Abstract
Despite the fact that hormonal therapy has been employed in the management of ovarian cancer for more than 40 years, there is limited information available in the peer-reviewed medical literature to document the beneficial impact of the strategy, either on improvement in cancer-related symptoms or prolongation of survival. Existing data suggest that approximately 5–10% of ovarian cancer patients treated with a hormone-based strategy in the second-line setting will achieve evidence of substantial tumor shrinkage, with a larger proportion of individuals likely to demonstrate stabilization of the disease process for a highly variable time interval. The major advantage with the use of hormonal treatments is the well-recognized and highly favorable toxicity profile associated with this class of antineoplastic agents.
Keywords
It has been more than 40 years since the initial report of the use of a hormonal agent as a management strategy for patients with advanced ovarian cancer [1]. Justification for this approach included the critically important role of female hormones in the normal physiology of ovarian function, and evidence for the antineoplastic effects of hormonal manipulation in the treatment of other cancers (e.g., breast and prostate).
Further support for the concept that the administration of hormone-based therapy might influence the clinical course of established ovarian cancer is provided by the observation that a high percentage of both normal and malignant ovarian cells contain estrogen and progesterone receptors [2], a well-recognized feature of breast cancers that are able to respond to this therapeutic approach. This observation led to the reasonable hypothesis that the administration of similar hormonal agents to patients with ovarian cancer might result in tumor regression, or at least a slowing of the rate of progression of the cancer.
Progesterone therapy of advanced ovarian cancer
The initial attempts at hormonal treatment of ovarian cancer focused on progestational agents. One simple theory supporting this strategy was that progesterone might counteract any estrogenic effects stimulating tumor growth.
Unfortunately, available preclinical, observational and population-based data do not provide strong support for a role of estrogen in either the pathogenesis or progression of ovarian cancer [3]. In fact, based on limited existing data [4], it is currently common practice for oncologists to administer estrogen preparations to women with advanced ovarian cancer to treat the often highly distressing effects of estrogen-deprivation resulting from surgically-induced menopause.
Despite the lack of a hypothesis strongly supportive of the use of progestational agents in the treatment of ovarian cancer, early experience with this management strategy was reported to be fairly positive, at least in terms of observed anticancer responses [5–7]. For example, one such report noted that 15 of 23 patients with advanced ovarian cancer experienced a response following progesterone therapy [6].
However, it should be noted that the criteria for ‘response’ in the era where this class of drugs was routinely administered was not nearly as rigorous as currently employed in cancer clinical trials, in general, and ovarian cancer, in particular. Thus, it should be not surprising to learn that more contemporary studies of the use of progesterones in ovarian cancer have failed to confirm the level of activity noted in the early studies [8–13].
One early report reported that 11 of 24 ovarian cancer patients responded to a regimen of high-dose progesterone (megestrol acetate) therapy [7] but, again, a subsequent report found much less biological activity for this strategy [13]. Furthermore, high doses of progestational agents are associated with far greater toxicity (e.g., weight gain, fluid retention, steroid-like effects) than the lower dose levels routinely employed in the management of breast cancer.
Tamoxifen treatment of advanced ovarian cancer
With the introduction of tamoxifen into the oncologist's armamentarium as a remarkably well-tolerated and highly active treatment for receptor-positive breast cancer, it was natural to explore this agent in the treatment of advanced epithelial ovarian malignancies. As a result, a number of studies employing this agent have been reported in the peer-reviewed oncology literature over the past 10–15 years [14–23].
Tamoxifen in the treatment of ovarian cancer.
Very well tolerated agent.
Approximately 10% overall objective response rate in previously chemotherapy-treated patients, including women with clinically-defined platinum-resistant disease (cancer progression during treatment, or recurring less than 6 months following the completion of primary therapy).
Unknown impact of the agent on either progression-free or overall survival.
No clinical evidence that the agent enhances the effectiveness of cytotoxic chemotherapy.
Reasonable drug choice when a major goal of therapy is to minimize the toxicity of treatment.
Box 1 provides a summary of the findings of these trials. While the overall objective response rate (10%) in ovarian cancer is certainly quite modest, the highly favorable toxicity profile of the agent makes this drug an excellent option for a patient with progressive disease who desires additional treatment, but where a major goal of such therapy is also to minimize side effects. In contrast to cytotoxic chemotherapy, tamoxifen is not associated with the risk of significant emesis, anemia, neutropenia, thrombocytopenia, renal dysfunction, neuropathy or mucositis/stomatitis. One report of a large study (n = 155 patients) employing tamoxifen in advanced ovarian cancer noted that the majority of objective responses (3 of 4) occurred in patients with endometrioid morphology [18]. While an interesting finding, other groups have not found (or at least reported) this specific association between tumor histology and response to tamoxifen.
Of particular relevance, and in striking contrast to what is observed in breast cancer, studies of tamoxifen use in ovarian cancer have failed to establish a clear relationship between the presence of hormonal receptors on the malignant cells and response to this antineoplastic agent [17]. While it is reasonable to argue that these trials were conducted in an era when the technology associated with receptor measurement was far less sophisticated than it is today, the unquestionable distinction between the two malignancies in both the overall opportunity to achieve a biological response to tamoxifen, and the relevance of receptor physiology in defining the population where that activity will most likely be observed, must be considered strong evidence of major differences in the pathogenesis of the two cancers.
In recent years tamoxifen has been employed as a management strategy for asymptomatic patients who experience a confirmed rise in the serum cancer antigen (CA)-125 level following the completion of primary chemotherapy [24]. It is now well recognized that a rising CA-125 level is extremely strong evidence of the presence of progressive cancer, even if physical examination and radiographic evaluation fail to reveal definite evidence of the disease. While studies have suggested that the majority of patients in this clinical setting will be found to have other evidence of progressive cancer within several months of a confirmed doubling of a ‘normal’ CA-125, a not insignificant percentage of patients will remain asymptomatic for more than a year following such documentation of antigen-defined disease progression. In this setting, where patients may reasonably desire treatment, the use of a very well tolerated agent, with known antineoplastic effectiveness, may be considered the most rational currently available management strategy.
It should be noted that the reported experience with tamoxifen (and all other hormonal agents) in ovarian cancer consists principally of noncomparative Phase II trials, retrospective reviews of institutional experience, and meta-analyses of this limited literature. The available Phase III trial data have failed to demonstrate that the addition of tamoxifen to standard cytotoxic chemotherapy improves outcome [25]. Furthermore, to the best of this author's knowledge, there have been no reported randomized trials directly comparing cytotoxic chemotherapy with tamoxifen as a treatment of recurrent or resistant ovarian cancer.
It is also important to note the theoretical concern that the addition of a ‘cytostatic agent’ (tamoxifen) to a ‘cytotoxic agent’ (chemotherapy) could actually reduce the effectiveness of treatment by interfering with the ability of the cytotoxic drug to produce direct killing of the tumor cells.
A final point regarding a potential role for tamoxifen in the treatment of ovarian cancer relates to the provocative preclinical data suggesting that the agent can enhance cisplatin-induced cytotoxicity [26–28]. Unfortunately, while one clinical study suggested that the addition of tamoxifen to cisplatin could overcome platinum resistance in ovarian cancer [29], this experience could not be confirmed in a subsequent trial reported by a second investigative team [30].
Experience with other hormonal agents in ovarian cancer
A number of other, newer classes of hormonal agents have been examined in Phase II trials as second-line ovarian cancer treatment strategies [31–39]. For example, most recently a 16% response rate with 37% disease stabilization was reported for the use of second-line letrozole in estrogen receptor-positive patients (n = 43) with ovarian cancer (responses documented by declines in the CA-125 antigen level) [38].
In addition, impressive biological activity and prolonged disease stabilization associated with several drugs has been noted in individual case reports in this patient population [39,40].
However, at present, it is not possible to know if any of these hormonal anticancer agents are superior to tamoxifen. Furthermore, it is likely that all new hormonal agents will be substantially more expensive than tamoxifen (now a generic drug), and it will be difficult for any agent to be shown to have a more favorable toxicity profile, especially in the setting where the drug will only rarely be administered for periods in excess of 12 months.
Thus, the role of the newer classes of hormonal agents in the management of ovarian cancer remains quite undefined. A direct comparison to tamoxifen, or an alternative management strategy, in a Phase III trial in the treatment of recurrent or resistant ovarian cancer would be of considerable interest.
Conclusion
Despite more than 40 years of research efforts examining hormonal treatment of ovarian cancer, a precise role for this strategy remains uncertain. A further unanswered question is the optimal agent to be employed, and the timing of its use, in the management paradigm of this malignancy.
However, it is clear there is a critical need in ovarian cancer for agents that can improve symptoms and delay tumor progression, but that also have the extremely favorable toxicity profile of hormonal therapy. This fact alone is a sufficient justification to consider hormonal therapy in current disease management and continue to explore this class of agents in well-designed and -conducted clinical trials.
Executive summary
Hormonal therapeutic strategies have been employed in the management of ovarian cancer for more than 40 years.
The initial hormonal drugs employed in the management of ovarian cancer were progestational agents.
While early reports of use of this class of agents were quite favorable, subsequent studies revealed a much lower objective response rate.
Approximately 10% of ovarian cancer patients treated with tamoxifen in the second-line setting will achieve evidence of an objective response to this therapeutic regimen.
There is no evidence that adding tamoxifen to chemotherapy improves outcome compared with the use of either agent alone.
Other hormonal agents have been examined in the management of ovarian cancer, including most recently letrozole.
However, currently, outside the setting of a clinical trial, there does not appear to be any available data to justify employing one of the newer hormonal anticancer agents, rather than tamoxifen, in the second-line management of ovarian cancer.
The major justification for using hormonal therapy as a second-line treatment option in ovarian cancer is the extremely favorable side effect profile for this class of agents.
This is a particularly relevant point as ovarian cancer is increasingly being viewed as a ‘chronic disease process’ where cure may not be the ultimate outcome, but where prolonged survival of excellent quality is a realistic objective of second-line treatment strategies.
There is an important need for randomized Phase III trials to be conducted to define a precise role for hormonal therapy in the management of ovarian cancer.
Future perspective
Currently, long-term survival is possible in a large percentage of individuals with ovarian cancer, even following the documentation of disease recurrence. This observation suggests it is reasonable to consider management of the malignancy in some patients as a very serious chronic disease, similar to severe insulin-dependent diabetes or medication-controlled congestive heart failure, where the goal of treatment is to prolong survival while at the same time optimizing the overall quality of life [41]. In this setting, hormonal therapy is a particularly attractive management strategy.
Options to explore a possible role for hormonal therapy in ovarian cancer management in Phase III randomized trials include:
Maintenance treatment following the attainment of a clinically-defined complete response to primary platinum–taxane chemotherapy;
Treatment of asymptomatic patients with a rising CA-125 antigen level following completion of platinum chemotherapy;
Palliative therapy following disease progression after the administration of more than two or three prior cytotoxic programs.