Bone Marrow Transplantation: International Comparisons of Availability
and Appropriateness of Use (Chapter Report, 03/07/94, GAO/PEMD-94-10).

The U.S. health care system has been criticized for encouraging the
"overuse" of the newest and most costly medical treatments. This report
examines the use of one complex, expensive, high-technology medical
treatment--allogeneic bone marrow transplantation--in the United States
and in nine foreign countries: Australia, Canada, Denmark, France,
Germany, the Netherlands, New Zealand, Sweden, and the United Kingdom.
During this procedure, which can cost upwards of $125,000 in the United
States, the patient's bone marrow is destroyed and replaced with marrow
from a healthy donor. GAO found that U.S. leukemia patients were less
likely than those in six of the foreign countries to receive bone marrow
transplants in time to potentially cure them. Although U.S. doctors
perform the operation about as frequently as those in other
industrialized nations, they often wait until the disease is more
advanced and the patient's chances for recovery are less promising.
These findings challenge the assumption that the United States relies
more than other medically advanced nations on new and complex
treatments. U.S. patients, for good or ill, have not been the most
likely to receive a transplant for any of the clinical conditions
examined.

--------------------------- Indexing Terms -----------------------------

 REPORTNUM:  PEMD-94-10
     TITLE:  Bone Marrow Transplantation: International Comparisons of 
             Availability and Appropriateness of Use
      DATE:  03/07/94
   SUBJECT:  Comparative analysis
             Cancer
             Cancer research
             Health surveys
             Patient care services
             Health statistics
             Quality-of-life data
             Foreign governments
             Quality control
             Medical research
IDENTIFIER:  Australia
             Canada
             Denmark
             France
             Germany
             Netherlands
             New Zealand
             Sweden
             United Kingdom
             National Marrow Donor Program
             
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Cover
================================================================ COVER


Report to the Ranking Minority Member, Subcommittee on Health,
Committee on Ways and Means, House of Representatives

March 1994

BONE MARROW TRANSPLANTATION -
INTERNATIONAL COMPARISONS OF
AVAILABILITY AND APPROPRIATENESS
OF USE

GAO/PEMD-94-10

Comparisons of Availability and Appropriateness of BMT


Abbreviations
=============================================================== ABBREV

  ALL - Acute lymphoid leukemia
  AML - Acute myeloid leukemia
  BMT - Bone marrow transplant
  CLL - Chronic lymphoid leukemia
  CML - Chronic myeloid leukemia
  GVHD - Graft-versus-host disease
  HLA - Human leukocyte antigen
  IBMTR - International Bone Marrow Transplant Registry
  IARC - International Agency for Research on Cancer
  MSD - Matched sibling donor
  OECD - Organization for Economic Cooperation and Development
  SEER - Surveillance, Epidemiology, and End Results

Letter
=============================================================== LETTER


B-255961

March 7, 1994

The Honorable William M.  Thomas
Ranking Minority Member
Subcommittee on Health
Committee on Ways and Means
House of Representatives

Dear Mr.  Thomas: 

Your predecessor as Ranking Minority Member, the Honorable Willis D. 
Gradison, Jr., asked us to examine differences in the availability of
health services and outcomes across developed countries.  This
report, one of two prepared in response to that request, describes
the variation among the United States and nine other medically
advanced countries in the use of allogeneic bone marrow
transplantation, an expensive and complex medical therapy.  The other
report, Cancer Survival:  An International Comparison of Outcomes
(GAO/PEMD-94-5), examines survival from four specific forms of cancer
across two locations, the United States and the Canadian province of
Ontario. 

If you have any questions or would like additional information about
this study, please call me at (202) 512-2900 or Robert L.  York,
Director of Program Evaluation in Human Services Areas, at (202)
512-5885.  Other major contributors are listed in appendix IV. 

Sincerely yours,

Eleanor Chelimsky
Assistant Comptroller General


EXECUTIVE SUMMARY
============================================================ Chapter 0


   PURPOSE
---------------------------------------------------------- Chapter 0:1

The emergence of each new medical "breakthrough" challenges health
care systems to contain the ever-growing cost of care while ensuring
patient access to the most beneficial treatments that medical science
has developed.  As the United States considers revising its health
care system, two very different perspectives on how our society
utilizes medical advances have entered into the debate.  On one side
are those who believe that U.S.  patients are afforded higher quality
care largely because they have greater access to the most advanced
medical technologies.  Others argue that many of the ills of the
health care system derive from the overuse of the newest and most
expensive medical treatments.  This report empirically examines
utilization patterns for one complex, costly, high-technology medical
treatment:  allogeneic bone marrow transplantation.  By comparing
these patterns across 10 countries, GAO presents a comparative,
international perspective on the use of a complex and expensive
therapy in the United States. 

This report responds to a request from the Ranking Minority Member on
the Health Subcommittee of the House Committee on Ways and Means.  It
describes how medically advanced, industrialized countries allocate
bone marrow transplants.  The evaluation, concerned primarily with
comparisons between the United States and the other countries, is
based on two dimensions of quality in health care:  availability and
appropriateness.  A study question addresses each of these
dimensions:  Do patients who need transplants get them?  and Are
transplants performed at a point that optimizes benefits while
minimizing risks? 


   BACKGROUND
---------------------------------------------------------- Chapter 0:2

Allogeneic bone marrow transplants treat diseases of the bone marrow
by destroying the diseased marrow of the patient (with either
radiation or chemotherapy) and then infusing healthy marrow from a
suitable donor.\1 Bone marrow transplants are both complex (requiring
advanced technologies) and expensive.  In the United States, patient
charges for allogeneic transplantation commonly exceed $125,000. 
Transplantation is recognized as a standard treatment option for
patients with many different diseases but is most often used in the
treatment of three types of leukemia:  chronic myeloid leukemia
(CML), acute lymphoid leukemia (ALL), and acute myeloid leukemia
(AML).  Although a transplant sometimes offers the only chance of
cure for patients with these diseases, it often leads to serious
complications and sometimes to death.  Therefore, its use requires a
careful weighing of potential benefits and harm to the patient. 

GAO obtained both incidence data for leukemia and the most recently
available data on all allogeneic transplants conducted in the United
States and nine other countries:  Australia, Canada, Denmark, France,
Germany, the Netherlands, New Zealand, Sweden, and the United
Kingdom.  The data on transplants came from the 208 centers that
performed them during the period 1989-91 and covered approximately
10,000 patients. 


--------------------
\1 The other major type of bone marrow transplant involves marrow
drawn from the patient, is referred to as an autologous transplant,
and is generally used to treat different diseases than those treated
by allogeneic transplants. 


   RESULTS IN BRIEF
---------------------------------------------------------- Chapter 0:3

GAO found that for the years 1989-91, the observed patterns placed
the United States near the middle of the 10 countries on both the
availability of transplantation and the appropriateness of its use. 
Along the dimension of availability, the position of the United
States varied, depending on the type of leukemia.  U.S.  patients
with chronic myeloid leukemia, a disease that could be cured only
with transplantation, were less likely to receive a transplant than
patients with that disease in six other countries.  U.S.  patients
with acute myeloid leukemia, however, were more likely to receive a
transplant than patients in seven other countries.  The relative
standing of the United States also varied along the dimension of
appropriateness.  The time from diagnosis to transplantation for U.S. 
patients with acute leukemia was relatively short.  Despite this
fact, the United States still had relatively more patients (with any
of the three leukemias) receiving transplants at less favorable
stages of the diseases than was true in most of the other countries. 
In the case of chronic myeloid leukemia, five other countries were
ahead of the United States in providing transplants in the early,
most favorable stage.  GAO found evidence that, relative to other
countries, some U.S.  patients for whom the treatment offers few
likely benefits received transplants, while others who could benefit
more did not. 


   PRINCIPAL FINDINGS
---------------------------------------------------------- Chapter 0:4

Overall, the most bone marrow transplants per capita were performed
in France, where the concentration was unevenly divided between a
high rate of transplants for the acute leukemias and a low rate for
chronic myeloid leukemia.  The patterns observed for Canada were
consistently with or ahead of those for the United States on the
dimensions of both availability and appropriateness, with a total
number of bone marrow transplants per capita slightly greater than
that of the United States.  The patterns for Germany showed that
availability was relatively low but that appropriateness measures
were more varied. 

The role of bone marrow transplantation in patient management differs
for each of the three leukemias.  Therefore, GAO's findings on
availability and appropriateness are discussed in more detail for
each disease. 


      CHRONIC MYELOID LEUKEMIA
-------------------------------------------------------- Chapter 0:4.1

The only curative therapy for CML during the 1989-91 period was bone
marrow transplantation, and this treatment was most likely to be
effective in the early stage of the disease.  Thus, allocating
transplant resources well for CML required having relatively high
availability (because transplantation was the only cure) and
providing transplants during the early stage (chronic phase) of the
disease. 

The U.S.  position for CML was roughly in the middle of the 10
countries for both availability and appropriateness.  Approximately a
third of recently diagnosed U.S.  patients who were under the age of
55 received bone marrow transplants during 1989-91 and 70 percent
received transplants while their disease was in the first chronic
phase.\2 Canada, Sweden, and the United Kingdom were the countries
that had both a higher rate of transplantation for CML than the
United States and a larger percentage of transplants performed while
patients were in first chronic phase. 


--------------------
\2 Patients aged 55 and older were generally not considered to be
suitable candidates for bone marrow transplants because the
complications that often accompany the treatment become more severe
with age. 


      ACUTE LYMPHOID LEUKEMIA
-------------------------------------------------------- Chapter 0:4.2

ALL, unlike CML, can often be cured with chemotherapy.  This fact is
reflected in the considerably lower transplantation rates that were
observed for ALL than for CML.  With the exception of France (which
had a rate 50-percent higher than any other country), the rates for
ALL patients generally fell along a continuum that ranged from 3
percent in Denmark to 15 percent in the United Kingdom. 

The relative effectiveness of chemotherapy in treating ALL also makes
it difficult to assess appropriateness for the full population of
patients.  Therefore, GAO focused on specific groups of transplant
patients in its examination of appropriateness.  One such group was
adult ALL patients, who, because they are less likely than children
to respond to chemotherapy, should be considered for transplantation
at earlier stages of the disease.  The United States, Germany, New
Zealand, and Australia were the four countries where a relatively
large proportion of adult ALL patients (approximately 20 percent)
received their transplant later in the progress of their disease. 
This pattern of late-stage transplants suggests a reliance on
chemotherapy beyond the point at which it is most likely to be
effective. 


      ACUTE MYELOID LEUKEMIA
-------------------------------------------------------- Chapter 0:4.3

The best approach for continuing therapy of AML patients who have
achieved a first complete remission has not yet been clearly
determined.  Part of the uncertainty stems from the difficulty in
identifying which patients will remain in remission with continued
chemotherapy (and therefore do not need a transplant) and which
patients will relapse and would benefit from a transplant.  Although
higher or lower rates do not, therefore, indicate which countries are
doing better in treating AML, there are criteria for evaluating the
observed patterns.  For example, the longer patients continue in
first remission, the more likely it is that they have been cured by
conventional chemotherapy.  Therefore, the greater the percentage of
transplants performed late in first remission, the greater the
likelihood that at least some patients who did not need them were
receiving transplants.  In addition, the prognosis for patients who
receive transplants when their disease is advanced is much poorer
than for patients receiving transplants at an earlier stage, so few
patients should receive transplants at a stage later than second
remission. 

Transplantation rates for AML were consistently higher than for ALL
and generally exhibited little variation.  Again, however, patients
in France were almost twice as likely to receive a transplant as were
AML patients in any other country.  For patients who received
transplants in first remission, those in France and the United States
were most likely to receive the treatment rapidly, though waiting
times were generally short for all countries.  As to appropriateness,
relatively few AML patients received transplants at an advanced stage
of their disease, although this occurred more frequently in the
United States than elsewhere. 


      IMPLICATIONS
-------------------------------------------------------- Chapter 0:4.4

These findings on availability and appropriateness, presented for the
first time in this report, apply specifically to allogeneic bone
marrow transplantation in the management of three diseases.  These
findings are thus quite narrow; however, this report has two larger
implications.  First, the data allow the 10 countries, and the bone
marrow transplant communities within each, to see how they compare
with other medically advanced societies on two dimensions of health
care quality.  Such comparisons can serve as either the impetus for
change (in situations where quality can be improved) or as evidence
that current practices and policies should be maintained. 

Second, GAO's findings raise questions about two prevalent views of
health care quality in the United States.  Both views, that high
quality is achieved through an abundance of high-technology medicine
or that the overuse of medical technology detracts from quality by
exposing patients to unnecessary risks, rest on a common assumption: 
that the United States relies on the newest and most complex
treatments more than do other economically advanced countries.  The
findings in this report challenge that assumption.  The patterns GAO
observed demonstrate that U.S.  patients, for good or ill, have not
been the most likely to receive a transplant for any of the clinical
conditions examined. 


   RECOMMENDATIONS
---------------------------------------------------------- Chapter 0:5

This report contains no recommendations. 


   ADVISORY BOARD COMMENTS
---------------------------------------------------------- Chapter 0:6

This report does not examine any agency program; thus, no agency
comments were requested.  However, the findings from the study were
presented to a project advisory panel whose comments and suggestions
have been incorporated into the report.  (See appendix III for the
list of advisers.)


INTRODUCTION
============================================================ Chapter 1

The emergence of each new and costly medical treatment challenges
health care systems to contain the ever-growing cost of care and at
the same time to ensure patient access to the most beneficial
treatments that medical science has developed.  In the United States,
the question of whether a reformed health care system can meet the
expectation of most Americans for ready access to the newest, costly,
high-technology medical treatments looms large.  In an effort to
inform the ongoing debate on health care reform on the availability
and appropriateness of care across health systems, we have examined
patterns of care in 10 industrialized nations for one sophisticated
therapy, bone marrow transplantation. 

Our work was undertaken at the request of the Ranking Minority Member
of the Subcommittee on Health of the House Ways and Means Committee. 
In the sections that follow, we describe bone marrow transplantation
(BMT) generally and how it is used specifically in the treatment of
leukemia.  We then present the detailed objectives of our work, its
scope, and the methodology used to carry out the research. 


   BACKGROUND
---------------------------------------------------------- Chapter 1:1

The term "bone marrow transplant" refers to two distinct types of
therapy.  In one category are allogeneic transplants.  These
procedures are used primarily to treat diseases of the bone marrow
and involve the collection of marrow from a donor other than the
patient.  Bone marrow is the spongy tissue in the cavities of the
bones that produces the components of blood and the immune system. 
The intent of allogeneic transplants is to destroy the diseased
marrow (with either chemicals or radiation), thereby curing the
disease.  After this, the donor's marrow is infused into the patient. 

The other major class of transplants is autologous bone marrow
transplants.\1 These transplants are directed at a wide variety of
diseases and involve marrow obtained from the patient.  Autologous
transplants can involve therapy that is directed at many different
types of cells, not necessarily diseased marrow.  However, the
intensity of therapy is such that the marrow cells are killed as a
consequence of the therapy.  Therefore, marrow from the patient is
harvested before the start of therapy and then reinfused into the
patient once therapy against the disease has been completed.  That is
why this form of therapy is sometimes referred to as "high-dose
chemotherapy with bone marrow rescue." Also, autologous transplants
are sometimes used as an alternative to allogeneic transplants in
situations where no suitable donor can be found.  In those situations
(that is, when autologous transplants are used to treat diseases of
the marrow), after the marrow is collected from the patient, it is
sometimes treated in a process called purging in an effort to remove
or destroy any diseased cells before reinfusion. 

Both forms of transplantation share a number of important
characteristics:  both are in a state of technological flux, with
advances in the delivery of the therapy continuing to be made; both
are complex procedures relying on many different types of medical
expertise; and both are expensive.  This report focuses on allogeneic
transplants only.  Compared with autologous transplants, allogeneic
transplants are generally more established but more complex and more
expensive.  Therefore, they offer an opportunity to study how the
allocation of "high-tech, high-cost" medicine varies under different
health care systems. 


--------------------
\1 Bruce D.  Cheson et al., "Autologous Bone Marrow Transplantation: 
Current Status and Future Directions," Annals of Internal Medicine,
110:1 (Jan.  1, 1989), 51-65. 


      BONE MARROW TRANSPLANTATION
-------------------------------------------------------- Chapter 1:1.1

Allogeneic bone marrow transplantation is a standard treatment option
for some patients with certain types of cancer and for some fatal
noncancerous disorders.  As successful experience with BMT has
accumulated, the list of established indications has broadened. 
Today there are several diseases or groups of diseases for which BMT
is a standard therapy:  chronic myeloid leukemia, acute leukemia,
Hodgkin's disease and non-Hodgkin's lymphoma, multiple myeloma,
neuroblastoma, myelodysplasia, aplastic anemia, transfusion dependent
thalassemia, and severe combined immune deficiency.\2 Bone marrow
transplantation is also being evaluated and increasingly applied in
the treatment of other types of cancer, metabolic disorders, and
immunodeficiencies, but its effectiveness in treating these diseases
is not yet clearly established. 


--------------------
\2 Testimony of Claude Lenfant, Director, National Heart, Lung, and
Blood Institute before the Subcommittee on Labor, Health and Human
Services, and Education of the House Committee on Appropriations,
U.S.  Congress, Departments of Labor, Health and Human Services,
Education, and Related Agencies Appropriations for 1993, Part 3
(Washington, D.C.:  U.S.  Government Printing Office, 1992) p.  657. 


         A RESOURCE-INTENSIVE
         MEDICAL TECHNOLOGY
------------------------------------------------------ Chapter 1:1.1.1

Allogeneic transplantation is an aggressive, complex therapy that
includes many separate procedures and encompasses four phases:  (1)
identification of a donor, (2) pretransplant conditioning, (3)
transplantation, and (4) prevention and treatment of complications.\3
Each is discussed in turn. 

Finding a donor.  Central to allogeneic transplantation is the
availability of a suitable donor.  Suitability is determined by the
compatibility of the donor's tissues with the patient's tissues. 
This determination is made by comparing human leukocyte antigens
(HLA), located on the white blood cells of both donor and recipient. 
The best chance for a match is among siblings; the likelihood of a
match decreases as one moves to more distant family members and then
to non-family members.  Importantly, the poorer the HLA match, the
higher the likelihood of complications and the poorer the prognosis
for the transplant. 

In the United States, one estimate is that 30-40 percent of
candidates for a bone marrow transplant have a relative who would be
a suitable donor.\4 In cases where no relatives are suitable, other
donors are typically sought through national donor registries. 
Locating a suitably matched unrelated donor is often difficult and
time-consuming, and the cost is high.  In the United States, in the
period 1987-91 only about 20 percent of searches for an unrelated
donor through the National Marrow Donor Program, the largest U.S. 
donor registry, were successful.  The search for a donor on the
registry generally required 5-6 months.\5

Pretransplant conditioning.  In preparation for transplantation, the
patient undergoes extensive laboratory and diagnostic tests followed
by intensive doses of chemotherapy or radiation to kill diseased
marrow.  A patient also receives drugs to suppress the immune system
so that the body will not reject the transplanted marrow.  During
this phase of the treatment, side effects almost always occur because
chemotherapy and radiation are toxic to normal cells as well as to
diseased cells.  Side effects can include nausea, vomiting, diarrhea,
lowered blood counts, and damage to vital organs.  Other drugs are
used to prevent or treat these side effects.  Because the patient's
immune system is severely weakened, the patient is susceptible to
infections from bacteria, fungi, viruses, parasites, or other foreign
matter.  For this reason, the patient is usually placed in protective
isolation, given antibiotics to fight infection, and sometimes
provided with hematopoietic growth factors to stimulate cell growth. 
Throughout the conditioning period, the patient is monitored daily
and receives periodic blood and platelet transfusions. 

Transplantation.  Soon after chemotherapy or radiation therapy is
completed, the patient receives the donated marrow through an
intravenous catheter.  This marrow travels through the bloodstream to
the bone marrow cavities, where, in a process called engraftment, the
transplanted marrow begins to manufacture new blood cells. 
Engraftment usually occurs within 14 to 30 days after
transplantation. 

Prevention and treatment of complications.  In the months immediately
following the marrow infusion, life-threatening complications may
follow, with the four most common being graft rejection or failure,
graft-versus-host disease (GVHD), infection, and recurrence of the
original disease.  Just as whatever remains of the patient's original
immune system may reject the marrow graft, in GVHD the newly
transplanted marrow may attack the patient's body.  GVHD can be
either temporary or chronic and can vary from a mild to a
life-threatening disease.  Drugs are used to reduce the risk and
severity of GVHD and to treat it when it occurs.  Similarly, drugs
are also used to prevent and treat any infections, which are likely
during this period because of the patient's weakened immune system. 
Additionally, direct toxicities from the conditioning regimen can
continue to cause complications and can lead to death.  The severity
of these reactions to BMT generally increases with age; thus,
transplants are rarely performed on older patients.  Those aged 55
and older are not generally considered suitable candidates. 

Because it usually involves expensive drugs, blood products,
continual laboratory testing, special environmentally protective
isolation hospital rooms, intensive nursing care, and often extensive
use of radiotherapy equipment, BMT is a very expensive therapy.  In
the United States, patient charges for allogeneic transplantation
commonly exceed $125,000.  However, charges vary considerably
depending on the initial response of the patient to the treatment,
the extent of any subsequent complications, and the length of the
patient's hospital stay. 


--------------------
\3 Alfred A.  Rimm et al., "Use of a Clinical Data Registry to
Evaluate Medical Technologies:  Experience for the International Bone
Marrow Transplant Registry," International Journal of Technology
Assessment in Health Care, 7:2 (1991), 182-93. 

\4 Mortimer M.  Bortin, Mary M.  Horowitz, and Alfred A.  Rimm,
"Increasing Utilization of Allogeneic Bone Marrow Transplantation: 
Results of the 1988-1990 Survey," Annals of Internal Medicine, 116:6
(Mar.  15, 1992), 505-12. 

\5 U.S.  General Accounting Office, Bone Marrow Transplants: 
National Program Has Greatly Increased Pool of Potential Donors
(GAO/HRD-93-11; Nov.  4, 1992), pp.  9-10. 


         TRANSPLANTATION IN THE
         TREATMENT OF LEUKEMIA
------------------------------------------------------ Chapter 1:1.1.2

Allogeneic transplantation is a standard treatment option for several
of the most common types of leukemia.  Leukemia is a collective term
for several distinct malignancies that originate in the blood-forming
cells, arising mostly in bone marrow.  The presence of leukemic cells
interferes with the production of normal red and white blood cells
and platelets. 

Leukemias are classified by cell type as either lymphoid or myeloid
and by clinical behavior as either acute or chronic.  Acute leukemia
usually begins abruptly and progresses rapidly; symptoms develop
quickly and are intense.  Chronic leukemia usually develops more
slowly, often over a period of many years.  The four basic forms of
leukemia are chronic myeloid leukemia (CML), acute lymphoid leukemia
(ALL), acute myeloid leukemia (AML), and chronic lymphoid leukemia
(CLL).\6 Table 1.1 shows some distinctive features associated with
specific leukemias. 



                          Table 1.1
           
            Features of Specific Types of Leukemia


Clinical
behavior      Lymphoid                Myeloid
------------  ----------------------  ----------------------
Acute         Predominant childhood   Predominant acute type
              type; peak in children  in old age; most
              under 5                 common type in mid-
                                      adulthood

Chronic       Predominant type in     Predominant chronic
              old age; uncommon       type in mid-adulthood
              before mid-adulthood
------------------------------------------------------------
Source:  Moyses Szklo, "Are Further Epidemiologic Studies of Leukemia
Needed?" American Journal of Epidemiology, 112:2 (1980), 228. 

We found that 77 percent of all allogeneic transplants in 1989-91 in
the 10 countries we studied were performed to treat either CML, ALL,
or AML.\7 Yet, the role of BMT in the treatment of each disease
differs, and these differences are critical for interpreting patterns
of BMT use. 


--------------------
\6 Lymphoid leukemia is also called lymphocytic, lymphatic, and
lymphoblastic.  Myeloid leukemia is also called granulocytic,
myelocytic, myelogenic, and myelogenous.  Acute nonlymphocytic
leukemia is a broader term that includes AML as well as several rarer
forms of leukemia. 

\7 BMT is not a common therapy for CLL because the disease almost
always occurs after middle age, and transplantation is rarely done
for patients aged 55 and older. 


         STAGES OF LEUKEMIA AND
         THERAPY
------------------------------------------------------ Chapter 1:1.1.3

All three types of leukemia that are treated with BMT progress
through different "stages" or "phases," and these are crucial in
determining the appropriateness of a bone marrow transplant.\8

In general, the earlier in the progression of a disease that a
transplant is performed, the better the prognosis for the patient. 
However, in the early stages of acute leukemia, it is often difficult
to distinguish between patients who will be cured by conventional
chemotherapy and those who will eventually require a bone marrow
transplant.  Given that BMT is a dangerous procedure, exactly when
the risks of the procedure outweigh the dangers from the disease is
difficult to determine.  Further, this point will differ for each of
the diseases.  The specific stages of each disease and the
implications for defining when transplantation is most appropriate
are discussed in greater detail in the respective chapters on CML,
ALL, and AML (chapters 3-5). 


--------------------
\8 Mortimer M.  Bortin et al., "Changing Trends in Allogeneic Bone
Marrow Transplantation for Leukemia in the 1980s," Journal of the
American Medical Association, 268:5 (Aug.  5, 1992), 607-12. 


   OBJECTIVES
---------------------------------------------------------- Chapter 1:2

The central objective of this report is to evaluate the use of bone
marrow transplantation in different national health systems. 
Specifically, our interest is in answering two questions: 

  Do patients who need transplants get them?  and

  Are transplants performed at a point that optimizes benefits while
     minimizing risks? 

Each of these questions relates to a dimension of health care
quality.  The first addresses the availability of transplant services
and provides information on how likely it is that patients in each
country who could benefit from a transplant would receive one.  The
second question is directed at the issue of appropriateness.  Given
that there are better and worse times to perform a transplant, we
examine when in the progression of disease transplants are typically
performed.  The criteria used in assessing appropriateness,
therefore, involve the stage of the patients' diseases at the time of
transplant. 

Each question is answered by examining how patterns of BMT use
compare across national health care systems.\9 The focus on patterns
rather than on individual cases has two implications.  One is that
our conclusions are general rather than specific.  When we say that
the likelihood of transplantation is higher in one country than
another, this refers to the population of patients, not to
individuals (whose likelihood may vary considerably within
countries).  Similarly, when we conclude, for example, that a pattern
of early transplants is "appropriate," this does not mean that each
case of early transplantation represents appropriate care or that any
later transplant would be inappropriate.  Rather, the conclusion is
that one pattern is generally more consistent than others with the
clinical criteria that define appropriate care. 

The focus on patterns also means that our study is descriptive; that
is, our intent is to provide evidence on where a patient is most
likely to receive a transplant or to receive it at an optimal time. 
We do not set out to explain why one health care system "does better"
in these patterns than the others.  Numerous factors (including
clinical philosophy, patient behavior, total resources, system
capacity, payment mechanisms, and practice controls, to name but a
few) may play some role in answering "why," but that question is
beyond the scope of this report. 


--------------------
\9 Throughout this report we use the terms country and health care
system interchangeably. 


   SCOPE
---------------------------------------------------------- Chapter 1:3

This report examines the availability and appropriateness of
allogeneic bone marrow transplantation in the United States and nine
other countries:  Australia, Canada, Denmark, France, Germany, the
Netherlands, New Zealand, Sweden, and the United Kingdom.\10 All are
economically advanced democracies whose health systems vary in many
ways including their organization, basic incentive structures, and
how much each spends on health care.\11 In some, nearly all
physicians are salaried; in others, only hospital-based physicians
are; and in still others, such as the United States, most inpatient
as well as ambulatory care is paid for on a fee-for-service basis. 
Similarly, the large majority of hospitals are publicly owned and
administered in some countries and privately in others, while in a
third set, neither type predominates.  Independent of ownership and
control, these hospitals may be paid by the service provided, by
number of days from admission to discharge, through a fixed annual
budget, or in some complex combination.  In some cases, the national
government manages the whole health care system; in others,
subnational governments are dominant; and sometimes, different levels
of government control different parts of the system.  Nongovernmental
or quasi-governmental organizations, such as sickness funds, also
play an important role in some systems in both creating the physical
capacity to offer different types of services and allocating the
financial resources to pay for those services.  The one element that
the other nine systems have in common, in contrast to the United
States, is that they all have put in place some type of financing
mechanism that ensures that access to health care services does not
depend on the patient's ability to pay for them. 

For each of the systems, we reviewed the 3-year period 1989-91, the
most recent years for which comprehensive BMT data could be obtained. 
We did not examine how the transplants were performed (that is, such
factors as drugs used, length of hospital stay, type and frequency of
irradiation), nor did we gather data on patient outcomes (for
example, recurrence of disease or survival). 


--------------------
\10 Germany refers to western Germany only, and the designation
United Kingdom refers to England, Wales, and Scotland. 

\11 In 1991, the United States spent $2,868 per person on health
care, exceeding spending in Canada, the next-highest spender, by 50
percent.  At the other end of the range, New Zealand spent $1,047 and
the United Kingdom $1,043 per person.  For these and other data
comparing health care expenditures in the 10 countries as well as in
14 others, see George J.  Schieber, Jean-Pierre Poullier, and Leslie
M.  Greenwald, "Health Spending, Delivery, and Outcomes in OECD
Countries," Health Affairs, 12:2 (Summer 1993), 120-29. 


   METHODOLOGY
---------------------------------------------------------- Chapter 1:4


      DATA NEEDS
-------------------------------------------------------- Chapter 1:4.1

To assess the availability of BMT in each of the countries, we needed
complete counts of the number of transplants performed in each
country and indication of the diseases for which those transplants
were performed.  To estimate rates of transplantation, taking account
of variations in the population of the countries and the incidence of
disease, we needed to know the size of the population and the annual
number of cases of CML, ALL, and AML.  To examine the appropriateness
of the transplants, we sought data on the stage of disease at time of
transplant.  Finally, to measure timeliness of transplantation, we
needed to know the date of diagnosis and the date of transplant. 


      DATA SOURCES
-------------------------------------------------------- Chapter 1:4.2

The patient-level data to address all three objectives were collected
from one of three sources:  the International Bone Marrow Transplant
Registry (IBMTR), the Sociï¿½tï¿½ Franï¿½aise de Greffe de Moï¿½lle, and a
survey of BMT centers in the 10 study countries not routinely
contributing to the IBMTR database. 

IBMTR, based at the Medical College of Wisconsin, collects and
analyzes clinical data on allogeneic bone marrow transplantation from
approximately 200 transplant centers around the world.  The Sociï¿½tï¿½
Franï¿½aise de Greffe de Moï¿½lle maintains a database on all bone marrow
transplants performed in French BMT centers.  Not all BMT centers
regularly submit data to IBMTR; thus, we arranged for IBMTR to survey
all nonparticipating BMT centers to ensure that we had comprehensive
data for this report.  The response rate to the survey was 84
percent.  For the small number of centers that did not respond, we
obtained data on the number of transplants performed from two earlier
surveys.\12 Overall, we assembled data on approximately 10,000
transplants performed in the 3 years at 208 transplant centers in the
10 countries.  In compiling these data, we did not independently
verify data supplied by any of the sources.  Appendix I provides a
detailed description of the sources and construction of our BMT
databases. 

National population data for calculating BMT per capita ratios were
provided by the Center for International Research of the U.S.  Bureau
of the Census and by British Information Services.  Data on leukemia
incidence rates for the period 1983-87 (the most recent period for
which comparable data were available) came from cancer registries in
each of the countries other than Germany.  For Germany, we assumed
that its leukemia incidence rates were equal to the average incidence
rates of the nine other countries.  We have confidence in this
assumption for three reasons.  First, international variation in
disease incidence for the leukemias is considerably less than it is
for other cancers.\13 Second, the number of cases of disease
estimated by using average incidence approximates estimates of
incidence provided by German oncologists.  Additionally, the ranking
of German transplant rates relative to other countries remains the
same whether one uses transplant rates computed using population as
the denominator (for which we have precise data) or using disease
incidence (with the average leukemia incidence assumption for
Germany) as the denominator. 


--------------------
\12 For a description of one survey, limited to European centers, see
A.  Gratwohl et al., "Bone Marrow Transplantation in Europe:  Major
Geographical Differences," Journal of Internal Medicine, 233:4 (Apr. 
1993), 333-41, and A.  Gratwohl, "Bone Marrow Transplantation
Activity in Europe 1990," Bone Marrow Transplantation, 8:3 (Sept. 
1991), 197-201.  An IBMTR survey of centers worldwide is described in
Bortin, Horowitz, and Rimm (1992). 

\13 Clark W.  Heath, Jr., "The Leukemias," in Cancer Epidemiology and
Prevention, eds.  David Schottenfeld and Joseph F.  Fraumeni, Jr. 
(Philadelphia:  W.B.  Saunders, 1982), p.  730. 


      ANALYSIS
-------------------------------------------------------- Chapter 1:4.3

The analysis plan for this study consisted of two general components. 
One primarily involved calculating rates and ratios.  Some
complexities in this component of the work were introduced by the
need to estimate the cancer incidence rates for countries where there
were no national registries.  For those countries, we estimated
national incidence rates from subnational registries.  Additionally,
we had to convert incidence rates to estimates of the actual number
of leukemia cases in each country.  Appendix II provides a full
explanation of our sources and estimation methods for the computation
of the disease incidence rates. 

The other analytic task involved establishing criteria for each
disease that could be used to define when a transplant was
appropriate, including the time perspective on benefits and risks. 
We relied on the published literature on BMT to establish these
criteria and then had the criteria reviewed by a panel of medical
scientists expert in the treatment of leukemia.\14 (See appendix III
for the list of advisers.)

Additional background information was obtained from interviews with
medical directors at 24 transplant centers in the United States and
40 transplant centers in nine other countries.  Our medical panel
advised us in the conduct of the research and reviewed this report. 


--------------------
\14 Because our focus was on BMT during 1989-91, this report relies
primarily on the clinical literature that was published before 1992. 


   ORGANIZATION OF THE REPORT
---------------------------------------------------------- Chapter 1:5

Chapter 2 presents data addressing the overall patterns of BMT
utilization in each of the 10 countries.  Chapters 3-5 contain our
findings on each of the three leukemias:  CML, ALL, and AML.  Each
chapter presents data on the availability and appropriateness of BMT
for one of these leukemias.  Our general conclusions and their
implications are presented in chapter 6. 


PATTERNS OF TRANSPLANTATION
============================================================ Chapter 2

This chapter describes variation in the overall patterns of bone
marrow transplantation for the populations of 10 countries.  Across
health care systems, the utilization of this therapy provides one
example of relative access to medical technology.  We measured such
utilization in two ways.  First, we determined overall rates of
transplantation in each of the countries, taking into account the
size of national populations.  Then, in chapters 3-5, to capture
national utilization differences taking account of variation in
disease, we estimated the likelihood of transplantation for patients
with each of three types of leukemia. 


   RATES OF TRANSPLANTATION
---------------------------------------------------------- Chapter 2:1

The most basic measure of treatment frequency is a simple count of
the number or incidence of treatments during a given year.  However,
to draw meaningful conclusions from comparisons of incidence across
national populations, it is necessary to account for differences in
population size.  Incidence rates are computed by dividing the total
number of treatments occurring in a country during a given year by
the national population in that year.  For ease of comparison,
incidence rates are expressed in this report as cases per million
persons. 

Because allogeneic transplantation was rarely used for patients aged
55 and older, we calculated rates for the age range 0-54.\1

Table 2.1 presents the number of transplants performed during 1989-91
in each of the 10 countries.\2 The table also presents the annual
incidence rates of BMT--the number of people receiving allogeneic
transplants per year per million people under age 55 for each
country.  Table 2.1 and all subsequent tables in this report order
the countries by their ranks in the column of principal interest,
usually the last column. 



                          Table 2.1
           
            Annual Rates of Allogeneic Bone Marrow
                       Transplantation


                                    Population   Transplants
                        Transplant     aged 0-   per million
Country                        s\a        54\b      per year
----------------------  ----------  ----------  ------------
France                       1,708        42.6          13.4
Sweden                         168         6.3           9.0
Canada                         576        21.5           8.9
Australia                      369        13.9           8.8
United Kingdom               1,000        40.4           8.2
United States                4,873       199.9           8.1
Denmark                         90         3.9           7.8
New Zealand                     59         2.7           7.4
Netherlands                    232        11.7           6.6
Germany\c                      757        44.9           5.6
------------------------------------------------------------
\a For the period 1989-91. 

\b In millions, for 1991. 

\c The population figure for western Germany is for 1990, the latest
available. 

Table 2.1 shows that the rate in France was distinctly higher than
that in the other countries.  While there was more than a two-fold
difference in national rates between the highest and lowest
countries, most national rates lay on an evenly spread continuum with
the United States near the middle. 

The rates in table 2.1 are one indication of how resources are
distributed in health care systems.  For example, more resources per
capita were allocated to BMT in France than in the United States. 
Germany used the fewest resources per capita for transplants among
the 10 countries. 


--------------------
\1 During 1989-91, only 1.2 percent of transplant patients in the 10
countries were aged 55 or older.  No patients aged 50 and over were
transplanted in Denmark and New Zealand, and no patients aged 55 and
over in Australia and Sweden.  Patients aged 55 and over constituted
one-half of 1 percent of transplants in Canada, the United Kingdom,
France, Germany, and the Netherlands, and 1.6 percent of transplants
in the United States. 

\2 Data on patient's country-of-residence were not available.  All
tables in this report indicate the country where therapy was
performed, not where patients resided, so the transplant figures
include any patients referred from other countries. 


   TRANSPLANTATION FOR LEUKEMIAS
---------------------------------------------------------- Chapter 2:2

Across the 10 countries, 77 percent of allogeneic transplants during
the period were for CML, ALL, or AML.  The remainder were for
lymphoma and other malignancies, severe aplastic anemia, and other
nonmalignant diseases.  Table 2.2 displays the distribution of
allogeneic transplants by disease. 



                          Table 2.2
           
            Distribution of Allogeneic Bone Marrow
                 Transplantation by Disease\a


                      Transplant                       Other
Country                        s   CML   ALL   AML   disease
--------------------  ----------  ----  ----  ----  --------
New Zealand                   59   41%   24%   30%        6%
United Kingdom             1,000    31    28    22        18
United States              4,873    34    20    28        19
Canada                       576    34    13    32        21
Germany                      757    33    18    26        22
Australia                    369    30    20    27        23
Netherlands                  232    20    23    27        30
Denmark                       90    33    16    20        31
Sweden                       168    26    18    22        35
France                     1,708    18    25    21        36
------------------------------------------------------------
\a For the period 1989-91; percentages may not add to 100 because of
rounding. 

From table 2.2, we can see that the proportion of all transplants for
the three leukemias varied from 65 percent in France and Sweden to 94
percent in New Zealand, with the United States and four other
countries clustered around 80 percent.  Consequently, France and
Sweden used a larger proportion of transplant resources for other
diseases. 

The next three chapters report our findings on the availability and
appropriateness of bone marrow transplants for each of three
leukemias. 


CHRONIC MYELOID LEUKEMIA
============================================================ Chapter 3

Chronic myeloid leukemia is a disease of particular interest for
assessing the availability and appropriateness of bone marrow
transplantation.  This is because it is both a relatively common form
of leukemia and one for which BMT is the only established curative
therapy.  The next section examines in detail the basis for assessing
the availability and appropriateness of bone marrow transplantation
given the specific clinical characteristics of CML.  Drawing on both
the medical literature and our panel of expert advisers, we developed
four specific measures of availability and appropriateness.  We then
applied these criteria to the 10 health care systems under study.  We
describe the position of the United States relative to the other
systems on each measure individually and on all four taken together. 


   EVALUATION CRITERIA
---------------------------------------------------------- Chapter 3:1

As the term "chronic" implies, CML is a disease that typically
develops over an extended period of time.  In the initial stage of
the disease, the symptoms are generally mild and the patient's
quality of life is high.  This stage will often last several years;
however, at some point, the disease will progress from this "chronic
phase" to a transitional stage (accelerated phase) and from there to
the terminal stage of the disease, called "blast crisis."

Chemotherapy may minimize symptoms during the chronic phase but does
not stop progression to the advanced stages of the disease and
death.\1 In one study, approximately half the patients treated with
conventional chemotherapy died within 5 years of diagnosis,
increasing to over 80 percent after 7 years.\2

Interferon, a naturally occurring biological agent, has recently been
shown to delay this progression for some patients.\3

However, during the 1989-91 period covered in this study,
interferon's use in the treatment of CML was investigational and it
was not generally available to patients as an alternative to
chemotherapy.\4

Bone marrow transplantation, by contrast, offered patients during
this period the potential for long-term cure from the disease.  IBMTR
data collected from transplant centers around the world showed that
53 percent of patients receiving transplants in chronic phase were
alive 6 years later.\5 Most of those who died did so in the 12 months
following the procedure, almost all from complications of the
treatment such as infections or graft-versus-host disease.\6 Many of
these patients would probably have lived somewhat longer had they not
received a transplant.  However, the larger number of patients who
survived the procedure obtained a much greater increase in overall
survival through eradication of the disease. 

Given the risks associated with the treatment, it might seem
reasonable to wait to transplant until the chronic phase was over. 
Unfortunately, the probability of success decreases the longer one
waits and, in particular, once the disease has progressed to the
accelerated or blast crisis stage.\7 While that transformation takes
place, on average, 3 years after diagnosis, for many patients it
occurs sooner and without warning.\8 Therefore, it is recommended
that CML patients who are eligible for a BMT (that is, have a
suitable donor and meet the age and health status requirements)
undergo the treatment within a year of diagnosis.\9


--------------------
\1 Philip McGlave, "Bone Marrow Transplants in Chronic Myelogenous
Leukemia:  An Overview of Determinants of Survival," Seminars in
Hematology, 27:3, Supp.  4 (July 1990), 23-30. 

\2 E.  Donnall Thomas and Reginald A.  Clift, "Indications for Marrow
Transplantation in Chronic Myelogenous Leukemia," Blood, 73:4 (Mar. 
1989), 861-64. 

\3 Moshe Talpaz et al., "Interferon-Alpha Produces Sustained
Cytogenetic Responses in Chronic Myelogenous Leukemia," Annals of
Internal Medicine, 114:7 (Apr.  1, 1991), 532-38. 

\4 McGlave (1990), p.  23. 

\5 McGlave (1990), p.  24. 

\6 McGlave (1990), p.  25. 

\7 Thomas and Clift (1989), p.  862; McGlave (1990), p.  24.  Even
patients who go into accelerated phase and then are brought back into
chronic phase with chemotherapy do significantly less well than those
who are in their first chronic phase. 

\8 McGlave (1990), p.  25. 

\9 Thomas and Clift (1989), p.  862. 


      MEASURES OF AVAILABILITY
-------------------------------------------------------- Chapter 3:1.1

As noted, bone marrow transplantation represents the only established
curative therapy for CML; thus, our advisory panel recommended that
we assess the availability of bone marrow transplants in the 10
countries through a comparison of the proportion of patients with CML
who received transplants.  To do this, we needed to relate the number
of transplants for CML patients to the frequency of the disease in
each country. 

The lack of effective alternative therapies meant that we did not
have to account for patients cured by other treatments. 
Nevertheless, we did not assume that a transplant would be justified
in every case.  For many patients, the risks associated with the
procedure may well outweigh the likely benefits.  As noted above,
older patients are typically not eligible for a transplant; many
patients die from the effects of the procedure; and some patients who
undergo a transplant will not be cured of the disease. 

However, for patients under 55 years of age, the proportion for whom
the risks outweigh the benefits should be fairly small and of roughly
comparable magnitude in each country.  Therefore, the relative
frequency of transplantation for CML across the 10 countries should
provide an indication of the relative likelihood that those patients
who would benefit from a transplant could actually receive one.  For
this measure, the higher the proportion of patients receiving
transplants, the greater the apparent availability. 

We also measured the availability of transplants for CML by examining
how long it took for a system to provide them.  If, for example, a
country lacked sufficient capacity to perform transplants, resulting
in queues or delays in referring patients to transplant centers, then
it would generally take longer to provide patients with transplants
than it would in a country that had sufficient capacity.  This may
especially be an issue for CML patients, since they tend to be the
ones whose procedure is delayed if a more urgent case (such as an
acute leukemia patient) needs a transplant.  On this measure, then,
shorter waits for a transplant may be taken as an indicator of
greater availability. 


      MEASURES OF APPROPRIATENESS
-------------------------------------------------------- Chapter 3:1.2

We addressed the appropriateness of treatment through two indicators: 
(1) the proportion of patients transplanted in first chronic phase,
and (2) the proportion transplanted within a year of diagnosis. 
Here, the presumption was that if a transplant is to be performed,
the procedure should be done when it is most likely to have a
positive outcome for the patient.  Appropriate care would thus be
indicated by a higher proportion of patients receiving their
transplants in the first chronic phase, since the outcomes for such
patients are much better than for patients receiving transplants in
accelerated phase or blast crisis. 

The time from diagnosis to transplant is of interest for two reasons. 
First, it indicates the relative degree of risk tolerated in each
system that patients might progress to a later stage before their
transplant is performed.  Second, some evidence suggests that even
among patients in first chronic phase, those transplanted with less
delay will have better results.\10 Therefore, a higher proportion of
patients receiving transplants within 1 year of diagnosis is probably
indicative of more appropriate care. 

Of the two indicators, the first is more definitive, as numerous
studies have shown that substantially worse outcomes are experienced
by patients who received transplants in stages other than first
chronic phase.\11 The two measures of appropriateness should be
related, but not perfectly, since the chronic phase extends well
beyond a year for many patients, while for a minority, the disease
may progress more rapidly. 


--------------------
\10 Thomas and Clift (1989), p.  862. 

\11 In addition to McGlave (1990) and Thomas and Clift (1989), see
Joseph E.  Sokal et al., "Prognostic Discrimination Among Younger
Patients With Chronic Granulocytic Leukemia:  Relevance to Bone
Marrow Transplantation," Blood, 66:6 (Dec.  1985), 1352-57; John M. 
Goldman, "Bone marrow transplantation for chronic myelogenous
leukemia," Current Opinion in Oncology, 4 (1992), 259-63; and Jeffrey
S.  Miller and Philip B.  McGlave, "Therapy for chronic myelogenous
leukemia with marrow transplantation," Current Opinion in Oncology, 5
(1993), 262-69. 


   LIKELIHOOD, TIMING, AND STAGE
   OF TRANSPLANTS
---------------------------------------------------------- Chapter 3:2

In the following sections, we present our findings on the likelihood,
timing, and stage of transplants for CML patients in the 10
countries. 


      THE LIKELIHOOD OF RECEIVING
      A TRANSPLANT
-------------------------------------------------------- Chapter 3:2.1

To assess the likelihood that patients would receive a transplant, we
first needed to determine how many potential candidates for
transplantation there were in each country between 1989 and 1991. 
Using a range of data sources described in appendix II, we estimated
for each country the annual number of new CML cases for persons under
the age of 55.  We then related this number to the number of
transplants performed in that country over the study period to
construct a national disease-specific BMT ratio.  (The calculations
are described in more detail in appendix II.) This ratio represents
the rate of tranplantation; that is, the likelihood that CML patients
under age 55 in each country would receive BMT as part of their
leukemia treatment by the end of the second calendar year following
the year of diagnosis of their disease.  The rates also describe the
relative likelihood of receiving a BMT across countries.  For
example, a rate twice another would indicate that a patient in one
country was twice as likely to receive a transplant as a patient in
another country within the specified time. 

Table 3.1 presents the tranplantation rates for CML in the 10
countries.  For some countries, such as Sweden, Denmark, and New
Zealand, the number of transplants is small.  That means that random
fluctuation from year to year by even a few cases could significantly
affect the rates and thus the rankings of these countries. 



                          Table 3.1
           
                Transplantation Rates for CML

Country                                               Rate\a
--------------------------------------------------  --------
Sweden                                                   .54
United Kingdom                                           .48
New Zealand                                              .46
Denmark                                                  .41
Canada                                                   .39
Australia                                                .38
United States                                            .35
Netherlands                                              .33
France                                                   .32
Germany                                                  .26
------------------------------------------------------------
\a Ratio of the incidence of allogeneic bone marrow transplantation
performed within 2 calendar years following the year of diagnosis to
estimated annual incidence of CML; for transplants performed in
1989-91 on patients aged 0-54. 

Table 3.1 shows that from one-quarter to one-half of CML patients in
the countries received a bone marrow transplant within the specified
period, a two-fold difference between least and most.  The countries
were fairly evenly distributed over the range.\12

The United States was below the middle of the range, in a cluster of
countries where about one-third of CML patients were transplanted. 
German patients had the lowest likelihood of transplantation, while
those in Sweden had the highest. 


--------------------
\12 Because the rate is calculated using the annual incidence of the
disease in each country, it can be affected to some degree by patient
travel between countries to receive a transplant.  Data on
country-of-residence were not available. 


      THE TIMING OF TRANSPLANTS
-------------------------------------------------------- Chapter 3:2.2

The time from diagnosis to transplantation for CML patients is shown
in table 3.2.  We restricted this analysis to those patients whose
donor was a member of the patient's family (ranging from 67 percent
of all CML transplants in Denmark to 96 percent in Australia).  This
largely reduces variations in timing caused by having to search for
suitable unrelated donors. 



                          Table 3.2
           
           Months From Diagnosis to Transplantation
                      for CML Patients\a


                                                       Total
Country                   5%   25%   50%   75%   95%   cases
----------------------  ----  ----  ====  ----  ----  ------
New Zealand              1.8   5.9   6.8   8.8  69.7      10
Netherlands              3.0   6.5   8.1  12.3  58.6      38
Sweden                   4.0   6.1   8.6  11.9  24.8      41
United States            2.8   5.2   9.0  21.6  72.4     972
Canada                   3.3   6.2  10.0  20.5  63.6     146
France                   4.0   6.8  11.2  22.2  70.3     177
United Kingdom           2.9   7.3  11.8  17.2  36.4     164
Australia                4.9   9.4  13.8  25.6  81.4      91
Denmark                  7.0  14.0  15.2  22.3  42.3      19
Germany                  4.9   9.9  15.4  24.4  59.4     145
------------------------------------------------------------
\a For related-donor transplants performed in 1989-91. 

As can be seen in table 3.2, the median time from diagnosis to
transplant--the point at which 50 percent of the patients who were
treated with BMT had received their transplants--varied from a low of
6.8 months in New Zealand to a high of 15.4 months, or more than
twice as long, in Germany.  The United States was the fourth most
rapid in terms of the median time-to-transplant.  In Australia,
Denmark, and Germany, the median occurred more than a year following
diagnosis.  In looking at the 75th percentile, it can be seen that
the bulk of patients had received their transplants within 12 months
in New Zealand, the Netherlands, and Sweden; whereas in the remainder
of the countries, this point occurred from a year-and-a-half to two
years following diagnosis.  The United States had one of the broadest
ranges, with relatively more patients transplanted both very quickly
(in less than 3 months) and very late (more than 6 years following
diagnosis). 

Table 3.3 presents the percentage of CML patients transplanted within
1 year of diagnosis, the time period associated with better outcomes. 
We again limited this analysis to patients whose donor was related. 



                          Table 3.3
           
           CML Patients Transplanted Within 1 Year
                        of Diagnosis\a

                                           Total
Country                                    cases     Percent
------------------------------------  ----------  ----------
New Zealand                                   10         80%
Sweden                                        41          76
Netherlands                                   38          74
United States                                972          61
Canada                                       146          58
France                                       177          52
United Kingdom                               164          52
Australia                                     91          42
Germany                                      145          36
Denmark                                       19          11
------------------------------------------------------------
\a For related-donor transplants performed in 1989-91. 

Table 3.3 shows that patients had longer waits in some countries than
in others.  Within 12 months, one-half or more transplant patients in
all of the countries except Denmark, Germany, and Australia had been
treated. 


      STAGE OF DISEASE AT
      TRANSPLANTATION
-------------------------------------------------------- Chapter 3:2.3

Table 3.4 presents, for each country, the percentage of transplants
for CML that were performed in the first chronic phase of the
disease.  As with the prior examination of time, the analysis is
limited to transplants with related donors. 



                          Table 3.4
           
             CML Transplants Performed in Chronic
                           Phase\a

                                           Total
Country                                    cases     Percent
------------------------------------  ----------  ----------
Netherlands                                   38         82%
Canada                                       155          79
Sweden                                        41          78
United Kingdom                               198          78
Germany                                      188          73
Denmark                                       20          70
United States                                975          70
Australia                                     88          67
France                                       190          65
New Zealand                                   12          50
------------------------------------------------------------
\a For related-donor transplants performed in 1989-91. 

Table 3.4 shows a 32-percentage-point difference (50 percent to 82
percent) across countries in the proportion of related-donor
transplants performed in the initial stage of the disease--when the
therapy offered the best curative potential.  In systems wherea high
proportion of patients were transplanted in first chronic phase,
physicians may have referred appropriate candidates quickly and had
services available.  Alternatively, systems providing transplants to
a high proportion of patients in first chronic phase may simply not
have performed transplants on patients whose disease was advanced at
the time of diagnosis or had progressed before a transplant could be
performed. 

Four-fifths or more of Canadian and Dutch transplant patients
received transplants in first chronic phase, compared to about
two-thirds of patients in France and Australia and just half of
patients in New Zealand.\13 However, this variation is substantially
smaller than that observed in median time-to-transplant and in the
proportion transplanted within 1 year.  Moreover, in the systems
where the smallest percentage of CML patients were transplanted
within a year of diagnosis (Germany and Denmark), the proportion of
patients receiving transplants in the most favorable stage of the
disease was comparable to that in the United States and several other
systems that tended to transplant their patients more quickly. 


--------------------
\13 The small number of cases in Denmark and New Zealand, however,
make their rates more uncertain than those of the other countries. 


   CONCLUSIONS
---------------------------------------------------------- Chapter 3:3

Variation in the use of bone marrow transplantation for CML provides
considerable insight concerning the relative performance of these 10
health care systems in providing this complex and expensive
procedure.  CML is the diagnosis where bone marrow transplants are
most clearly the curative therapy of choice and where treatment in
the early stage of the disease is most certainly advantageous. 
However, the disease progresses relatively slowly for most patients,
and they can be kept waiting if the resources available to perform
transplants are relatively scarce (though with increasing risk that
the disease will convert to a less treatable stage).  Thus, we
assessed these systems on two measures of availability--the
proportion of CML cases that received transplants and the time from
diagnosis to transplantation--and two measures of
appropriateness--the proportion of patients receiving transplants in
first chronic phase and the proportion transplanted within 1 year. 


      AVAILABILITY
-------------------------------------------------------- Chapter 3:3.1

In terms of the two measures of availability, the United States fell
roughly in the middle of the 10 countries.  The overall likelihood of
transplantation was moderate.  On the measure of time-to-transplant,
the United States started rapidly, transplanting the highest
percentage of BMT patients within 6 months of diagnosis.  This
implies readily available transplant capacity.  However, the United
States also was very slow to provide transplants to some.  This could
reflect any of a number of factors, including regional shortages of
capacity, limitations in the ability of some patients to pay for the
procedure, patient willingness, physician referral patterns, or
differences in treatment philosophy. 


      APPROPRIATENESS
-------------------------------------------------------- Chapter 3:3.2

U.S.  performance also fell roughly in the middle for the two
measures of appropriateness.  Both on the percentage of CML patients
receiving transplants within 12 months and the percentage receiving
them in first chronic phase, a number of other countries appear to
have a more appropriate pattern of utilization of transplant
resources.  In the United States, along with Australia, France, and
New Zealand, patients with advanced disease (and therefore poorer
prognoses) had greater access to this expensive, high-technology,
potentially life-saving treatment.  This implies that a larger
proportion of resources was spent on patients for whom the
expectation of benefit was lower. 


      OVERALL
-------------------------------------------------------- Chapter 3:3.3

In general, different systems outperformed the United States on
different measures of availability and appropriateness.  Sweden
ranked high on all four measures.  The Netherlands and New Zealand
ranked high on three of the four, including both indicators involving
time-to-transplant.  However, the Dutch performed transplants on a
relatively small proportion of their CML patients, while in New
Zealand, a low percentage of patients were transplanted in first
chronic phase.  In all, six other systems (Sweden, United Kingdom,
New Zealand, Denmark, Canada, and Australia) transplanted a higher
proportion of their CML cases than did the United States, and five
(Netherlands, Canada, Sweden, United Kingdom, and Germany) performed
transplants on a higher percentage of patients in first chronic
phase. 

The United States, however, was not distinctly worse than average on
any of the four measures.  This was also true for Sweden, Canada, and
the United Kingdom.  Germany, by contrast, was at or near the bottom
on three dimensions (all but stage of disease at transplantation) and
Denmark on two (both timing dimensions). 


ACUTE LYMPHOID LEUKEMIA
============================================================ Chapter 4

The use of bone marrow transplantation in the treatment of acute
lymphoid leukemia is well established, but its role differs from that
for chronic myeloid leukemia, discussed in the preceding chapter.  In
treating ALL, BMT primarily serves as salvage therapy when
chemotherapy has failed to provide a cure.  In this chapter, we
explain our basis for examining the availability and appropriateness
of bone marrow transplantation for ALL.  We then describe our
findings for the 10 health care systems under study, with particular
attention to the position of the United States relative to the other
systems, and discuss the findings in terms of our measures of
availability and appropriateness. 


   EVALUATION CRITERIA
---------------------------------------------------------- Chapter 4:1

ALL begins in an acute phase, which rapidly advances.  If the disease
is untreated, life expectancy is less than 1 year.\1

However, treatment is available that can extend the life of the
majority of patients, many of whom appear to be cured.\2 The goal of
treatment is to achieve "remission," an eradication of any signs of
disease.  This is typically brought about by chemotherapy.  ALL is
highly responsive to chemotherapy, especially in children.\3 The
patient in remission is followed to monitor any recurrence of the
disease, or "relapse." If a relapse occurs, a second round of therapy
is initiated. 

For most patients with ALL, cure rates using chemotherapy are so high
that BMT is usually reserved as salvage therapy for this disease upon
relapse.\4 Some risk, however, is associated with waiting to perform
a transplant until after a relapse.  Patients who receive transplants
while they are in complete remission have the best prognosis; those
with advanced disease (second relapse or beyond) have a poorer
prognosis.\5 Thus, just as with CML, the chances of a transplant
being successful become poorer as the disease progresses.  This
creates a tension in treating ALL in that the earlier in the
progression of the disease, the less likely BMT is necessary but the
more likely it will be successful.  Additionally, the risks of the
treatment are sufficiently high that a careful evaluation is required
to avoid performing transplants on patients already cured by the
chemotherapy. 

Transplantation is not viewed as a salvage therapy for every ALL
patient.  Certain categories of patients are considered to have so
high a risk of not responding to chemotherapy or of relapsing that
BMT is seen as legitimate primary therapy.  Included in this category
are patients who have certain chromosomal abnormalities, who have a
high leukocyte level at diagnosis, or who require more than 4-6 weeks
of chemotherapy to achieve a remission.\6 In addition, some consider
most adult patients with ALL to be high-risk patients because, in
general, the older the patient, the poorer the prognosis.  However,
there is evidence that adult patients can be classified as standard
risk or high risk on the basis of the above prognostic indicators.\7

For high-risk patients, a BMT would be considered an appropriate
treatment option even when they are in first remission.  However, for
standard-risk patients, a BMT would be less appropriate unless they
have failed at least one round of conventional chemotherapy. 


--------------------
\1 Peter H.  Wiernik, "Acute Leukemias of Adults," in Cancer: 
Principles and Practice of Oncology, 2nd ed., chap.  45, eds. 
Vincent T.  DeVita, Jr., Samuel Hellman, and Steven A.  Rosenberg
(Philadelphia:  J.B.  Lippincott, 1985), pp.  1711-37. 

\2 Clinicians are hesitant to pronounce a leukemia patient as "cured"
since there is always some chance that the disease may recur, but a
patient is typically considered to be cured if there has been no
recurrence of the disease within 5 years. 

\3 Stephen J.  Forman and Karl G.  Blume, "Allogeneic Bone Marrow
Transplantation for Acute Leukemia," Hematology/Oncology Clinics of
North America, 4:3 (June 1990), p.  521. 

\4 Philip B.  McGlave, "The Status of Bone Marrow Transplantation for
Leukemia," Hospital Practice, 20 (Nov.  15, 1985), 97-110. 

\5 Frederick R.  Appelbaum and E.  Donnall Thomas, "Treatment of
Acute Leukemia in Adults With Chemoradiotherapy and Bone Marrow
Transplantation," Cancer, 55:9 Supp.  (May 1, 1985), 2202-09; Richard
Champlin and Robert Peter Gale, "Bone Marrow Transplantation for
Acute Leukemia:  Recent Advances and Comparison With Alternative
Therapies," Seminars in Hematology, 24:1 (Jan.  1987), 55-67. 

\6 Nelson J.  Chao and Karl G.  Blume, "Bone Marrow Transplantation: 
What Is the Question?" Annals of Internal Medicine, 113:5 (Sept.  1,
1990), 340-41. 

\7 McGlave (1985), p.  105. 


      MEASURES OF AVAILABILITY
-------------------------------------------------------- Chapter 4:1.1

Given that bone marrow transplantation is a recommended therapy for
the treatment of ALL patients who relapse and for those with
"high-risk" disease, it needs to be available to appropriate
candidates.  We assessed the availability of bone marrow transplants
in the 10 countries through computation of the proportion of patients
with ALL who had received transplants by the end of the second
calendar year following the year of diagnosis.  This provided an
estimate of the likelihood for each country that a patient with ALL
would receive a transplant.  To do this, we related the number of
transplants for ALL to the estimated level of the disease in each
country.  As with our examination of CML, this analysis was limited
to patients under age 55 because it is rare for BMTs to be performed
on older patients. 

Our analysis allows for an examination of the relative levels of use
of the procedure across countries.  Thus, a country with a ratio
twice that of another performed transplants on twice the proportion
of its ALL patients.  However, we cannot say what level of
transplantation is best.  Many patients are cured by chemotherapy and
do not need a transplant; thus, projecting the base level at which
transplants for ALL should be performed is not possible.  In
addition, the 3-year time frame of our study may be insufficient to
capture some patients whose disease remains in check for an extended
period following diagnosis, but who will ultimately relapse and
receive a transplant. 

As an additional measure of the availability of the treatment, we
examined the time from diagnosis to transplantation for that subset
of patients who received their transplant in first remission.  The
"time-to-transplant" is not a meaningful measure of availability for
patients transplanted at later stages of the disease because of
variability among these patients in how long their disease was in
remission before a relapse occurred.  However, for patients who are
recommended to receive a transplant in first remission (those who are
considered high risk), the sooner the transplant is performed, the
better, primarily because up to 5 percent of these patients will
relapse every month.  In this instance, delays in obtaining a
transplant can indicate poor availability.\8


--------------------
\8 The proportion of acute leukemia patients who fail to achieve even
a first remission through chemotherapy (primary induction failure)
that receive transplants would also provide insight on the relative
availability of transplantation in different systems.  This is
because BMT offers these patients a small but real chance of cure
when their prospects would otherwise be nil.  However, our data, as
reported in the following sections, can only describe the proportion
of transplants that are provided to patients experiencing primary
induction failure.  We do not know what proportion of patients in
this situation undergo BMT. 


      MEASURES OF APPROPRIATENESS
-------------------------------------------------------- Chapter 4:1.2

The time from diagnosis to transplantation for patients receiving a
transplant in first remission is also an indicator of the
appropriateness of care, because long waits for receiving a
transplant increase the chances that high-risk patients will see
their disease progress.  A pattern of long waits for patients
receiving transplants while in first remission also presents another
concern about appropriateness.  Because some proportion of even
high-risk patients will have been cured by chemotherapy, at some
point there will be a change in the probabilities favoring
transplantation over waiting to see if a relapse occurs.  That is,
the longer a patient has waited without relapsing, the higher the
probabilities become that the patient has been cured by chemotherapy. 
Thus, if the wait extends long enough, the risks of receiving a
transplant may begin to outweigh the risks of waiting.  At this
point, a transplant would be less appropriate because the patient may
already have been cured. 

In addition to examining time-to-transplant, we also examined the
stage of disease as an indicator of appropriateness.  The focus was
on the percent of transplants performed on patients with advanced
disease (that is, past second remission).  However, just as with
time, we restricted our examination of stage to a subgroup of ALL
patients.  Excluded from the analysis were pediatric patients.  The
focus on adults was based on research that showed that many adults
respond relatively poorly to chemotherapy.\9 Therefore, continued
rounds of chemotherapy would be less appropriate for these patients
than they would be for children.  Although uncertainty remains among
clinicians as to whether adult patients should receive transplants in
first remission or only after relapse, their relatively poor
responsiveness to chemotherapy means that waiting until adult
patients relapse a second time before providing a BMT would be less
appropriate than providing the transplant in first or second
remission. 


--------------------
\9 Mary M.  Horowitz et al.  "Chemotherapy Compared with Bone Marrow
Transplantation for Adults with Acute Lymphoblastic Leukemia in First
Remission," Annals of Internal Medicine, 115:1 (July 1, 1991), 13-18. 


   LIKELIHOOD, TIMING, AND STAGE
   OF TRANSPLANTS
---------------------------------------------------------- Chapter 4:2

The sections that follow present our analyses of the likelihood,
timing, and stage of transplants for ALL patients in 10 countries. 


      THE LIKELIHOOD OF RECEIVING
      A TRANSPLANT
-------------------------------------------------------- Chapter 4:2.1

To assess the availability of BMT to treat ALL, we needed to
determine how many potential candidates for transplantation there
were in each country between 1989 and 1991.  As discussed in the
previous chapter, we used a range of data sources (described in
appendix II) to construct a disease-specific transplantation rate. 
This rate represents the likelihood that ALL patients under age 55 in
each country would receive BMT as part of their leukemia treatments
by the end of the second calendar year following the year of
diagnosis.  The rates also describe the relative likelihood of
receiving a BMT across countries. 

Table 4.1 presents these rates for ALL in the 10 countries.  As noted
previously, for some countries, particularly Sweden, Denmark, and New
Zealand, the number of transplants performed is small, which means
that random fluctuations from year to year by even a few cases could
significantly affect the rates and thus the rankings of these
countries. 



                          Table 4.1
           
                Transplantation Rates for ALL

Country                                               Rate\a
--------------------------------------------------  --------
France                                                   .23
United Kingdom                                           .15
Netherlands                                              .11
Sweden                                                   .09
Australia                                                .08
United States                                            .07
Germany                                                  .06
Canada                                                   .05
New Zealand                                              .04
Denmark                                                  .03
------------------------------------------------------------
\a Ratio of the incidence of allogeneic bone marrow transplantation
performed within 2 calendar years following the year of diagnosis to
estimated annual incidence of ALL; for transplants performed in
1989-91 on patients aged 0-54. 

Because the ALL cure rate with standard chemotherapy is high,
especially in children, the transplantation rates for ALL were lower
than those for CML.  However, we still found variation in the use of
BMT to treat ALL.  Table 4.1 shows that ALL patients in France were
considerably more likely to receive a BMT as part of their therapy
than patients in any of the other countries.\10

Patients in Denmark and New Zealand had the lowest probabilities of
transplantation.  Transplantation rates in the other countries ranged
from just above that minimum to about two-thirds of the French rate,
with the United States near the middle of the range for the remaining
countries.\11

During the 3 years of interest to our study (1989-91), French
physicians had in place several nationwide randomized clinical trials
comparing transplantation and chemotherapy for acute leukemia.  These
large-scale trials may have resulted in more patients receiving
transplants than would otherwise have been expected.\12


--------------------
\10 Because the time frame might not be sufficiently long to obtain
an accurate picture of the proportion of ALL patients receiving BMTs,
we also computed the ratio of all transplants performed for the
disease in 1989-91 (irrespective of date of diagnosis) to the disease
incidence.  The relative rankings of the countries was essentially
the same. 

\11 In addition, just as for CML, the rates in some countries may be
influenced by patient travel between countries to receive
transplants. 

\12 The transplant resources required for the acute leukemia trials
(physicians, beds, staff, drugs, etc.) could conceivably have served
to depress the rates of transplantation for CML or other conditions
to some unknown extent. 


      THE TIMING OF TRANSPLANTS
-------------------------------------------------------- Chapter 4:2.2

The time from diagnosis to transplantation for those patients
receiving a transplant in first remission is shown in table 4.2. 
This analysis was restricted to first remission transplants (those
cases where BMT was used as primary therapy and not reserved as
salvage therapy for patients who relapsed).  For these patients, the
sooner the transplant is performed, the better, to avoid the risk of
relapse.  In addition, the analysis was limited to patients whose
donor was related, to eliminate any effects on timing from delays
caused by the search for an unrelated donor. 



                          Table 4.2
           
           Months From Diagnosis to Transplantation
                      for ALL Patients\a


                                                       Total
Country\\b                5%   25%   50%   75%   95%   cases
----------------------  ----  ----  ====  ----  ----  ------
France                   2.6   3.2   3.7   4.4   6.6     117
Canada                   3.1   3.9   4.7   5.9  11.5      26
United States            2.5   3.6   4.7   7.7  16.4     135
Germany                  3.3   4.1   5.2   8.0  14.9      18
Sweden                   3.7   4.1   5.2   6.0   8.8       8
United Kingdom           3.0   4.4   5.2   7.3  11.4      81
Netherlands              4.0   5.1   6.2   8.4  10.5      26
Australia                3.6   5.1   7.2   7.7   9.2      16
------------------------------------------------------------
\a For patients in first remission at time of transplant;
related-donor transplants performed in 1989-91. 

\b Denmark and New Zealand are not included in this table; Denmark
had no ALL patients transplanted in first remission, and New Zealand
had only one. 

If we look at the time frames in table 4.2, we see that all the
countries made a rapid start on providing transplants to these
patients.  The median time from diagnosis to transplantation (that
point at which 50 percent of patients had received their transplants)
varied from a low of 3.7 months in France to a high of 7.2 months, or
about twice as long, in Australia.  The United States was the second
most rapid, along with Canada, in terms of the median
time-to-transplant.  At the 75th percentile, variation across the
countries was quite small, with seven systems bunched in a
two-and-a-half-month range (France was the exception, with 95 percent
of its cases receiving transplants by a similar point in time). 
Evidently, all these systems were able to offer transplants to ALL
patients fairly quickly when BMT was chosen as the primary therapy. 


      STAGE OF DISEASE AT
      TRANSPLANTATION
-------------------------------------------------------- Chapter 4:2.3

Table 4.3 presents the number and percentage of adult patients
receiving transplants for ALL by stage of disease at the time of
transplantation.  Again, we restricted this analysis to those
patients whose donor was a member of the patient's family, to remove
any possible effects on disease progression during the search for a
suitable unrelated donor. 



                                    Table 4.3
                     
                     Stage of Disease at Transplantation for
                               Adult ALL Patients\a

                            First                   Second
            Induction    complete        First    complete    Advanced     Total
Country     failure\b   remission      relapse   remission   disease\c     cases
---------  ----------  ----------  -----------  ----------  ----------  --------
Australia          3%         44%          15%         18%         21%        34
Canada              3          68            3          22           5        37
Denmark             0           0            0         100           0         2
France              4          72            4          20           1       164
Germany             5          33            7          37          19        43
Netherlan           3          63            3          22           9        32
 ds
New                 0          25            0          25          50         4
 Zealand
Sweden              0          33           17          42           8        12
United              2          72            4          17           6        85
 Kingdom
United              5          33           18          25          20       342
 States
--------------------------------------------------------------------------------
\a For related-donor transplants performed in 1989-91.  Adult is
defined as patients aged 17 and older. 

\b Induction failure refers to patients in whom chemotherapy has
failed to induce a complete remission. 

\c Advanced disease refers to patients who are in their second
relapse or beyond. 

Transplantation by stage of disease appears to fall into two patterns
for adult ALL patients.  Well over half of Canadian, French, Dutch,
and British transplant patients were treated in first remission while
the majority of patients in other countries received their
transplants at first relapse or later.  Further, in the United
States, Australia, and Germany, about 20 percent of patients with ALL
who received a transplant were at an advanced stage of the disease,
while in New Zealand half the patients were at this stage. 


   CONCLUSIONS
---------------------------------------------------------- Chapter 4:3

The comparative assessment of systems in their treatment of acute
lymphoid leukemia is complicated because BMTs are not necessarily
called for in the case of this disease.  Many patients (especially
children) are cured by chemotherapy alone, so lower rates of
transplantation and transplantation at later stages of disease may be
more consistent with proper care than higher rates at earlier stages. 
We examined the availability of BMTs for ALL with two measures:  the
proportion of ALL patients who received transplants and the time from
diagnosis to transplantation for patients transplanted in their first
complete remission.  We also used time-to-transplant as a measure of
appropriateness of care, along with the stage of disease at which the
transplant was provided. 


      AVAILABILITY
-------------------------------------------------------- Chapter 4:3.1

We looked at two measures of availability.  Overall, the United
States was among the majority of countries that transplanted a fairly
low proportion of its ALL patients.  In terms of time-to-transplant,
the United States was the fastest system to begin performing
transplants, indicating a ready availability of BMTs for this
disease.  However, the United States was also the country with
patients transplanted at the longest interval following diagnosis. 
Only the United States and Germany had more than 5 percent of their
patients who would ultimately receive a first remission transplant
still awaiting the procedure 1 year after diagnosis.  Just as for
CML, where a similar distribution was found, any of a number of
factors, including regional shortages of capacity, limitations in the
ability of some patients to pay for the procedure, patient
willingness to undergo the treatment, physician referral patterns, or
differences in treatment philosophy could explain this pattern. 

France stood out from all the other countries on the measures of
availability in that it transplanted ALL patients at a substantially
higher rate than the others and was by far the fastest in providing
transplants to its first remission patients.  Thus, the French
implemented a treatment policy for ALL that provided BMTs quickly and
more extensively than we found in the other nine systems.  This may
be related to the large-scale clinical trials in France on
transplantation for acute leukemia, among other factors. 


      APPROPRIATENESS
-------------------------------------------------------- Chapter 4:3.2

With regard to the measures of appropriateness, the United States
appears to fall somewhat below the middle.  For patients transplanted
in their first complete remission, the issue of appropriateness of
time-to-transplant is whether some patients waited so long for a
transplant that the risks of disease progression no longer outweighed
the risks of the procedure.  This appeared to be a particular concern
in the United States and, to a lesser extent, in Germany.  In both
these countries, more than 5 percent of these patients waited over a
year following diagnosis before the procedure was performed. 

Regarding stage of disease at transplantation, the United States is
among four countries in which a substantial proportion of transplants
were for patients with advanced disease.  Among adults,
transplantation at earlier stages of the disease is more appropriate
than with advanced disease, when the prognosis is much poorer.  The
relatively high proportion of adult patients transplanted with
advanced disease in the United States means that a higher proportion
of the resources expended in the United States on transplantation for
ALL were going to patients with relatively poorer prognoses. 

Because the overall level of transplantation for the disease in the
United States is moderate, the relatively high number of patients
being transplanted with advanced disease points to a difference in
the treatment pattern for the disease, not an overall higher level of
use of the technology.  In addition, the United States is alone in
transplanting any of its ALL patients in first remission more than 18
months beyond diagnosis.\13 The experts who reviewed these data
viewed such transplants as clearly outside the boundaries of
appropriate treatment. 

Looking at stage of disease in the other countries, four
systems--Canada, France, the United Kingdom, and the
Netherlands--distinguished themselves in that well over half of their
ALL transplants were done in first complete remission.  While France,
the United Kingdom, and the Netherlands are the systems that
transplanted the highest proportion of patients with ALL, Canada had
a much lower rate.  On the one hand, France, the United Kingdom, and
the Netherlands appear to have used BMT as a primary therapy for a
broader range of ALL patients than the other countries.  The pattern
in Canada, on the other hand, with its moderate overall rate of
transplantation for ALL, was more consistent with an approach that
concentrated transplant resources on the high-risk patients who
benefit most from BMT in first complete remission. 

Transplants performed for ALL represent a significant portion of the
resources devoted to BMT in each system.  However, currently, there
are no clear lines where it can be stated that a system provides
"enough" or "too many" transplants for ALL.  The boundaries for
appropriate and inappropriate care are much broader for this disease
than for CML, and in almost all instances, the care patients received
in all these countries fell within those boundaries. 


--------------------
\13 There were patients in United States receiving transplants more
than 3 years following diagnosis. 


ACUTE MYELOID LEUKEMIA
============================================================ Chapter 5

Acute myeloid leukemia is the most common type of leukemia in young-
and mid-adulthood and accounts for the great majority of adult acute
leukemia cases.  Bone marrow transplantation has been an established
treatment for this disease for more than a decade.\1 To evaluate the
availability and appropriateness of transplantation for AML in the 10
health care systems, we identified from the clinical literature
specific criteria for this diagnosis.  Below, we describe these
criteria, and then we present data describing how patients in the 10
countries vary in their likelihood of receiving a transplant, the
timing of transplants, and the stage of disease at the time of
transplantation.  The chapter concludes with an assessment of how the
United States compares to the other countries on the availability and
appropriateness of allogeneic transplantation for AML. 


--------------------
\1 Robert Dinsmore et al., "Allogeneic Bone Marrow Transplantation
for Patients With Acute Nonlymphocytic Leukemia," Blood, 63:3 (Mar. 
1984), 649-56. 


   EVALUATION CRITERIA
---------------------------------------------------------- Chapter 5:1

AML advances rapidly, and if untreated, the life expectancy for
patients is less than 1 year.\2 Therefore, immediate treatment to
bring the patient into remission is critical.  Intensive chemotherapy
(induction therapy) is often successful in the initial treatment of
AML, and approximately 60-75 percent of patients achieve a remission. 
Once this occurs, patients are treated with several courses of
intensive consolidation therapy and then followed closely with no
further therapy.  Unfortunately, many patients who achieve a first
complete remission relapse within 12-18 months.  Further
chemotherapy, called reinduction therapy, can induce a second
remission in one-third of patients and, occasionally, a third
remission.  However, each remission following the first relapse tends
to be shorter than the one preceding it, and almost always a relapse
eventually occurs that does not respond to chemotherapy.  Long-term
survival for AML patients, therefore, largely depends upon achieving
and maintaining the first remission.  Once a patient relapses, a bone
marrow transplant offers the best prospect of a cure. 

Some AML patients are cured by the initial round of chemotherapy but
many are not; thus, whether continued chemotherapy alone or
transplantation is the optimal therapy for patients who have achieved
a first remission is still being debated.\3 Part of the uncertainty
stems from the difference between short- and long-term results.  With
conventional chemotherapy, drug-associated mortality is low, but
patient survival rates decline gradually over time owing to death
from relapse.  With transplantation, treatment-related mortality is
higher in the first 2 years, but if the patient survives the therapy,
the likelihood of cure is greater than it is with conventional
chemotherapy.\4 Adding to the uncertainty is the difficulty in
identifying which patients will relapse (and therefore might benefit
from a transplant) and which patients will stay in remission (and
therefore will do better if not subjected to the risks of a
transplant).  However, the longer a patient continues in first
remission, the less likely it is that the patient will subsequently
relapse.  Thus, the relative risks and benefits between chemotherapy
and transplantation change over time, even for the same patient. 


--------------------
\2 Peter H.  Wiernik, "Acute Leukemias of Adults," in Cancer: 
Principles and Practice of Oncology, 2nd ed., chap.  45, eds. 
Vincent T.  DeVita, Jr., Samual Hellman, and Steven A.  Rosenberg
(Philadelphia:  J.B.  Lippincott Co., 1985), pp.  1711-37. 

\3 As of 1992, after the period studied in this report, published
trials suggested that transplantation is equivalent and possibly
superior to chemotherapy, while no trials suggested the superiority
of chemotherapy.  Rajesh Chopra and Anthony H.  Goldstone, "Modern
Trends in Bone Marrow Transplantation for Acute Myeloid and Acute
Lymphoblastic Leukemia," Current Opinion in Oncology, 4:2 (Apr. 
1992), 247-58. 

\4 Philip B.  McGlave, "The Status of Bone Marrow Transplantation for
Leukemia," Hospital Practice, 20 (Nov.  15, 1985), 97-110. 


      MEASURES OF AVAILABILITY
-------------------------------------------------------- Chapter 5:1.1

Given that the best course of treatment is uncertain, rates of
transplantation for patients with AML comparable to those for CML
patients should not be expected.  Continued chemotherapy may be the
most appropriate treatment for patients for any of several reasons. 
First, because of the patient's age or the lack of a suitable donor,
transplantation may not be a relevant consideration.  Second, BMT
itself is sometimes a cause of life-threatening complications and
early mortality, while chemotherapy alone does cure some patients. 
Thus, physicians need to evaluate for each individual patient the
risk of transplantation against the risk of conventional therapy in
terms of survival and quality of life. 

At the aggregate level, the relative likelihood of transplantation
for AML tells us something about how available transplantation is in
each of the countries for patients with this disease.  However, all
the uncertainties mentioned above make it inappropriate for us to
conclude that countries that have higher (or lower) rates of
transplantation are doing a better job of treating AML.  The rates
simply inform us about the relative distribution of resources for
transplantation for this disease. 

As an additional measure of the relative availability of transplants,
we examined the time from diagnosis to transplantation for patients
who received the treatment in first remission.  Time-to-transplant is
not meaningful for patients who receive transplants at later stages
of the disease because of the variability in how long these patients
were in remission before a relapse occurred.  However, as with ALL,
for those patients who are recommended for transplantation in first
remission, the sooner the transplant is performed, the better.  In
this instance, longer times to provide the treatment can indicate
poorer availability. 


      MEASURES OF APPROPRIATENESS
-------------------------------------------------------- Chapter 5:1.2

The uncertainties surrounding optimal therapy for AML patients also
make it difficult to evaluate the appropriateness of care.  Two
criteria, however, can be used.  One of these is time-to-transplant
from the point of diagnosis for patients who receive transplants
while they are in first remission.  For these patients, it is clear
that the earlier they are treated, the more likely they are to
benefit from the procedure.  This is true for two reasons.  One is
that the cumulative likelihood of relapse increases as time passes
and transplantation is more likely to succeed when the disease is in
the first complete remission, rather than in first relapse or in
second remission.\5 Second, the longer a patient goes without a
relapse, the more likely it is that the remission will continue
without a transplant.  Both these factors together indicate that if a
patient is to receive a bone marrow transplant while in first
remission, earlier is better. 

The second criterion we used to measure appropriateness is the stage
of the disease at time of transplantation.  As mentioned above, it is
difficult to discriminate between patients who will relapse (and,
therefore, should be transplanted while in first remission) and
patients who will be cured by chemotherapy alone (and, therefore, do
not benefit from a transplant).  However, research has demonstrated
that after a patient has relapsed, it is best to transplant as soon
as possible.  For some patients, it is feasible to transplant
immediately, rather than subject that patient to a second round of
intensive chemotherapy.\6 In other cases, it is appropriate for the
patient to be reinduced into a second complete remission and then
transplanted.  By this point, all AML patients considered eligible
for transplantation should have the procedure performed.  At any
later stage (second relapse, third remission, and so forth) their
prospects for a positive outcome are notably diminished.\7


--------------------
\5 R.A.  Clift et al., "The Treatment of Acute Non-lymphoblastic
Leukemia by Allogeneic Marrow Transplantation," Bone Marrow
Transplantation, 2:3 (Oct.  1987), 243-58. 

\6 Frederick R.  Appelbaum and E.  Donnall Thomas, "Treatment of
Acute Leukemia in Adults With Chemoradiotherapy and Bone Marrow
Transplantation," Cancer, 55:9 Supp.  (May 1, 1985), 2202-09. 

\7 F.R.  Appelbaum et al., "Timing of Bone Marrow Transplantation for
Adults with Acute Nonlymphocytic Leukemia," Autologous Bone Marrow
Transplantation:  Proceedings of the Fourth International Symposium,
eds.  K.A.  Dicke et al.  (Houston:  University of Texas M.D. 
Anderson Cancer Center, 1989), 21-26. 


   LIKELIHOOD, TIMING, AND STAGE
   OF TRANSPLANTS
---------------------------------------------------------- Chapter 5:2

We provide our analyses of the likelihood, timing, and stage of
transplantation for AML in the sections that follow. 


      THE LIKELIHOOD OF RECEIVING
      A TRANSPLANT
-------------------------------------------------------- Chapter 5:2.1

As in previous chapters, we have constructed a disease-specific BMT
utilization-to-incidence ratio to represent the rate of
transplantation.  The rates in table 5.1 represent the likelihood
that AML patients under age 55 in each country would receive BMT as
part of the their leukemia treatments by the end of the second
calendar year following the year in which they were diagnosed.  The
rates also describe the relative likelihood, across countries, of
receiving a transplant.  As in previous tables, when the number of
events is small--the situation for New Zealand, Denmark, and
Sweden--random fluctuation from year to year in the number of
patients, by even a few cases, could noticeably affect the rates and
thus the rankings of countries. 



                          Table 5.1
           
                Transplantation Rates for AML

Country                                               Rate\a
--------------------------------------------------  --------
France                                                   .50
Canada                                                   .27
United States                                            .23
United Kingdom                                           .20
Australia                                                .20
New Zealand                                              .19
Netherlands                                              .18
Sweden                                                   .17
Germany                                                  .13
Denmark                                                  .10
------------------------------------------------------------
\a Ratio of the incidence of allogeneic bone marrow transplantation
performed within 2 calendar years following the year of diagnosis to
estimated annual incidence of AML; for transplants performed in
1989-91 on patients aged 0-54. 

Table 5.1 shows that French patients, at 50 percent, had the highest
probability of receiving a transplant.\8 The probability was almost
twice that of patients in any of the other nine countries.  In the
United States, nearly one-fourth of AML patients received transplants
as part of their therapy.  That ratio was slightly lower than
Canada's and slightly higher than in five other countries.  Patients
in Denmark and Germany had the lowest likelihood of transplantation. 
For each country, the likelihood of transplantation for patients with
AML was greater than for patients with ALL and, except for France,
less than for CML patients. 


--------------------
\8 As noted in the previous chapter, the high rate of transplantation
in France for acute leukemias may have been related in part to
nationwide clinical trials then ongoing to compare the efficacy of
BMT to chemotherapy for treating AML and ALL. 


      THE TIMING OF TRANSPLANTS
-------------------------------------------------------- Chapter 5:2.2

Table 5.2 presents data on time-to-transplant for patients who
received a transplant while in first remission.  To ensure that
variations due to the availability of donors were not incorporated,
the table includes data only on patients receiving related-donor
transplants. 



                          Table 5.2
           
           Months From Diagnosis to Transplantation
                      for AML Patients\a


                                                       Total
Country                   5%   25%   50%   75%   95%   cases
----------------------  ----  ----  ====  ----  ----  ------
France                   2.5   3.0   3.6   4.7   7.4     143
United States            2.4   3.4   4.4   5.8  10.2     367
Canada                   2.6   3.8   5.3   7.6  13.2      82
Netherlands              3.9   4.6   5.4   6.2   8.7      46
Sweden                   3.0   4.6   5.6   7.1   9.1      25
Germany                  3.3   4.9   5.7   7.2   9.9      75
Australia                3.3   4.5   6.0   8.7  12.2      38
Denmark                  4.8   5.0   6.4   8.2   9.8       7
United Kingdom           3.9   5.3   6.4   7.6  10.8     102
New Zealand              3.8   6.3   6.5   6.8   7.1       8
------------------------------------------------------------
\a For patients in first remission at time of transplant;
related-donor transplants performed in 1989-91. 

The table shows that the median times from diagnosis to
transplant--the time when 50 percent of BMT patients in each country
had received a transplant--ranged from 3.6 months in France to 6.5
months in New Zealand.  More than three-fourths of French and U.S. 
patients transplanted in first remission were treated within 6
months.  In Denmark, the United Kingdom, and New Zealand, the
corresponding figures were less than one of every two patients. 


      STAGE OF DISEASE AT
      TRANSPLANTATION
-------------------------------------------------------- Chapter 5:2.3

Table 5.3 presents the percentage of transplants for AML conducted in
each stage of disease.  Again, the data are restricted to
related-donor transplants to eliminate the possibility that variation
is caused by the search for a suitable donor. 



                                    Table 5.3
                     
                     Stage of Disease at Transplantation for
                                  AML Patients\a

                            First                   Second
            Induction    complete        First    complete    Advanced     Total
Country     failure\b   remission      relapse   remission   disease\c     cases
---------  ----------  ----------  -----------  ----------  ----------  --------
Australia         13%         46%          33%          5%          2%        82
Canada              8          68           11          10           2       134
Denmark             0          54           15          31           0        13
France              8          68            5          16           3       277
Germany             6          67            7          14           6       168
Netherlan           4          82            2           9           4        56
 ds
New                 0          80            0          20           0        10
 Zealand
Sweden              9          66            9          11           6        35
United              6          79            8           6           1       158
 Kingdom
United              8          47           21          17           7       974
 States
--------------------------------------------------------------------------------
\a For related-donor transplants performed in 1989-91. 

\b Induction failure refers to patients for whom chemotherapy has
failed to induce a complete remission. 

\c Advanced disease refers to patients who are in their second
relapse or beyond. 

In table 5.3, we see that the patterns for the United States were
quite distinct from those for most other countries.  Most obvious is
the relatively low percentage of transplants that occurred while
patients were in first remission.  Here, the United States was joined
only by Australia in transplanting less than half its BMT patients
during this stage of the disease.  Additionally, the United States
provided transplants to relatively more patients with advanced
disease than any other country, although the differences were small. 


   CONCLUSIONS
---------------------------------------------------------- Chapter 5:3

Just as for ALL, the comparative assessment of the 10 countries in
their treatment of AML is complicated because transplants are not
necessarily called for in caring for these patients.  Some are cured
by chemotherapy alone, so transplantation is not clearly indicated
unless and until a patient relapses.  However, if a transplant is to
be performed, the prognosis is better if the patient receives the
transplant in the first complete remission of the disease.  In
assessing how the 10 health care systems handled the treatment of
AML, we examined the availability of BMTs using two measures:  the
proportion of patients who received transplants and the time from
diagnosis to transplant for patients who received transplants in
their first complete remission.  We also used time-to-transplant as a
measure of appropriateness of care, along with the stage of disease
at which the transplant was provided. 


      AVAILABILITY
-------------------------------------------------------- Chapter 5:3.1

Our data on availability cannot indicate which countries had the
"right" amount of transplantation.  The data simply show that France
was unique in the level of transplantation, with a French AML patient
almost twice as likely to receive a transplant as those in any other
country.  For the United States, the data show levels of
transplantation on par or slightly higher than that of most other
countries (besides France).  The United States was among the quickest
to begin providing transplants and second only to France in the time
required to treat the bulk of its patients, indicating good
availability of transplant services for patients with AML. 


      APPROPRIATENESS
-------------------------------------------------------- Chapter 5:3.2

The question of whether a transplant should be done remains open for
many patients with AML.  However, the benefits of acting quickly for
those patients who do receive transplants are fairly well
established.\9 Here, the patterns exhibited by patients in the United
States and most of the other systems are largely positive.  The
United States was second only to France in the speed with which
patients in first complete remission received transplants.\10
However, even the slowest systems transplanted half these patients
within slightly more than 6 months of diagnosis and 95 percent within
a little more than a year. 

In terms of stage of disease, the United States, Australia, and
Denmark were least likely to transplant in first complete remission. 
Patients in these countries appear more likely to have been treated
under an alternative strategy, in which BMT was reserved for those
who relapse from their first complete remission.  Since the reported
outcomes of the two strategies are equivalent, neither is more
appropriate.  While the United States also led in the number of
patients receiving transplants in still later stages, the overall
frequency was low (only 7 percent of U.S.  transplants for AML). 

In short, U.S.  patients with AML experienced similar levels of bone
marrow transplantation availability and appropriateness relative to
those in the other health care systems examined.  The one major
exception was the much higher rate of transplantation in France. 


--------------------
\9 Appelbaum and Thomas (1985), p.  2206. 

\10 The only qualification is that, as with CML and ALL, a small
group of patients seemed to wait a long time before receiving a
transplant.  While the United States was second fastest in providing
transplants for 75 percent of the patients, the last 5 percent waited
longer than their counterparts in six other countries. 


CONCLUSIONS AND IMPLICATIONS
============================================================ Chapter 6

In the previous chapters, we have examined how the utilization of one
costly, high-technology medical treatment varied across 10 national
health care systems.  We looked in particular at the patterns
displayed in the use of bone marrow transplantation in the treatment
of three prevalent forms of leukemia:  chronic myeloid leukemia,
acute lymphoid leukemia, and acute myeloid leukemia.  This chapter
summarizes the principal findings from our study.  After presenting
these, we discuss their implications. 


   SUMMARY OF FINDINGS
---------------------------------------------------------- Chapter 6:1

Our objectives were to determine, from a comparative perspective, the
availability of transplants (that is, the likelihood that patients
who needed transplants would receive them) and the appropriateness of
the observed patterns (the extent to which transplants occurred at a
time when they optimize the risk-benefit ratio to the patient). 

In terms of the first dimension, viewed across the three common types
of leukemia for which transplantation is a standard treatment option,
we found that the placement of the American health care system
varied, but was never at either extreme of availability.  For the two
acute leukemias, alternative treatments may work as well as
transplantation for many patients and pose less risk.  For these
conditions, the only conclusion that can be drawn is that the United
States was not unique in using this expensive procedure when its
relative advantages were less clear.  However, for CML, a disease
that could be cured only by transplantation, we found that U.S. 
patients were less likely to receive a transplant than were patients
in some other countries. 

The placement of the United States also varied along the dimension of
appropriateness.  The intervals from diagnosis to transplantation
were among the shortest for the majority of U.S.  transplant patients
with acute leukemia.  However, some patients in the United States
waited longer for their transplants than patients in any other
country.  Further, higher proportions of U.S.  patients (in the case
of each of the leukemias) received transplants at a relatively late
stage of the disease compared to patients in most of the other
countries.  The implications of this pattern are less clear for the
acute leukemias (where the optimal stage of intervention is less well
defined) than for the management of CML.  In the latter case, the
substantial number of U.S.  CML patients who were transplanted with
advanced disease has negative implications for the quality of care
provided.  This is especially true because the overall rate of
transplantation for CML was not particularly high in the United
States.  Thus, the relatively large percentage of transplants
performed on poor prognosis patients in the U.S.  means that
relatively fewer good prognosis patients received transplants in this
country than was the case elsewhere. 


   IMPLICATIONS
---------------------------------------------------------- Chapter 6:2

We have presented data for a single treatment and how it is used in
the management of three diseases.  Bone marrow transplantation is
just one example of very expensive, complex, high-technology
therapies.  It cannot be assumed that our findings for BMT would
necessarily hold true for other such procedures or for a wider range
of medical interventions.  In light of this uncertain
generalizability beyond bone marrow transplantation, as well as the
descriptive nature of our findings, what larger implications, if any,
do our results suggest? 

First, by presenting international data on utilization of BMT, this
report informs members of the transplant community about how their
treatment patterns compare to those of their colleagues in other
countries.  For other medical procedures, such as Caesarian section
deliveries, hysterectomies, and prostatectomies, the presentation to
practitioners of national and regional variations in practice
patterns has led to a reconsideration of the indications for
treatment, particularly among those who diverge most markedly from
the others.  Our international findings should facilitate and
encourage a comparable discussion both within individual countries
and across the international bone marrow transplant community.  For
example, the U.S.  transplant community could consider why, to a
greater extent than was true elsewhere, patients in the United States
for whom the treatment offered fewer likely benefits (for example,
those in advanced stages of leukemia) often received transplants,
while others who could benefit more did not. 

Second, our findings on bone marrow transplantation raise questions
about two contrasting views of how the United States uses medical
technology.  One perspective sees higher utilization of costly,
high-technology therapies as evidence of a greater availability of
state-of-the-art medicine to the public.  The other views higher
utilization of these therapies in this country as indicative of
wasteful and potentially harmful overuse of available technology. 

Both views rest on the assumption that expensive, high-technology
medicine is used to a far greater extent in the United States than in
other economically advanced countries.  However, the findings
presented in this report challenge that assumption.  Although the
United States did better on some dimensions (time-to-transplant for
acute leukemia) and less well on others (stage of disease for CML
transplants), on no measure did it surpass the other nine countries
studied.  Further, the data show that some countries that have been
characterized in the public debate as much more restrictive in the
provision of sophisticated health care treatments actually had levels
of transplantation that were equivalent to, if not greater than,
those of the United States. 


DATA SOURCES
=========================================================== Appendix I

To describe the patterns of utilization of bone marrow transplants in
the 10 countries in the study, we needed to obtain data on patients
receiving transplants from all the transplant centers in each
country.  This appendix discusses the data sources from which we
derived the information on the number of transplants, the stage of
disease at transplantation, and the time from diagnosis to
transplant.  These sources include the International Bone Marrow
Transplant Registry based at the Medical College of Wisconsin, the
Sociï¿½tï¿½ Franï¿½aise de Greffe de Moï¿½lle, and three surveys. 

Our initial source of information was the IBMTR, which collects
detailed information on all allogeneic bone marrow transplants
performed at approximately 200 transplant centers worldwide,
representing more than 50 percent of the transplant teams in the
world.  The primary database contains clinical information about each
of more than 15,000 patients who have received bone marrow
transplants since 1970. 

The Sociï¿½tï¿½ Franï¿½aise de Greffe de Moï¿½lle is a professional society
that collects data for research on bone marrow transplants performed
at French institutions.  A total of 35 centers contributed data to
the society on allogeneic BMTs in 1989-91, while only 14 of these
centers participate in the IBMTR.  For France, we obtained data on
transplants from the society rather than from IBMTR.\1

Although most transplant centers contribute data to IBMTR, some
centers do not participate, or at some hospitals with multiple
transplant teams (e.g., pediatric and adult), one or more teams may
not participate.  Also, some centers only submit certain types of
cases to the registry.  We therefore surveyed all the transplant
teams in the remaining nine countries, other than France, for which
the IBMTR database could not provide comprehensive information. 

We used the IBMTR Directory of Bone Marrow Transplant Teams to
identify all the institutions at which allogeneic bone marrow
transplantation was done.  After cross-checking this directory with
lists of transplant centers obtained in some of the countries and
published lists from the European Bone Marrow Transplant Group, we
identified transplant teams at more than 100 transplant centers from
which we needed information.\2 This included some teams that
participate in IBMTR but whose data were not complete owing to lags
in reporting.  We arranged for IBMTR to send a questionnaire to each
team, and to follow up by telephone or telefax with any who had not
responded.  Eighty-four percent of the transplant teams surveyed
responded with information on their transplant activities. 

Each team surveyed was asked to provide data on the number of
transplants performed, the stage of disease at the time of
transplantation, and the interval from diagnosis to transplant for
each patient.  However, if a team's records did not allow for ready
retrieval of this information, it was requested to supply summary
information on the number of transplants performed, the type of
disease, and stage at transplantation, but not on the interval from
diagnosis to transplant. 

For each of the transplant teams that did not respond to the survey
or that provided only partial information, we obtained data from that
older surveys:  a worldwide survey that IBMTR had conducted in 1991
and an annual study of European transplant centers.\3 The data
available on these centers were limited to the number of transplants
performed and did not include information on the stage of disease or
the interval from diagnosis to transplant.  The IBMTR survey covered
only the years 1988-90.  We obtained the number of transplants
performed in 1991 in two ways:  either from the annual European Bone
Marrow Transplant Group study, or (for non-European centers) by
assuming that the number of transplants performed in 1991 at each
center was equal to the average number performed there the preceding
2 years. 

The number of transplant cases and transplant centers provided by
each data source for each country are shown in table I.1. 



                                    Table I.1
                     
                      Data Sources for Number of Allogeneic
                            Bone Marrow Transplants\a


Country        Cases     Centers       Cases     Centers       Cases     Centers
--------  ----------  ----------  ----------  ----------  ----------  ----------
Australi         306          12          18           1          45           1
 a
Canada           223           5         347           6           6           1
Denmark            0           0          90           1           0           0
France       1,708\e          35           0           0           0           0
Germany          184           3         521           9          52           1
Netherla         138           3          94           2           0           0
 nds
New               32           2           0           0          27           1
 Zealand
Sweden           138           3          30           1           0           0
United           390          10         381          15         229           5
 Kingdom
United         1,148          33       3,500          50         225           8
 States
================================================================================
Total          4,267         106       4,981          85         584          17
--------------------------------------------------------------------------------
\a For transplants performed in 1989-91. 

\b International Bone Marrow Transplant Registry database of
transplants performed worldwide. 

\c Survey conducted for this study of transplant centers for which
the IBMTR data were not complete. 

\d For centers that did not respond to the GAO survey, a 1991 IBMTR
survey of all transplant centers in the world was used as the source
of information.  For European centers, data from this survey were
supplemented by data from the European Bone Marrow Transplant Group. 

\e Groupe d'ï¿½tude des Greffes de Moï¿½lle Osseuse, Rapport D'activitï¿½
1991, p.  2, tableau 1. 

In total, we obtained data on 9,832 transplants performed at 208
transplant centers.  As noted above, this provided complete
information on the number of transplants performed, but the data on
stage of disease and interval from diagnosis to transplant were not
complete for all cases.  For those cases from the IBMTR survey, we
had neither stage nor time information, and time data were also
unavailable on cases from the centers responding to our survey who
supplied only summary data tables. 


--------------------
\1 Data were obtained from the society and from a report of one of
its predecessors, the Groupe d'ï¿½tude des Greffes de Moï¿½lle Osseuse. 

\2 A.  Gratwohl et al., "Bone Marrow Transplantation in Europe: 
Major Geographical Differences," Journal of Internal Medicine, 233:4
(1993), 333-41.  A.  Gratwohl, "Bone Marrow Transplantation Activity
in Europe 1990," Bone Marrow Transplantation, 8:3 (1991), 197-201. 

\3 For a description of the IBMTR survey, see Mortimer M.  Bortin,
Mary M.  Horowitz, and Alfred A.  Rimm, "Increasing Utilization of
Allogeneic Bone Marrow Transplantation:  Results of the 1988-1990
Survey," Annals of Internal Medicine, 116:6 (Mar.  15, 1992), 505-12. 
For a description of the survey of European centers, see Gratwohl et
al.  (1993) and Gratwohl (1991). 


COMPUTATION OF RATES
========================================================== Appendix II

We presented the rates for allogeneic bone marrow transplantation for
CML, ALL, and AML in chapters 3, 4, and 5.  This appendix describes
how those rates were computed.  We begin by describing how we
estimated the number of cases of each of these three forms of cancer
in each of the countries.  We then show how we used our data on
transplants in combination with the estimated incidence to determine
the relative likelihood of transplant in each country.  The final
section of this appendix discusses the reasonableness of the
estimates. 


   COMPUTATION OF DISEASE
   INCIDENCE
-------------------------------------------------------- Appendix II:1

We used several sources of data on cancer incidence to estimate the
number of cases of CML, ALL, and AML for each country.  For most of
the countries, we employed data assembled by the International Agency
for Research on Cancer (IARC), an affiliate of the World Health
Organization.\1 However, for the United States, we drew directly from
data produced by the Surveillance, Epidemiology, and End Results
(SEER) program of the National Cancer Institute.  The SEER data cover
approximately 10 percent of the population in the United States.  We
also obtained data on cancer incidence in Sweden from the Swedish
National Cancer Registry and in the Netherlands from the Dutch Cancer
Registry. 

To use these data, we had to overcome two limitations.  One was that
some of the countries in our study do not have national cancer
registries that collect data on the full national population.  In
France, population-based registries in six departments in the
northern, eastern, and southern sections of the country represent
about 7 percent of the national population.  In Australia, the six
available registries cover 84 percent of the population.  In both
cases, we derived estimates of national incidence rates for CML, ALL,
and AML from an extrapolation of the data from the registries
weighted by their relative populations.  We also combined data for
separate population groups to obtain an overall national rate for New
Zealand (Maoris and non-Maoris) and the United Kingdom (England,
Wales, and Scotland).\2

The Saarland has the only cancer registry with population-based
incidence data for the western portion of the recently reunited
Germany.  (Since the German Democratic Republic had a completely
different health care system, we limited our analyses to the German
lï¿½nder (states) that belonged to the Federal Republic of Germany
before 1990).  Because the Saarland represents just 1.7 percent of
the population for western Germany, these cancer rates might not
reflect those in other parts of the country.  Therefore, we chose to
compare Germany to the other countries based on an assumed incidence
rate for each disease that was the average for the other nine
countries.  As noted in chapter 1, this approach seemed reasonable
for three reasons:  (1) it results in a ranking for Germany
consistent with that obtained using total national populations, (2)
leukemia incidence rates do not vary that much among countries
overall, and (3) these incidence estimates are in line with those
suggested independently by German oncologists. 

The second obstacle in estimating incidence was that IARC reported
incidence data for each leukemia in the form of single
age-standardized rates for males and females in each registry.  An
age-standardized incidence rate removes the effect of differences in
age distributions among countries.  What it represents is the number
of new leukemia cases per 100,000 population which would have
occurred during 1 year if the actual rates observed in a country in
specific age categories (0-4, 5-9, and so forth) had operated in the
standard world population with an arbitrary proportion of people in
each age group.  While age-standardized incidence rates are preferred
for many types of international comparisons, our analyses required an
estimate of the actual number of leukemia cases experienced in each
country.  Moreover, we needed to estimate the number of cases of
disease in the population eligible for transplantation, generally
below age 55. 

To convert national male and female age-standardized rates to an
estimate of the number of cases diagnosed in this subset of the
overall population, we did the following.  We made the assumption
that the relative distribution of cases across age groups would be
fairly constant among countries.  That is, if a country had an
overall age-standardized rate that was 50-percent higher than
another's, the incidence rate in each five-year age category would be
50-percent higher in the first country.  SEER provided the
age-specific rate for each 5-year age group from 0 to 54 in the
United States for each of the three leukemias.  Using the ratio of
the age-standardized rates for males and females in the United States
to those in each of the other countries, we derived an age and
gender-specific rate for each country that was proportionately higher
or lower than that of the United States for each age and gender
category.  This rate was then multiplied by the actual size of the
male or female population of that country in that age group.  Summing
this result across all the age and sex categories 0 to 54 for males
and females produced an estimated count of leukemia cases that could
have been candidates for BMT in each country.  The estimates for each
disease for each country are shown in table II.1. 



                          Table II.1
           
            Estimated Annual Incidence by Disease


Country                              CML       ALL       AML
------------------------------  --------  --------  --------
Australia                             77       202       149
Canada                               128       320       209
Denmark                               19        54        52
France                               247       459       208
Germany                              256       528       474
Netherlands                           42       114       109
New Zealand                           13        47        31
Sweden                                25        80        65
United Kingdom                       163       450       346
United States                      1,159     2,827     1,850
------------------------------------------------------------

--------------------
\1 D.M.  Parkin et al., eds., Cancer Incidence in Five Continents,
Volume VI.  IARC (Lyon, France, 1992). 

\2 All of our analyses of the United Kingdom exclude Northern Ireland
because its population is not covered by any cancer registry and so
incidence data were unavailable. 


   LIKELIHOOD OF TRANSPLANT
-------------------------------------------------------- Appendix II:2

To calculate the proportion of newly diagnosed patients that received
transplants (and thereby remove the effect of cases that were
"backlogged" from previous years), we stratified the cases according
to the calendar year in which they were diagnosed.  We calculated the
proportion of cases transplanted in (1) the same year as the
diagnosis, (2) the year following that of diagnosis, and (3) the
second year following that of diagnosis.  We then added the three
proportions together to obtain the proportion transplanted by the end
of the second full year following the year of diagnosis. 

Each of the individual proportions (within the same year, the
following year, and the second year after diagnosis) was itself
calculated from 3 years of data.  We computed the proportion of cases
transplanted in the same year as the diagnosis by taking as the
numerator the average of the number of cases (1) diagnosed in 1989
and transplanted in 1989, (2) diagnosed and transplanted in 1990, and
(3) diagnosed and transplanted in 1991.  As the denominator, we used
our estimate for the annual incidence of the disease in question
(CML, ALL, or AML). 

For the proportion of cases transplanted in the year following
diagnosis, we averaged the number of cases (1) diagnosed in 1988 and
transplanted in 1989, (2) diagnosed in 1989 and transplanted in 1990,
and (3) diagnosed in 1990 and transplanted in 1991.  Again, this
average number for the three sets of cases was placed over the
estimated annual incidence to calculate the proportion of cases
transplanted in the year after diagnosis. 

Finally, for the third component of the overall ratio (the proportion
of cases transplanted in the second full year following that of
diagnosis), we counted (1) cases diagnosed in 1987 and transplanted
in 1989, (2) cases diagnosed in 1988 and transplanted in 1990, and
(3) cases diagnosed in 1989 and transplanted in 1991 and placed their
average over the same annual incidence figure.  By adding all three
proportions, we arrived at an estimated rate of transplantation for a
3-year period in which each component of the total was based on cases
diagnosed in 3 different years. 


   REASONABLENESS OF ESTIMATES
-------------------------------------------------------- Appendix II:3

The rate at which allogeneic bone marrow transplants can be performed
is limited by the ability to find a suitable marrow donor.  The most
likely place to find donors is among the siblings of the patient, yet
even here, the likelihood that any individual sibling will be an
ideal donor (HLA-matched) is only one in four.  In situations where a
matched sibling donor (MSD) cannot be found, the search expands to
include other family members, mismatched siblings, and HLA-matched
unrelated donors (identified through donor registries).  Although the
likelihood of finding donors through any of these mechanisms is
unknown, the inability to identify a donor occurs frequently enough
to make one skeptical about national rates of allogeneic BMT that
exceed 40 or 50 percent. 

Because some of our rates were in this range, we reviewed our
computations to verify that both the data and the algorithm were
correct.  Further, we examined what component of each rate was
comprised of matched sibling donor transplants.  In this way, we
could determine whether the rates were higher than expected because
the likelihood of finding a related donor is greater than what was
assumed or because more matched unrelated, matched
nonsibling-related, and mismatched related-donor transplants were
performed than expected.  Table II.2 shows the results of these
computations, giving both the overall rate and the rate for matched
sibling donor transplants. 



                          Table II.2
           
            Disease-Specific Transplant Rates for
             All Transplants and Matched Sibling
                     Donor Transplants\a



Country           Total  MSD\b   Total  MSD\b   Total  MSD\b
---------------  ------  -----  ------  -----  ------  -----
Australia         37.8%  27.9%    7.6%   6.2%   20.2%  17.2%
Canada             38.5   30.6     5.4    4.2    27.2   23.4
Denmark            40.7   26.8     3.1    1.9     9.5    6.5
France             32.1   26.3    23.0   19.9    50.2   45.3
Germany            26.2   22.2     5.6    4.8    13.4   12.7
Netherlands        32.8   25.3    11.0   10.7    18.4   16.3
New Zealand        46.1   33.5     3.7    2.5    18.6   18.6
Sweden             54.2   51.2     8.8    8.2    17.3   14.7
United Kingdom     48.2   36.8    15.2   13.5    20.4   18.0
United States      35.2   22.1     6.8    4.6    22.5   17.4
------------------------------------------------------------
\a For transplants performed in 1989-91. 

\b MSD refers to percentage of all cases of the disease in which
patients received a transplant from an HLA-matched sibling. 

As can be seen from the table, in some instances the rate for matched
sibling donor transplants was higher than what might be expected. 
For example, the rate for CML in Sweden and AML in France are
particularly striking.  Despite this divergence from expectations,
however, we remain confident that the estimates are reasonable
approximations.  Whereas in the case of France we know that the
incidence estimates may be somewhat imprecise because of the absence
of a national registry, the same is not true for Sweden, where the
incidence data are firm and still we find that one of every two cases
with CML had an available sibling donor. 


ADVISORY PANEL
========================================================= Appendix III

Frederick R.  Appelbaum, M.D.
Professor of Medicine
University of Washington
Director, Division of Clinical Research
Fred Hutchinson Cancer Research Center
Seattle, Washington

Bruce Cheson, M.D.
Head of Medicine Section
Cancer Therapy Evaluation Program
National Cancer Institute
Bethesda, Maryland

Mary M.  Horowitz, M.D., M.S.
Scientific Director
International Bone Marrow Transplant Registry
Associate Professor of Medicine
Medical College of Wisconsin
Milwaukee, Wisconsin


MAJOR CONTRIBUTORS TO THIS REPORT
========================================================== Appendix IV


   PROGRAM EVALUATION AND
   METHODOLOGY DIVISION
-------------------------------------------------------- Appendix IV:1

Marcia G.  Crosse
Eric A.  Peterson
George Silberman
Richard C.  Weston


   EUROPEAN OFFICE
-------------------------------------------------------- Appendix IV:2

Michelle Grgich

In addition to these staff, who formed the core of the project,
members of the international bone marrow transplant community made
considerable contributions.  Physicians, nurses, hospital
administrators, and government officials in each of the countries
gave substantial time and effort to attend meetings, provide data,
and answer questions.  Without this gracious support, this project
would not have been possible. 

