Doxorubicin + Cisplatin vs Doxorubicin + 24-h Paclitaxel + Filgrastim in Endometrial Carcinoma

Abstract & Commentary

Synopsis: Doxorubicin and 24-h paclitaxel plus filgrastim was not superior to doxorubicin and cisplatin in terms of response, PFS or survival in advanced endometrial cancer.

Source: Fleming G, et al. Ann Oncol. 2004;15: 1173-1178.

Most patients with endometrial cancer present with early stage disease and are cured with local therapy. However, the prognosis for patients with inoperable stage III or IV, or recurrent, endometrial cancer remains poor. Prior to the availability of taxanes, anthracyclines and platinum compounds represented the most active cytotoxic agents, each producing single-agent responses in the range of 20-30%. In 1993, the Gynecologic Oncology Group (GOG) reported 45% of patients responding (including 22% complete responses) to the combination of 60 mg/m2 doxorubicin plus 50 mg/m2 cisplatin in advanced or recurrent endometrial carcinoma. This was significantly superior in a randomized trial to the 27% response obtained from doxorubicin alone.

Overall survival (OS), however, was not significantly better in the combination arm, with a median of 9 months. Similarly, a randomized phase II/III trial conducted by the European Organization for the Research and Treatment of Cancer/Gynecologic Cancer Cooperative Group reported 43% of patients responding using a doxorubicin/cisplatin doublet vs 17% responding using doxorubicin only. Survival was not significantly superior in the combination arm (9 vs 7 months). The GOG evaluated single-agent paclitaxel 250 mg/m2 as a 24-h continuous infusion with granulocyte colony-stimulating factor (G-CSF) support in previously untreated patients.

Overall, 36% of patients responded, including 14% who experienced complete responses. The current study was performed to determine whether 24-h paclitaxel plus doxorubicin and filgrastim was superior to cisplatin plus doxorubicin in patients with endometrial cancer with respect to response, progression-free survival (PFS) and OS.

Comment by Stuart M. Lichtman, MD

Patients with measure stage III/IV endometrial cancer were randomized to one of two treatment arms. Arm 1, the standard treatment arm, consisted of doxorubicin 60 mg/m2 intravenously followed immediately by cisplatin 50 mg/m2 IV. Patients who had received prior pelvic radiotherapy or who were older than age 65 were to receive reduced starting doses of doxorubicin 45 mg/m2 and cisplatin 40 mg/m2. The treatment plan for arm 2, the experimental treatment arm, consisted of 50 mg/m2 of doxorubicin on day 1 administered by IV bolus or brief infusion followed 4 hours later by paclitaxel at a dose of 150 mg/m2 administered as a 24-h infusion.

Filgrastim was to be given subcutaneously at a dose of 5 mg/kg on a daily basis, starting on day 3 of each cycle and continuing until day 12 or until the white blood cell count (WBC) was at least 10,000/mm3 (post nadir). Patients who had received prior pelvic radiotherapy or who were older than age 65 years were to receive reduced starting doses of doxorubicin 40 mg/m2 and paclitaxel 120 mg/m2. Treatment was continued for 7 cycles, or until disease progression or unacceptable toxicity necessitated therapy discontinuation. Doses were reduced for grade 3 or 4 WBC, granulocyte or platelet toxicity, and could be re-escalated if subsequent cycles produced toxicity of no more than grade 1. Filgrastim was to be added for patients on arm 1 who had persistent grade 4 hematological toxicity or treatment delays despite dose reduction. Response was measured according to standard GOG criteria. Three hundred and twenty-eight patients with primary stage III, stage IV or recurrent endometrial carcinoma were enrolled and 317 patients are included in the survival analysis (157 on arm 1, and 160 on arm 2). Three hundred and thirteen patients received at least one cycle of therapy and were evaluable for toxicity (156 on arm 1 and 157 on arm 2).

Patient characteristics, with the exception of age at entry, were well balanced between the arms. Arm 2 had more patients older than 61 years (69% vs 58%). Sixty-nine percent of patients on arm 1 and 64% of patients on arm 2 received an initial dose reduction because of prior pelvic radiation and/or age older than 65 years. Seventy patients on arm 1 (45%) and 78 patients on arm 2 (49%) received all 7 cycles of therapy. Median follow-up for those alive at last contact was 61 months. No improvement in response was observed for the experimental arm. The overall response rate was 40% in arm 1 and 43% in arm 2. The common odds of response ratio in arm 2 relative to arm 1 stratified by PS was 1.12. Patients with prior pelvic radiotherapy were overall less likely to respond (35%, both arms combined) than were patients with no prior pelvic radiotherapy (48%, both arms combined). Statistically significant factors related to poorer response included PS of 2, prior radiotherapy, liver metastases, and disease that was recurrent after presentation at an earlier stage. There were no significant differences in PFS or OS between the 2 treatment arms. Median PFS was 7.2 months on arm 1 and 6 months on arm 2. Adjusting for PS, the hazard ratio relative to arm 1 is 1.01. Median OS was 12.6 months on arm 1 and 13.6 months on arm 2. Adjusting for PS, the death hazard ratio relative to arm 1 is 1.00. Statistically significant factors predicting for longer OS include good PS, grade 1 histology, extrapelvic disease other than lung and abdomen but including the liver, and months to first recurrence.

Hormonal therapy can produce responses in a minority of patients with advanced endometrial cancer. However, most endometrial cancers will not respond to hormonal treatment, and those that do will eventually become refractory. The GOG has been systematically evaluating new cytotoxic agents for activity in endometrial cancer, and phase II data suggest that paclitaxel is among the most active agents ever tested. It was hoped that inclusion of paclitaxel in a first-line chemotherapy regimen would both improve response rates (and, by association, symptoms) and prolong patient survival. However, substituting paclitaxel for cisplatin in a first-line chemotherapy regimen did not positively effect response rates, PFS or OS. The main predictors of poorer outcome were performance status and prior radiotherapy. Older age was not an adverse prognostic factor. The study design called for dose reduction based on age and prior radiotherapy. Dose reductions based on age alone and not based on other factors such as comorbidity, endorgan dysfunction, poor performance or functional status are rarely necessary. In fact, these arbitrary dose modifications, which in this study was the majority of patients may have contributed to reduced response rates. Trials using a 3-h paclitaxel infusion have been shown to have substantial activity in endometrial cancer and shorter, less myelotoxic infusions have replaced more prolonged infusions in treating most tumor types. Other investigators have combined 3-h paclitaxel with carboplatin, which is less neurotoxic than cisplatin and also has activity in endometrial cancer;2 preliminary results of that combination are also encouraging.3 Conclusions from this trial can include that the lack of improvement in the paclitaxel + doxorubicin arm may be due to the fact that cisplatin or carboplatin may be essential in the therapy of endometrial cancer. The latter hypothesis is supported by a very recent trial.4

The benefit seen in prior trials with paclitaxel may have been due to factors such as patient selection. In terms of other therapy, the role of adjuvant radiation therapy has been defined much more clearly in recent years, at least for patients with stage I and very early stage II disease. Pelvic radiation therapy dramatically reduced the risk of locoregional recurrence in three randomized controlled trials. None of these trials revealed a significantly beneficial effect of radiotherapy on survival. The adjuvant medical therapy of endometrial cancer remains poorly investigated.

A systematic review and meta-analysis of the Cochrane Collaboration revealed that the adjuvant use of progestational agents may indeed be dangerous. They do not significantly reduce the risk of recurrence and endometrial cancer-related death, but significantly increase the risk of non-cancer-related death. Numerous small trials have investigated the efficacy of adjuvant chemotherapy in endometrial cancer, but were not adequately powered to detect a difference in survival.5 Adjuvant chemotherapy with doxorubicin and cisplatin has been compared with whole abdominal radiation therapy in stage III and IV disease, and chemotherapy turned out to be superior to radiotherapy with regards to progression-free (hazard ratio, 0.81) and overall survival (hazard ratio, 0.71; P < 0.05). The combination of doxorubicin and cisplatin is considered standard therapy based upon 2 trials that revealed a very moderate advantage of the combination over single drug doxorubicin, despite the greater toxicity experienced with the combination.

References

1. Fleming GF, et al. Ann Oncol. 2004;15(8):1173-1178.

2. Burke TW, et al. Gynecol Oncol. 1993;51(3):397-400.

3. Dimopoulos MA, et al. Gynecol Oncol. 2000;78(1): 52-57.

4. Fleming GF, et al. J Clin Oncol. 2004;22(11): 2159-2166.

5. Steer C, Harper P. Best Pract Res Clin Obstet Gynaecol. 2001;15(3):447-467.

Stuart M. Lichtman, MD, FACP, Associate Professor of Medicine, NYU School of Medicine, Division of Oncology; Don Monti Division of Medical Oncology, North Shore University Hospital, Manhasset, NY, is on the Editorial Board of Clinical Oncology Alert.