Summary of main results
We did not identify any trials that compared the effectiveness and safety of neoadjuvant or adjuvant chemotherapy with or without radiotherapy in combination with surgery for women with ovarian carcinosarcoma. Therefore, there is currently no evidence to determine whether any form of chemotherapy, with or without radiotherapy, in combination with surgery is better or worse in terms of prolonging survival, QoL or toxicity.
We specified OS and DFS as the primary outcomes of interest. Quality of life should perhaps be the main focus if future trials are conducted since treatment related morbidity is likely to degrade the quality of the time that women live. This is especially important in women with ovarian carcinosarcoma where a number of retrospective studies and case reports have shown very poor survival rates (Andersen 1989; Brown 2004).
Quality of the evidence
No studies met the inclusion criteria for this review, so there is no evidence to assess.
Potential biases in the review process
Two review authors independently carried out a comprehensive search, including a thorough search of the grey literature, and all references were sifted. We were restrictive in our inclusion criteria with regards to types of studies as we planned to only include RCTs, as we suspected that some of the NRS designs were dubious and would have been prone to selection bias. No relevant NRSs appeared to use appropriate statistical adjustment or were of adequate quality. Therefore, we attempted to ensure that we did not overlook any relevant evidence by searching a wide range of sources and ensuring the review was not based on poor quality evidence by excluding case reports and poor quality retrospective studies. We felt it was better to highlight the need for RCTs, or at the very least good quality NRSs, rather than report the results of low quality studies that are very likely to be misleading.
The greatest threat to the validity of the review is likely to be publication bias, that is studies that did not find the treatment to have been effective may not have been published. We were unable to assess this possibility as we did not find any studies that met the inclusion criteria.
Agreements and disagreements with other studies or reviews
Two prospective Gynecologic Oncology Group (GOG) studies looked at the outcomes of women diagnosed with ovarian carcinosarcoma, but these studies included too few women in order to make reliable comparisons (Morrow 1986; Tate Thigpen 2004).
Morrow 1986 registered 15 women with a diagnosis of ovarian carcinosarcoma who were treated with combinations of surgery, chemotherapy and radiotherapy depending on the stage of the disease. A combination of vincristine, dactinomycin and cyclophosphamide was used in some women. Survival was better in women with early stage disease or with a smaller residual tumour volume.
Tate Thigpen 2004 studied the cytotoxic effect of platinum in women diagnosed with ovarian carcinosarcoma. The median progression-free interval was 5.2 months and the median OS was 11.7 months (n = 130). Forty-four women were evaluable for response and showed an overall response of 20%. Survival was favourable for women with non-measurable disease and also in women who responded to platinum. Adverse effects were not uncommon. We agree that this is one of the largest prospective series of women with carcinosarcoma ovary studied so far. The recruitment took 20 years, which makes it difficult to compare various cytotoxic drugs along with platinum. Despite the platinum response being similar to uterine carcinosarcoma, it is still lower than the conventional epithelial ovarian tumours, which means that platinum alone as a cytotoxic drug may not be effective in improving survival in ovarian carcinosarcoma. This was confirmed by Brown 2004 who compared epithelial ovarian tumours with carcinosarcoma of the ovary in their retrospective case series and found an inferior response to platinum-based chemotherapy in the carcinosarcoma group.
A recent case-control study (Rauh-Hain 2011) reviewed 50 cases of ovarian carcinosarcoma of the ovary, each case was matched to two women with serous ovarian epithelial carcinoma. Shorter time to recurrence, increased platinum resistance, poorer prognosis with suboptimal cytoreduction and poorer OS were noticed in women with ovarian carcinosarcoma compared to serous epithelial ovarian cancer. Jonson 2006 looked at 17 cases of ovarian carcinosarcoma and 87 women with uterine carcinosarcoma and found no difference in survival between the two groups.
The Chun KC, Cicen 2008 and Duska 2002 studies reported a retrospective analysis of 40, 26 and 28 women diagnosed with ovarian carcinosarcoma, respectively, and showed improved survival with optimal debulking and platinum-based combination treatment. A platinum combination with taxanes was used in two studies (Chun KC; Duska 2002) and a combination of platinum and Ifosfamide was used in the Cicen 2008 study. Recruitment took 15 to 20 years with various chemotherapeutic agents being used over that period of time, which makes it difficult to compare various regimens. A retrospective series of 31 women (Rutledge 2006) showed improved survival with optimal debulking and the use of ifosfamide and cisplatin chemotherapy compared to a carboplatin and taxol combination. The median OS was 21 months for the whole group.
Signorelli 2009 reviewed 41 women with ovarian carcinosarcoma over a period of 11 years. The women underwent surgery and were given platinum-based combination chemotherapy. The overall survival was 20 months. The response to the platinum-based combination (anthracycline, alkylating agent) was good but was associated with high toxicity and the numbers in the two chemotherapeutic regimens were small. Prendiville 1994 reported a series of 20 women over a 10-year period. The analysis showed a median survival of 14 months and suggested that platinum and cyclophosphamide may be useful therapy following surgery. Chang 1995 studied 37 women with ovarian carcinosarcoma and found stage to be an independent prognostic factor and single agent platinum to be effective to some extent. Sutton 1994, in their phase II trial, reviewed 32 women who were previously treated with platinum-based chemotherapy for ovarian carcinosarcoma and were administered ifosfamide; they found ifosfamide to have activity.
Harris 2003 retrospectively reviewed 40 women diagnosed with ovarian carcinosarcoma. Eighty per cent presented with advanced stage disease. More than 50% had bulky disease, associated with worse prognosis, and the majority received platinum-based chemotherapy following surgery. Overall, the one- and five-year survival rates were 40% and 7.5% respectively, which is much lower than for serous epithelial ovarian carcinoma. Leiser 2007 reviewed 30 women with a diagnosis of ovarian carcinosarcoma. All the women had stage III or IV ovarian carcinosarcoma except one who had stage II disease. Fifty-seven per cent had optimal cytoreduction and all women received platinum and taxane as first-line chemotherapy. The three- and five-year survival rates were 53% and 30% respectively. Even though there was a trend towards a better response rate with optimal cytoreduction, it did not affect OS. Muntz 1995 reviewed 27 women with a diagnosis of ovarian carcinosarcoma and found advanced stage to be a significant prognostic factor. Less than 50% of women underwent optimal cytoreduction. The majority received platinum-based chemotherapy. Few women were treated with postoperative radiotherapy. There was a trend towards improved survival with optimal cytoreduction and platinum-based chemotherapy but it was difficult to interpret because of the small numbers.
All the above mentioned studies consistently confirmed that the OS is poor in women with ovarian carcinosarcoma as compared to epithelial serous ovarian carcinoma. Most studies have confirmed that platinum has some activity in this tumour type. Other variables such as suboptimal cytoreduction, feasibility for cytoreduction and increased platinum resistance have been commented upon by some studies. A major improvement in survival has not been seen in this group of women despite extrapolating cytoreduction and platinum-based combination therapy. All the above studies had inadequate or no comparison groups for various adjuvant regimens and most of the studies were retrospective case series, and hence inferences cannot be made scientifically. The difficulty in recruiting women for a prospective trial, which has limitations because of the rarity of the tumour, is obvious.