Despite advances in ovarian cancer chemotherapy regimens, there is a high rate recurrence. Second-line ovarian cancer therapy often aims at prolonging survival and time to symptom recurrence. When disease progression or recurrence occurs after primary chemotherapy, choice of subsequent therapy must be individualized.
Due to poor response rates with repeat dosing with platinum agents, second-line treatment for platinum-resistant patients usually involves a cytotoxic agent that uses a different mechanism. These agents include topoisomerase inhibitors (etoposide, topotecan), alkylating agents (ifosfamide, cyclophosphamide), and other chemotherapies (doxorubicin, gemcitabine, docetaxel).
At this time, no one drug combination has been shown to be more efficacious; thus, currently, there is no standard-of-care salvage treatment recommendation.
Moreover, these agents used at the maximum tolerated doses may be difficult to administer and are often associated with severe side-effects, sometimes requiring hospitalization.
Not surprisingly, therefore, patient attitudes to toxic chemotherapy regimens for advanced, platinum resistant, ovarian cancer are often negative, as the adverse effects of treatment often seem to outweigh any potential benefits. Thus, the introduction of newer approaches, having improved or at least equivalent efficacy but reduced toxicity, are highly desirable. Therapy must be individualized according to previous response, toxicities, and patient wishes.
Instead of only using short bursts of toxic MTD chemotherapy with long breaks to allow recovery from the harmful side effects, there is now a shift in thinking towards the view that more compressed or accelerated schedules of drug administration using much smaller individual doses than the MTD would be more effective, not only in terms of reducing certain toxicities, but perhaps even improving anti tumour effects as well . The most recent refinement of this concept is called "metronomic" chemotherapy, which refers to the frequent, even daily, administration of chemotherapeutics at doses significantly below the MTD, with no prolonged drug-free breaks.
Metronomic chemotherapy has been defined as a variation of dose-dense therapy with the important exception that it is not necessarily dose intense, the cumulative dose might actually be significantly less or equal to MTD-based chemotherapy, thus reducing or perhaps even eliminating in some cases serious drug-induced toxicities, and hence the need for growth-factor support . Unlike MTD chemotherapy that presumably mainly targets (proliferating) tumour cells, frequent or continuous low-dose chemotherapy appears to inhibit preferentially the endothelial cell activity of the tumours' growing vasculature . The basis of this surprising selectivity may have a number of mechanisms.
One is believed to involve inhibition of tumour angiogenesis as a result of chemotherapeutic drug targeting of dividing endothelial cells found in growing tumour-associated blood vessel capillaries.
Moreover, human vascular endothelial cells in vitro are sensitive to the growth inhibiting effects of ultra low concentrations of paclitaxel, in contrast to many other normal cell types or tumour cell types. These effects can be amplified by long-term, continuous exposure, which can also result in apoptosis of endothelial cells . Such effects may be secondary to induction of an endogenous inhibitor of angiogenesis, thrombospondin-1, induced by low-dose chemotherapy by as yet unknown mechanisms, rather than direct inhibition of endothelial cell growth, or survival . In addition, the mobilization, viability and levels of angiogenesis contributing to circulating endothelial progenitor cells may be strongly suppressed, and in a sustained manner, by metronomic chemotherapy .
Among the numerous preclinical schedules using different cytotoxic drugs, the oral and daily low-dose administration of cyclophosphamide has been extremely successful in human prostate and breast cancer xenograft mouse models. It has also been successful in spontaneously arising islet cell pancreatic carcinoma, even when the treatment is initiated on advanced, late stage bulky tumours, at least when combined with a targeted anti-angiogenic drug and upfront MTD chemotherapy [11, 12]. This efficacy is accompanied by absent or low-grade toxicity on tissues otherwise highly sensitive to the respective regimen of the same drug.
For these reasons we used oral daily low-dose cyclophosphamide for our patient, who because of her bad performance status was against undergoing another traditional line of chemotherapy. To our knowledge this is the first report showing the feasibility and the efficacy of cyclophosphamide metronomic chemotherapy for palliative treatment in advanced epithelial ovarian cancer. This is a simple therapy that can be administered on an outpatient basis. Our patient received treatment while performing normal daily activities at home and a high quality of life was maintained.
Probably this good clinical response was due to the anti-angiogenetic effect of cyclophosphamide in blocking progression of the disease without any toxicity, together with successful colostomy to improve the general condition of the patient.
The hypothetical anti-angiogenic and anti-tumour effects of low-dose metronomic chemotherapy regimens in mice can be amplified significantly by the concurrent administration of a second drug that is highly specific for activated endothelial cells (e.g., antibodies to vascular endothelial growth factor receptor-2 [VEGFR-2], PEX [C-terminal hemopexin-like domain of matrix metalloproteinase (MMP)-2], anti-VEGF antibodies, and anti-endoglin antibodies). Experiments testing such 'metronomic' schedules of chemotherapy alone or combined with anti-VEGF compounds showed promising anti-tumour activity . A recent phase II study evaluated bevacizumab and low dose 'metronomic' oral cyclophosphamide and found encouraging response rates in 29 patients (6 partial response, 17 stable disease, 6 progressive disease) and progression-free survival at 6 months for 47% of the patients . Despite the encouraging preliminary results reported at the 2005 Meeting of the American Society of Clinical Oncology, this non randomized study presents several limitations: the small number of patients evaluated, the lack of randomization that does not allow discrimination between the activity of 'metronomic' chemotherapy and that of the selective anti-VEGF compound; and, finally, the fact that no correlation with potential markers of angiogenic activity was determined. Currently no definitive clinical data are available because no randomized trial comparing conventional versus metronomic with dose-dense schedules has been concluded .