Abstract
Aim: The aim of the present study was to evaluate a consecutive series of ovarian carcinosarcomas with regard to prognosis, treatment and prognostic factors. Patients and Methods: A consecutive series of 81 ovarian carcinosarcomas from two well-defined geographic regions were studied with regard to survival, type of primary and adjuvant therapy and prognostic factors. All patients but one underwent primary surgery and some patients also received adjuvant chemotherapy (platinum-based) alone or in combination with radiotherapy. Univariate and multivariate Cox proportional regression analysis was used. Survival was analyzed by the Kaplan–Meier technique and differences were assessed by the log-rank test. Results: The mean age of the patients was 73 years. Fifty-one patients received adjuvant chemotherapy and nine patients pelvic irradiation. The 5-year overall survival rate was 10%. Adjuvant therapy (any type) and six completed cycles of chemotherapy were highly significant factors with regard to improved overall survival rate. The only significant tumor-associated prognostic factor was the International Federation of Gynecology and Obstetrics (FIGO) grade of the tumor. FIGO stage, site of metastatic spread, tumor size, histology, DNA ploidy, and tumor necrosis were non-significant factors. Therapy was rather well-tolerated and 29 patients (57%) completed at least six cycles of adjuvant chemotherapy. Conclusion: Adjuvant and completed chemotherapy according to the treatment plan were the most important prognostic factors. FIGO grade (grade 3 vs. 1-2) of the epithelial component of the tumor was also a significant prognostic factor in multivariate Cox analysis.
The term carcinosarcoma was first used by Virchow in 1864. He described a tumor with both carcinomatous and sarcomatous parts (1). This tumor originating from the ovary has been recognized clinically and pathologically since the 1950s (2). The main part of carcinosarcomas arises in the genital tissue, and extragenital sites are extremely rare (3).
Histologically, carcinosarcomas consist of both epithelial and mesenchymal components.
These tumors have been classified as sarcomas, but today, because of their clinical behavior, many of them are more closely related to carcinomas (e.g. endometrial carcinosarcomas). The epithelial part of the carcinosarcoma seems to be most important for the prognosis and survival. Carcinosarcomas are most likely to spread by the lymphatic pathways in contrast to pure sarcomas, which usually spread hematogenously. Ovarian carcinosarcomas (OCS) have a pattern of spread that is similar to that of epithelial ovarian cancer, with early dissemination to the serosa and peritoneum of the abdominal cavity (4, 5).
OCS account for 1-4% of all primary ovarian carcinomas (6). According to an analysis of the Surveillance, Epidemiology and End Results (SEER), the rate of OCS is 0.19 per 100,000 women (7). Calculated from these figures 10-30 new cases per year with this diagnosis would be the result for Sweden. Despite their rarity, they cause a relatively great proportion of cancer-related mortality. Lacking early symptoms, more than 70% of the cases present in an advanced stage (stage III-IV) (8). The prognosis is poor in all stages. In the 1980s, more than 50% of patients with stage I OCS and more than 80% of patients with stage III and IV OCS were dead within one year (9). Two decades later, the outcome is still unfavorable. The median overall survival for patients with OCS is 8-9 months (10). Women with OCS are older than those with epithelial ovarian cancer, but with similar clinical symptoms and patterns of spread. Compared with epithelial ovarian cancer, they have a poorer WHO performance status (11). Due to the rarity of OCS, it is not possible to present large series of patients with this diagnosis, and therefore our knowledge on how to treat this disease is poor and the long-term prognosis is not wel-known.
Tumor characteristics of the complete series (n=81).
Patients and Methods
Patients. Two complete geographical series of OCS of International Federation of Gynecology and Obstetrics (FIGO) stages I-IV, treated during the years 1981-2005 in Gothenburg and Örebro Medical Regions were included in this study, evaluating surgery and postoperative adjuvant chemotherapy and radiotherapy. Overall, 81 patients were included in the study (Table I). The mean age at diagnosis of the patients was 72.7 years (range=39-92 years).
Tumors. Eleven tumors were FIGO stage I (13.6%), 14 tumors stage II (17.3%), 47 tumors in stage III (58.0%), and 9 tumors stage IV (11.1%). The primary surgery was total abdominal hysterectomy in 48 cases (59.3%), and Wertheim-Meigs surgery in one case (1.2%). In 17 cases (21.0%), only multiple biopsies were taken due to advanced disease (Table II). The surgery was performed at 11 local departments of Gynecology and Obstetrics, but all patients were referred to the Departments of Gynecological Oncology at Gothenburg or Örebro University Hospitals for postoperative evaluation and treatment.
Pathology. The pathology specimens were reviewed at the Departments of Pathology at the University Hospitals of Örebro and Gothenburg. The reference pathologists for gynecological oncology were responsible for this review, as for all types of gynecological pathology during this time period. This work was part of routine pathology and the examinations were mainly based on hematoxylin/eosin (H/E) sections, but immunostaining was also used when regarded as necessary for a correct diagnosis. Of this series, 81 cases had a localization of the malignancy in the ovaries or the fallopian tubes and all were classified as carcinosarcomas. The prognostic factors reported for these tumors were: grade of the epithelial component, presence of heterologous components, tumor necrosis, lymphovascular space invasion (LVSI), tumor size, DNA ploidy and S-phase fraction. The number of mitotic figures was not available for this series. Since this was a retrospective study, data for all prognostic factors were not available in all cases.
Surgical technique used in the complete series.
Adjuvant radiotherapy. The time interval between surgery and start of the adjuvant therapy (external beam radiotherapy or chemotherapy) was 4-8 weeks. The type of radiotherapy was postoperative adjuvant pelvic irradiation. Two or four-field techniques were used. Photon beams were used and given daily, five days a week. Patients treated with external beam therapy also received intracavitary vaginal brachytherapy as a boost to the upper two-thirds of the vaginal walls. The dose per fraction ranged from 2.5 Gy to 5.0 Gy (specified at 5 mm below the surface of the vaginal wall) and the number of fractions was two. Radiotherapy was given to nine patients, in three patients in combination with chemotherapy (Table III).
Adjuvant chemotherapy. In 51 patients, platinum-containing (cisplatin or carboplatin) chemotherapy was administered. Anthracyclines (doxorubicin), taxanes (paclitaxel) and cyclophosphamide were also frequently included in the chemotherapy regimens. Chemotherapy was given as the only postoperative therapy or treatment to 48 patients and in combination with radiotherapy to three patients (Table IV).
Follow-up. All patients were followed-up for at least 10 years and no cases were lost to follow-up. The mean follow-up time was 46.7 months (range=4-119 months) for all patients alive as of June 30, 2012. During all visits, symptoms and signs related to the therapy were recorded. The first follow-up visit was after one month, then every three months during the first year, every four months during the second and third years, and every six months up to five years, then annually up to 10 years. All data were collected in computerized databases at the Departments of Gynecological Oncology, Gothenburg or Örebro.
Statistics. For the statistical analyses, survival curves were generated using the Kaplan–Meier technique and differences were tested with the chi-square or log-rank tests. The chi-square test was also used for comparison of proportions, and the independent t-test for comparing means. Cox proportional univariate and multivariate regression analyses were performed with regard to prognostic factors and survival data. p-Values <0.05 were regarded as statistically significant. The Statistica (StatSoft, Inc., Tulsa, OK, USA) software package (version 11, 2012) was used for the statistical analyses.
Type of radiotherapy, targets and schedules used.
Adjuvant chemotherapy schedule and completed regimen.
Results
In the complete series of 81 ovarian and tubal carcinosarcomas, 21 tumors (25.9%) exhibited progression before or during treatment. Twenty-three recurrences (28.4%) were recorded. Pelvic and regional (pelvic lymph nodes) recurrences were recorded in seven cases (8.6%), and distant metastases in 16 cases (19.8%). The median time from treatment to recurrence was 9.6 months (range=2-71 months). During follow-up, a further 26 patients had progressive disease, and in all, 69 patients died of their disease.
Primary surgery with standard bilateral salpingo-oophorectomy was performed in 64 cases (79.0%) and hysterectomy was performed in 48 cases (59.3%). In only four cases (4.9%) was lymphadenectomy or lymph node sampling performed. Ascitic fluid was present in 54 cases (66.7%) and pleural effusion in 8 patients (9.9%). Cytology of the peritoneal fluid or washings was performed in 45 cases (55.6%). Omentectomy was performed in 58 cases (71.6%). Intestinal resection was part of the surgery in 18 patients (22.2%). At surgery, 68 women (84.0%) had tumor spread outside the ovaries and the fallopian tubes (Table V). In 10 patients (12.3%), various complications associated with surgery were recorded.
Sites of metastatic disease at primary surgery.
The presence of positive peritoneal cytology had no influence on the overall survival rate (log-rank test; p=0.463). In 35 out of 48 (72.9%) evaluable samples of peritoneal fluid, malignant cells were present. In one case (FIGO stage IV), no surgery was performed. The site of metastatic tumor spread outside the ovaries had no significant impact on the overall survival rate (log-rank test; p=0.746). Patients with no metastatic extraovarian spread at diagnosis had a 5-year overall survival rate of 25.5% and patients with metastatic spread a 6.2% (log-rank test; p=0.13).
Radiotherapy (external beam therapy with/without brachytherapy) was administered in nine cases (11.1%) all together. In all 9 cases it was as postoperative adjuvant therapy. In 72 cases no radiotherapy was given. Pelvic irradiation (anterior-posterior fields or four-field) was the technique used for the external-beam therapy. Adjuvant vaginal brachytherapy was also used as a boost.
Fifty-one patients were treated with postoperative chemotherapy. All patients received a platinum-containing regimen. Overall, 29 patients (56.9%) received the planned number (≥6 cycles) of chemotherapy cycles. Fourteen patients stopped chemotherapy due to tumor progression during treatment. Toxicity, deteriorated general well-being, or personal reasons were reasons for premature stop of chemotherapy in the remaining eight patients. In three patients (5.9%), death was associated with side-effects of the chemotherapy.
At 12 months, the overall survival rate of the complete series was 37.2% and at five years only 9.7%. In stage I cases, the 5-year survival rate was 30.3% and in stage II, 9.5%. There were no significant differences in survival for patients with tumors in stages II-IV (Figure 1). In the complete series, 69 patients (85%) died due to their carcinosarcomas and three (3.7%) due to other diseases. The 5-year recurrence-free survival rate was 9.7%. In stages I-II, it was 19.7%, and in stages III-IV, the recurrence-free survival was only 5%. Patients treated with adjuvant chemotherapy alone had similar overall survival rate as patients treated with chemotherapy plus radiotherapy or radiotherapy alone (log-rank test; p=0.359). However, patients receiving any type of adjuvant therapy had a highly significant superior overall (Figure 2) and recurrence-free survival compared with patients treated with surgery alone (log-rank test; p=0.0003). These differences in survival rates were true for the complete series of all stages, but also for stages I-II (log-rank; p=0.008) and for the advanced stages (III-IV) (log-rank; p=0.016), respectively.
The overall survival rate according to FIGO stage at diagnosis.
Cox univariate proportional regression analysis with overall survival as an end-point showed that the age of the patient, tumor size, adjuvant therapy and six completed cycles of chemotherapy were statistically significant prognostic factors. FIGO stage and grade were of borderline significance. Radiotherapy added to chemotherapy, tumor necrosis, DNA ploidy, S-phase fraction, site of recurrences were non-significant factors. In a multivariate Cox proportional regression analysis, adjuvant therapy (chemotherapy with/without radiotherapy), six completed courses of platinum-containing chemotherapy, and the FIGO grade of the epithelial component of the tumor were statistically highly significant and independent prognostic factors, after correction for the age of the patient, FIGO stage, and tumor size (Table VI).
For 26 tumors, analysis of DNA ploidy was available and 96% of the carcinosarcomas were non-diploid (aneuploid or tetraploid). The mean S-phase fraction was 15.4% (range=4.3-25.0%). However, DNA ploidy and S-phase fraction were not significantly (p=0.500, and p= 0.936, respectively) associated with overall survival rate in univariate or multivariate analyses.
The overall survival rate according to surgery with/without adjuvant therapy.
Tumors with homologous or heterologous elements (p=0.895), with or without necrosis (p=0.338) had similar prognoses. Tumor grade of the epithelial component of the carcinoma had a highly significantly (risk ratio=1.592; p=0.002) influence on the recurrence-free survival rate, as well as on the overall survival rate in multivariate analysis (risk ratio=4.146; p=0.010).
The median tumor size of this series was 14.1 cm, with a range of 3-40 cm. Tumor size was significantly associated with overall survival rate (risk ratio=1.051; p=0.012) in univariate Cox analysis but not in multivariate analysis (Table VI).
Acute tissue reactions during irradiation were common, e.g. diarrhea, and were recorded in half of the cases. Late tissue reactions after irradiation (any type and grade) were recorded in only one patient out of nine treated with radiotherapy.
In all, 48 patients received chemotherapy as the only treatment and in three cases, in combination with radiotherapy. In 29 out of 51 patients (56.9%), all cycles of chemotherapy were completed according to the treatment plan. Bone marrow toxicity was infrequent and only eight (15.7%) patients discontinued the treatment due to this side-effect. Deterioration of physical status and of tumor progression were more common reasons for an incomplete chemotherapy course. In three patients (5.9%), the cytotoxic treatment per se was associated with the death of the patient (Table VII).
Discussion
We present a consecutive series of OCS from two geographical regions in Sweden with approximately two and a half million inhabitants. In a 20-year period, we recorded 81 cases of OCS. Women with this rare diagnosis are mostly elderly and indeed, the mean age of the patients in this series was 72.7 years. The mean reported age in other series in the literature is 58-66 years (8, 10-12). There is no simple explanation why women in our study were older than those in other studies. However, since our series is consecutive, without selection and recruited from two well-defined geographical areas, our figure is probably representative of an unselected Swedish cohort of OCS.
Cox proportional regression analyses of prognostic factors for overall survival.
Tumor stage at diagnosis, the most important prognostic factor, does not vary greatly in different studies. At the time of diagnosis, about 80% of patients have tumors of stage III or IV (8, 10, 11). In our study, 70% of the tumors were of advanced stages and a relatively high percentage (17.3%) was of stage II as well. As shown in Figure 1, there were no significant differences in survival rate for patients with tumors of stage II to IV. Only stage I was associated with a better prognosis. In multivariate Cox analysis, FIGO stage was not a significant and independent prognostic factor for the overall survival rate. The only tumor-associated prognostic factor in our study was FIGO grade of the epithelial component of the tumor (grade 3 versus grade 1-2). Patients with grade 3 tumors had a worse prognosis, both in univariate and multivariate analyses after correction for other prognostic factors.
Surgical debulking has been investigated in patients with OCS. Widespread metastases with aggressive growth make surgical management difficult. It has been shown that optimal debulking is associated with improved survival (10, 13). In our series, 43% of the patients were optimally debulked at the primary surgery in stage III or IV. This corresponds well to 45% in a study by Kyoung-Chul et al. (8). More than 10% of our patients were operated-on initially by a general surgeon due to bowel symptoms. The intention of optimal debulking surgery was not always present in these cases and many of the patients were left with residual tumor despite almost half of the tumors being of stage II. In a recent review of the literature, Del Carmen et al. found that over 90% of women had tumor spread outside the ovaries at surgery (14). Our corresponding figure was 85%. Even higher figures could be expected if lymphadenectomy or node sampling had been a routine part of the primary surgery.
Cytotoxic side-effects.
In a study by Garg et al., the association of lymphadenectomy and survival was investigated (12). In a series of more than 900 patients, slightly more than 40% of the cases underwent extended surgery with lymphadenectomy. The risk of death was reduced by 34% after lymphadenectomy compared with no lymphadenectomy (hazard ratio=0.66, 95% CI=0.56-0.78).
Most investigators advocate a platinum-containing chemotherapy regimen as the treatment of choice in the adjuvant treatment of patients with OCS. Our policy and treatment preferences were also in line with this. Adjuvant chemotherapy (with our without radiotherapy) and a completed course of at least six cycles of chemotherapy were highly significantly associated with an improved overall survival rate. However, the optimal combination regimen has not yet been determined due to a shortage of randomized studies. Two principal options have been discussed. One of these options is a combination of a platinum analogue and ifosfamide. A number of studies suggest this combination to be preferable (15, 16). On the other hand, Kyoung-Chul et al. (8) found a superior median overall and progression-free survival with a combination of a platinum agent and paclitaxel.
The 5-year overall survival rate in our series was only 10%. Brown et al. reported a 5-year survival rate of 15% in a series of 70 patients (10). On the other hand, Harris et al. presented a 5-year survival rate of only 7.5% among 40 patients (11). In the middle of the 1990s, Di Silvestro et al. reported data on 246 patients in the literature with carcinosarcoma. The median survival was only 6 to 12 months and more than 70% of the patients were dead of their disease within one year (19). The median overall survival time of our series was 9.7 months. Even in early stages (I and II), more than half of the patients were dead in the first year after diagnosis (5). In our study, 69 out of 81 patients (85%) died of their disease during follow-up.
Obviously, not all ovarian carcinosarcomas are sensitive to chemotherapy. A drug resistance assay to exclude non-active chemotherapeutic agents would be preferable in the future (17, 18). Patients not benefitting from intensive chemotherapy might be identified in this way and unnecessary suffering and adverse events avoided. The vast majority of women with OCS die of their disease, furthermore, the period from diagnosis to death is rather short. In addition, intensive therapy is likely to reduce the performance status (10, 11). Improved knowledge is needed to advise our patients with advanced-stage disease as to whether or not they will benefit from adjuvant chemotherapy. More attention should be directed towards development of more well-tolerated palliative chemotherapy for patients with advanced or recurrent disease.
However, further research and development of new treatment strategies for this highly malignant ovarian malignancy are most important. Until then, platinum-based adjuvant chemotherapy after primary surgery is recommended for patients with carcinosarcomas of the ovary.
- Received January 6, 2013.
- Revision received February 14, 2013.
- Accepted February 15, 2013.
- Copyright© 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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