A) Relatively recent drugs
The duration of the course trastuzumab (Herceptin®)
A trial of 9-weeks of trastuzumab treatment has been compared to 52 weeks treatment. Both arms were similar in outcome [3]. We assume that these preliminary results need to be confirmed in a larger sample. In addition to the cost savings from the shortened treatment interval with trastuzumab, we could expect further reduction in costs due to fewer hospitalizations and less need for supportive treatment.
Evidence based cost effective prescription of drugs
Limiting use of trastuzumab (Herceptin®) to women with localized disease and known HER2/neu-positive status, as suggested by Yarney and colleagues[4] is a cost-effective use if resources are available, even with the additional costs of HER2/new testing.
Low dose, prolonged infusion gemcitabine
The encouraging response of phase I-II trials of low dose gemcitabine in prolonged infusion in the treatment of certain solid cancers, e.g. non small cell lung cancer, breast, pancreas and bladder cancers deserves further investigation. The explanation for these responses caused by low doses (of 250 mg and 180 mg/m2 for 6, 24 hours respectively) lies in the saturation of deoxcytidine kinase which occurs after short infusion at conventional doses. This enzyme is needed for conversion of gemcitabine into its active form gemcitabine triphosphate. While short usual infusion leaves most of the drug unmetabolized, prolonged infusion apparently leads to a higher intracellular concentration of the active metabolite [5]. More studies are needed in different clinical settings to verify the effectiveness and cost implications of extended (six hours infusion), using reduced drug dosages.
The Glivec® International Patient Assistance Program (GIPAP)
is a worldwide program to provide imatinib (Glivec®) at no cost to patients with chronic myelogenous leukemia (CML) or gastrointestinal stromal tumor (GIST) in 81 countries who would not otherwise have access to comprehensive reimbursement for the treatment[6]. This example could be explored for other drugs with other parties.
Interrupted courses of treatment
Aromatase inhibitors (AI), when given as interrupted course, probably would also be effective as continuous therapy after prior tamoxifen and/or AI treatment. The hypothesis is that AI interrupted courses may cause estrogenic stimulation and enhance response of residual resistant cells[7]. We cite this example not for application as a finally proven scientific and economically sound approach, but as an example of the possibilities for interrupting the continuity of a treatment course without compromising the result. The principle implied by this intriguing example merits further study.
Pharmacokintetic based studies in lapatinib therapy
According to recent studies, it is shown that lapatinib when taken orally with food -not on an empty stomach as cited frequently–yields an increased plasma level. Lower oral doses administrated with food and with grapefruit juice could effectively inhibit the enzyme CYP3A and thereby could provide comparable effect. Up to 80% of the dose and the cost of the drug could be reduced by this approach [8]. More studies are needed in this field.
- There are greater possibilities in using oral cancer drugs [9]. The oral route for cancer therapy may decrease costs due to fewer hospital inpatient admissions and outpatient chemotherapy intravenous sessions. Obviously, this approach requires careful study in diverse communities. Questions of cost-effectiveness and best practices relating to oral and self-administered agents are of considerable interest in LMCs where facilities and providers may be particularly scarce.
B) Essential and conventional systemic cancer drugs
The following concise points relate to what some refer to as "the essential and conventional" systemic cancer drugs:
Fortunately, the pharmaceutical arsenal of "essential and conventional systemic anticancer drugs" still constitutes the basis of this treatment modality. In addition, these conventional drugs are relatively inexpensive. For breast cancer the list would include CMF (Cyclophosphamide, Methotrexate and 5 Fluorouracil), FAC (5 Fluorouracil, Doxorubicin and Cyclophosphamide), Tamoxifen and Ovarian ablation.
Innovative strategic thinking and approaches should be encouraged to improve the availability and accessibility of first-line systemic anticancer treatments as part of the comprehensive breast cancer control plan for underserved countries. An example of novel chronology and mode of drug administration that tests additional mechanisms of actions and indications is the metronomic use of prolonged, low oral doses of cyclophosphamide and methotrexate as palliative breast cancer treatment [10]. While an example of new applications for relatively old and less expensive drug is the use of Cisplatin in triple negative breast cancer patients [11].
Generic equivalents for off-patent drugs
offer the possibility of less expensive treatment. However, the quality and bioequivalence of generics used in developing countries should be assured by regulations or developing a transparent system for international testing. To overcome difficulties in achieving large scale feasibility in quality control, we suggest working at the small scale level to test random samples or pilot settings upon invitation from the local authorities in some developing countries.
Pharmcogenomic studies
Tamoxifen requires enzymatic activation by CYP 450 enzymes for the formation of clinically relevant metabolites 4-OH-tamoxifen and endoxifen which both have a greater affinity to the estrogen receptors and ability to inhibit cell proliferation when compared to the parent drug. The key enzyme in this bio-transformation is the CYP2D6. Recent pharmacological and clinical pharmacogenetics evidence suggests that genetic variants and drug interaction by CYP2D6 inhibitors influence plasma concentration of active tamoxifen metabolites and thereby improve treatment outcome of breast cancer patients treated by adjuvant tamoxifen [12]. It is speculated that the benefit of 5 years of adjuvant tamoxifen may even exceed that achieved through "upfront" AI treatment in postmenopausal CYP2D6 wt/wt genotype patients. Despite its expenses and technological requirements, we assume that, CYP2D6 genotyping prior to treatment could open new avenues for individualization of endocrine treatment. Hence, unnecessary treatment and costs extending over years could be avoided. However, we stress the need for wider studies to test cost effectiveness in different communities and the feasibility of technology transfer via international scientific cooperation.
Another approach would be to help develop the required infrastructure for the clinical research and trials with pragmatic goals that would be ideally suited to LMCs, few suggestions for this are:
For older drugs
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a)
To tailor treatment to patients, community and tumor factors (based on clinical, pathological and biological factors).
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b)
To address economic considerations, cost-effectiveness and quality of life issues within each community or region.
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c)
To test innovative combinations or different schedules of administration of older (and relatively cheaper) drugs that might lead to previously improved therapeutic index or applicability to specific societies. Such investigations usually are not supported by pharmaceuticals companies and international conferences, although they might be of benefit to science and cancer patients in LMCs.
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d)
To test new uses of a relatively old and less expensive drugs (as earlier cited in the use of Cisplatin in triple negative breast cancer patients).
For novel drugs
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e)
Conducted with appropriate ethical guidelines and international oversight, clinical research would provide broader and more transparent access to novel drugs, and would enhance professional education and training in LMCs. Such an approach would assist companies in streamlining the development of new drugs.
