Carcinosarcoma is a rare malignant tumor composed of both epithelial (carcinomatous) and mesenchymal (sarcomatous) components [
Although surgery is the primary treatment, several retrospective studies were performed to determine which adjuvant therapy is best: chemotherapy and/or radiotherapy [
At our institution, we treated a comparatively large number of uterine carcinosarcoma patients between 2000 and 2011 despite its rarity. Management of this cancer included surgery alone, surgery plus chemotherapy, surgery plus radiation therapy, and a combination of surgery, chemotherapy, and radiation therapy. In 2005, our institution replaced “pelvic RT and/or chemotherapy” with “high dose rate (HDR) vaginal brachytherapy plus chemotherapy” as the preferred treatment of carcinosarcoma patients based on our clinical experience and reported evidence. In this study, we review our experience of treating carcinosarcoma patients and report the results of local control, distant metastasis control, and overall survival rate.
After the approval of our institutional review board, we reviewed all medical records of patients who were diagnosed with uterine carcinosarcoma from January 2000 to November 2011. There were a total of 83 patients. Three were excluded due to incomplete treatment history. A further 11 patients with distant metastases were excluded. Three patients who declined surgery were excluded and another two died before surgery. Four patients presented a different final pathology although the initial biopsy showed carcinosarcoma. The remaining 60 patients with stage I–III disease limited to pelvis were included in this study. All patients staged using legacy FIGO stages were restaged using the FIGO 2010 standard based on their pathology reports. The mean age of these patients was 65 years (range 39–86). The time of diagnosis was considered to be the pathology report date of either biopsy or surgical procedure, whichever was earlier. The average follow-up length was 34 months (range 1 to 124). Time from diagnosis to recurrence and death or latest contact was also calculated.
All patients underwent surgery. The most commonly used chemotherapy protocol at our institution was concurrent cisplatin every 3 weeks with radiation, followed by carboplatin and taxol (3–6 cycles, carboplatin AUC = 5 and taxol 175 mg/m2−). Radiotherapy included external beam radiation therapy (EBRT) to the whole pelvis using 10–18 MeV photons generated by a linear accelerator and HDR vaginal cylinder brachytherapy was performed using HDR Iridium 192 after-loading technique. Radiation treatment modalities included EBRT alone, vaginal cuff brachytherapy alone, and EBRT plus brachytherapy. Before 2005, the most commonly used radiation therapy regimen was EBRT to the pelvis using a four-field box technique (45–50.4 Gy) with or without HDR brachytherapy using Ir192 (usually 6-7Gy in one fraction, only one patient received 6 Gy × 2). After 2005 brachytherapy was the preferred treatment choice with 15–18 Gy delivered in 3 fractions in most cases. The dose was prescribed to 5 mm beyond the cylinder surface. One patient who received both chemotherapy and radiotherapy received only 27 Gy EBRT due to acute radiation induced enteritis and small bowel obstruction.
Chi-square test, Fisher’s exact test, or Student’s
Median followup for all surviving patients was 3.61 years (with a range of 0.477–10.35) with an average follow-up time of 2.8 years for all patients included in this study. Median age at diagnosis was 65.5 years old. Median time from diagnosis to surgery is 24 days (range 0–179). Only two patients underwent surgery beyond 2 months after diagnosis. The delay in these two cases was for patient’s personal reasons.
Table
Patients’ characteristics in each group and their corresponding TLR (time to local recurrence), TTM (time to metastasis), and overall survival. To be included in range, patients have to have an event (such as local recurrence, distant metastasis, or death) in the corresponding category.
Surgery alone, |
Surgery and Chemo, |
Surgery and RT, |
Surgery, RT, and Chemo, |
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Age | ||||||||
Median | 66 | 69 | 67 | 62 | ||||
Range | (39–84) | (57–78) | (46–86) | (46–76) | ||||
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% |
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% |
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% |
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% | |
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Stage | ||||||||
I | 14 | 67 | 3 | 57 | 5 | 42 | 10 | 50 |
II | 2 | 9 | 0 | 0 | 4 | 33 | 0 | 0 |
III | 5 | 24 | 4 | 43 | 3 | 25 | 10 | 50 |
Surgery | ||||||||
TAH-BSO | 1 | 5 | 2 | 29 | 3 | 25 | 2 | 10 |
TAH-BSO PLND | 5 | 24 | 0 | 0 | 1 | 8 | 1 | 5 |
TAH-BSO PPLND | 15 | 71 | 5 | 71 | 8 | 67 | 17 | 85 |
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Time to local recurrence | ||||||||
<6 mo. | 2 | 0 | 0 | |||||
≥6–12 mo. | 1 | 1 | 2 | |||||
>12–24 mo. | 1 | 0 | 3 | |||||
>24–36 mo. | 1 | 0 | 0 | |||||
>36 mo. | 0 | 0 | 1 | |||||
Median (years) | 0.75 | 0.68 | 1.29 | |||||
Range (years) | (0.18–2.44) | (0.67–3.24) | ||||||
Unspecified mass(es) | 2 | 0 | 2 | |||||
Vaginal cuff | 3 | 0 | 4 | |||||
Lymph mode(s) | 0 | 1 | 0 | |||||
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Time to metastasis | ||||||||
<6 mo. | 0 | 0 | 1 | 0 | ||||
≥6–12 mo. | 1 | 0 | 2 | 1 | ||||
>12–24 mo. | 1 | 1 | 0 | 3 | ||||
>24–36 mo. | 2 | 0 | 0 | 0 | ||||
>36 mo. | 0 | 0 | 0 | 1 | ||||
Median (years) | 1.42 | 1.96 | 0.76 | 1.24 | ||||
Range (years) | (0.62–2.86) | (0.17–0.84) | (0.96–3.24) | |||||
Lung/pleural | 3 | 0 | 3 | 1 | ||||
Brain | 0 | 1 | 2 | 0 | ||||
Bowels | 1 | 0 | 0 | 2 | ||||
Soft tissue/muscle | 2 | 0 | 0 | 3 | ||||
Liver | 0 | 0 | 0 | 1 | ||||
Bladder | 0 | 0 | 0 | 1 | ||||
Lymph node(s) | 0 | 0 | 0 | 1 | ||||
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Overall survival | ||||||||
Median (years) | 2.28 | 2.3 | 4.8 | 3.3 | ||||
Range (years) | (0.08–3.69) | (0.28–2.42) | (0.25–4.9) | (0.85–3.33) | ||||
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Follow-up time | ||||||||
Median (years) | 1.92 | 0.48 | 1.78 | 2.66 | ||||
Range (years) | (0.07–10.35) | (0.28–3.65) | (0.25–6.27) | (0.84–7.12) |
Patients’ characteristics in different radiotherapy groups.
Radiation therapy | Brachytherapy and EBRT, |
EBRT only, |
Brachytherapy only, |
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Age | ||||||
Median | 65 | 61 | 63 | |||
Range | (46–76) | (50–76) | (47–86) | |||
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% |
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% |
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% | |
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Stage | ||||||
I | 2 | 20 | 4 | 50 | 9 | 64 |
II | 2 | 20 | 2 | 25 | 0 | 0 |
III | 6 | 60 | 2 | 25 | 5 | 36 |
Chemotherapy | 6 | 60 | 6 | 75 | 8 | 57 |
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Local recurrence | 2 (20%) | 4 (50%) | 1 (7%) | |||
Unspecified mass(es) | 1 | 1 | 0 | |||
Vaginal cuff | 1 | 2 | 1 | |||
Lymph mode(s) | 0 | 1 | 0 | |||
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Distant metastases | 5 (50%) | 2 (25%) | 2 (14%) | |||
Lung/pleural | 4 | 0 | 1 | |||
Brain | 1 | 0 | 1 | |||
Bowels | 2 | 0 | 0 | |||
Soft tissue/muscle | 2 | 2 | 0 | |||
Liver | 0 | 1 | 0 | |||
Bladder | 1 | 0 | 0 | |||
Lymph node(s) | 0 | 1 | 0 | |||
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Radiation toxicity | 8 (80%) | 6 (75%) | 2 (14%) | |||
Grade 1-2 | 7 | 3 | 1 | |||
Grade 3-4 | 1 | 3 | 1 |
Forty-five patients had total abdominal hysterectomy and bilateral salpingoophorectomy, (TAH-BSO) and pelvic and paraaortic lymph node dissection (PPLND); 8 patients had TAH-BSO; 7 had TAH-BSO and pelvic lymph node dissection (PLND). The surgical distribution appears not to be different among 4 groups (
Statistical differences were tested between different treatment groups without further stratification by age and stage. Age and stage variations were tested between every two groups. Age analyses showed that surgery alone included older patients than the patient group who received surgery plus chemotherapy plus radiotherapy (
Stage distribution difference analyses showed that more stage II patients were included in the surgery plus RT group than compared to the group of all three treatments combined (
In this study, 9 out of 21, 3 out of 7, 7 out of 12, and 12 out of 20 patients survived following surgery alone, surgery plus chemotherapy, surgery plus radiation therapy, and a combination of surgery, chemotherapy, and radiation therapy groups, respectively. The estimated 1-year OS and 3-year OS for those who had surgery alone were 71% and 44%, respectively. The 1-year OS and 3-year OS were estimated to be 91% and 61% for those who had surgery with radiotherapy. Patients who had surgery plus chemotherapy had a calculated 1-year OS of 57% and a calculated 3-year OS of 28%. In addition, 1-year OS and 3-year OS are 90% and 62%, respectively, in the trimodality treatment group. Moreover, the 1-year, 3-year, and 5-year overall survival for all 60 patients during the past 12 years are 80%, 53%, and 43%, respectively. The 5-year overall survival of all patients encountered our institution including stage IV disease is 36%.
With an average follow-up time of 2.8 years, 12 patients developed local recurrence and 14 patients developed distant failure. Median time to local recurrence and median time to distant metastases were 0.99 years and 1.27 years, respectively. True median time to local recurrence and median time to distant metastases cannot be calculated here as less than 50% of the population experienced the event. For these 60 patients, the overall 1-year local recurrence rate (LRR) is 11.2% and the 3-year LRR is 24.7%. The 1-year and 3-year distant recurrence rates are 11.6% and 23.4%, respectively.
Further data analysis showed that the combination of surgery plus chemotherapy plus radiation therapy and surgery plus radiation therapy showed significant improvement of OS compared to surgery alone (
All stages, overall survival by treatment. (a) Surgery alone versus surgery plus radiotherapy (
Our data suggests that trimodality therapy with surgery plus chemotherapy plus radiation therapy and surgery plus radiation therapy likely improves OS compared to surgery plus chemotherapy. However, due to the limited number of patients in each group, this did not reach statistical significance (
Surgical stage I, overall survival by treatment. Surgery alone versus surgery plus radiotherapy (
In addition to overall survival, we also compared local recurrence and distant metastasis free survival among all three groups (
Surgical stage III, distant metastasis by treatment. Surgery plus radiotherapy versus surgery plus chemoradiation therapy (
We compared different radiation therapy modalities in the group of surgery plus radiation and the group of surgery plus chemoradiation. Patients in the brachytherapy alone group showed equally effective decreased local recurrence rate (LRR) compared to the group that received EBRT alone (
(a) All stages, local recurrence by radiotherapy. Brachytherapy only versus EBRT only (
Adverse side effects were analyzed among different radiation regimens and graded according to Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. In patients who received EBRT, grade 1-2 side effects with the most common being GI irritations such as diarrhea and rectal urgency were noted in ten out of 18 patients (56%). Four out of 18 patients developed grade 3-4 side effects (22%). Three patients developed small bowel obstruction (SBO) and one of them underwent surgical resection. One patient developed severe enteritis, for which she had intestinal resection. One patient in the brachytherapy only (
The most common surgical complications in these patients are wound dehiscence (5 patients), incisional hernia (3 patients), and postoperative ileus (3 patients).
Our single-institution findings demonstrate that 15% of surgically staged uterine carcinosarcomas presented with distant metastasis, 43% presented with disease outside of the uterus, and only 43% presented with stage I disease. These numbers are comparable with previous studies given different patient populations and surgical techniques [
Chemotherapy and radiotherapy have demonstrated efficacy for carcinosarcoma patients [
Both EBRT and LDR brachytherapy have been reported to promote locoregional free survival [
Side effects were noted to be higher with EBRT compared to brachytherapy only. Chemotherapy may also contribute to the side effects. In our study no difference in toxicity was noted between EBRT, with or without chemotherapy. However, in the brachytherapy group, the addition of chemotherapy contributes to the GI side effects.
The median survival of our patients is 24.5 months as calculated from date of diagnosis with a median delay of 24 days between diagnosis and surgery, compared to 16 months reported in other studies [
Uterine carcinosarcoma is a rare, aggressive malignant tumor with poor prognosis. Multiple treatment modalities published in the literature show impact on local control and overall survival. Surgery plus adjuvant radiation and chemotherapy shows superior survival even in early stages in our study. Nevertheless, a randomized multi-institutional prospective clinical trial is needed to confirm the optimal treatment approach.
Hualei Li, Mindi J. TenNapel, Amina Ahmed, MD, Lilie Lin, MD, Sudershan K. Bhatia, and Geraldine Jacobson declare that there is no conflict of interests regarding the publication of this paper.