close

Вход

Забыли?

вход по аккаунту

?

Study of the nutritional value of black cumin seeds (Nigella sativaL)

код для вставкиСкачать
1903
COMMENTARY
See referenced commentary on pages 1900 –2,
editorial on pages 1887–9, and original article on
pages 2143–9, this issue.
Details on the design and results of the Phase II
trials have already been published.1,5,6
The Unconventional Di Bella
Cancer Treatment
Supported by a specific act of the Italian Parliament.
The committees and members of the Italian Study
Group for the Di Bella Multitherapy Trials are as
follows. Research Coordinating Center: D. Greco,
R. Raschetti, B. Caffari, F. Chiarotti, R. Da Cas, B.
De Mei, G. Di Giovambattista, M. Maggini, F. Menniti-Ippolito, S. Modigliani, P. Popoli, P. Ruggeri, S.
Spila-Alegiani, C. Tomino, G. Traversa, P. Bruzzi, T.
Gamucci. Steering Committee: G. Benagiano, D.
Amadori, P. Bruzzi, E. Buiatti, E. Ciranni, F. Cognetti, G. Colucci, P.F. Conte, G. Di Bella*, D. Greco,
S. Iacobelli, F. Mandelli, E. Marubini, M. Massotti,
S. Monfardini, F. Oleari, R. Raschetti, G. L. Sannazzari, L. Tomatis, U. Veronesi. (*Dr. G. Di Bella,
the son of Dr. L. Di Bella, only participated in the
first two meetings of the Steering Committee. On
many occasions, he strongly disagreed with the
performance and results of the trials. No part of
the current article has been discussed with or
endorsed by Dr. G. Di Bella.) International Review
Board: P. Calabresi (Rhode Island), F. Cavalli (Bellinzona, Switzerland), P. Kleihues (Lyon Cedex,
France), J.G. Mc Vie (London, UK), H. Pinedo (Amsterdam, The Netherlands), K. Sikora (Lyon Cedex,
France), T. Tursz (Villejuif Cedex, France). Independent Endpoint Evaluation Committee: A. R. Bianco,
R. Labianca, P. L. Rossi Ferrini, G. Simonetti, A.
Sobrero. Investigators: Ancona—R. Cellerino, S.
Antognoli, R. Berardi, R. Bracci, P. Lippe, F. Pulita;
Aosta—F. Di Vito, D. Martinod, M. Musi; Aviano—A. Veronesi, R. Lazzarini; Bari—G. Colucci
(Principal Investigator [PI]), V. Attolico, F. Giotta, M.
Longo, E. Maiello; Bologna—S. Tura, F. Gherlinzoni, M. Tani; Bolzano—H. Amor, P. Borona, F.
Girardi, C. Graiff; Cagliari—G. Broccia, M. G. Corona, A. Desogus, V. Mascia, S. Pasqualucci; Catania—G. Failla, M. R. Aiello, S. Cordio, P. Finocchiaro. Chieti—S. Iacobelli (PI), E. Melena, M. De
Tursi, M. T. Scognamiglio, N. Tinari; Forlı̀—D.
Amadori (PI), M. Maltoni, O. Nanni, F. Scardovi, P.
Serra; Genoa—R. Rosso, F. Boccardo, A. Barp, T.
Coli, M. Grimaldi; Milan—N. Cascinelli, L. Ascani,
E. Bajetta, P. Bidoli, A. Cassata, D. De Candis, W.
Giannessi, G. Procopio; Milan—S. Di Donato, A.
Boiardi, D. Cerri, M. Eoli, A. Silvani; Milan—U.
Veronesi (PI), M. Colleoni, N. Rotmensz; Naples—S. Monfardini (PI), G. Comella, A. De Matteis, A. Gravina, C. Gridelli, F. Perrone, M. R.
Salzano, C. Sandomenico; Naples—C. Battista, G.
Iodice, R. Fico, A. Nicchia; Padua—M. Lise, G. L.
De Salvo, E. Di Lenardo, G. Iadicicco; Palermo—B.
Agostara, I. Cafarelli; Perugia—M. Tonato, F.
Radicchi, S. Sorbolini, O. Taschini; Pisa—P. F.
Conte (PI), A. Carmignani, L. Del Mastro, A. Gen© 1999 American Cancer Society
A Reflection on the Italian Experience
Giuseppe Traversa, M.D.1
Marina Maggini, D.Biol.1
Francesca Menniti-Ippolito, M.Sc.1
Paolo Bruzzi, M.D.2
Flavia Chiarotti, M.Sc.1
Donato Greco, M.D.1
Stefania Spila-Alegiani, D.Biol.1
Roberto Raschetti, M.Sc.1
Giuseppe Benagiano, M.D.1
for the Italian Study Group for the Di Bella Multitherapy Trials
1
Istituto Superiore di Sanità, Rome, Italy.
2
Istituto Nazionale Ricerca sul Cancro, Genoa, Italy.
O
n November 13, 1998, the great hope raised among Italians by the
multidrug anticancer treatment scheme developed by a Modena
physiologist, commonly known as Multitrattamento Di Bella (MDB,
Di Bella Multitherapy), received a substantial blow. On that date, the
government-sponsored clinical trials were concluded, with completely negative results.1 It was almost 1 year from the time when the
issue blasted to public attention, although the MDB was not a new
discovery. Indeed, Luigi Di Bella had begun to treat cancer patients
more than 20 years before, using a combination of different substances; his multitherapy evolved over the years and the full list of
substances that he used throughout this period comprised more than
100 drugs. Nonetheless, the compounds most frequently used in the
last 10 years, constituting the backbone of what became known as
MDB, were only a handful: somatostatin (or its synthetic equivalent,
nari, C. Orlandini; Potenza—L. Manzione, A. Dinota, G. Lombardi; Reggio Calabria—G. Gasparini,
M. G. Arena, M. Fanelli, F. Modafferi, A. Morabito;
Rome—F. Mandelli (PI), P. Fazi, F. Mauro, M.
Martelli, C. Ricci, M. Vignetti; Rome—F. Cognetti
(PI), A. D’Alessio, S. De Marco, V. Ferraresi, T.
Gamucci, D. Giannarelli, E. Magnani, P. Rellecati,
E. M. Ruggeri, M. Zeuli; Turin—G. L. Sannazzari
(PI), M. Borgognone, R. Chiò, A. Gasco, R. Ragona,
M. Sacco, R. Soffietti, R. Verna, M. Tessa;
Turin—A. Pileri; Trento—E. Galligioni, A. Lucenti,
F. Moltrer, F. Paolazzi.
Muzzi, Director), for the production of the melatonin tablets and retinoid solution and the Group for
the supervision and control of custom-made drugs
of the Istituto Superiore di Sanità, Roma (E. Ciranni, Director; R. Alimenti, S. Alimonti, G. Cavazzutti, L. Gagliardi, B. Gallinella, G. Incarnato, F. La
Torre, A. Mosca, G. Multari, L. Turchetto, L. Valvo).
The authors thank the Stabilimento Chimico
Farmaceutico Militare, Florence, Italy (Colonel G.
Received April 26, 1999; revision received July 22,
1999; accepted July 29, 1999.
Address for reprints: Giuseppe Traversa, M.D., Department of Epidemiology and Biostatistics, Istituto
Superiore di Sanità, Viale Regina Elena 299, 00161
Rome, Italy.
1904
CANCER November 15, 1999 / Volume 86 / Number 10
octreotide), melatonin, bromocriptine, and a “syrup”
containing vitamins and retinoic acid; in most cases,
Dr. Di Bella added a cytotoxic agent, usually cyclophosphamide or hydroxyurea.
Today, several months after the Italian public was
informed that MDB was ineffective, it seems appropriate to reflect on the entire experience; the exercise
should be of interest to the scientific community at
large and the oncologist in particular. Specifically, in
this commentary we propose to analyze what transformed a nonconventional therapy, recommended by
a physician operating on a solo basis in a private
office, into a national priority; to revisit the discussions that took place in Italy among oncologists, politicians, prosecutors, and magistrates; and to analyze
the role of the media in promoting and diffusing this
alternative anticancer treatment. We will also briefly
describe how the trials were conducted under almost
unbearable public pressure and which were the principal findings; what controversies arose while the trials were being carried out; and what issues were debated after their conclusion.
The Background of the Di Bella Case
Many different arguments have been put forward to
explain why, more than 20 years after Dr. Di Bella
started proposing his cure for all cancers, at the end of
1997 the public and the mass media suddenly and
unexpectedly started paying sustained attention to
this physiologist and his treatment (Table 1).
In the background is the chronic difficulty that
oncologic centers have in providing adequate supportive care to critically ill patients: too often, patients
and their relatives are left alone to face the disease.
This situation, however, cannot alone explain what
happened.
A first important issue was the cost of Dr. Di
Bella’s treatment for patients. MDB, unlike all other
approved anticancer treatments, could not be paid for
by the National Health Service (NHS) and, because of
the price of somatostatin, the financial burden on
patients and families was often unaffordable: 1 month
of treatment amounted to some 7500 Euros. This led
to the creation of associations of patients and their
relatives, which, by requesting the Government to
eliminate this “clear discrimination” between the poor
and the rich, galvanized public opinion.
At this stage the role of media became more and
more critical and started a self-feeding chain reaction.
The leading anchorman of a national commercial television networks conducted, on November 16, 1997,
the first program entirely dedicated to the Di Bella
case. According to statistics kept by the Osservatorio
della comunicazione radiotelevisiva di Pavia (Obser-
vatory of Radio and Television Communications) during the period between December 16, 1997, and January 17, 1998, the daily proportion of prime time news
devoted to the Di Bella case reached 36% (the average
share was 8.4%). In most instances, journalists praised
the MDB (between 47% and 83% of the total time
allotted to this topic on the 6 most popular television
networks).2 The opinion of all those who appeared as
guests on television programs was also strongly polarized. By and large, Dr. Di Bella was praised for his
humanity and the quality of his contacts with patients.
The percentage of those interviewed who expressed a
positive opinion ranged between 91% and 100%,
depending on the network.2 During the period
mid-December 1997 through mid-January 1998, the
number of published newspaper articles about MDB
amounted to more than 100 per newspaper.2
With this coverage, no one should be surprised at
the tremendous impact the MDB treatment had on
cancer patients. The number of those who requested
the treatment rose exponentially; patients who were
denied the costly treatment appealed to local magistrates to force the NHS to pay for it. In December 1997,
for the first time, a local magistrate ordered a local
health authority to provide MDB to a patient free of
charge. In the following months, several hundred patients (no exact number is available) received the MDB
on the basis of courts’ actions. The mounting tide of
demand for the right to MDB treatment contributed to
the creation of a larger movement, that for “a generalized freedom of treatment,” and this immediately
became a political issue.
Dr. Di Bella claimed he could cure (and that he
had indeed cured) up to 100% of his patients with a
variety of cancers, and that even terminal patients
could improve with his treatment. In interview after
interview, he expressed the opinion that the absence
of any published evidence was not a weakness,3 because, he claimed, he had been ostracized by his own
university years previously as well as by members of
the “oncology clique,” who were eager to protect their
links with the pharmaceutical industry.
In this scenario, the profound skepticism expressed from the beginning by the scientific community completely backfired. Far from being considered
a rational point of view, the position held by the top
scientists and oncologists was often considered by
many to be further proof of the impermeability of the
establishment to anything from the outside. As the
popularity and credibility of Dr. Di Bella grew faster
and faster, that of official medicine reached its nadir.
During the summer and autumn of 1997, the Italian National Committee for Drugs (Commissione
Unica del Farmaco) rejected a request to release so-
The Di Bella Case/Traversa et al.
1905
TABLE 1
Chronology of the Di Bella Case
1963
1969
1971
1977
1981
1997
1997
1997
1997
1997
1998
1998
1998
1998
Dr. Di Bella starts his experiments in his private laboratory, mainly using melatonin to treat patients affected by various diseases.
A communication on the effect of melatonin on platelet turnover in rats is presented at the 45th Congresso della Società Italiana di Biologia Sperimentale,
Sassari, Italy.
This is the year for which the first patient record is present in Dr. Di Bella’s archive.
Dr. Di Bella adds somatostatin to his protocol of therapy.
Dr. Di Bella claims to have obtained good results in treating patients with various cancer types using somatostatin, bromocriptine, melatonin, and
cyclophosphamide (Abstract book, 2nd International symposium of somatostatin, Athens, Greece, June 1–3).
July 17—Two associations of patients organize and publicize a conference of Dr. Di Bella (Hotel Excelsior, Rome).
August 5—The Italian National Committee for Drugs refuses to include somatostatin in their list of drugs for compassionate use (for all cancer patients)
paid for by the National Health Service (NHS).
September 18—Cancer patients demonstrate against the Minister of Health, demanding freedom of treatment and MBD paid for by the NHS.
November 16—The first television program entirely dedicated to Dr. Di Bella is broadcast.
December 16—A local magistrate orders a local health authority to treat a cancer patient with MDB without charge. The fact was widely reported by
Italian national newspapers.
January 9, 10—Two Italian regions (Puglia and Lombardia) decide on free administration of MDB.
January 14—The Italian National Cancer Advisory Committee and Dr. Di Bella reach an agreement on the decision to conduct trials to test MDB
anticancer activity.
February 15—Cancer patients demonstrate in St. Peter’s Square during the Pope’s Sunday prayer.
February 17—The Italian Parliament approves specific legislation authorizing the conduct of the trials.
matostatin and octreotide for the compassionate
treatment of patients with all cancer types and, thus,
to provide them free of charge. At the moment of the
study, the two drugs were provided free of charge only
for selected indications (for which scientific evidence
was available): somatostatin for severe hemorrhage of
the upper gastrointestinal tract and octreotide for gastrointestinal and pancreatic endocrine tumor syndromes.
In December 1997, Dr. Di Bella and his followers
were asked to submit to the National Cancer Advisory
Committee clinical records of patients who were considered to have been successfully treated. After an
initial refusal, about 70 clinical records were submitted. When carefully examined, these records provided
little evidence to support the effectiveness of MDB.
This finding was confirmed, several months later,
when the results of a study conducted with the archive
of patients treated by Dr. Di Bella was presented.
By January 1998, hundreds of patients were being
treated with the MDB and an even greater number
was pressuring the Minister of Health to receive the
treatment free of charge. Then, under the combined
pressure of patients, media, local magistrates, and
politicians, the negative initial official position became untenable and had to be gradually reconsidered.
At that stage, the Minister of Health stated publicly
that she would consider the possibility of a free administration of the MDB, but only after the positive
conclusion of appropriate clinical trials.4
At the end of January, after several meetings between Dr. Di Bella and the National Cancer Advisory
Committee, a consensus was reached to recommend
that a series of Phase II clinical trials be conducted to
test the anticancer activity of MDB. A written agreement was signed that described the type of cancers to
be included in the trials, the procedures to be performed, and the standardized regimen to be utilized.
In spite of the fact that Dr. Di Bella himself signed
the document, consensus on the decision to conduct
the trials was far from unanimous. On the one hand,
the majority of Di Bella supporters were against the
trials, fearing that they were a diversion intended to
postpone the time of the free availability of the combination treatment for all patients. They went public
in stating that because of bias or conflicts of interest,
oncologists would not give MDB the opportunity of a
fair evaluation. On the other hand, a number of physicians and scientists expressed the opinion that the
decision to conduct 10 clinical trials in the absence of
any published evidence was unethical. In the end, the
decision to carry out the clinical trials received great
support from the Italian oncology community and the
National Cancer Advisory Committee; the participation of the most prominent oncologic centers in Italy
was therefore assured.
Preparations for the trials continued, and on February 17, 1998, the Italian Parliament approved a specific legislation authorizing the conduct of the studies.
The Istituto Superiore di Sanità (Italian National Institute of Health) was given the responsibility of organizing and coordinating the conduct of the trials.5
The Trials
A total of 11 Phase II clinical trials were planned. Ten
addressed eight different types of cancers; in addition,
1906
CANCER November 15, 1999 / Volume 86 / Number 10
one study was specifically designed to evaluate the
MDB in patients (affected by different tumors) who
were critically ill.
The following cancers were studied: non-Hodgkin
lymphoma; chronic lymphoid leukemia; breast carcinoma in women age $70 years who were eligible for
surgery; breast carcinoma with Eastern Cooperative
Oncology Group performance status [ECOG PS] 0 –2);
breast carcinoma with ECOG PS 3– 4; nonsmall cell
lung carcinoma; colorectal carcinoma; pancreatic carcinoma; head-neck and esophageal carcinoma; and
glioblastoma. The critically ill patients suffered from
metastatic tumors originating from the lungs, esophagus, stomach, pancreas, liver, colon, rectum, bladder,
endometrium, or cervix uteri and ovary.
Special attention in designing the study was devoted to ethical aspects. For each study a specific
informed consent form was prepared. After receiving
the form, patients had to wait 48 hours to confirm
their participation in the study.
The aim of the study was to determine whether
the MDB regimen had antitumor activity worthy of
further controlled clinical evaluation. The main endpoint of each study was measurable clinical activity.
Details of the design and conduct of the trials have
already been reported.1,6,7
The protocols were approved by the National
Cancer Advisory Committee and by an ad hoc Ethical
Committee. A Steering Committee, which was composed of the principal investigators of each trial, the
son of Dr. Di Bella, a group of statisticians and epidemiologists, and researchers of the National Institute of
Health, was put in charge of the practical conduct of
the study. A research coordination unit, created within
the Italian National Institute of Health, coordinated all
phases of the study.
To ensure independent confirmation of all diagnoses, a committee of five members (listed in the
footnotes at the beginning of this article), chosen from
among oncologists and radiologists not involved in
the trials, was charged with the review of all iconographic materials utilized in the evaluation of objective responses to the treatment.
Finally, a panel of seven scientists (listed in the
footnotes), selected from among leading international
experts in oncology, acted as supervisors of the entire
study. Each part of the study was reviewed by and
discussed with this international review board.
METHODS
The enrollment of patients started in the 26 oncology
centers identified throughout Italy as suitable for the
study, in the middle of March 1998. More than 200
people were involved in all phases of the study.
The main eligibility criteria, common for all protocols, were as follows: age $18 years, histologically or
cytologically confirmed diagnosis of neoplastic disease, measurable and/or assessable lesions, advanced
stage of disease, no prior MDB treatment, and signed
informed consent. In the trial of nonsmall cell lung
carcinoma, both patients with no previous chemotherapy and patients in progression after first-line
chemotherapy were enrolled, although results were
analyzed separately in the two strata. Patients with
advanced pancreatic carcinoma had not previously
been treated with chemotherapy. All other patients
had already undergone chemotherapy and/or hormonal therapy; they were admitted only if the treatment course had been completed at least 4 weeks
before the beginning of the trial. For all patients ECOG
PS was evaluated.
The treatment consisted of daily administration of
melatonin (by mouth [os], 20 mg), bromocriptine (os,
2.5 mg), solution of retinoids (os, 7 g), somatostatin
(slow subcutaneous injection, 3 mg over 8 hours), or
octreotide (subcutaneous injection, 1 mg). Hydroxyurea (os, 1 mg) was added to the treatment of patients
with glioblastoma, and cyclophosphamide (os, 50 mg)
was added for patients who were not terminally ill,
with time of administration varying according to the
specific protocol.
Patients were treated until progression occurred
or unacceptable toxicity developed. For the evaluation
of the anticancer activity of MDB, all patients were
observed until one of the following events occurred:
complete or partial response (confirmed after 4
weeks), disease progression, death, discontinuation of
treatment because of toxicity, or voluntary abandonment.
The MDB anticancer activity was expressed as the
proportion of complete or partial objective responses,
according to the definition accepted by the World
Health Organization (WHO).8 The evaluation of objective response was performed utilizing different schedules, depending on individual protocols: every month
for chronic lymphoid leukemia and lung carcinoma;
every 2 months for non-Hodgkin lymphoma, breast
carcinoma, colorectal carcinoma, head-neck and
esophageal carcinoma, and advanced solid neoplasms; and at 3 months for pancreatic carcinoma and
glioblastoma.
The sample size for each of the studies was calculated on the basis of the minimum number of patients
required to demonstrate a predefined level of anticancer activity.9 For the calculations, a one-tail test was
applied, taking into account the proportion of partial
or complete responses expected under the hypothesis
of inactivity (p0) or sufficient anticancer activity (p1) of
The Di Bella Case/Traversa et al.
1907
TABLE 2
Selected Characteristics of the Patients Included in the MDB Trials (n 5 386)a
Breast carcinoma
Lung carcinoma
Lymphoid
Colorectal Pancreatic Head and neck
Advanced
Lymphoma leukemia 0–2
3–4
Treated Untreated carcinoma carcinoma cancer
Glioblastoma neoplasms
(n 5 32)
(n 5 22) (n 5 33) (n 5 34) (n 5 65) (n 5 51) (n 5 34)
(n 5 29)
(n 5 32)
(n 5 20)
(n 5 34)
% females
Median age (yrs)
Median mos from diagnosis
% previous surgery
% previous chemotherapy
% previous hormone
therapy
% previous radiotherapy
ECOG PS (%)
0
1
2
3
4
40
58
34
25
100
30
62
62
14
100
100
54
78
91
94
100
59
58
91
94
20
62
12
35
100
10
67
3
33
—
62
63
21
100
100
41
69
3
66
—
9
62
34
69
100
50
61
10
100
—
71
70
14
62
68
—
41
—
4
82
70
85
76
—
60
—
23
—
29
—
7
—
94
—
100
6
15
22
25
22
31
—
68
18
9
4
—
39
39
21
—
—
—
3
3
74
21
12
52
35
—
—
23
59
18
—
—
32
35
32
—
—
34
48
17
—
—
3
44
53
—
—
—
30
70
—
—
—
—
9
29
62
MDB: Di Bella Multitherapy; ECOG PS: Eastern Cooperative Oncology Group performance status.
a
This table was first published in BMJ (Italian Study Group for the Di Bella Multitherapy Trials. Evaluation of an unconventional cancer treatment [the Di Bella Multitherapy]: results of Phase II trials in Italy. BMJ
1999;318:224–8) and is reproduced by permission.
the MDB, with an alpha error equal to 5% and a power
of 95%. The p0 ranged from 5% to 10% and p1 from
20% to 30%; consequently, the number of patients
needed in each protocol ranged from 24 and 69, and
the minimum number of responses necessary to recommend further investigation varied between 2 and
12. Only in the glioblastoma trial was Simon two-stage
optimal design followed.10 Kaplan–Meier survival
analysis was applied to estimate the cumulative incidence and the median time to progression.11
RESULTS
All patients were enrolled between March and July.
One of the trials on breast carcinoma (preoperative
treatment with MDB and tamoxifen) was discontinued
in May because, over a period of more than 2 months,
only 2 patients had opted to participate in this study.
The final analysis considered a total of 386 patients who fulfilled the eligibility criteria. The main
characteristics of these patients are summarized in
Table 2. The detailed results of trials have already been
reported and published.1,6,7
In summary, these results indicate that, at the
beginning of the trials, a good majority of all patients
were in fair-to-good condition; in addition, 21% of
them had not received any previous chemotherapy.
Although no patient experienced complete remission, in 3 cases a partial response could be documented: a man age 52 years with a non-Hodgkin lym-
phoma, a woman age 50 years with breast carcinoma,
and a man age 50 years with a nonendocrine pancreatic carcinoma. All three of these patients had disease
progression after 350 days, 182 days, and 355 days,
respectively. At the time of the scheduled evaluation of
response, 47 patients (12%) had stable disease; for
these subjects treatment was therefore continued. In
June 1999, only 7 of these patients were still receiving
MDB.
The time to disease progression is illustrated in
Figure 1 for all patients. The median time to progression was about 1 month for patients with chronic
lymphoid leukemia, patients with breast carcinoma in
poor condition (ECOG PS 3– 4), and critically ill patients. It was less than or approximately 2 months for
those with non-Hodgkin lymphoma, breast carcinoma
(ECOG PS 0 –2), previously treated lung carcinoma,
colorectal carcinoma, pancreatic carcinoma, headneck or esophageal carcinoma, and glioblastoma. Previously untreated lung carcinoma patients had the
longest median time to progression (almost 3
months).
With only 3 partial responses among 386 patients,
the results of the trials were considered incompatible
with the initial claim that the MDB might represent a
cure for any type of cancer. The possibility that, for a
specific cancer among those included in the trials,
there might be a therapeutic efficacy of clinical interest is also remote.
1908
CANCER November 15, 1999 / Volume 86 / Number 10
FIGURE 1. (A–D) Time to disease progression is shown for patients included in the trials of Di Bella Multitherapy (Kaplan–Meier survival analysis). (E–H) Time
to disease progression is shown for patients included in the trials of Di Bella Multitherapy (Kaplan–Meier survival analysis).
The Di Bella Case/Traversa et al.
The Debate in Italy
Conducting the trials was not an easy experience for
the investigators at the 26 centers or for those responsible for the overall coordination, because there was
an absolute need to produce convincing evidence
quickly. It is fair to say that, in our opinion, both
objectives were attained. Within approximately 1 year
from the beginning of the Di Bella case, a scientifically
valid response was provided to patients, physicians,
scientists, and politicians.
Putting aside the technical, logistic, and managerial difficulties, two major general problems were encountered: the progressively increasing critical attitude regarding the conduct of the trials by Dr. Di Bella
and his followers, and the roles played by public prosecutors and local magistrates.
Dr. Di Bella’s son, who is a physician, was a member of the Steering Committee but participated only in
the first two meetings (in February and March 1998).
As soon as the enrollment of patients started, there
was a gradual increase in the criticism of how recruitment was being carried out; this was followed by a
series of diverse critical remarks (which changed in
nature as the study progressed). Initially, it was argued
that Dr. Di Bella had not actually agreed on the details
of the study protocols and the therapeutic regimen.
Then it was argued that, though he had signed the
protocols, the therapeutic regimen was different from
the one he has currently adopted.12
Later the criticism shifted to focus on a bias in the
selection of patients. It was argued that a vast majority
of the patients enrolled were terminally ill. The fact of
the matter is that only two protocols included terminal cancer patients. Whereas one could question, on
theoretic grounds, the choice to extend the study to
terminally ill patients, the fact remains that many such
patients received compulsory treatment by the NHS
with the MDB, under orders by local courts. Not to
have tested MDB in these cases would have been
irresponsible under the circumstances. Indeed, these
were the patients (with their relatives) who were
mostly seeking the MDB.
Another criticism was the alleged possibility that
previous chemotherapy cycles might have had a “negative” influence on the efficacy of the MDB. On the
face of it, however, this statement was in sharp contrast to the initial repeated declarations by Dr. Di Bella
that the MDB was effective even when other anticancer treatments had failed. The inclusion of a number
of patients with lung carcinoma previously untreated
with other regimens served to dispel this claim, because these patients also had a complete absence of
objective response.
1909
It is worth noting that most of criticisms started as
soon as it became clear that the trials were actually
going to be carried out; they increased throughout the
study as information on patients who had died in spite
of the MDB was spread, and became strongest when
the first final results (for four protocols) were made
public by the end of July 1998.13,14
This situation is of some interest because it illustrates the peculiarity of many trials conducted to assess unconventional treatments. Usually, the clinical
researcher launches a trial to demonstrate the validity
of his or her own therapeutic hypothesis against a null
hypothesis of no effectiveness. He or she knows that
any flaw discovered by independent critics in the design or in the conduct of the trial will hinder the
rejection of the null hypothesis, that is, demonstration
of the validity of the treatment. In the MDB trials,
those who supported the effectiveness of the treatment, and in particular Dr. Di Bella himself, were by
their own choice only marginally involved in the design and conduct of the trials. As a consequence, their
critical review of the trials started from a reverted null
hypothesis, based on the assumption that the treatment was indeed effective: accordingly, any flaw they
perceived in the design or conduct of the trials was
interpreted to be supportive of its effectiveness. It is
this reversion of the roles of the scientific debate (researcher vs. independent scientific reviewers) that
contributes to a climate of reciprocal distrust. This can
be avoided only if the supporters of an unconventional treatment follow the rules that are mandatory
worldwide to assess new treatments. Unfortunately,
this does not happen very frequently.
It is still a matter of debate whether, in similar
conditions, and given the large number of patients
willing to receive the MDB, it might have been preferable to carry out Phase III comparative trials.15–17
Obviously, there are arguments for and against this.
On the one hand, if the results of Phase II trials were
encouraging, Phase III trials would be carried out anyway. On the other hand, the decision to initiate with a
Phase III trial may turn out to be neither feasible nor
ethical. Is it possible to ask patients who seek a specific unconventional treatment to agree to random
assignment to a conventional one as well?
Another issue that deserves specific mention relates to the inquiries made by public prosecutors in
several Italian cities regarding the correctness of the
trials. Nearly all stages and elements of the trials became objects of close scrutiny. In the future, this may
represent a recurrent scenario in the evaluation of
unconventional treatment efficacy, in which the proponents of a treatment may decide to take legal action, after an initial agreement, to stop the process of
1910
CANCER November 15, 1999 / Volume 86 / Number 10
objective evaluation. What we argue is the concern
that if a “trial gets under trial during the trial” a potential conflict of interest may arise. If the investigators become the objects of scrutiny during the course
of the study, which are the guarantees for the patients
involved that every decision made by the investigators
is adopted exclusively in their best interest? Moreover,
why should the best interests of patients be better
served by prosecutors who often ignore even the basis
of clinical testing, rather than by steering committees,
independent review boards, and ethical committees?
The broader issue of “freedom of treatment”
raised by Dr. Di Bella and his supporters deserves
discussion. There are two major aspects to consider,
namely, the duty of health authorities to regulate
treatments that can be offered to patients, and the
selection of treatments paid for by the NHS.
Regulatory authorities base their evaluations
solely on the available evidence regarding the efficacy
and toxicity of new treatments, whereas the decision
to reimburse for a given treatment takes into account
other factors as well, such as cost-effectiveness. Prescribing the Di Bella treatment was perfectly legal,
because all the individual drugs were marketed in Italy
(with different indications), with the exception of the
retinoid solution that had to be prepared in pharmacies. The law in Italy allows a physician to prescribe
any registered drug, under his own responsibility, for
indications different from the approved ones. This,
however, was not the main issue. It was the high cost
per month of MDB that became the critical issue because of the perceived injustice between wealthy patients who could afford the treatment and poor patients who could not. This was the basis for the
decisions of a number of local magistrates throughout
Italy to force the NHS to provide MDB at no cost.18
The ensuing national debate revolved around the right
to decide which treatments can be undertaken by
willing individuals and who has to decide about their
reimbursement. The answer to both questions is definitely not straightforward. Central to the issue are two
conflicting ethical values: the need to protect patients
and citizens from ineffective or even harmful treatments, and the freedom of an individual to choose
treatments even in the absence of scientific evidence
of their effectiveness. Can this right be dependent on
whether or not a patient can financially afford the
treatment? The fact is that this freedom represents a
right of every citizen, though no financial support can
be claimed when evidence of efficacy is lacking.
All of this exists against a background of limited
financial resources on the part of the NHS, which is
financially unable to satisfy even all the needs for
treatment “of proven efficacy.” The conclusion that no
clear-cut solution exists seems indisputable; therefore,
the only possible way to cope with these problems is
to couple regulatory action with adequate and credible information for the public at large. In the Di Bella
case a majority of Italians initially felt that the information provided by health authorities was not sufficient to label MDB “ineffective.” As a consequence,
the refusal by the NHS to provide it was regarded as a
proof of prejudice on the part of the scientific establishment. We must conclude that those who labeled as
“irrational” the desire of thousands of desperate patients to “try” MDB failed to recognize that for many of
these patients the choice might have been a rational
one. If, in fact, conventional treatments offer no
chance of cure, a treatment that promises cure (i.e., a
very large benefit) could indeed be the best option, as
long as the probability that it will fulfill this promise is
greater than zero. In fact, the Decision Theory holds
that the expected benefit is equal to the size of the
benefit multiplied by the probability of achieving it.
The repeated anecdotal media reports of “incurable”
patients who were “cured” by the Di Bella treatment,
or at the very least benefited from it, definitely made
this probability greater than zero for the vast majority
of individuals lacking the scientific information necessary to discard these reports, unless they had been
verified. Not surprisingly, many physicians shared this
view, even though they were skeptical about the potential effectiveness of MDB.
To provide up-to-date information on MDB, from
the planning stage it was decided to make public the
results of the trials as soon as they became available.
In this respect, it is worth noting that the presentation
of the results of 4 protocols on July 28, 1998, had
almost no effect on the number of requests for MDB.
The Di Bella group continued to present patients who
claimed to have been cured with the MDB as proof of
the lack of validity of the trial findings. To desperate
people who had lost all hope, a single patient who
claimed to have been cured may have been far more
convincing than the results for hundreds of other subjects included in the trials.
Only after the communication of the final trial
findings on November 13, 1998, a change in the public
perception started to materialize. The complete results were received by the public without any widespread negative reaction. Even the politicians and
journalists who had spoken in favor of Dr. Di Bella
seemed to have accepted the idea that the case was
about to be concluded.
CONCLUSIONS
It is our opinion that the Di Bella case was created by
different concomitant factors. An important one was
The Di Bella Case/Traversa et al.
the high cost of the treatment; another critical factor
was the reaction of the media, which is more often
than not guided by the imperative “first of all, do not
kill the news (in pursuit of the truth).” This cynical
attitude played a major role in diffusing, among hopeless patients, great expectations for an untested treatment. If we have to learn from this experience and
avoid future repetition of such sagas, it is necessary
that the public, and therefore the government, rely on
credible scientific institutions for guidance. However,
this will occur only if the medical community is perceived as dedicated to the patients’ well-being, rather
than to personal and corporate interests.
Today, almost 8 months after the presentation of
the final data, the situation seems to have stabilized to
the point that the publication of further negative findings concerning a survival study of patients treated
with MDB outside the Phase II trials19 did not fuel a
new, appreciable controversy. The rapid performance
and the completion, within 1 year, of the trials disproving the Di Bella claims provided solid ground for
a more rational discussion and gave a basis to the
government’s decision not to approve MDB as an
anticancer treatment. Finally, the need to rely on evidence provided by clinical trials to accept a new treatment has been reaffirmed; the wide public discussion
that took place throughout the country contributed to
the spread of this principle outside the narrow confines of the scientific community.
REFERENCES
1.
2.
3.
4.
Italian Study Group for the Di Bella Multitherapy Trials.
Evaluation of an unconventional cancer treatment (the Di
Bella Multitherapy): results of phase II trials in Italy. BMJ
1999;318:224 – 8.
Osservatorio della comunicazione radiotelevisiva di Pavia. Il
caso Di Bella nella televisione e nella stampa italiana. Roma,
RAI-ERI, 1999.
Abbasi K. Di Bella’s miracle method. BMJ 1998;316:1617.
Support for a pragmatic health minister [editorial]. Nature
1998;392:421.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
1911
Government of Italy. DL n. 23 del 17 febbraio 1998. Disposizioni urgenti in materia di sperimentazioni cliniche in
campo oncologico e altre misure in materia sanitaria. G.U.
n. 39 del 17 febbraio 1998.
Gruppo di Coordinamento Centrale per la Sperimentazione
del Multitrattamento Di Bella. Risultati della Sperimentazione del Multitrattamento Di Bella (MDB): protocolli 4, 6, 8,
10. Roma: Istituto Superiore di Sanità. 1998. Report No:
Rapporti ISTISAN;98/17.
Gruppo di Coordinamento Centrale per la Sperimentazione
del Multitrattamento Di Bella. Risultati della Sperimentazione del Multitrattamento Di Bella (MDB): protocolli 1, 3, 5,
7, 9. Roma: Istituto Superiore di Sanità. Servizio per le Attività Editoriali, 1998. Report No. Rapporti ISTISAN; 98/24.
Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting
results of cancer treatment. Cancer 1981;47:207–14.
Levental BG, Wittes RE. Research methods in clinical oncology. New York: Raven Press, 1988.
Simon R. Optimal two-stage designs for phase II clinical
trials. Control Clin Trials 1989;10:1–10.
Bland JM, Altman DG. Survival probabilities (the Kaplan–
Meier method). BMJ 1998;317:1572.
Pellegrini R. Di Bella’s method of curing cancer is becoming
popular in Italy. BMJ 1998;317:52.
Brera GR, Violato C. Methodological and ethical difficulties
in clinical oncology studies. Lancet 1998;352:1391.
Raschetti R, Bruzzi P, for the Di Bella Multitreatment Italian
Trial Coordinating Group. Methodological and ethical difficulties in clinical oncology trials. Lancet 1999;353:153– 4.
Müllner M. Di Bella’s therapy: the last word? BMJ 1999;318:
208 –9.
The Editorial Committee of the Italian Study group for the
Di Bella Multitherapy Trials. Raschetti R, Bruzzi P, Greco D,
Menniti-Ippolito F, Spila-Alegiani S, Traversa G, et al. We
totally disagree with Müllner’s view. BMJ 1999;318:1074.
Liberati A, Magrini N, Patoia L, Pagliaro L. Missing the forest
while looking at the tree. BMJ 1999;318:1073– 4.
More clinical judgement, fewer “clinical” judges [editorial].
Lancet 1998;351:303.
Gruppo di Coordinamento Centrale per la Sperimentazione del Multitrattamento Di Bella. Risultati della Sperimentazione del Multitrattamento Di Bella (MDB): Studio
osservazionale. Roma: Istituto Superiore di Sanità. Servizio per le Attività Editoriali, 1999. Report No. Rapporti
ISTISAN; 99/12.
Документ
Категория
Без категории
Просмотров
3
Размер файла
119 Кб
Теги
cumino, black, sativa, nigella, stud, seeds, values, nutrition
1/--страниц
Пожаловаться на содержимое документа