Uterine carcinosarcoma (UCS) is a neoplasm composed of malignant-appearing epithelial and mesenchymal elements.1 Although they can arise in any genital organ, they are found most frequently in the uterus, where they represent less than 4% of malignant neoplasms.2
Uterine carcinosarcomas are increasingly considered to be endometrial carcinomas that demonstrate sarcomatoid differentiation.3–6 They are histologically heterogeneous and clinically aggressive neoplasms. The sarcomatous component may be composed of homologous or heterologous tissue.1 Stage of disease seems to be the most important prognostic factor in UCS.7,8 Clinicopathologic features associated with worse outcome in early-stage UCS include deep myometrial invasion, lymphovascular space involvement, histology of the carcinomatous component, and presence of heterologous elements.9–11 A recent retrospective study of patients with surgically staged stage I UCS showed that the presence of heterologous sarcomatous elements was a strong negative prognostic factor.12
In a prospective study by the Gynecologic Oncology Group, 53% of patients with stage I to stage II UCS recurred within 5 years of initial therapy.13 This poor long-term recurrence-free interval contrasts with that of other high-grade endometrial cancers, where 5-year survival in stage I disease is approximately 80% or better. Additional studies have confirmed recurrence rates of 53% to 56%, most of which include an extrapelvic site.14,15 Five-year disease-free survival for advanced-stage UCS is dismal: 13% for stage III and 0% for stage IV disease.16,17
A series of Gynecologic Oncology Group trials have identified active agents for UCS. High objective response rates were reported for cisplatin (RR, 28%–42%), ifosfamide (RR, 29%–36%), paclitaxel (RR, 18%), and doxorubicin (RR, 10%–25%).18–20 ,21–23 Studies of adjuvant therapy have shown that adjuvant chemotherapy is favored over whole abdominal radiation.24 Combination chemotherapy with paclitaxel plus ifosfamide increased survival compared to ifosfamide alone,25 and paclitaxel-carboplatin achieved high objective response rates as first-line therapy in patients with measurable disease.17
Whereas these studies have helped outline chemotherapy approaches for UCS as a group, it is not known whether patients with UCS in which the sarcomatous portion shows rhabdomyosarcoma (RMS) differentiation have similar treatment outcomes as those without RMS differentiation. We have previously retrospectively investigated outcomes of chemotherapy-based versus radiation-only adjuvant treatment for completely resected stage I to stage IV UCS, but that study excluded patients with UCS with RMS differentiation. There are no data that suggest that treating the predominant tumor component (ie, RMS, when present) is preferable to standard therapy.26–28
MATERIALS AND METHODS
A waiver of authorization was approved by the Memorial Sloan-Kettering Cancer Center (MSKCC) institutional review board committee before conducting this retrospective study.
Memorial Sloan-Kettering Cancer Center electronic medical records from 1990 to 2012 were reviewed for patient’s age, diagnosis date, type of primary surgery, residual disease at completion of primary surgery, stage based on International Federation of Gynecology and Obstetrics 2009 staging criteria, treatment (chemotherapy and radiation therapy), dates of progression and death, site(s) of first recurrence, and toxic adverse effects. Previously untreated patients with completely resected stage I to stage IV UCS with RMS differentiation were eligible for inclusion in the analysis. Patients had to have undergone total abdominal hysterectomy, bilateral salpingo-oophorectomy, and maximal resection of all gross intra-abdominal and pelvic disease. Treatment had to have been initiated within 8 weeks after the initial surgery.
Patients had to have received either adjuvant chemotherapy with or without pelvic radiation therapy (RT), or pelvic RT alone, to be included. Both groups may have also received intravaginal brachytherapy (IVRT) as part of adjuvant therapy. All histologic diagnoses were confirmed by an MSKCC gynecologic pathologist.
The patients were categorized into 2 groups: chemotherapy with or without pelvic RT, or pelvic RT alone. Stage groups were dichotomized as 2009 International Federation of Gynecology and Obstetrics stages I and II or stages III and IV.
Sites of recurrence were classified as abdomen, bone, brain, lung, mediastinal lymph node, pelvic lymph node, pelvis, and vagina. Patients with multiple sites of recurrence were counted once for each site. Adverse events of treatment were graded based on the Common Terminology Criteria of Adverse Events version 4.0.
Overall survival was defined as the time from the surgery date to either the date of death for those patients who died or the last follow-up date for those who were alive. Progression-free survival (PFS) was defined as the time from the surgery date to either the progression date or the date of death or the last follow-up, whichever occurred first. Owing to the time-dependent nature of the adjuvant therapy variable, landmark analysis was conducted using 8 weeks after surgery as the chosen landmark time. Overall survival and PFS rates were estimated by the Kaplan-Meier method. The univariate P values in survival analysis were obtained by using the log-rank test. All the analyses were performed by using SAS 9.1.
Sixty-one patients were identified. Five patients were excluded for having received no adjuvant treatment, and 3 patients were excluded for progression within 8 weeks of surgery, leaving 53 patients with UCS with RMS differentiation for analysis. Patients’ characteristics are detailed in Table 1. Twenty-one of the 53 patients had disease stages I to II, and 32 of the 53 patients had disease stages III to IV. The median age was 64 years (range, 50–88 years). The patient race distribution was as follows: white, 75.5% (40); black, 17.0% (9); other, 7.6% (4). Eastern Cooperative Oncology Group (ECOG) performance status rates were the following: ECOG 0, 50.9% (27); ECOG 1, 41.5% (22); and ECOG 2, 7.6% (4). The median body mass index was 27.9 kg/m2 (range, 18.6–44.7 kg/m2). Cancer antigen 125 was less than or equal to 35 in 36 patients (75%) and greater than 35 in 12 patients (25%). Fourteen patients (26.4%) had a history of estrogen receptor–positive breast cancer (BCA) that predated diagnosis of UCS with RMS, and all of these patients received tamoxifen therapy for a median of 5 years (range, 1–5 years). Comorbid medical conditions in this patient cohort included 37.7% (20 patients) hypertension, 30.2% (16 patients) hyperlipidemia, and 22.6% (12 patients) diabetes mellitus.
All tumors were morphologically biphasic, showing both malignant carcinomatous and sarcomatous components. As a rule, both the carcinoma and sarcoma were high grade. The carcinomas usually showed hybrid features and were typically difficult to classify. The rhabdomyosarcomatous component ranged from focal to diffuse and was usually evident by morphology; but in 16 (32.1%) of 32 cases, it was confirmed with immunohistochemical stains such as myogenin or Myo-D1 (Supplemental Figures 1 and 2, http://links.lww.com/IGC/A185).
Adjuvant treatment was chosen by physician’s discretion, incorporating such parameters as disease, stage, age, performance status, and medical comorbidities. In general, patients with higher-stage disease received chemotherapy with or without RT. Seventy-five percent of the patients who received RT alone had early-stage disease, and 70.7% of the patients who received chemotherapy with or without RT had advanced-stage disease. Pelvic RT was delivered at 5040 cGy in patients who were subsequently to receive IVRT at 1500 cGy. When Pelvic RT was administered alone or in combination with chemotherapy, generally, a dose of 5040 cGy was delivered. In 2 cases, the patients received 4100 cGy and 4500 cGy out of a planned 5040 cGy in combination with chemotherapy owing to grade II diarrhea. The patients who received IVRT received between 1500 and 2100 cGy.
Of the 53 patients who met inclusion criteria and received adjuvant treatment for completely resected UCS with RMS differentiation, 41 patients received chemotherapy with or without RT (stage I [9/41 patients], stage II [3/41 patients], stage III [11/41 patients], and stage IV [18/41 patients]). Twelve of 53 patients received RT alone (stage I [4/12 patients], stage II [5/12 patients], stage III [2/12 patients], and stage IV [1/12 patients]).
Among the 41 patients who received chemotherapy, 63.4% received paclitaxel-carboplatin chemotherapy. Details regarding the remaining chemotherapy regimens utilized are shown in Table 2.
Of the chemotherapy agents used, paclitaxel, 175 mg/m2, administered as a 3-hour infusion plus carboplatin area under the curve (AUC) 5 to 6, was administered approximately every 3 weeks for 4 to 6 cycles. Of the patients treated with paclitaxel-carboplatin chemotherapy, 81.5% completed 6 cycles of therapy. Cisplatin, 50 mg/m2, was administered weekly for 5 to 6 weeks when given in combination with pelvic RT. Docetaxel was administered at 75 mg/m2 over 1 hour. Liposomal doxorubicin was administered at 30 mg/m2. Ifosfamide was dosed at 1200 to 1500 mg/m2 × 3 days in combination with mesna (at variable doses), and doxorubicin was dosed at 20 mg/m2 × 3 days.
Adverse Effects of Treatment
The frequency and severity of treatment-related adverse events are summarized in Supplementary Table 1, http://links.lww.com/IGC/A185. Overall, both chemotherapy with or without RT and RT alone were well tolerated. Predominant grade 2 toxicities in the chemotherapy with or without RT group included fatigue (17.1%), diarrhea (7.3%), and peripheral neuropathy (7.3%). Grade 3 events including neutropenia (4.9%), fatigue (2.4%), and skin toxicity in the form of hand-foot syndrome (2.4%) were the most common. One case (2.4%) of grade 4 neutropenia with accompanying grade 2 febrile illness occurred on the ifosfamide-doxorubicin regimen. Predominant grade 2 toxicities in the RT alone group included diarrhea (33.3%), fatigue (25%), and nausea/vomiting (16.7%). No grade 3 or 4 toxicities occurred in this group.
Patterns of Recurrence
Among the 53 patients, 39 recurred within 3 years. Twenty-nine (70.7%) of 41 of patients in the chemotherapy with or without pelvic RT group had recurrence, and 9 (75%) of 12 of patients in the RT alone group had recurrence. Although sample size limits generalization, lung/mediastinal LN metastases seemed to be more common among the RT-alone group. When distant recurrences were combined, 80% of the RT-alone group versus 64.7% of the chemotherapy-treated patients had distant recurrence. These data are summarized in Supplementary Table 2, http://links.lww.com/IGC/A185.
Progression-Free Survival and OS
At the time of analysis, 35 patients had died. One patient died without progression, and the remaining 14 patients were alive without progression. The median follow-up time for patients without progression was 38.8 months (range, 4.9–112.4 months). The median PFS for the whole cohort was 13.4 months (range, 10.5–17.0 months) (Fig. 1). The 3-year PFS rate for the entire cohort was 19.6% (9.6%–32.2%). The median PFS by stage was 15.9 months (12.2–[not estimable]) for stage I/II disease vs 11.2 (range, 6.7–16.1 months) for stage III/IV disease (P = 0.012; Fig. 2). After 8 weeks of being progression free, the median PFS by treatment type was 13.1 months (range, 8.7–20.8 months) for chemotherapy with/without pelvic RT with/without IVRT versus 10.4 months (range, 1.2–25.9 months) for RT alone (P = 0.498) (Supplementary Figure 3, http://links.lww.com/IGC/A185). The 3-year PFS rate was 20.7% (9.1%–35.5%) for the chemotherapy with/without pelvic RT with/without IVRT cohort versus 16.7% (range, 2.7–41.3%) for the RT-alone cohort.
The median OS for the entire cohort was 23.0 months (range, 16.9–34.3 months) (Fig. 3). The 3-year OS rate for the entire cohort was 33.4% (range, 20.1–47.2%). The median OS by stage was not yet reached for stage I/II disease versus 20.9 months (range, 15.5–29.6 months) for stage III/IV; P = 0.004 (Fig. 4). After 8 weeks, the median OS by treatment type was 23.6 months (range, 14.6–34.5 months) for chemotherapy with/without pelvic RT with/without IVRT versus 16.9 (range, 1.8–45.8) months for RT alone (P = 0.501) (Supplementary Figure 4, http://links.lww.com/IGC/A185). The 3-year OS was 28.1% (range, 14%–44.1%) for the chemotherapy with/without pelvic RT with/without IVRT cohort versus 27.8% (range, 6.7%–54.5%) for the RT-alone cohort.
Uterine carcinosarcoma with RMS differentiation is a very rare and aggressive disease associated with poor outcomes, and scant data exist to guide physicians in the management of these malignancies. Our prior results showed that 60.5% of patients with UCS without RMS differentiation treated at MSKCC received paclitaxel-carboplatin as first-line, adjuvant chemotherapy for completely resected stage I to stage IV disease.29 The aim of this study was to specifically explore the UCS with RMS differentiation group and describe the OS and PFS of this patient population after adjuvant therapy for completely resected disease.
Similar to our prior study, we found that paclitaxel-carboplatin was the most commonly used systemic treatment (administered to 63.4% of the patients who received adjuvant chemotherapy), and a total 68% of the chemotherapy group of patients were treated with some form of a taxane-platinum doublet. Of the patients, 19.5% were treated with an ifosfamide-based doublet. Paclitaxel-carboplatin chemotherapy was well tolerated in this patient population, with 81.5% of the patients having completed 6 cycles of therapy. In our current study, the stage of disease significantly affected PFS and OS. Although not reaching statistical significance owing to limited sample size, our results suggest that chemotherapy alone or in combination with radiation therapy is associated with longer PFS and OS compared to radiation therapy alone. Distant recurrences were more common in the radiation-only group.
When making cross-study comparisons of PFS and OS among patients who received adjuvant chemotherapy, the median PFS and median OS in our prior UCS without RMS differentiation publication (n = 38) were 15 months (11–25 months) and 67 months (23–89 months) (Supplementary Figures 5 and 6 http://links.lww.com/IGC/A185. In contrast, the median PFS and OS in our current study of UCS with RMS differentiation (n = 41) were 13 months (11–17 months) and 23 months (17–34 months). Both studies were closely matched with regard to the percentage of patients with early-stage versus late-stage disease (Supplementary Table 3, http://links.lww.com/IGC/A185). One potentially important difference between these 2 studies is that the follow-up time for the current study (UCS with RMS differentiation group) is longer than that of the previous study (UCS without RMS group). A prospective study to compare outcomes between patients with UCS with and without RMS differentiation is warranted.
Interestingly, we found that 26.4% patients had a history of estrogen receptor–positive breast cancer that predated diagnosis of UCS with RMS, and all of these patients had received adjuvant tamoxifen therapy for a median of 5 years. We postulate that in these cases, tamoxifen therapy may have been related to the development UCS with RMS differentiation. Similar findings have been reported in other studies30,31 including a recent study, which revealed that among high-grade endometrial cancers, a higher proportion of patients who used tamoxifen developed UCS compared with those who did not use tamoxifen (60% vs 30%, P = 0.038).32 Additionally, 63.5% of our patient population was overweight or obese; and hypertension (37.7%), diabetes mellitus (22.6%), and hyperlipidemia (30.2%) were also highly prevalent comorbidities in our patient population. The role of these factors in the risk for UCS with RMS differentiation also warrants further exploration.
Overall, adjuvant paclitaxel-carboplatin was well tolerated in the UCS with RMS differentiation cohort, and was the most used adjuvant chemotherapy regimen at MSKCC during the study interval. Patients with early-stage disease with RMS differentiation had superior survival outcomes compared to late-stage patients. Whereas it is plausible that adjuvant chemotherapy was associated with better median survival outcomes compared with radiation only, this comparison did not reach statistical significance, perhaps owing to small sample size limitations. Survival outcomes for patients with advanced-stage UCS with RMS differentiation seem particularly poor. Evaluation of this specific group of patients in prospective studies may be warranted.
1. McCluggage WG, Haller U, Kurman RJ, et al. Mixed epithelial and mesenchymal tumours. In: Tavassoli FA, Devilee P, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Breast and Female Genital Organs. Lyon, France: IARC Press; 2003.
2. Nielsen SN, Podratz KC, Scheithauer BW, et al. Clinicopathologic analysis of uterine malignant mixed Mullerian tumors. Gynecol Oncol. 1989; 34: 372–378.
3. Bitterman P, Chun B, Kurman RJ. The significance of epithelial differentiation in mixed mesodermal tumors of the uterus. A clinicopathologic and immunohistochemical study. Am J Surg Pathol. 1990; 14: 317–328.
4. McCluggage WG. Malignant biphasic uterine tumours: carcinosarcomas or metaplastic carcinomas? J Clin Pathol. 2002; 55: 321–325.
5. McCluggage WG. Uterine carcinosarcomas (malignant mixed Mullerian tumors) are metaplastic carcinomas. Int J Gynecol Cancer. 2002; 12: 687–690.
6. Sreenan JJ, Hart WR. Carcinosarcomas of the female genital tract. A pathologic study of 29 metastatic tumors: further evidence for the dominant role of the epithelial component and the conversion theory of histogenesis. Am J Surg Pathol. 1995; 19: 666–674.
7. Amant F, Cadron I, Fuso L, et al. Endometrial carcinosarcomas have a different prognosis and pattern of spread compared to high-risk epithelial endometrial cancer. Gynecol Oncol. 2005; 98: 274–280.
8. Sartori E, Bazzurini L, Gadducci A, et al. Carcinosarcoma of the uterus: a clinicopathologic multicenter CTF study. Gynecol Oncol. 1997; 67: 70–75.
9. Dinh TV, Slavin RE, Bhagavan BS, et al. Mixed Mullerian tumors of the uterus: a clinicopathologic study. Obstet Gynecol. 1989; 74: 388–392.
10. Iwasa Y, Haga H, Konishi I, et al. Prognostic factors in uterine carcinosarcoma
: a clinicopathologic study of 25 patients. Cancer. 1998; 82; 512–519.
11. Major FJ, Blessing JA, Silverberg SG, et al. Prognostic factors in early-stage uterine sarcoma. A Gynecologic Oncology Group study. Cancer. 1993; 71: 1702–1709.
12. Ferguson SE, Tornos C, Hummer A, et al. Prognostic features of surgical stage I uterine carcinosarcoma
. Am J Surg Pathol. 2007; 31: 1653–1661.
13. Silverberg SG, Major FJ, Blessing JA, et al. Carcinosarcoma (malignant mixed mesodermal tumor) of the uterus. A Gynecologic Oncology Group pathologic study of 203 cases. Int J Gynecol Pathol. 1990; 9: 1–19.
14. Spanos WJ, Peters LJ, Oswald MJ. Patterns of recurrence in malignant mixed mullerian tumor of the uterus. Cancer. 1986; 57: 155–159.
15. Nordal RR, Thoresen SO. Uterine sarcomas in Norway 1956–1992: incidence, survival, and mortality. Eur J Cancer. 1997; 33: 907–911.
16. Sartori S, Bazzurini L, Gadducci A, et al. Carcinosarcoma of the uterus: a clinicopathological multicenter CTF study. Gynecol Oncol. 1997; 67: 70–75.
17. Powell MA, Filiaci VL, Rose PG, et al. Phase II evaluation of paclitaxel and carboplatin in the treatment of carcinosarcoma of the uterus: a Gynecologic Oncology Group study. J Clin Oncol. 2010; 28: 2727–2731.
18. Sutton GP, Blessing JA, Rosenshein N, et al. Phase II trial of ifosfamide and mesna in mixed mesodermal tumors of the uterus: a Gynecologic Oncology Group study. Am J Obstet Gynecol. 1989; 161: 309–312.
19. Sutton GP, Blessing JA, Photopulos G, et al. Gynecologic Oncology Group experience with ifosfamide. Semin Oncol. 1990; 17(suppl 4) (suppl 4): 6–10.
20. Thigpen JT, Blessing JA, Orr JW Jr, et al. Phase II trial of cisplatin in the treatment of patients with advanced or recurrent mixed mesodermal sarcomas of the uterus: a Gynecologic Oncology Group study. Cancer Treat Rep. 1986; 70: 271–274.
Radiation; Adjuvant treatment; Chemotherapy; Uterine carcinosarcoma; Rhabdomyosarcoma; Completely resected
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© 2013 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.