Objective
We evaluated association of prognosis of endometrial carcinoma patients and treatment-free intervals (TFIs).
Study Design
We compared the effectiveness of second-line chemotherapy performed for patients with TFIs of 6-12 months and 12 or more months following a first-line chemotherapy based on taxane (paclitaxel) and carboplatin, with or without the anthracycline (TC).
Results
Progression-free and overall survivals were significantly shorter in patients with TFIs of 6-12 months than those with TFIs of 12 or more months. Among the patients who received similar second-line chemotherapy, response rates of 15 patients with TFIs of 12 or more months and 7 patients with TFIs of 6-12 months were 67% and 43%, respectively. Progression-free survival was significantly worse in those with TFIs of 6-12 months (median, 7 months) than those with TFIs of 12 or more months (median, 12 months).
Conclusion
Our small retrospective analysis suggests that recurrent endometrial carcinomas with TFIs of 6-12 months can be regarded as being partially sensitive to TC-based chemotherapy.
Endometrial carcinoma is the fourth most common cancer of women in the United States, and its incidence has been increasing steadily during the last 3 decades. The prognosis for early-stage endometrial carcinomas is often extremely good; however, it remains extremely difficult to completely cure the more advanced and the recurrent cases. Irradiation has been performed as the standard postoperative adjuvant therapy for cases with obvious risk factors for recurrence and for almost all advanced cases. Recently, systemic chemotherapy has begun to be used as an adjuvant therapy for advanced cases because it has been reported to significantly improve the prognosis of these cases.
Like endometrial cancer, ovarian carcinoma is also common in the United States. The gold standard of therapy for ovarian carcinomas includes aggressive cytoreductive surgery coupled with chemotherapy. The significant effect of the surgical debulking step for ovarian carcinomas has been supported by the subsequent high sensitivity of any remaining tumor to chemotherapy. The length of the treatment-free interval (TFI) before tumor recurrence has been demonstrated to be a strong indicator for the likely response to the application of a second-line chemotherapy for the ovarian carcinomas. Those relapsing within 6 months of the end of first-line treatment often had disease that was likely to be highly resistant to the original first-line drugs and also usually had a low response rate to other second-line chemotherapies.
By contrast, patients with TFIs of 6 or more months had a higher chance of responding well, either to a rechallenge with the platinum-based first-line treatment (defined as platinum sensitive) or to other drugs. Among them, those with a TFI of 6-12 months, although considered as partially sensitive cases, still exhibited a relatively worse response to second-line chemotherapy using carboplatin (after a standard first-line combination chemotherapy using paclitaxel and carboplatin [TC]) than those with a TFI of 12 or more months. For those ovarian carcinoma patients with a 6-12 month TFI after the first-line TC therapy, a combination chemotherapy of pegylated liposomal doxorubicin and carboplatin was shown to provide a better prognosis.
Recently, the effectiveness of similar types of chemotherapy for advanced endometrial cancer cases, using combinations of platinum, taxane, and adriamycin, have been reported. We, and others, have demonstrated the beneficial role that cytoreductive surgery has in these difficult cases. Moreover, we have demonstrated that a differential TFI of less than 6 or 6 or more months was significantly associated with the predictable response to second-line chemotherapy and survival prognosis.
In our current study, the response to second-line chemotherapy, after a failure of a first-line chemotherapy of platinum and taxane (with or without adriamycin) in patients with a TFI of 6-12 months was compared with those with a TFI of 12 or more months to evaluate whether the patients with the shorter time to recurrence were able to be considered partially sensitive to chemotherapy.
Materials and Methods
Patients
All patients in the present study were diagnosed within the Departments of Obstetrics and Gynecology of the Osaka University and the Osaka Rosai Hospitals of Osaka (Japan) as having a recurrent endometrial carcinoma. Our departments used either a monthly delivered combination of taxane (paclitaxel) and platinum (carboplatin) with or without the anthracycline, epirubicin (TEC or TC, respectively) or a weekly administered TC regimen as a first-line adjuvant therapy for resected endometrial carcinomas and also as the first-line salvage-therapy for unresected and recurrent diseases.
In the first-line TEC treatment, paclitaxel (150 mg/m 2 ), carboplatin (area under the curve [AUC] 4), and epirubicin (50 mg/m 2 ) were administered intravenously every 3-4 weeks. The dose of chemotherapy drugs appropriate for our Japanese population was determined in phase I/II studies we had previously conducted (submitted). In the monthly TC therapy, paclitaxel (175 mg/m 2 ) and carboplatin (AUC 5) were administered intravenously every 3-4 weeks, based on published protocols. In the weekly TC regimen, paclitaxel (80 mg/m 2 ) and carboplatin (AUC 2) were administered intravenously on days 1, 8, and 15 on a 4 week cycle. We will describe both the monthly administered and weekly administered TC regimen as TC therapy in the present report; the TEC and TC regimens will be called the TC-based regimen.
Patients were enrolled in this study after providing their written informed consent. Patients were recruited if they were treated by a second-line chemotherapy for their recurrent disease, after first having an initial first-line adjuvant or salvage TEC or TC therapy. All the patients had measurable disease equal to or larger than 10 mm by a computerized tomography (CT) scan. The diseases were observed in the abdominal cavity in 24 cases (83%), retroperitoneal lymph nodes in 16 cases (55%), and other distant tissues including lung and supraclavicular and inguinal lymph nodes in 10 cases (34%).
A regimen of a second-line chemotherapy was determined by an informed choice of the patients in this retrospective study. The clinicopathological features of these cases, including the age of the patient, the histology and initial stage of the disease, and the regimen of the first and second-line chemotherapies, were retrospectively reviewed utilizing their clinical records, including physical examination notes, radiological reports, operative records, and histopathology reports. The histological diagnoses were made by authorized pathologists from the Departments of Pathology of the Osaka University and the Osaka Rosai Hospitals.
Methods
The tumors were assessed with a helical CT scan at baseline and every 3 treatment courses thereafter. Previously described standard criteria from the World Health Organization and others were used to evaluate the therapeutic effect of the second-line chemotherapy. A complete response (CR) was defined as the disappearance of all known disease, determined by 2 observations not less than 4 weeks apart. Partial response (PR) was defined as a 50% or more reduction in the summed products of the 2 largest perpendicular dimensions of bidimensionally measurable lesions, for at least 4 weeks. Stable disease (SD) was defined as a less than 50% decrease, or a less than 25% increase, of tumor size, with no new detectable lesions. Progressive disease (PD) was defined as a greater than 25% increase in tumor size or the appearance of new lesions.
Progression-free survival (PFS) was measured from the date of the last administration of chemotherapy to the date of the radiologic or pathologic relapse or to the date of the last follow-up. Overall survival (OS) was defined as the period from the start of chemotherapy to the patient’s disease-specific death or the date of the last follow-up, as previously described. The TFI was defined as the period between the last administration of first-line chemotherapy and the initiation of the second-line chemotherapy, as previously described.
As second-line chemotherapy, some patients received TEC or TC, including weekly TC, and others were given docetaxel (30 mg/m 2 ) and CPT-11 (60 mg/m 2 , irinotecan) (docetaxel plus CPT-11) on days 1 and 8, on a 3-4 week cycle, or daily oral medroxyprogesterone acetate (MPA) (400-600 mg/day). The dose and schedule of administration of docetaxel plus CPT-11 appropriate for our Japanese population was determined in our previous phase I/II study (to be described in detail elsewhere). We define the second-line chemotherapy after the first-line TEC or TC therapy using TEC or TC as a similar regimen to the first-line chemotherapy in the present study.
Statistical analysis of effect of second-line chemotherapy
The association of TFI with clinical characteristics was analyzed by Fisher’s exact test. The association between sensitivity to second-line chemotherapy and TFI was analyzed by Fisher’s exact test. PFS and OS curves determined by a TFI were constructed using the Kaplan-Meier method and were evaluated for statistical significance by the log-rank test. The multivariate Cox proportional hazards model was used to calculate the significant factors contributing to OS after second-line chemotherapy. Results were considered to be significant when the P value was less than .05.
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