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Secondary Cytoreductive Surgery for Patients With Relapsed Epithelial Ovarian Carcinoma: Who Benefits?

Posted on: Friday, 22 October 2004, 03:00 CDT

Introduction:

The role of secondary cytoreductive surgery (SCR) in the management of women with recurrent ovarian cancer continues to he debated. In the current study, Zang et al. address the feasibility of SCR and its impact on survival in women with relapsed disease.

Methods:

* This prospective study was open between January 1998 and December 2001.

* Eligibility criteria: women with disease recurrence ≥ 3 months after completing primary therapy; ECOG performance status ≤ 2; patient consent; resectable disease as determined by two senior gynecologic surgeons.

* Exclusion criteria: parenchymal hepatic metastasis; major medical morbidities prohibiting a major surgical resection.

* One hundred and twenty-three eligible patients 'were targeted over a 4-year enrollment period'.

* Optimal cytoreduction was defined as surgery achieving residual disease ≤ 1 cm in largest diameter.

* Second-line chemotherapy was administered to all patients; this included a variety of options including paclitaxel, docetaxel, etoposide, ifosfamide, hexamethylmelamine, hydroxycamptothecine, gemcitabine, navelbine and re-treatment with either intravenous or intraperitoneal platinum-based regimens. Some patients with localized recurrences received external beam radiation.

* Survival analyzes were completed using life tables and the Kaplan-Meier method; stepwise Cox regression analysis was used to look at the prognostic influence of various factors.

Results:

* One hundred and seventeen patients were entered into the study.

* Median age was 53 years (range 20-78).

* Median progression-free interval (PFI) from completion of primary therapy was 15.4 months.

* Forty-six women (39.3%) had salvage chemotherapy prior to the SCR.

* At the time of surgery, the disease was noted to he localized to a solitary site in 33 patients (28.2%).

* At the completion of SCR, 11 patients (9.4%) had no gross residual tumor, 61 (52.1%) had residual disease ≤ 1 cm, and 45 (38.3%) had > 1 cm residual tumor.

* The success of surgery was significantly higher in the 33 women with localized recurrence (optimal SCR in 87.9% of those patients compared to 51.2% in patients with multifocal recurrent disease).

* The surgical morbidity was limited (7.7%) and there was no perioperativc mortality.

* There was a significant correlation hetween the outcome of SCR and survival. The 5-year survival rates by residual disease after SCR were as follows: 61.4% for patients left with no macroscopic tumor; 21.1% for those left with residual tumor ≤ 1 cm in largest diameter; and 4.5% for those left with residual tumors exceeding 1 cm.

* Survival data and regression analyzes identified the following factors to be associated with prolonged survival: solitary site of recurrence; optimal SCR; good ECOG (Eastern Cooperative Oncology Group) performance status (0 or 1); and > 6 cycles of salvage chemotherapy after SCR. Interestingly, survival was not significantly affected by the PFI.

Selected references:

Eisenkop SM, Firedman RL, Spirtos NM. The role of secondary cytoreductive surgery in the treatment of patients with recurrent epithelial ovarian carcinoma. Gancer 2000;88:144-53

Scarabelli C, Gallo A, Carbone A. Secondary cytoreductive surgery for patients with recurrent epithelial ovarian carcinoma. Gynecol Oncol 2001;83:504-12

Commentary:

A number of studies have been published addressing the role of secondary surgical cytoreduction (SCR) in the management of women with recurrent epithelial ovarian cancer. It has been hard to draw any definite conclusions because of the many limitations of the published literature. First, many of the studies are retrospective and thus can be flawed by a significant selection bias. Second, there is a significant heterogeneity in the patient population with respect to the progression-free interval after primary therapy and the type of salvage therapy used prior to and after secondary cytoreduction. Third, various surgical endpoints have been used for the survival analyzes. Some investigators have implied that optimal surgery means no gross residual disease, whereas others have used various cut-offs for the size of largest residual tumor, ranging from 0.5 to 2 cm. However, despite all these problems the existing data strongly suggest that women who are left with no residual disease after a SCR seem to reach a prolonged overall survival.

The study by Zang et al. is the third prospective study published in the past 5 years looking at the role of SCR. The study by Eisenkop reported on 114 consecutive patients who presented with recurrent ovarian cancer; 106 of those underwent SCR. Optimal cytoreduction, defined as residual disease < 0.5 cm, was achieved in 90 patients (85%); of those, 87 (82%) were left with no gross residual disease. The median survival of women left with any macroscopic residual disease was 19.3 months, compared to 44.4 months in patients left with no macroscopic disease. Scarabelli et al. evaluated 177 consecutive patients presenting with recurrent ovarian cancer, and decided to perform surgery on 149 of them. Optimal cytoreduction, defined as residual disease ≤ 1 cm, was achieved in 104 patients (70%); 53 (36%) patients had no macroscopic disease at the end of surgery. There was a significant survival advantage to women who had optimal surgery. The study by Zang et al. supports these conclusions regarding the impact of residual disease after SCR on patients' survival. The authors report other interesting findings. First, the extent of recurrent disease had the most significant impact on survival. Women with solitary recurrences tend to have the longest survival. Although this might be a reflection of tumor biology, one can argue that these are the patients who will benefit the most from an aggressive approach to salvage treatment, including a secondary tumor debulking. Second, the time to relapse after completion of PFI had no impact on prognosis. In the univariate analysis, women with PFI > 24 months had the longest median survival of 40 months after secondary cytoreduction. However, the impact of PFI on survival was lost in the multivariate analysis. The authors argue that patients who recur as early as 3 months after primary therapy might benefit from a salvage surgery.

Such a conclusion is hard to support in view of the small number of patients, the lack of data indicating how many of the patients were platinum-resistant and the fact that the median survival of women who recurred within 3-12 months was 18 months. To put that in perspective, the median survival of all their patients with suboptimal cytoreduction was 20 months.

Emerging data suggest that combination salvage chemotherapy provides a survival advantage over single agent chemotherapy. In the recently published ICON IV study, the combination of paclitaxel and platinum in the salvage setting resulted in a 5 month survival advantage compared to conventional platinum-based chemotherapy. These results need to be taken into account when discussing the options of salvage therapy for recurrent ovarian cancer. In the study by Zang et al., the number of salvage chemotherapy cycles was a predictor of survival. However, the heterogeneity of salvage chemotherapy regimens used precludes any analysis and conclusion with regard to the prognostic impact of the type and duration of salvage chemotherapy treatments.

The benefit of SCR is an important question and needs to be studied in a randomized trial that will prospectively enroll a sufficient number of patients. The emerging data on salvage combination chemotherapy also raises the question of whether there will be any benefit from combining salvage surgery with multi-agent chemotherapy. The Gynecologic Oncology Group is addressing this in their current trial, GOG protocol 213. Women presenting with recurrent ovarian cancer will first be randomized to chemotherapy versus surgery, followed by chemotherapy. There will be a secondary randomization between one of five platinum-based combination chemotherapy arms, and a control arm defined as single-agent carboplatin followed by a paclitaxel in a third-line setting. Hopefully, the results of this trial as well as an ongoing similar European study will shed some light as to the optimal management of recurrent ovarian cancer.

Zang RY, Li ZT, Tang J, Cheng X, Cai SM, Zhang ZY, Teng NN. Cancer 2004; 100:1152-61

Further reading:

Cantu MG, Buda A, Parma G, et al. Randomized controlled trial of single-agent paclitaxel versus cyclophosphamide, doxorubicin, and cisplatin in patients with recurrent ovarian cancer who responded to first-line platinum-based regimens. J Clin Oncol 2002;20:1232-7

Parmar MK, Ledermann JA, Columbo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO- OVAR-2.2 trial. The Lancet 2003;361:2099-107

Commentary by: Adnan Munkarah, MD, Wayne State University, Detroit, MI

Copyright CRC Press Jun 2004

Source: Women's Oncology Review

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