The "Win-Win" initiative: a global, scientifically based approach to resource sparing treatment for systemic breast cancer therapy
Ahmed Elzawawy1,2,3,4,5
1Clinical Oncology Department, Faculty of Medicine, Suez Canal University, Egypt 2Alsoliman Radiation Oncology Unit, Port Said, Egypt 3Early Detection and Cancer Chemotherapy Unit, Port Said General Hospital, Egypt 4ICEDOC: International Campaign for Establishment and Development of Oncology Centers & ICEDOC's Experts in Cancer without Borders, USA 5SEMCO: South and East Mediterranean college of Oncology, Egypt World Journal of Surgical Oncology 2009, 7:44doi:10.1186/1477-7819-7-44
The electronic version of this article is the complete one and can be found online at: 2009 Elzawawy; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract
Worldwide, breast cancer is the most frequent malignancy among females. Its incidence
shows a trend towards an increase in the next decade, particularly in developing countries
where less than of 5% of resources for cancer management are available. In most breast
cancer cases systemic cancer treatment remains a primary management strategy. With
the increasing costs of novel drugs, amidst the growing breast cancer rate, it can be safely
assumed that in the next decade, newly developed cancer drugs will become less
affordable and therefore will be available to fewer patients in low and middle income
countries. In light of this potentially tragic situation, a pressing need emerges for science-
based innovative solutions.
In this article, we cite examples of recently published researches and case management
approaches that have been shown to lower overall treatment costs without compromising
patient outcomes. The cited approaches are not presented as wholly inclusive or definitive
solutions but are offered as effective examples that we hope will inspire the development
of additional evidence-based management approaches that provide both efficient and
effective breast cancer treatment
We propose a "win-win" initiative, borne in the year of 2008 of strategic information
sharing through preparatory communications, publications and our conference
presentations. In the year 2009, ideas developed through these mechanisms can be
refined through focused small pilot meetings with interested stakeholders, including the
clinical, patient advocate, and pharmaceutical communities, and as appropriate (as
proposed plans emerge), governmental representatives. The objective is to draw a realistic road map for feasible and innovative scientific strategies and collaborative actions that could lead to resource sparing; i.e. cost effective and tailored breast cancer systemic treatment for low and middle income countries. Conclusion
The intended result would assure sustained affordability and accessibility in breast cancer
systemic therapy for patients in low and middle income countries. As an added benefit, the
example of breast cancer could be expanded to include other cancers in diverse settings
around the world.
By the year 2020, 70% of the twenty million new cancer cases will occur in countries that collectively have only five percent of the global resources for cancer control Breast cancer is the most frequent cancer among females. Globally the incidence of breast cancer is increasing, and the rate of increase is highest in developing countries. This trend provides every indication that the need for systemic anticancer agents will continue to increase over the next ten years. The pharmaceutical companies are developing increasingly expensive novel anticancer molecules with no indication that the rapidly escalating cost of new treatments will ease in future. Improvements in the overall and disease-free survival rates and quality of life are not commensurate with the soaring costs of cancer treatment. The major markets for the leading pharmaceutical industry are in the United States, Western Europe and Japan; and while these regions may be able to meet the increased cost of treatment, it can be safely assumed that the cost of novel anticancer drugs will continue to expand as an insurmountable obstacle to care for an ever greater proportion of cancer patients in Low and Middle Income Countries (LMCs) where the majority of the world's population live. This discomforting reality confronts us with difficult challenges that merit the spirited engagement of regional and international health leaders. Breast Cancer, with its predictable increase in incidence, and multiple available, effective treatment options provides an excellent starting point for developing economically sustainable cancer control strategies that could be tailored in LMCs for other forms of cancer as well. Aims and hopes
It is our aim to establish a scientific initiative to expand availability of resource sparing
Breast Cancer Systemic Therapy (BCST) and hope that such strategy may meet the
demand for effective, affordable breast cancer care for patients who would otherwise be
left without scientifically valid treatment options.
This communication reviews examples of recent and ongoing scientific researches and suggestions that could lead to lower costs of BCST without compromising overall patient outcomes. These findings, this summary, and subsequent detailed publications, and conference presentations can provide a basis for pilot meetings to launch a "win-win" scientific initiative based on cooperation and collaboration of stakeholders; whereby markets are created or maintained for effective cancer therapies, and patients are assured access to these interventions regardless of where in the world they reside. 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 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 colleagueis 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 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
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 cell 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 More studies are needed in this field.
- There are greater possibilities in using oral cancer drugs 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 While an example of new applications for relatively old and less expensive drug is the use of Cisplatin in triple negative breast cancer patients 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 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
a) To tailor treatment to patients, community and tumor factors (based on clinical,
pathological and biological factors).
b) To address economic considerations, cost-effectiveness and quality of life issues within each community or region. 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. 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
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.
Future directions and conclusion
On behalf of ICEDOC's Experts in Cancer without borders (ICEDOC is The International Campaign for Establishment and Development of Oncology Cente we propose "The win-win initiative". It starts with communications and publications. Then, we propose to hold small pilot working meetings with representatives of interested parties and willing leading pharmaceutical companies. Next, we would look to larger meetings and collaborative actions with a broader range of participants. • To create a Think Tank or what Franklin Roosevelt described as "A Brain Trust", opened for innovative scientific thoughts and ideas that could lead to cost -effective systemic treatment for more breast cancer patients in LMCS. • To develop a strategy to coordinate ongoing efforts and initiatives. • To recommend areas of innovative clinical research that address the needs of LMCs • To identify key components and infrastructure needs in LMCs to support research • To determine the key barriers to pharmaceutical companies in investing in LMCs research and provide a strategy to overcome those barriers. -Investment in creating infrastructure will create new markets -Old drugs can bring new profits and its use may pave ways for novel drugs. The outcome of the communications and meeting for the year 2009 would be a road map for the win-win initiative • An actionable strategy opened for contribution, collaboration and coordinating efforts and ideas. • Formation of a collaborative task force group that aims at more availability and affordability of systemic cancer therapy in LMCs. • A published report on recommended research and key components. Finally, no leadership role, or claim to invention is being made. There are many key players and stakeholders in the world. Coordination and cooperation are needed. Competing interests
The author declares that they have no competing interests. Acknowledgements
I thank Dr. Pamela Haylock, Secretary General of ICEDOC, Texas, USA and Mr. Dan Rutz, (ICEDOC), Sr.Communications Specialist, National Center for Health Marketing (NCHM), Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, USA and former senior medical correspondent of CNN, USA for their valuable advice in editing the text. Also, I present special thanks to Dr. Hossam Elbahaie, (ICEDOC), Port Said, Egypt, for his assistance in preparing the manuscript. References
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