RATIONING OF HIGH DOSE CHEMOTHERAPY WITH PERIPHERAL BLOOD STEM-CELL TRANSPLANTATION (PBSCT) FOR BREAST CANCER IN TAIWAN
Agnes L.F. Chan,
Department of Pharmacy,
Chi Mei Medical Center,
BSc Pharm, MHA.
An-I Liang, MD,
Vice President of Chi Mei Medical Center,
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To evaluate the high-dose of chemotherapy with autologous stem-cell support for breast cancer from clinical and ethical perspectives on rationing.
The case of a 50- year- old woman with infiltrating ductal carcinoma of the right breast with more than 10 auxiliary lymph nodes metastasis raises controversy of how to ration high dose chemotherapy with peripheral blood stem-cell rescue.
Should a patient
in early stage breast cancer with poor prognosis or with metastatic breast cancer
receive high-dose chemotherapy followed by peripheral blood stem-cell transplantation
(PBSCT). Indispensable clinical information including treatment guidelines,
risk-to-benefit ratios, disease free survival and overall survival rate as well
as cost effectiveness data should be evaluated before making the decision to
transplant or not to transplant. Unless more clinical data to support the use
of high-dose chemotherapy in patients with breast cancer shows significant improvement
in disease free survival compared with conventional-dose chemotherapy, the associated
morbidity, mortality and cost of treatment will not be acceptable. From a clinical
perspective, it is not necessary to transfer transplantation technology rapidly
from the academic teaching hospitals before results of large, randomized trials
and good pharmacoeconomic data are available. There is no obligation to provide
medically futile care. In the face of rising health care expenditures, rationing
seems to be an effective way to control health care costs.
There are some recent pharmacoeconomic evaluations of total cost, cost-effectiveness ratios of patients receiving high-dose chemotherapy and peripheral blood stem-cell support, but it is controversial.1-3
An ethical argument for rationing cannot be made because of the lack of a clear clinical and societal consensus on specific criteria for rationing of healthcare dollars. Clinical studies on efficacy, survival rate and risk of contamination are very limited.4 The decision to use high-cost, high-risk therapy in the case presented is made according to treatment guidelines available in an individual hospital. This supposes that the patient consented to therapy and believes that there is little to lose with ABMT and that it is the only reasonable approach in an otherwise hopeless situation.
Many cost containment strategies for the reimbursement of drug expense were established recently by the Bureau of National Health Insurance in Taiwan to cope with the continuously increased health care expenditures which has risen at about twice the rate of inflation last 10 years period.5a The main strategies such as case payment, shrinking reimbursement for in-patient care in the 1990s to reduce the average length of stay have failed to control hospital costs. Additionally, factors of population growth, waste of drug resources, new technologic innovation, the aging of the population, the rising cost of patient care, the increase in the number of breast cancer patients will be responsible for upward trends in expenditures5.
The continuing introduction of new technologies, such as transplantation generates a virtually unlimited demand for medical services on the one hand, while on the other, these new technologies are often not completely evaluated and studies of the cost to benefit ratios are controversial. Rationing while widely advocated, might be the effective way to control health care costs6-8 and can be broadly defined as "societal toleration of inequitable access to health services acknowledged to be necessary by reference to appropriate clinical guidelines.9 The continued progress in medical technology, the increasing demands of patients, and the consideration of health care cost will result in different definition of rationing. Physicians may not agree with rationing or restricting access because their focus is on patient care and regard for the individual. This article, therefore, will describe a case receiving high cost, high risk therapy with accompany by an analysis from the clinical standpoint and ethical perspectives on rationing.
A 50 year-old woman was diagnosed to have infiltrating ductal carcinoma of the right breast with 16 auxiliary LN metastasis. She took estrogen therapy for about ten years because of a total hysterectomy. The estrogen receptor (ER) and progesterone receptor (PR) was unknown at that time. She had received 2 cycles of adjuvant chemotherapy with cyclophosphamide, epirubicin and 5-fluoruracil (CE60F) regimen in Oct 1998. This was then followed by intensive-chemotherapy of CE120F in Nov. 1998 and peripheral blood stem cells harvest. High dose chemotherapy with PBSCT was prepared , unfortunately, local recurrence was noted in Jan. 1999. A radical mastectomy was performed and pathology revealed that tumor size was larger (6×4.5×3cm) than before (4×4×3cm) and 7 more auxiliary LN had metastasized. ER and PR both were negative as well as intra-tumor lymphavascular permeation and perineural invasion. The physician decided to utilize high dose chemotherapy with one cycle of carboplatin, thiotepa and cyclophosphamide (CTCb) regimen and peripheral blood stem cell support on Feb. 1999: (total 4.493x 1011 cells/kg CD34+ cell was infused).
The patient developed neutropenic fever and septic shock after high dose chemotherapy and finally she died of acute renal failure and acute respiratory distress syndrome. According to the review of a total of 4 patients who were suffering from infiltrating ductal breast cancer stage II to III, HDC-PBSCT was used as an adjuvant therapy. After the median follow-up period of 2-3 years, two patients died of the same complications during hospitalization as the above-mentioned case, but two patients had about 2-3 years of disease-free survival. We cannot conclude the reasons of low survival rate, so we stopped the treatment strategy till now. This article are intended to examines the clinical and ethical considerations of whether high dose chemotherapy with peripheral blood stem cell support should be continued as an adjuvant therapy for high- risk breast cancer patients who come to our institution.
HDC-PBSCT for breast cancer still remains inconclusive at best.. If the decision as to whether to use high dose chemotherapy with PBSCT includes: (1) overall survival rate and quality of life; (2)patient preferences and cost of care; (3) the benefits versus risks of Therapy; and (4)treatment complications; then the introduction of autologus peripheral blood stem cells supported high-dose chemotherapy would not become standard consolidation therapy for patients with metastatic breast cancer and standard adjuvant therapy for patients with high-risk breast cancer outside clinical studies. Additionally, the only information for stem-cell supported high dose chemotherapy was from pilot and phase I/II. Studies,11-12 although the four randomised studies of high-dose regimens with stem cell support as adjuvant therapy for high risk breast cancer included a total of 1467 patients.13-15 (CALGB[Peters W Petal], SBG 9401[Bergh J et al], Dutch [Rodenhuis et al, Lancet 1998;352:515-21] and MD Anderson [Hortobagyi GN et al, J Natl Cancer Inst 200; 92:225-333]. None of these studies showed a statisically significant survival advantage for high dose regimens with stem-cell support as consolidation therapy.
What then, should be done about the
high-dose stem-cell-supported strategy? The completed and updated phase III
studies should be allowed to "mature" further and be updated.16-18
The results of recent study by Stadtmaner et al were negative with respect to
improvement in disease-free or overall survival.19 Also a very large trial of
adjuvant chemotherapy for breast cancer, in which two or four times the usual
combined dose of alkylating agents had no advantage over conventional doses
of these drugs, the conclusion was that the clinical benefit for the high-dose
chemotherapy and HDC-PBSCT is not known and all patients should be enrolled
onto a clinical trial. 20-22
In order to provide more safe and effective treatment, the following problem-solving measures are suggested to resolve the dilemma as to whether to use HDC-PBSCT as an adjuvant therapy. This approach includes: identifying the patient's problem; collecting patient-specific and essential information; generating and evaluating the alternatives from a risk-benefit and economic Perspective; and ¯implementing the recommendations. The dilemma in this case can be described as should a patient who developed local recurrence during the course of dose intensified chemotherapy continue to receive the procedure of HDC-PBSCT.
As mentioned above in step and, patient specific data are collected, which shows a 50-year-old woman with a diagnosis of infiltrating ductal carcinoma with 16 auxiliary LN. She had received courses of adjuvant chemotherapy with cyclophosphamide 600ug/m2, epirubicin 60mg/m2 and 5-Fu 600mg/m2. The patient's history was compiled with the hospital tumor board guidelines on the use of HDC-PBSCT for high risk primary breast cancer patients who have the number of auxiliary LN metastases of more than 6 or ratio of LN(+) of metastasis ½, no more than 55 years of age, performance status ECOG 2.
The National Health Insurance plan
in Taiwan covered drug expenses, however, the part of peripheral blood stem
cell transplantation is not covered. The hospital physician supposed that her
expected benefits would be at least 5 years disease-free survival and prolonged
overall survival compared with conventional therapy. Actually, the patient died
within one week. We suggested that physicians should assess the patient from
both the positive and negative sides with convincing evidence available to date
whether HDC-PBSCT is superior to conventional-dose chemotherapy in any stage
of breast cancer. 32
Clinical information regarding breast cancer and its treatment is an arena filled with controversy. High dose chemotherapy with autologous stem cell support as applied to the treatment of breast cancer has shown promise for over 15 years. There are still some negative randomized trials concluded recently that high dose chemotherapy with autologous stem cell support does not result in further reduction in risk of recurrence, but adds substantial morbidity by an increased risk of complications.27
The recent studies of HDC-PBSCT did not show significant evidence that HDC is superior to conventional dose chemotherapy indicated outside of clinical trial.28-29 A prospective randomized phase III study will be crucial to complete and obtain the data when all studies reach a mature status to determine the efficacy and effective of high dose chemotherapy and autologous stem cell in breast cancer.30-31 Regarding the third step, it involved generating and evaluating the alternative from the economic and risk-benefit perspective. In this case, a cost-effectiveness analysis has indicated an unfavorable ratio, assuming 5 years of life gained. The most sensitive assumption was the potential gain in life expectancy. Thus, if patients gained only one year of life, there was an increase in the cost effectiveness ratio. An estimated life expectancy for this case resulted in a decreased cost-effectiveness ratio. In evaluating the risk versus benefit of PBSCT, it is noted that high dose chemotherapy will induce toxicity e.g. neutropenia and thrombocytopenia and even sepsis. The benefits and survival rate from HDC-PBSCT appear limited as compared to standard chemotherapy.
The last step involves implementing the recommendations. The patient met the criteria of the hospital's guidelines and PBSCT was performed according to the guidelines. If the physician takes the likelihood of survival and recurrence into consideration, HDC- PBSCT would not be used, unless the survival rate and cost-effectiveness ratio is significantly higher than conventional chemotherapy. At least, it was not readily accepted for a prolonged period of time in spite of many randomized studies. Recently, the challenge is to evaluate modalities that will limit the potential for re-growth by eliminating minimal residual disease and thereby reduce unacceptable recurrence rates. These include new chemotherapy agents, antibodies directed at molecules sometimes over expressed on breast cancer cells, non-cross resistant chemotherapy , apoptosis inducing agents, targeted radiation or cytotoxins, small molecules aimed at selective metabolic pathway inhibition, or combinations of these.34
The decision to use high cost and high-risk treatment for breast cancer patients reflects ethical dilemmas that is in an ethical framework of patient choice, evidence of effectiveness and equity 35. The Taiwan Health Authority should set up a priorities forum as quickly as possible to provide advice on rationing decisions and on an ethical framework. Physicians in Taiwan are not usually asked to consider whether particular services are "worth" the cost of providing them besides considering the clinical implications of their decisions. Traditionally, the majority of physicians do not have the concept of rationing. They have, by training and tradition, considered a moral obligation to use their powerful pen to access tests and treatments of contemporary, scientific medicine that they believe is needed to help the patient. In the face of rising expenditures, the concept of rationing and ethics should be started to educate both physicians and patients. They must acknowledge that no resource, including health care, is unlimited.
In this case, there is an ethical dilemma regarding the provision of treatment of high-technique with potentially limited benefits and rare solid evidence of the additional length of life that the treatment brings. It is at this point that questions of ethics begin to appear. Some people agree with the explicit government policy to improve the health of the population as a whole by increasing the length of peoples lives and the number of years people spend free from illness but it does not sit easily with the notion of justice. An adjusted life year (QALY) will be used as an approach for rationing because in QALYs and other such devices actually lie a deep moral concern. Since there is a need for it, the physicians have little to say about the justice of any particular way of distributing healthcare.
The advocates of rationing are in the USA and United Kingdom. This is because
of the continued escalation of their health care costs. The Health and Human
Services department in the United States and the National Health Service in
the United Kingdom might be forced to limit expenditures by restricting services.
A similar phenomenon is appearing in Taiwan. The continual introduction of new
and expensive high technology generates a virtually unlimited demand for medical
services, which may result in overuse of services and inefficient use of facilities.
If we restrict the use of high-cost technology when it may have limited benefit
for the patient, it seems unfair for them. However, if the response of the patient
to receiving new and expensive technology is not good, who should determine
whether it is to be continued or not? We believe that rationing from a medical
and ethical perspective may be the effective way to control the overuse of new
medical technology. In addition, we in Taiwan, believe that billions of US dollars
are wasted for the practice of defensive technology and utilization of new drugs.
In order to eliminate or deny inefficient use of new technology or medicine
with limited benefits, the legitimate guidelines should be developed by The
Taiwanese health authority. The methods of evidence-based medicine can be viewed
as a mechanism for rationing and tools for improving the quality of rationing
1. R. Kath. Pharmacoeconomic evaluation of high-dose chemotherapy and peripheral
blood stem cell support in high-risk or poor-prognosis malignancies. J Cancer
Res Clin Oncol 1998;124:288-290.
2. Lucey C. New approach to administrative medical deciscon-making: evidence-based medicine using high dose chemotherapy/bone marrow transplant for breast cancer. South Med J 1998;91(2):196-201.
3. Dix SP. High-dose chemotherapy with autologous stem cell rescue in the outpatient setting. Oncology (Huntington) Feb 2000;14(2):171-85,185-6,191-2.
4. Gianni AM. Siena S. Efficacy, toxicity, and applicability of high-dose sequential chemotherapy as adjuvant treatment in operable breast cancer with 10 or more involved auxiliary nodes; five year results. J Clin Oncol 1997;15:2312-21.
5. William B. Hospital cost containment in the 1980s. N Engl J Med 1991;324:1037-42.
5-a.Country Report on Economic Policy and Trade Practices: Taiwan.
6. Chris Heginbotham C. Rationing. BMJ 1992;304:496-499.
7. Arnold S. The trouable with rationing. N Engl J. Med 1990;323(13):911-913.
8. Arnold S. Is rationing inevitable? N Engl J Med 1990;322(25):1809-1810.
9. David M. Rationing by patient choice. JAMA 1991;265(1):105-108.
10. Hadorn DC, Book RH. The health care resource allocation debate:Defining our terms. JAMA 1991;266:3328-3331.
11. Blum JL, Jones SE. Guidelines for systemic therapy of early stage breast cancer. Breast Cancer Res Treat 1997;43:259-276.
12. Peter W, Ross M. High dose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer. J Clin Oncol 1993;11:1132-43
13. Antman K. Rowlings P. High dose chemotherapy with autologus hematopoietic stem-cell support for breast cancer in North America. J Clin Oncol 1997;15:1870-79.
14. Antman KH. Critique of the high-dose chemotherapy studies in breast cancer: a positive look at the data. J Clin Oncol 1999;17 (suppl 11):30-34.
15. Hortobagyi GN. High-dose chemotherapy for primary breast cancer:facts versus anecdotes. J Clin Oncol 1999;17 (suppl 11):25-29.
16. Bergh J. Where next with stem-cell-supported high-dose therapy for breast cancer? Lancet 2000;355:944-945.
17. Basser RL. New developments in high-dose chemotherapy for breast cancer. Recent Results Cancer Res 1998;152:355-67.
18. Jentsch K, Hoffken HG. High dose chemotherapy and peripheral blood stem cell transplantation in breast carcinoma. Zentralbl Chir 1998,123 Suppl 5:162-4.
19. Stadtmauer EA, O Neill A. et al. Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem cell transplantation for metastatic breast cancer. New Engl J Med 2000;342:1069-1076.
20. Fisher B, Anderson S, et al. Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer:findings from national surgical adjuvant breast and bowel project 13-22. J Clin Oncol 1997;15:1858-69.
21. Henderson IC, Berry D, Demetri G, et al. Improved disease-free (DFS) and overall survival from the addition of sequantial paclitaxel but not from the escalation of doxorubicin dose level in the adjuvant chemotherapy of patients with node-positive primary breast cancer. Prog Proc Am Soc Clin Oncol 1998;17:101a. bstract.
22. Lippman M. High dose chemotherapy plus autologous bone marrow transplantation for metastatic breast cancer. New Engl J Med 2000;342(15):1119-1120.
23. Buzdar AU, Hortobagy GN. Hortobagy. Recent advances in Adjuvant therapy of breast cancer. Semin Oncol 1999;26(suppl 12):12-27.
24. Bezwoda WR, Seymour L, Dansey R. High-dose chemotherapy with hematopoietic rescue as primary treatment for metastatic breast cancer: a randomized trial. J Clin Oncol 1995;13:2483-89.
25. Bezwoda WR. Randomised, controlled trial of high dose chemotherapy versus standard dose chemotherapy for high risks, surgical treated, primary breast cancer. Proc ASCO 1999;18:2(abstr 4).
26. Bezwoda WR. Randomised controlled trial of high dose chemotherapy versus standard dose chemotherapy for high risk, surgically treated, primary breast cancer. Eur J Cancer 1999;35(suppl 4):230 (abstr 902).
27. Rodenhuis S. The status of high-dose chemotherapy in breast cancer. Oncologist 2000 Oct;5(5):369-375.
28. Hortobagyi GN, Buzdar Au, et al. Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma. J. Natl. Cancer Znst. 2000,92(3):225-33.
29. Hudis CA, Munster PN. High dose therapy for breast cancer. Semin Oncol 1999;26(1):35-47.
30. Gluck S. Stewart D. High-dose therapy in breast cancer: out of favor but not of promise. Bone Marrow Transplant 2000,25(10):1017-9.
31. Baynes RD, Dansey RD. High dose chemotherapy and autologous stem cell transplantation for breast cancer. Cancer Investigation 2000;18(5):440-455.
32. Hillner BE, Smith T. Efficacy and cost-effectiveness of autologous bone marrow transplantation in metastatic breast cancer. JAMA 1992;267:2055-2061.
33. Bergh J. High-dose chemotherapy for breast cancer. Lancet 2000;356:595-596.
34. Hope T, Hicks N. Rationing and the health anthority. BMT 1998;317(7165):1067-1069.
35. Ray D, Baynes, Roger D et al. High-Dose Chemotherapy and Hematopoietic Stem Cell Transplantation for Breast Cancer: Past and Future? Semin Oncol 2001; 28:377-388
36. Petrou S, Wolstenholme J. A review of alternative approaches to health care resource allocation. Pharmacoeconomic 2000;18(1):33-43.
37. Norheim, O F. Health care rationing-are additional criteria needed for assessing evidence based clinical practice guidelines?BMJ 1999;319(27):1426-1429.