ARTICLE
Auteur(s) : D
Oppenheim1, B Geoerger2, O
Hartmann2
1Pediatrics Department, and Unit of Psycho-oncology,
Institut Gustave Roussy, 94805 Villejuif Cedex, France
2Pediatrics Department. Institute Gustave Roussy, 94805
Villejuif, France
The importance of clinical trials and especially phase I trials has
gained momentum these last years in oncology [1] and in pediatric
oncology [2, 3]. The Department of Pediatric Oncology at the
Institute Gustave Roussy initiated such trials in 1994. Most of
these studies were conducted with other centers of the SFOP
Pharmacology Group (French Society of Pediatric Oncology) and with
the UKCCSG New Agents Group in the UK. These trials in Pediatrics
have given rise to a new and complex situation and raise many
clinical and ethical issues [4] to which care providers as well as
parents are more and more attentive. Since 2003, to accompany the
informed consent process, a tape recorded interview with the
psycho-oncologist is routinely proposed to parents and adolescents
in order to help them to reflect upon the medical situation, the
meaning of the proposition and the reasons why they accept or
refuse. We present one of these interviews. The maternal concern
F’s mother expressed was so sensitive and profound that her account
could be helpful [5] to care providers and parents faced with a
similar situation.
Medical history
F., a 7 year-old girl had been treated since the age of 2 for a
malignant germinal tumor. She had already received several
conventional and investigative treatments and undergone several
operations. As her illness was progressing anew, a phase I-II study
was proposed which the parents accepted.
The interview with F.’s mother
Why did you accept the trial?
“This is not the first study. All the conventional treatments have
been used and none of them were efficient, but they were able to
control the illness and gain time. We know that there is no drug
able to cure her. Very sensitive markers indicate that the disease
is still present but we don’t know where. Therefore the surgeon
proposed intervening ‘blindly’ but there would be major permanent
sequels. The word ‘blindly’ stopped us in our tracks: it is
excessive to propose a treatment without knowing where you are
heading. The study was proposed as an alternative, and we accepted
it to avoid the operation and to gain more time, even a week, but
not really believing that it could cure F. We did not accept it
through altruism. F. has already given a great deal to others and
to medicine.”
Was this operation the limit to what you could possibly
accept?
“My husband and I had reached a point where we are able to accept
everything although it depended on the way it was presented. With
time, we accepted everything even what we had considered
unacceptable at the outset. If the doctors had told me what was
going to happen then, I would have jumped out the window. I don’t
know if there is a limit to what I can bear, neither if one day I
will be able to say ‘Stop!’ If nothing else is possible, we would
have even accepted that operation like we accepted the colostomy. I
don’t know whether I still believe in anything, in what is proposed
to me, but I accept it. I no longer ask myself any questions.”
“I am no longer interested in the constraints and the adverse
effects of the trial although I know a lot about this drug. I have
gone through so many ordeals with F. that I said to myself that we
can solve everything. The long term is too far off to worry about
it and I have been living so long with the short-term problems that
I have become insensitive to it.”
What about the discussions with the doctors?
“I clearly distinguished them. I asked the doctor who is taking
care of her why he had proposed this drug which is the next logical
step in the clinical treatment even though I am well aware of what
a phase I trial is. I knew he had chosen the best treatment for F.
I discussed the technical aspects of the trial with the doctor in
charge of the research program. It is better when each interlocutor
has a clearly defined place, but the clinician must remain in
charge. We were proposed such trials in another country but I
refused them because I felt that the patients were simply given a
number and that I was only dealing with someone primarily concerned
by his research.”
What did you tell F.?
“I told her that the markers indicated that small grains of the
disease remained hidden, that the doctors were proposing a new drug
instead of a heavy operation with sequels, but they were not sure
of its efficiency. I felt she understood enough. She said she had
had enough of treatments but she did not seem broken nor worn out.
I wonder whether I told her only to relieve myself of my doubts and
to burden her with the decision. I know that I asked her to accept
what I perhaps would not accept. I couldn’t tell her that the
objective of all these treatments is to avoid her death but I think
she knows that.”
How useful are such interviews?
“It did not bother me. It helps you to put your thoughts in order,
even if I say to myself that it is better not to think, and better
to assume the choices we made.”
F. expressed very clearly and at different moments her point of
view: she agrees with any treatment as long as it is not too
painful nor too difficult to endure. She is well aware that all the
previous treatments were unable to cure her but she nevertheless
still hopes that a new treatment might be efficient. She does not
really think about this issue: she has got rid of this concern.
Comments
What can we learn from this mother about relational and ethical
issues in such situations?
How is the decision made? [6]
The proposition is more easily accepted if the parents have
confidence in the doctor and in the center, if they understand the
objectives and the methods (as they have understood the diagnosis
and the therapeutic protocol, and the shift from curative to
palliative treatment) [7, 8], if they do not feel under pressure to
accept it, if the child’s best interests take precedence over that
of research. Excessive confidence can, later on, when hope has
disappeared, abruptly turn into violent criticism and anger or
cause loud regrets and feelings of guilt which make the process of
grief more painful [9].
It is important to take into account whether and how the parents
strike a balance between the risks of the treatment and its
benefits. A study [10] showed that 12% of the parents of children
suffering from sickle cell anemia would accept 50% or more
short-term vital risks due to the treatment if there was even
minimal hope of recovery, and 24% refused any risk whatsoever even
with a 100% chance of recovery. But parents of children treated for
a cancer often say: “We have no choice; even if our child has only
one chance in a million of recovery we can’t lose it because later
on, if our child dies, we would feel responsible for his/her
death.” Another study [11] showed that patients accepted to
participate in a phase I trial not for altruistic reasons but
because they expected therapeutic benefits that often exceeded what
they could reasonably expect (but doctors shared a part of these
excessive expectations). F.’s mother courageously acknowledged that
she wanted to protect herself from the unbearable pain of losing F.
(this motivation leads other parents to search for any futile
treatment).
Informed consent
The quality of the informed consent is essential to avoid
misunderstanding [12]. It is considered sufficiently good by the
majority of authors [13-16], but not by all [17-19]. The parents
show they have understood during the dialogue, which requires
experience [20], skill and training [21], and how far they wish to
be informed [22]. They also say what they know and misunderstand,
the right and wrong ideas they may have, their fantasies, their
excessive or realistic expectations [23], and their objectives
which are not always the same as the doctors’ [24, 25]. The
children express their point of view in words, behavior, drawings,
etc [26]. Most often they are sufficiently aware of their situation
and can be precisely informed [27, 28].
Parents and adolescents can more authentically express their
consent when a true alternative is proposed, which cannot be “the
trial or nothing” nor “certain death without the trial, a slight
hope with.” The information must present the consequences and the
risks of the treatment in relation to its expected benefits, but
also this treatment in relation to other treatments even if they
are unrealistic, or other choices (such as enjoying life outside
the medical setting, even if it must be shorter) [29]: they can be
dismissed or approved in the discussion and do not remain in the
parents’ thoughts.
The doctor’s role and responsibility
The trust patients have in doctors greatly influences their
decision [6, 11]. Therefore, doctors must realize that the logical
and emotional reasons for their choices (of the study and of the
patient’s inclusion in it) are complex [30, 31] as is the balance
between their concerns as clinicians (the child’s and the parents’
well-being) and as researchers (benefits for children in the
future). This requires training [20] but also joint discussions
between clinicians, researchers, nurses, psycho-oncologists
involved in the care of the child, and colleagues well versed in
medical ethics.
What can hinder the parents’ decision?
Their contradictions: F’s mother was vigorous and desperate, “able
to accept everything” and eager to demand everything. Their
ambivalence : F.’s mother wanted and did not want to know, and
would not have been able to cope with early and exhaustive
information (the timing of the information imparted and its rhythm
must be carefully evaluated). They are exhausted, they often lose
their usual intellectual and social landmarks (they are living in a
unique pediatric oncology setting that others can hardly know and
imagine) and their sense of limits. They can also be depressed and
have an excessively pessimistic point of view. The responsibility
incumbent upon the doctors is considerable: they have to decide and
perform the treatment but must not influence the decision of the
parents who are in such great disarray that they may be capable of
demanding or accepting any proposition. When life is in danger, any
proposition can be valid as long as it exists in the medical field,
but the limits of what is ethically acceptable must be permanently
revised with progress in medicine [32].
‘Blindly’ made F.’s mother react (but she accepted ‘the
unknown’, which applies to the phase I-II trial). Parents react not
only to the content of what is proposed but also to the way it is
expressed [20, 33]. The words used may also express uneasiness,
emotion, ambivalence towards the trial, interest in the child or in
the success of the research etc. Therefore doctors have to question
themselves about their objectives, their motivations (excessive
faith in the trial could make them less attentive to the parents’
or the child’s reluctance), and sometimes about their vocation and
ideals [34]. F.’s mother said the trial had to be consistent with
clinical concerns and she trusted first and foremost those who had
taken on this responsibility from the onset. These care providers
are more capable of understanding the complexity of the parents’
and the child’s motivation and they can go beyond the first answer,
be it positive or negative, to the proposition and so avoid
misunderstandings and conflicts. On the other hand, an intense and
emotional relationship with the child and the parents could affect
the accuracy of their appraisal of the benefits and risks of the
trial. A psycho-oncologist can help the child, the parents and the
care providers to have a better understanding of the relationships
forged between them, of their motivations, fears and expectations,
and also answer the following questions: “Who is this patient for
me? Who am I for him/her? What are my aims, the conscious and the
unconscious ones, the primary and the secondary ones? What allows
me to do what I do to him/her?” Thus, they can better assume their
decision and its consequences, in the short (during the trial),
middle (the possible end of the child’s life) and the long (the
grieving period) term. A meeting on the inclusion of each child in
a phase I-II trial, with the treating physician, the research
physician, the nurses involved in the care of the child, the
psycho-oncologist, and if necessary an external colleague familiar
with ethical issues can also be helpful. Such meetings complete the
role of the Institutional Review Board which gives its advice on
the trial itself.
Ethical issues in such situations
The caregivers should go to great lengths to respect the main
ethical principles in the medical field, even more than in more
usual settings: autonomy, benevolence, non malevolence, justice and
dignity. But these principles are particularly difficult to uphold
in phase I-II trials [35]. Autonomy : we have described some of the
main reasons that hinder the parents’ and the child’s ability to
take and assume their decision. Benevolence and non malevolence :
the benefits for the patient are not null but weak (about 4.5% of
positive effects on the tumor for adult patients, and more for
children, and 0.5% of toxic deaths) [36]. Justice: if the drug
proves to be efficient the benefit for many other patients will be
considerable; if not, the knowledge gained by this trial will also
be useful to others. The doctors must also be attentive to the
reasons that make them propose the trial to a patient or what make
them decide not to. They are not social, economic, racial or
religious but could be affective and partly unconscious reasons.
The aim and the methodology of the phase I trial (to assess the
maximum tolerated dose) can be considered contradictory with the
principles of benevolence and non malevolence. But criteria other
than overall toxic effects could be proposed. Dignity must be
respected: doctors cannot propose everything (and not all arguments
are justified) nor should they accept all propositions from parents
or the patient, e.g. demands for a futile treatment [37], even when
there is tremendous or excessive hope in the success of the trial.
Shame, guilt or loss of self-esteem could occur later on.
Conclusion
Pediatric phase I-II trials raise many complex relational and
ethical issues. The medical and nursing staff, the parents, and the
adolescents have to make decisions in the patient’s best interests,
and bear the consequences in the short and in the long term. It is
easier when they are aware, as much as possible, of their
motivations, their realistic and unrealistic expectations and their
acceptance of the risks, with the help of the psycho-oncologist and
ethical meetings. It is also easier when all the alternatives the
doctors could propose and the parents and the child could think of
are discussed, taken into account or dismissed, in order to avoid
mutual misunderstanding and guilt. It is vital that the parents and
the child express what the limits of the unbearable and the
unacceptable are, of which the physicians should be aware. It is
also essential that the doctor in charge of clinical care from the
outset and the doctor in charge of research are different, but are
cooperating.
Acknowledgements
The authors thank Ms Lorna Saint-Ange for editing. Sincere thanks
to F.’s mother for what she taught us and for having accepted the
publication of this article.
References
1 American Society of Clinical Oncology. Critical role of phase I
trials in cancer treatment. J Clin Oncol 1997; 15: 853-9.
2 Pratt CB. The conduct of phase I-II clinical trials in
children with cancer. Med Pediatr Oncol 1991; 19: 304-9.
3 Vassal G, Pein F, Doz F, et al.
Feasibility of phase I and II trials in pediatric oncology. Proc Am
Soc Clin Oncol 1992; 11: 371.
4 Ault A. Children need more protection in clinical trials,
say IOM. Lancet 2004; 363: 1119.
5 Daugherty CK, Siegler M, Ratain MJ,
Zimmer G. Learning from our patients: one participant’s impact
on clinical trial research and informed consent. Ann Inter Med
1997; 126: 892-7.
6 Tait AR, Voepel-Lewis T, Malviya S.
Participation of children in clinical research: factors that
influence a parent’s decision to consent. Anesthesiology 2003; 99:
819-25.
7 Wolfe J, Klar N, Grier HE, et al.
Understanding of prognosis among parents of children who died of
cancer: impact on treatment goals and integration of palliative
care. JAMA 2000; 284: 2469-75; (15).
8 Fallowfield LJ, Jenkins VA, Beveridge HA. Truth
may hurt but deceit hurts more: communication in palliative care.
Palliat Med 2002; 16: 297-303.
9 Oppenheim D. Grandir avec un cancer. L’expérience vécue
par l’enfant et l’adolescent. Bruxelles: De Boeck, 2003.
10 Kodish E, Lantos J, Stocking C, et al.
Bone marrow transplantation for sickle cell disease. A study of
parents’ decision. N Engl J Med 1991; 325: 1349-53.
11 Daugherty C, Ratain MJ, Grochowski E,
et al. Perceptions of cancer patients and their physicians
involved in phase I trials. J Clin Oncol 1995; 13: 1062-72.
12 Daugherty CK. Impact of therapeutic research on informed
consent and the ethics of clinical trials: a medical oncology
perspective. J Clin Oncol 1999; 17: 1601-17.
13 Kupst MJ, Patenaude AF, Walco GA,
Sterling C. Clinical trials in pediatric cancer: parental
perspectives on informed consent. J Pediatr Hematol Oncol 2003; 25:
787-90.
14 Horng S, Emanuel EJ, Wilfond B, et al.
Descriptions of benefits and risks in consent forms for phase I
oncology trials. N Engl J Med 2002; 347: 2134-40.
15 Simon C, Eder M, Raiz P, et al. Informed
consent for pediatric leukemia research: clinician perspectives.
Cancer 2001; 92: 691-700.
16 Mason SA, Allmark PJ. Euricon study group.
Obtaining informed consent to neonatal randomised controlled
trials: interviews with parents and clinicians in the Euricon
study. Lancet 2000; 356: 2045-51.
17 Agrawal M, Emanuel EJ. Ethics of phase I oncology
studies: reexamining the arguments and data. JAMA 2003; 290:
1075-82.
18 Tait AR, Voepel-Lewis T, Malviya S. Do they
understand? (part I):parental consent for children participating in
clinical anesthesia and surgery research. Anesthesiology 2003; 98:
603-8.
19 Simon C, Zyzanski SJ, Eder M, et al.
Groups potentially at risk for making poorly informed decisions
about entry into clinical trials for childhood cancer. J Clin Oncol
2003; 21: 2173-8.
20 Jenkins VA, Fallowfield LJ, Souhami A,
et al. How do doctors explain randomised clinical trials to
their patients? Eur J Cancer 1999; 35: 1187-93.
21 Fallowfield L, Jenkins V, Farewell V,
Saul J, Duffy A, Eves R. Efficacy of a Cancer
Research UK communication skills training model for oncologists: a
randomised controlled trial. Lancet 2002; 359: 650-6.
22 Sreenivasan G. Does informed consent to research require
comprehension? Lancet 2003; 362: 2016-8.
23 Itoh K, Sasaki Y, Fujii H, et al.
Patients in phase I trials of anti-cancer agents in Japan:
motivation, comprehension and expectations. Br J Cancer 1997; 76:
107-13.
24 Caldwell PH, Butow PN, Craig JC. Parents’
attitudes to children’s participation in randomized controlled
trials. J Pediatr 2003; 142: 554-9.
25 Meropol NJ, Weinfurt KP, Burnett CB,
et al. Perceptions of patients and physicians regarding phase
I cancer clinical trials: implications for physician-patient
communication. J Clin Oncol 2003; 21: 2589-96.
26 Oppenheim D. Parents en deuil. Le temps reprend son
cours. Ramonville St Agne: Eres, 2002.
27 Hilden JM, Watterson J, Chrastek J. Tell the
children. J Clin Oncol 2000; 18: 3193-5.
28 Olechnowicz JQ, Eder M, Simon C,
Zyzanski S, Kodish E. Assent observed: children’s
involvement in leukemia treatment and research discussions.
Pediatrics 2002; 109: 806-14.
29 Gattellari M, Voigt KJ, Butow PN,
Tattersall MNH. When the treatment goal is not cure: are
cancer patients equipped to make informed decisions? J Clin Oncol
2002; 20: 503-13.
30 Caldwell PH, Butow PN, Craig JC.
Pediatricians’ attiiudes toward randomized controlled trials
involving children. J Pediatr 2002; 141: 798-803.
31 Estlin EJ, Cotterill S, Pratt CB,
Pearson AD, Bernstein M. Phase I trials in pediatric
oncoplogy: perceptions of pediatricians from the United Kingdom
Children’s Cancer Study Group and the Pediatric Oncology Group. J
Clin Oncol 2000; 18: 1900-5.
32 Burgio GR, Gluckman E, Locatelli F. Ethical
reappraisal of 15 years of cord-blood transplantation. Lancet 2003;
361: 250-2.
33 Weinfurt KP, Sulmasy DP, Schulman KA,
Meropol NJ. Patient expectation of benefit from phase I
clinical trials: linguistic consideration in diagnosing a
therapeutic misconception. Theor Med Bioeth 2003; 24: 329-44.
34 Balint M. The doctor, his patient and the illness.
London: Pitman, 1957. Edition française: Le médecin, son malade et
la maladie. Paris: Payot, 1968.
35 Daugherty CK. Ethical issues in the development of new
agents. Invest New Drugs 1999; 17: 143-53.
36 Roberts TG, Goulart BH, Suaitieri L,
et al. Trends in the risks and benefits to patients with
cancer participating in phase I clinical trials. JAMA 2004; 292:
2130-40.
37 Oppenheim D, Brugières L, Corradini N,
Vivant F, Hartmann O. An ethics dilemna: when parents and
doctors disagree on the best treatment for a child. Bull Cancer
2004; 91: 735-78b.
|
Printable version
Version PDF