NICE Guidelines for Ovarian Cancer: Recommendations Versus Standard Care

The National Institute for Clinical Excellence (NICE) is charged with providing to physicians in the United Kingdom the guidelines for treatment of various diseases, including ovarian cancer.[1] Currently, these guidelines in ovarian cancer recommend the use of paclitaxel/platinum combination therapy or platinum therapy alone as first-line treatment for ovarian cancer. The guidelines also recommend the use of topotecan or pegylated liposomal doxorubicin for treatment of patients with recurrent ovarian cancer. To be useful to the practitioner, such guidelines should be updated, as necessary. It is when the guidelines do not reflect the most up-to-date information, and when they appear to be at odds with ongoing clinical trials, that questions can be raised about their applicability.

The guidelines allow the physician to choose either single-agent platinum or paclitaxel in combination with platinum-based compounds (either cisplatin or carboplatin) as adjuvant therapy following surgery. For the vast majority of patients, the preferred platinum compound is carboplatin, and there is no reason why the guidelines should not specifically address this issue. The results of the 800-patient Gynecologic Oncology Group (GOG) trial (protocol 158)[2] of cisplatin plus paclitaxel vs. carboplatin plus paclitaxel, together with a similar trial from the AGO investigators in Europe,[3] clearly demonstrate that carboplatin plus paclitaxel is the preferred regimen. In the GOG trial, the relative risk (RR) of progression for carboplatin plus paclitaxel compared with cisplatin plus paclitaxel was 0.88 [95% confidence interval (CI), 0.75–1.03] and the RR of death was 0.84 (95% CI, 0.70–1.02). Median overall survival was 57.4 months for carboplatin plus paclitaxel-treated patients compared with 48.7 months for cisplatin plus paclitaxel. Coupled with the decrease in toxicity with the carboplatin regimen, there is little reason for the guidelines not to endorse carboplatin plus paclitaxel as the preferred regimen.

The results of GOG158 also have direct relevance on the NICE recommendation that either single-agent carboplatin or carboplatin plus paclitaxel be used as adjuvant therapy because no clear-cut advantage, primarily on the basis of ICON3,[4] has been established for the combination. However, questions have been raised regarding the ICON3 trial and its conclusion. It should be pointed out that there are at least seven large clinical trials currently in progress in which new adjuvant therapies are being, or have been, studied in patients with advanced ovarian cancer. The control arm in all these studies is carboplatin plus paclitaxel. I am not aware of any randomized trial currently in progress in which single-agent carboplatin is the “standard” therapy against which new investigational regimens are evaluated. Consequently, although the NICE guidelines recommend the use of paclitaxel/platinum combination therapy or platinum therapy alone as first-line treatment for ovarian cancer, clinical researchers have uniformly used carboplatin plus paclitaxel as the control arm in prospective randomized trials. Outside a trial, the combination of carboplatin plus paclitaxel, therefore, is justifiably the most widely used postoperative therapy in the United States for patients with advanced ovarian cancer.

The treatment of recurrent ovarian cancer remains an area of active clinical investigation. Until more recently, single-agent therapy with carboplatin was generally accepted as a “standard” therapy for patients with platinum-sensitive recurrent ovarian cancer. ICON4 demonstrated that paclitaxel in combination with platinum chemotherapy significantly improved progression-free and overall survival in patients with platinum-sensitive recurrent ovarian cancer vs. platinum alone.[5] This study has important implications, both for the treatment of patients with recurrent ovarian cancer, as well as for its use as an adjuvant therapy. The results of ICON4 are in direct contrast to ICON3, and no convincing argument has been made to explain why combination chemotherapy should be more effective than single-agent carboplatin in patients with recurrent ovarian cancer, whereas no benefit could be shown for combination chemotherapy in the adjuvant setting. In my opinion, the results of ICON4 merely add more evidence that combination chemotherapy with carboplatin plus paclitaxel is superior treatment to single-agent carboplatin in the adjuvant setting following surgery in patients with advanced ovarian cancer.

In patients with recurrent ovarian cancer, it does appear that there may be a paradigm shift in which platinum-sensitive patients will be treated with combination chemotherapy. The GOG is in the final stages of developing a multiarmed clinical trial in which several carboplatin-based combinations, including carboplatin plus paclitaxel, carboplatin plus gemcitabine, and carboplatin plus pegylated liposomal doxorubicin, will be compared with treatment with single-agent carboplatin in patients with platinum-sensitive recurrent ovarian cancer.

For patients with platinum-resistant recurrent ovarian cancer, the physician and patient are faced with a wide variety of choices. The NICE recommendation of topotecan or pegylated liposomal doxorubicin as second-line agents must be placed in context with other clinical trials that have shown similar efficacy of agents such as oral etoposide[6] and gemcitabine.[7] The NICE guideline that paclitaxel is not recommended as second-line (or subsequent) therapy in patients with recurrent ovarian cancer who have received the drug as part of their first-line treatment is not supported by the results of several phase II trials, which have demonstrated that weekly paclitaxel has substantial activity in heavily pretreated patients with platinum- and paclitaxel-resistant ovarian cancer.[8][9][10] There does not appear to be any justification for the NICE guidelines specifically not recommending paclitaxel in this patient population because it has activity comparable to pegylated liposomal doxorubicin and topotecan. The primary consideration for selection of second-line therapy in recurrent platinum-resistant ovarian cancer remains toxicity. However, a more recent update of the randomized comparison of pegylated liposomal doxorubicin vs. topotecan in patients with recurrent ovarian cancer shows an overall survival advantage for patients treated with pegylated liposomal doxorubicin.[11] Such clinical trials are important in providing physicians with more objective evidence regarding the merits of individual agents used in recurrent ovarian cancer.

In conclusion, the NICE guidelines provide recommendations on the use of chemotherapy in the adjuvant setting following cytoreductive surgery in untreated patients, as well as for patients with recurrent ovarian cancer. Despite the NICE guidelines, the control arm of prospective randomized trials throughout the world is carboplatin plus paclitaxel as the standard regimen against which new combinations are being tested. As such, in the United States, carboplatin plus paclitaxel remains the primary regimen for the vast majority of ovarian cancer patients following initial cytoreductive surgery. In recurrent disease, the NICE guidelines report on only two of a multiplicity of potential chemotherapeutic regimens that may be useful. The guidelines already may require some revision on the basis of the more recent results of the ICON4 trial, which may lead to a paradigm shift in the management of patients with platinum-sensitive recurrent ovarian cancer.