of chemotherapy. Patients in the control arm had undergone suboptimal cytoreduction (> 1 cm residual disease) followed by six cycles of the same chemotherapy (Table 2).

 

Table 2
Interval Cytoreductive Surgery in Advanced Ovarian Cancer
Features	EORTC Study[24]	GOG Study[25]
Eligible patients	319	424
Serous cancer	59%	76%
Stage IV	22%	6%
Chemotherapy	Cisplatin/cyclophosphamide	Cisplatin/paclitaxel
Median PFS Secondary surgery Chemotherapy only	18 mo 13 mo	12.5 mo 12.7 mo
Median overall survival Secondary surgery Chemotherapy only	26 mo 20 mo	36.2 mo 35.7 mo
EORTC = European Organisation for Research and Treatment of Cancer; GOG = Gynecologic Oncology Group; PFS = progression-free survival.

Once again, the patients who benefitted from interval surgical cytoreduction were those who initially responded to the chemotherapy but still had > 1 cm residual disease prior to the interval cytoreduction. No benefit was demonstrated if the patients failed to initially respond to the chemotherapy or if the disease found at the time of reexploration was > 1 cm maximum tumor diameter and could not be cytoreduced to < 1 cm residual disease.

GOG Trial

A subsequent GOG prospective randomized trial revealed no survival advantage when American gynecologic oncologists performed the initial suboptimal cytoreduction surgery and then, following three cycles of carboplatin and paclitaxel, attempted a second surgical cytoreduction followed by three additional cycles of chemotherapy.[25] The median overall survival for both the control arm (patients who underwent surgery followed by six cycles of chemotherapy) and the interval surgical cytoreduction arm was 36 months (Table 2). The GOG findings were consistent with GOG 111, which demonstrated that suboptimally cytoreduced patients have a median OS of 37 months.[26]

In contrast, the EORTC interval cytoreduction trial demonstrated a PFS survival of 18 months and an OS of 26 months.[24] The reason for the discrepancy in survival between the GOG and EORTC trials was that the GOG trial used carboplatin and paclitaxel as its standard therapy whereas the EORTC trial used carboplatin and cyclophosphamide—a regimen that is now recognized as inferior.[26]

Cytoreduction for Recurrent Disease

The role of cytoreductive surgery in the treatment of recurrent ovarian cancer is still being developed. Consensus in the literature supports aggressive cytoreduction for patients who have a prolonged disease-free survival following their initial diagnosis (12–18 months), solitary or a limited number of sites of recurrence identified by diagnostic imaging (2–5), and a good performance status (GOG 0–2).[27-36] When operating for recurrent ovarian cancer, complete tumor resection almost invariably is associated with a prolonged survival compared to leaving any residual disease (Table 3).

Table 3
Surgical Cytoreduction for Recurrent Ovarian Cancer: Median Survivals Based on Complete vs Incomplete Tumor Resection
			Median Survival
	Number of Patients	Complete Tumor Resection	Complete Tumor Resection	Incomplete Tumor Resection
Gronlund et al,[33] 2004	38	16 (42%)	51.8 mo	19.9 mo
Eisenkop et al,[31] 2000	106	87 (82.1%)	44.4 mo	19.3 mo
Zang et al,[32] 2004	117	11 (9.4%)	Not reached	26.0 mo (≤ 1 cm) 14.5 mo (>10)
Benedetti Panici et al,[36] 2007	47	37 (78.7)	61	19
Salani et al,[27] 2007	55	41 (74.5)	50	7.2
Harter et al,[28] 2006	267	124 (46.4)	45.2	19.7

One recent retrospective study of 57 patients with recurrent ovarian cancer reported that the three most important factors for overall survival by multivariate analysis were (1) a diagnosis-to-recurrence interval of ≤ 18 months (OS = 49 vs 3 months; P = .0013), (2) no microscopic tumor left after secondary cytoreduction (OS = 50 vs 7.2 months; P = .0001), and (3) one or two recurrence sites on diagnostic imaging studies (OS = 50 vs 12 months; P = .026).[27] The factors that make a patient most likely to benefit from secondary surgical cytoreduction are also the factors that make the patient most likely to benefit from secondary chemotherapy.

This article reviewed