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Papers
Evaluation of an
unconventional cancer treatment (the Di Bella multitherapy): results of phase II
trials in Italy
Italian Study Group
for the Di Bella Multitherapy
Trials
Correspondence to: Dr Roberto Raschetti, Istituto Superiore di Sanitą, Department of Epidemiology and Biostatistics, Viale Regina Elena, 299 00161 Rome, Italy roras@iss.it
Editorial by Müllner and p 268
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Abstract |
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Objective: To determine whether the treatment
known as Di
Bella multitherapy exerts antitumour activity worthy of further
controlled clinical evaluation.
Design: 11 independent multicentre uncontrolled phase II
trials relevant to 8 different types of cancer.
Setting: 26 Italian hospitals specialising in cancer treatment.
Subjects: 386 patients with advanced cancer were enrolled in
the trials between March and July 1998 and followed to 31 October
1998.
Interventions: Melatonin, bromocriptine, either somatostatin or
octreotide, and retinoid solution, the drugs that constitute Di Bella multitherapy,
were given to patients daily. Cyclophosphamide and hydroxyurea were
added in some trials.
Main outcome measures: Responses were assessed every 1, 2, or
3 months, depending on the specific trial, and toxicity was
evaluated using criteria developed by the World Health Organisation.
Results: No patient showed complete remission. Three patients
showed partial remission: 1 of the 32 patients with non-Hodgkin's
lymphoma; 1 of the 33 patients with breast cancer; and
1 of the 29 patients with pancreatic cancer. At the second
examination, 12% (47) of the patients had stable disease; 52% (199)
progressed; and 25% (97) died.
Conclusions: Di
Bella multitherapy did not show sufficient efficacy
in patients with advanced cancer to warrant further clinical testing.
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Key messages
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Introduction |
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In the past year there has
been extensive international media coverage of the allegedly successful treatment
in Italy of a number of malignant neoplasms with Di Bella multitherapy.
This is a multidrug, custom made medical treatment developed by
Luigi Di Bella,
an Italian physician, who over the past 25 years has perfected
and administered it on a private outpatient basis, claiming its
effectiveness in blocking, if not curing altogether, most cancers.
Over the past two years a number of associations have been created
to support this treatment; these associations mounted a campaign to
request that Di Bella
multitherapy be included among those cancer treatments considered to
be effective and that its cost thus be fully reimbursed by the
Italian national health service. When requested by the ministry of
health to submit scientific evidence of the effectiveness of Di Bella multitherapy,
Dr Di Bella failed to produce any published scientific paper;
therefore, the Italian national drug committee (the drug regulatory
authority in Italy) denied approval. Following growing public
demand, including public demonstrations, the national cancer
advisory committee advised the minister of health to perform a
series of uncontrolled phase II trials to test whether Di Bella multitherapy
had any clinical efficacy. 1 2
In February 1998 the
Italian parliament passed an act authorising that clinical trials be conducted
and making funds available for these trials3; the responsibility of coordinating the entire
effort was entrusted to the Istituto Superiore di Sanitą (the Italian
national institute of health). The National Cancer Advisory Committee
and Dr Di Bella
agreed on the types of cancer to be included in the trials and the
means of standardising the custom made drugs included in the
therapy. It was agreed to develop 11 independent protocols for
uncontrolled phase II trials on eight different types of advanced
stage cancer. The specific types of cancer were selected on the
basis of various factors, including anecdotal reports of successful
treatment with Di Bella
multitherapy, potential activity of some of the components of Di Bella multitherapy,
and the lack of effective treatment for the specific cancer.
The objective of the trials
was to determine whether Di
Bella multitherapy exerts antitumour activity worthy of further
controlled clinical evaluation (that is, phase III randomised
controlled trials). The main end point of each trial was the
objective response of reduction in tumour size. Here we present the
final results of the uncontrolled phase II trials.
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Patients and
methods |
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Study protocols
The following types of cancer were studied: aggressive non-Hodgkin's
lymphoma and chronic lymphoid leukemia in patients not eligible for
chemotherapy or radiotherapy of proved efficacy; breast cancer in
patients 
70 years of age who were eligible
for surgery; stage IV breast cancer in patients previously treated
with chemotherapy or endocrine therapy, or both, who had a
performance status 0-2 according to the Eastern Cooperative Oncology
Group (ECOG); stage IV breast cancer in patients not eligible for
conventional chemotherapy or hormonal therapy (ECOG performance status
3-4); metastatic non-small cell lung cancer in patients who had had
first line chemotherapy and in patients with no previous
chemotherapy; advanced colorectal cancer in previously treated
patients; advanced pancreatic carcinoma in patients without previous
chemotherapy; metastatic or recurrent squamous cell head, neck, and
oesophageal cancer in previously treated patients; recurrent glioblastoma
after surgery and conventional radiotherapy; and advanced solid
neoplasms (metastatic tumours originating from lung, oesophagus,
stomach, pancreas, liver, colon, rectum, bladder, endometrium and
cervix uteri, ovary) in terminally ill, untreatable patients. The
trial involving breast cancer in patients who were eligible for
surgery was discontinued after 2 months because only two
patients were enrolled.
Several
thousand patients requested treatment with Di Bella multitherapy during January and
February 1998. A waiting list of potentially eligible patients
who had requested the treatment was created for each protocol. For
the inclusion in the trials, patients were randomly selected from
the waiting lists.
In each
study, patients had to be at least 18 years of age, and they had to have
measurable or assessable lesions, histological or cytological
diagnosis of cancer, and no previous treatment with Di Bella multitherapy.
Detailed information on the study protocols and on the eligibility
criteria are available in two reports of the Istituto Superiore di
Sanitą 4 5 and, temporarily, on the internet
at the site of the Istituto Superiore di Sanitą (http://www.iss.it/).
The change
in tumour size was assessed after one, two, or three months, depending on the
specific trial, and the treatment status and vital status of all
patients was ascertained on 31 October. All trials were
conducted according to the requirements of good clinical practice.
A network
of 26 hospital cancer divisions selected by the steering committee of the
study group administered the drugs and measured the tumours. The
Istituto Superiore di Sanitą coordinated the trials and supervised
the production, purchase, and distribution of the drugs.
Components of treatment
Di Bella
multitherapy consists of the daily administration of a combination
of drugs: melatonin (20 mg), bromocriptine (2.5 mg),
somatostatin (3 mg) or octreotide (1 mg), and a solution of
retinoids (7 g). Hydroxyurea (1 mg/day) was added in the treatment
of glioblastoma, and cyclophosphamide (50 mg/day) was added, with
time of administration varying among trials, in the treatment of
all other types of cancer studied, except for terminally ill patients,
who represented the study populations of two trials (more severe
breast cancer and advanced solid neoplasia). Ascorbic acid
(1-2 g) and dihydrotachisterol (0.4-0.9 mg) were added to the
treatment during April-May 1998, following Di Bella's specific recommendation.
All drugs were given orally, except for octreotide (subcutaneous
injection) and somatostatin (slow subcutaneous injection; 3 mg
in 8 hours).
The
retinoid solution was composed of all-trans retinoic acid (0.5 g), 
carotene
(2 g), axerophtholum palmitate (0.5 g), and 
tocopheryl
acetate (1000 g). The melatonin tablets consisted of
melatonin-adenosine-glycine (2:9:5 mg/tablet). The melatonin tablets
and the retinoid solution were prepared as required, following Di Bella's directions,
by the Stabilimento Chimico Farmaceutico Militare (military
pharmaceutical chemical plant) in Florence in compliance with good
manufacturing practices; each batch was subject to quantitative and
qualitative control by the Istituto Superiore di Sanitą. The other
drugs included in the regimen are marketed in Italy and were
provided by pharmaceutical companies.
Study size
With the exception of trial on glioblastoma, which used Simon's two
stage optimal design,6 the trials used a one stage design
because it was thought that a sufficient number of patients could be
enrolled in a very short period. For each trial, a sample size that
would discriminate between p0 (insignificant activity)
and p1 (activity worthy of further clinical trials) with
a 5% probability of type I error and a 5% probability of type II
error was determined. The values for p0 and p1 were
established independently for each trial and varied from 5% to 10%
for p0 and from 20% to 30% for p1. Based on
these elements, the minimum number of responses that would be needed
to consider the regimen as worthy of further study was calculated
for each trial protocol. For a minimum number of responses ranging
from 2 to 12, the number of patients needed for each trial
was between 24 and 69.
Analysis
The primary analysis included all patients who fulfilled the major
eligibility criteria. The proportion of patients responding to
treatment was the end point for all trials. Responses were evaluated
according to the criteria of the World Health Organisation.7 A complete response was defined as the disappearance
of all known disease (determined by two observations not less than
four weeks apart); a partial response was defined as a decrease in
tumour size 50% (determined by two observations not
less than four weeks apart); for patients with chronic lymphoid leukaemia,
peripheral blood count and the bone marrow picture were considered.
Each patient was classified according to the best response observed
during follow up; patients whose disease showed no signs of
progression between any two observations were classified as stable.
The lesions were measured (by clinical examination, x ray,
computed tomography, etc) every 1, 2, or 3 months. An independent
end point evaluation committee (consisting of radiologists, oncologists,
and haematologists) did a blind review of the clinical records and
documents available for each patient to corroborate the evaluation made
by the participating hospitals. Patients with early progression and
those who died, as well as patients who discontinued treatment because
of toxicity, were included in the analysis of clinical outcome.
Adverse events were evaluated and graded on the basis of the WHO
toxicity criteria.7
The trial
protocols were approved by an ad hoc national ethics committee and by the
ethics committees of each hospital; patients were required to
provide written informed consent.
Each trial
was monitored by a clinical monitor. All clinical sites were audited by the
Istituto Superiore di Sanitą.
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Results |
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Between March and July
1998, 395 patients were enrolled in the trials. Nine of these
patients were excluded because they did not meet major eligibility
criteria; thus 386 patients were included in the analysis. Table
1 shows selected characteristics of each trial's
study population.
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The main results of each
trial are presented in table 2. None of the patients showed a complete
response. Three showed partial responses: one patient with
non-Hodgkin's lymphoma, one patient with less severe breast cancer,
and one patient with pancreatic cancer.
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At the second examination,
47 (12%) patients had stable disease, in 199 patients (52%) disease
had progressed, and 97 (25%) had died. In individual trials the
proportion of patients whose cancer progressed ranged from 38% to
70%, and the proportion of deaths ranged from 0% to 44%. Thirty two
patients (8%) discontinued the experimental treatment because of
toxicity or reasons not related to drug treatment.
Treatment status and
survival of the patients at 31 October 1998 (last date of follow up)
are shown on the BMJ's website. Overall, 16 (4%)
patients were still receiving treatment; 129 (33%) patients
were not receiving treatment; 219 (57%) patients had died; and
22 patients (6%) were lost to follow up. The 16 patients
who were still receiving Di
Bella multitherapy comprised three patients with a
partial response and 13 patients with stable disease.
All 395 patients
enrolled in the trials were evaluated for toxicity. During the observation
period (on average, each patient was treated for 2 months),
157 (40%) patients had a total of 273 drug side effects
(any grade of severity) associated with treatment, of which
64 events (in 41 (26%) patients) were classified as
"severe" (WHO grade 3-4). The proportion of adverse events
ranged from 5% among patients with glioblastoma to 77% among patients
with chronic lymphoid leukaemia. Patients with lung cancer and
glioblastoma who had not previously had chemotherapy had no severe
events, whereas more than one third of the patients with chronic
lymphoid leukaemia had a severe event. Most of the adverse events
(157) were of gastrointestinal nature: diarrhoea, vomiting, and
nausea. Somnolence was seen in 31 patients. In the trials
including cyclophosphamide, 30 cases of blood related toxicity
(anaemia, thrombocytopenia) were seen. All of these adverse events
were to be expected on the basis of the pharmacological properties
of the various drugs and had been described in the investigators'
brochure (which contained details of previous knowledge about the
drugs under investigation).
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Discussion |
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The results of these trials
indicate that Di Bella
multitherapy does not have sufficient efficacy in advanced cancer to warrant
further clinical testing. The three cases of partial response among
the 386 patients represent a 0.8% response rate, which is well
below any reasonable threshold for declaring that a new regimen shows
promise.
These low response rates
seem to rule out the possibility that the entire regimen has any effect over
and above the moderate activity already seen for some of its
components. Objective responses in patients treated with
somatostatin or its analogues have been described in phase II trials
in pancreatic, colorectal, and breast cancer.8 Retinoids are being extensively studied in
several haematological and solid malignancies, with results that
range from little or no effect to the spectacular success obtained
in acute promyelocytic leukaemia, where all-trans retinoic acid
induces complete remission in a high proportion of patients.8 Cyclophosphamide is one of the most
widely used anticancer drugs, as a single agent or in combination
chemotherapy regimens, and it is active in many haematological and
solid malignancies, including breast cancer and non-Hodgkin's
lymphoma.8 The 50 mg of cyclophosphamide daily
that was used in the multitherapy regimen is not much lower than the
dose commonly used in chemotherapy.
Overall, the results of
these trials fail to justify the use of Di Bella multitherapy and they even suggest
that it may be associated with considerable toxicity. Furthermore,
the observation that Di Bella multitherapy was discontinued after several
months in 85% of the patients because of progression, toxicity, or
death means that this treatment is unlikely to be effective in the
long term.
As in most phase II trials,
the eligibility criteria restricted the enrolment to patients who could not
receive standard treatments, since it would have been unethical to
withdraw from patients treatments of known efficacy. However, only
two trials (more severe breast cancer, and solid neoplasms among
terminally ill patients) focused on critically ill patients; in all
other trials, most patients had a fair to good performance status.
Terminally ill patients were included because of the increasing
number of court orders for terminal cancer patients to be given Di Bella multitherapy,
but the results of these two trials show that the treatment neither cures
nor stops the progression of tumours in patients with terminal cancer.
Eighty patients who had not
had previous chemotherapy were enrolled in two of the trials. Only one
pancreatic cancer patients showed any response, and no response was
seen in lung cancer patients who had not previously had chemotherapy.
The trials, with their
rigid treatment protocols, did not reproduce one element of the method that Di Bella claims is
crucial: tailoring the treatment to individual patients.
Unfortunately, no trial can be conducted without a treatment
protocol, and details on the criteria followed by Di Bella and his
disciples when adjusting the treatment have not been released.
Therefore, it cannot be ruled out that better results could have
been obtained by modulating treatment. However, in all trials the
protocols followed written indications provided by Di Bella. Furthermore,
the potential for widespread use of a new treatment is greatly
reduced if its effectiveness depends on the doctor's ability to
modulate it and no explicit criteria are available.
The Di Bella multitherapy
has been widely prescribed in Italy despite lack of scientific evidence. Given
the high mortality from cancer, it is not surprising that thousands
of people continue to seek unconventional treatments. Although
claims of "wonder drugs" are occasionally reported by the
media, public expectation in this case reached unprecedented levels
in Italy.
Phase III randomised
controlled trials (which were intended as a further step if results were
positive) would not have been feasible for both ethical and
practical reasons. On the one hand, preliminary evidence about the
antitumor activity of Di
Bella multitherapy was lacking and, on the other,
patients who were seeking this treatment would have hardly agreed to
be randomly allocated to different treatments. These uncontrolled
phase II trials, which were planned, conducted, and concluded in
less than 10 months, have given the Italian scientific
community a solid base for the ongoing debate. We believe that this
approach was the best way to cope with an unconventional treatment
that was gaining widespread public acceptance in the absence of
scientific evidence.
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Acknowledgments |
We thank
Colonel G Muzzi (director, Stabilimento Chimico Farmaceutico Militare,
Florence) for the production of the melatonin tablets and retinoids
solution; R Alimenti, S Alimonti, G Cavazzutti, L Gagliardi, B
Gallinella, G Incarnato, F La Torre, A Mosca, G Multari, L
Turchetto, L Valvo (Istituto Superiore di Sanitą, Rome) for the
supervision and control of custom made drugs. Special thanks to the
members of the International Review Board: P Calabresi (Rhode Island,
USA), F Cavalli (Bellinzona, Switzerland), P Kleihues (Lyon Cedex,
France), J G McVie (London, UK), H Pinedo (Amsterdam, Netherlands),
K Sikora (Lyon Cedex, France), T Tursz (Villejuif Cedex, France). We also thank M Kanieff for
linguistic revision, and Alfa Wasserman, Bracco, Crinos, IBI,
Istituto delle Vitamine, Italfarmaco, Lepetit, Mipharm, Novartis,
Sanofi Winthrop, Serono, Sigma Tau, Ucb Pharma, and Valeas for
providing drugs used in the trials.
*Dr G Di Bella, the son of Dr
L Di Bella,
participated at only 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 present article has been discussed or agreed with Dr G Di Bella.
Funding: The study was
specifically funded through an act of the Italian parliament.
Competing interests: None
declared.
website extra: An additional table and a list of members
of the study group can be found on our website www.bmj.com
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References |
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- Pellegrini R. Di Bella's method
of curing cancer is becoming popular in Italy. BMJ 1998; 317: 352
[Free Full Text] .
- Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10: 1-10[Medline].
- Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47: 207-214[Medline].
(Accepted 7 January 1999)
This article has been cited by other articles:
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Rapid Responses:
Read all Rapid Responses
Inappropirate
methodologies measuring alternative therapies
Susan Holloran
bmj.com, 20 Apr 1999 [Full text]
The
need for testing unconventional treatments for cancer
Richard G Fiddian-Green
bmj.com, 26 Jul 2003 [Full text]
Related letters in BMJ:
The
Di Bella multitherapy trial
Alessandro Liberati, Nicola
Magrini, Lucio Patoia, Luigi Pagliaro, R Raschetti, D Greco, F Menniti-Ippolito,
S Spila-Alegiani, G Traversa, G Benagiano, P Bruzzi, Marcus Müllner, and
Stephen J W Evans
BMJ 1999 318: 1073. [Letter]
Related editorials in BMJ:
Di Bella's therapy: the last word?.
Marcus Müllner
BMJ 1999 318: 208-209.
Other related articles in BMJ:
MULTIMEDIA
Book: Di Bella: the
Man, the Cure, a Hope for All.
Abi Berger
BMJ 1999 318: 268.
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