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Sunday, June 29, 2014

Les Français largement favorables à la légalisation de l’euthanasie

Un sondage paru dans le Parisien affirme que 89 % des Français seraient favorables à une loi autorisant l’euthanasie. On relève également que dans le cas d’un patient ne pouvant exprimer son choix, 53 % des Français considèrent que c’est à la famille que doit revenir la décision, quand 41 % estiment qu’elle appartient aux médecins et 6 % à la justice.

Question de mort

Du point de vue historique, les signes utilisés pour établir le diagnostic de décès ont évolué : du 18ème siècle jusqu’en 1950 environ, l’arrêt des battements cardiaques suffisait pour affirmer la mort du sujet. Dès 1959, les possibilités de suppléance cardiorespiratoire ont fait s’interroger sur les critères diagnostiques de la mort. Des auteurs (français) ont ainsi publié sur le coma dépassé ou la mort du système nerveux. Il y a donc actuellement deux entrées (cardiorespiratoire et/ou cérébrale) pour une seule « sortie », la mort.
Un rapport sur la détermination du décès, élaboré à l’initiative de l'Organisation Mondiale de la Santé, a été récemment publié (1). Les experts donnent une définition pragmatique de la mort : « la mort est la perte permanente de la capacité de conscience associée à la perte de toutes les fonctions du tronc cérébral, conséquences d’un arrêt circulatoire ou de lésions cérébrales catastrophiques ».
La définition proposée s’abstient de termes suggérant la mort d'un organe, comme « mort cérébrale » ou « mort cardiaque ». Elle réunit le cœur et le cerveau en une acception unique de la mort.

L’éditorial (2) qui commente ce rapport revient sur le terme « permanent » utilisé pour caractériser la perte d’une fonction et non pas « irréversible ». Permanent fait référence à une condition qui dure mais qui, en théorie, pourrait être inversée alors que irréversible signifie que la fonction ne pourra jamais être restaurée. En effet, avec les technologies actuelles, de nombreux organes peuvent être remplacés, ou leur fonction prise en charge. De nombreux organes, mais pas tous (le cerveau). Le mot permanent se réfère donc à la circulation. La fonction circulatoire peut, dans de nombreuses circonstances, être prise en charge par une réanimation cardiorespiratoire ou une circulation extracorporelle. Le mot permanent laisse une possibilité de choix.
Un des problèmes soulevé par cette définition est que la mort cérébrale n'est pas toujours acceptée comme la mort. L’éditorialiste prend l’exemple de Jahi McMath, une jeune fille de 13 ans, déclarée en état de mort cérébrale après une hémorragie massive et un arrêt cardiaque à la suite d’une intervention chirurgicale. Sa famille a rejeté le diagnostic de décès établi par les médecins et a sorti sa fille de l’hôpital pour pouvoir poursuivre la ventilation assistée et la nutrition entérale dans une structure privée. Au cours de la discussion de ce cas dans l’article le rapportant (3), il est précisé que « la mort a été fondamentalement considérée [par les médecins] comme un événement biologique ... les aspects ou points de vue juridique, éthique, culturel et religieux sur la mort n'ont pas été inclus ». Cependant, dans cet exemple, la fonction biologique justement se poursuit : la ventilation étant maintenue et le corps nourri, les fonctions circulatoire, hormonale et autres processus peuvent continuer.
Ce débat philosophique sur les définitions de la vie et de la mort est extrêmement intéressant et nécessaire, mais nous devons rester conscients des problèmes pratiques aux quels se confronte un médecin réanimateur. A cet égard, dans des conditions préalables définies et après un diagnostic techniquement correct de mort cérébrale, on peut déclarer le décès et prendre les mesures éventuelles en cas de don d’organes.
Dr Béatrice Jourdain
Références
1) Shemie SD et coll. : The International Guidelines for Determination of Death Phase 1 Participants, in collaboration with the World Health Organization (2014) International guideline development for the determination of death. Intensive Care Med., 2014; 40:788-97. doi: 10.1007/s00134-014-3242-7.
2) Kuiper M, Kompanje E : Only a very bold man would attempt to define death. Intensive Care Med 2014; 40: 897–899 DOI 10.1007/s00134-014-3259-y
3) Magnus DC, Wilfond BS, Caplan AL. : Accepting brain death. N Engl J Med. 2014; 370:891-4. doi: 10.1056/NEJMp1400930. doi:10.1056/NEJMp1400930

Saturday, June 28, 2014

Bonnemaison : des applaudissements qui dérangent 

 Publié le 28/06/2014

Paris, le samedi 27 juin 2014 - 
L’acquittement du docteur Nicolas Bonnemaison ce mercredi 24 juin a été à l’origine de nombreux commentaires sur les blogs de médecins et de juristes. Il faut dire que cette décision à l’encontre des réquisitions du Procureur général n’a laissé de surprendre et interroge nécessairement sur la conception de la médecine et de la justice. Il ne s’agit pas ici de relancer le débat autour de la légalisation de l’euthanasie active, mais de mesurer les conséquences d’un tel acquittement.

Retournement de veste de Bernard Kouchner

Pour le médecin auteur de "Perruche en automne", ce verdict est une remise en cause d’une des évolutions majeures de la médecine moderne qui a fait de l’inclusion du patient, de la nécessité de tout expliquer dans un souci de transparence absolu, de l’importance de ne pas s’ériger en supérieur, de véritables dogmes. L’idée n’a pas toujours été facilement acceptée. « J’ai du lutter contre ma tendance naturelle à croire que j’ai raison et à la prise de décision individuelle, sûr de ma science » admet Perruche qui estime cependant que le dialogue, qui est au centre de la pratique actuelle est primordial. « Ma génération a été nourrie d’un modèle opposé à celui du médecin paternaliste. On nous a appris à vouloir tuer ce père fouettard médecin. On nous a appris la décision collégiale, la discussion avec le patient, l’entourage. On nous a appris à expliquer, expliquer et encore expliquer. La loi sur le droit des malades est venue couronner et légitimer ce mouvement. Je pensais que la profession avait intégré l’importance du partage pour sortir de la position du médecin tout puissant, figure divine, imposant ses oukases. Je croyais bêtement que la société avait aussi intégré cette évolution majeure de la pensée médicale. Et patatras, voici l’affaire dite « Bonnemaison ». 

L’euthanasie n’est pas son combat ni le mien, ça tombe bien. Par contre, ses mots sont terribles, il veut protéger contre elles-mêmes les personnes, famille, équipe soignante, en prenant les décisions seul et en agissant seul. Ce point est celui qui me dérange le plus. Il va à l’encontre de tout ce en quoi je crois dans la pratique médicale. L’importance de la parole, de l’explication, de la pédagogie faites aux patients, à sa famille et aux soignants. L’importance du dialogue, car parfois on se trompe et la confrontation permet de rétablir une situation. (…) Que lui reproche la seule famille partie civile ? L’absence d’échange » résume-t-il. Ainsi s’étonne-t-il que ceux qui ont glorifié la communication entre les médecins, et parmi eux l’ancien ministre de la Santé, Bernard Kouchner, se félicite, acclame même la décision de la Cour d’assises de Pau. « Ce praticien a trahi une approche basée sur le dialogue. Alors quand je lis que M Kouchner le défend, je ne comprends plus. Quand je lis qu’on applaudit au verdict, je me dis que nous avons fait fausse route en promouvant cette approche. (…) Ce jugement me laisse un étrange gout dans la bouche, un peu amer », conclue-t-il.

Médecins modernes : ces étranges outils des désirs sociétaux

Ces « applaudissements », cette liesse qui s’est manifestée à l’annonce du verdict à Pau ont également marqué l’auteur de « Docteur du 16 ». Cependant, ce qui choque ce praticien dans les affaires Bonnemaison et Lambert c’est « l’instrumentalisation de la médecine » par la société. « La sociétalisation de la médecine fait des médecins les outils des désirs sociétaux (et l'histoire nous dira s'ils étaient fous ou non), ces désirs qui sont instrumentalisés ou justifiés par la philosophie des Droits : "J'ai le droit de..." Et gare à ceux qui ne s'y conforment pas (…). Dans le cas Bonnemaison que l'on a décrit comme "assassin par compassion" il semble que son instrumentalisation (les acclamations de la salle d'audience à l'annonce de l'acquittement en témoignent) par les associations ne fasse aucun doute » affirme ainsi l’auteur de ce blog connu pour son franc parler et qui ne cache pas son hostilité à une telle dérive.

Appel au parquet

Une analyse proche parcourt l’une des nombreuses notes consacrées à l’affaire Bonnemaison par le journaliste et médecin Jean-Yves Nau. Lui aussi, frappé par les « vivas » qui ont entouré l’annonce par les jurés de l’acquittement du médecin de Bayonne évoque pour sa part la nécessité pour le parquet de faire appel de cette décision. Il ne s’agit pas pour lui seulement de rappeler que le docteur Nicolas Bonnemaison, même s’il n’est probablement pas un « assassin » n’a nullement respecté les règles élémentaires qui s’appliquent dans le lien avec les malades et leur famille, mais de rappeler l’indépendance de la justice face à l’influence de la société et de la politique. « Les formidables acclamations de Pau ont un effet redoutable : elles brouillent le « débat » sans cesse annoncé, sans cesse reporté, sur la fin de vie. L’acquittement plus que médiatisé  de cet ancien médecin vient compliquer le travail dont Marisol Touraine était chargée mais qui vient d’être confié à Jean Leonneti (UMP) et Alain Claeys (PS). Stephane Le Foll, porte-parole du gouvernement a expliqué que l’acquittement de Nicolas Bonnemaison « confortait » la volonté de ce même gouvernement « faire évoluer » le cadre législatif ». M. Le Foll n’utilise pas pleinement son droit à la parole : il ne dit pas ce qu’il entend par « faire évoluer ». (…) Dans ce non-dit d’un politique qui a peur des ombres, l’acquittement de Nicolas Bonnemaison ajoute à l’obscurité. Loin d’éclairer il vient compliquer une tâche rendue plus délicate encore avec la décision du Conseil d’Etat dans l’affaire Lambert (…). Aujourd’hui le parquet peut faire appel de l’acquittement. Cela n’effacerait certes pas les acclamations saluant les jurés. Cela aurait toutefois le mérite de surligner devant l’opinion la gravité du sujet qui est ici abordé. Le mérite, aussi, de rappeler l’existence d’une indépendance de la justice. Vivas ou pas » analyse ainsi Jean-Yves Nau.

Juristes et médecins : des opinions différentes

Ainsi, on le voit, la blogosphère médicale observe avec un profond malaise cette décision d’acquittement. Pour lire une opinion très différente sur ce sujet, il faut se rendre (assez étonnamment !) sur le blog d’un spécialiste de la justice : le président du tribunal pour enfants de Bobigny, Jean-Pierre Rosenczveig estime en effet pour sa part que le verdict de Pau est une « décision courageuse », prise par une « cour » ayant « décidé de ne pas céder à l’hypocrisie » !

Aurélie Haroche

Letter to Cancer Center Directors: 

Progress in Quantitative Imaging As a Means to Predict and/or Measure Tumor Response in Cancer Therapy Trials

  1. © 2014 by American Society of Clinical Oncology
  2. James M. Mountz
  1. University of Pittsburgh, Pittsburgh, PA
  1. Corresponding author: James M. Mountz, MD, PhD, University of Pittsburgh Medical Center Health System, University of Pittsburgh, PET Facility, B-932, 200 Lothrop St, Pittsburgh, PA 15213; e-mail: mountzjm@upmc.edu.
  1. Thomas E. Yankeelov
  1. Vanderbilt University, Nashville, TN
  1. Daniel L. Rubin
  1. Stanford University, Palo Alto, CA
  1. John M. Buatti
  1. University of Iowa, Iowa City, IA
  1. Bradley J. Erikson
  1. Mayo Clinic, Rochester, MN
  1. Fiona M. Fennessy
  1. Brigham and Women's Hospital, Boston, MA
  1. Robert J. Gillies
  1. H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
  1. Wie Huang
  1. Oregon Health and Science University, Portland, OR
  1. Michael A. Jacobs
  1. Johns Hopkins University, Baltimore, MD
  1. Paul E. Kinahan
  1. University of Washington, Seattle, WA
  1. Charles M. Laymon
  1. University of Pittsburgh, Pittsburgh, PA
  1. Hannah M. Linden
  1. University of Washington, Seattle, WA
  1. David A. Mankoff
  1. University of Pennsylvania, Philadelphia, PA
  1. Lawrence H. Schwartz
  1. Columbia University, New York, NY
  1. Hyunsuk Shim
  1. Emory University, Atlanta, GA
  1. Richard L. Wahl
+ Author Affiliations
  1. Johns Hopkins University, Baltimore, MD
The purpose of this correspondence is to alert cancer center directors and their associated biomedical imaging programs about recent progress in quantitative imaging as a means to predict and/or measure tumor response to drug or radiation therapy, a development that is critical to (for example) implementing adaptive therapy trial designs. There have been a number of initiatives in this area by the National Cancer Institute (NCI) and the Radiological Society of North America (eg, the Quantitative Imaging Biomarkers Alliance1) to advance quantitative imaging methods that can be readily adopted by the NCI-funded cancer centers. These efforts can potentially position the NCI-funded cancer centers to collectively share resources to implement quantitative imaging methods into clinical trials. One substantive step cancer centers could take is to implement a formalized and systematic process to collaborate with radiology departments and imaging research centers to integrate advanced imaging into the clinical trial development process. As a result, oncology trial designs would be more likely to include appropriate imaging measures to provide accurate staging, intratherapy assessment, and follow-up evaluations.
By way of background, there is a growing need in both clinical practice and clinical trials for quantitative methods that can sensitively and accurately detect—and even predict—the response of tumors to therapy. Newly developed imaging techniques are showing promise by offering quantitative decision support results with only minimally invasive and user-independent methods. This capability necessarily involves advanced imaging methods that go beyond traditional radiography (eg, computed tomography or anatomic magnetic resonance imaging). Indeed, advanced imaging may provide more clinically relevant information—particularly in the context of targeted molecular therapeutics, the initial activities of which may be cytostatic, rather than cytotoxic. In addition, inflammatory responses to radiation and vascular disruptive agents have also challenged response assessment, with determination of progression versus pseudoprogression being particularly problematic.
The NCI has long recognized the potential of advanced quantitative imaging to provide minimally invasive biomarkers related to the underlying pathophysiological status of cancer, and to monitor the effects of targeted cancer therapies.2 Because advanced imaging methods are likely to provide an early indication of therapeutic efficacy, and can be repeated throughout a course of therapy to provide frequent monitoring of response, they are likely to play a fundamental role in guiding patient management in the future.3 As directors of NCI-designated cancer centers, you are uniquely positioned to initiate the important step of incorporating advanced imaging to improve the quality of clinical trials and, ultimately, patient care.
To expedite the development of advanced imaging biomarkers, the NCI established the Quantitative Imaging Network (QIN) in 2008 with its mission to “improve the role of quantitative imaging for clinical decision making in oncology by the development and validation of data acquisition, analysis methods, and tools to tailor treatment to individual patients and to predict or monitor the response to drug or radiation therapy.”4 QIN goals are to provide technical resources to support the incorporation of advanced imaging into clinical trials. For example, technical and methodologic developments in quantitative dynamic positron emission tomography and comprehensive multiparameter magnetic resonance imaging within the QIN have led to the maturation of a number of advanced imaging techniques to the point that they can be readily deployed in clinical trials. Specific examples include data collection methods for positron emission tomography/computed tomography that are minimally dependent on the different commercial imaging platforms, and methods of analysis that minimize operator dependence. In addition, NCI and QIN members are supporting public resources to permit data and tool sharing across the NCI-funded cancer centers to help develop a pipeline for greater adoption of more standardized clinical protocols.
In light of these developments, the Executive Committee of the QIN (Appendix Fig A1, online only) recommends that reinvigorated steps be taken to incorporate quantitative imaging methods into clinical trials whenever appropriate. Within an individual cancer center, we stress the importance of establishing an image analysis and data management laboratory that provides advanced imaging support from trial design to data analysis. Building this infrastructure requires establishing a strong collaboration among the cancer center leadership, the clinical trials office, the department of radiology and biomedical imaging research institute, and oncologists (radiation, medical, and surgical). This often includes expertise in bioinformatics, computer engineering, medical physics, and statistics that are naturally coordinated through the cancer centers. A mature knowledge base now exists (eg, the members of the QIN) to guide those who are interested in establishing such a program, and we encourage you to consider taking the first steps toward establishing a quantitative imaging program for cancer clinical trials at your institution.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) and/or an author's immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: Paul E. Kinahan, PET/X (U) Consultant or Advisory Role: James M. Mountz, ICON Medical Imaging; Thomas E. Yankeelov, Eli Lilly (C); Lawrence H. Schwartz, BioClinica (C), ICON Medical Imaging (C); Richard L. Wahl, Nihon Medi-Physics (C), Cellectar (C) Stock Ownership: None Honoraria: Thomas E. Yankeelov, Eli Lilly; David A. Mankoff, GE Healthcare, Philips Medical, Siemens Medical Research Funding: Paul E. Kinahan, GE Healthcare Expert Testimony: None Patents, Royalties, and Licenses: Richard L. Wahl, Naviscan Other Remuneration: None

ACKNOWLEDGMENT

Supported in part by National Institutes of Health Grant No. U01 CA140230 (J.M.M.) and P30 CA047904 (to University of Pittsburgh).

Appendix

Fig A1.

Fig A1.
Geographic locations of the 19 network centers of the participating institutions in the Quantitative Imaging Network (QIN). The Executive Committee of the QIN primarily consists of principal investigators from the National Cancer Institute (NCI) –funded U01 programs at each of the centers. The QIN grew from the NCI program announcement “Quantitative Imaging for Evaluation of Responses to Cancer Therapies.”4 The network is designed to promote research and development of quantitative imaging methods for the measurement of tumor response to therapies in clinical trial settings, with the overall goal of facilitating clinical decision making. Projects include the appropriate development and adaptation/implementation of quantitative imaging methods, imaging protocols, and software solutions/tools (using existing commercial imaging platforms and instrumentation) and application of these methods in current and planned clinical therapy trials. UCLA, University of California, Los Angeles; UCSF, University of California, San Francisco.

REFERENCES

  1. 1.
  2. 2.
  3. 3.
  4. 4.

Sketching the Human Experience

  1. Kruti Hawkins,Casey L. O'Brien andJustin L. Dwyer
Author Affiliations
  1. From the La Trobe University, Melbourne; St Vincent's Hospital, Melbourne; The University of Melbourne, Melbourne, Australia.
  1. Corresponding author: Kruti Hawkins, MA, Psychosocial Cancer Care, St. Vincent's Hospital, P.O. Box 2900, Fitzroy, Victoria, Australia 3065;  e-mail: krutikhatri24@gmail.com.
“I've always wanted to draw the human body. Can you teach me?” Paul asked before I had the chance to put down my sketchbook and pencils. “It's the most difficult thing to draw” he continued, leaving me to hurriedly introduce myself as the art therapy student in the psycho-oncology department.
The psychologist in our department had referred Paul in the hope that art therapy might offer him a way to express how he felt about his recent paralysis, feelings that he had only hinted at during their sessions. Art therapy is a powerful process that uses visual symbols created in the therapy to work through feeling states and experiences not easily articulated. It is especially helpful for those limited by language or held back by the ferocity of their distress.1 A growing body of evidence in cancer care reveals improvements in symptoms such as depression, anxiety, pain and fatigue, the benefits particularly apparent where the treatment is delivered by a qualified art therapist.2,3 Moreover, art therapy can reestablish a connection with oneself as coherent and enduring, a process described in the qualitative literature as “meaning making” and of special importance in cancer care where a disorienting sense of personal disintegration frequently accompanies diagnosis.4 My position in the psycho-oncology service acknowledged these benefits to patient care, and I was keen to meet Paul after I heard his story.
Paul was a single man in his fifties who worked as a health professional. He had a strong-willed and resilient personality bolstered by his athletic physique, which he had mobilized in his battle against lymphoma 9 years earlier. After many years of good health, he had been admitted to the hospital with relapsed lymphoma complicated by lower limb paralysis. In keeping with his usual coping strategy, he threw himself into his rehabilitation, insisting on “double doses” of physical therapy. He similarly embraced a psycho-oncology referral when his treating team anticipated he might need support adjusting to his paralysis.
At our first meeting, Paul struck me as friendly and approachable. His casual clothes and collegial manner suggested that he saw himself as a fellow professional rather than a patient. The process of art therapy privileges the patient's voice in guiding the work and understanding the symbols created. At Paul's bidding we began with technical aspects, using light and shadow to sketch real-life objects (Fig 1). After several quite structured sessions in which little emotionally salient material surfaced, Paul admitted to some frustration that his drawings did not emerge as he imagined. This dissatisfaction with the work he produced was apparent in his repetitive titling of each piece with “practice.” Our first sessions coincided with a plateau in his physical progress where his paralysis seemed permanent. In team discussion it became clear that Paul greatly valued achievement and saw himself as able to overcome any adversity with enough effort. This led him to become anxious with tasks he could not easily master, and now, confronted with an apparent stalemate in the presence of fellow health professionals, his attitude was one of self-reproach.
Fig 1.

Fig 1.
To address Paul's frustration with artistic realism, I led him towards more abstract and spontaneous art making using less constraining materials. During our eighth art therapy session, Paul experimented with acrylic paints and took pleasure in the ensuing mess, a process that can bring people into contact with the child-like aspects of themselves where emotions are less guarded.5 The colors and shapes evoked childhood memories of earning his place among his older brothers through his sporting prowess, and he lamented the loss of this physical connection through the cancer. Another piece observed from a distance symbolized a shield (Fig 2), and Paul quietly admitted “I want this shield to protect me from my illness, but……I think that I may just have to live with it.” Holding this protective visual metaphor in mind, Paul was able to safely explore his feelings about the irreversible nature of his illness, a process Moon described as “arting out” that empowers the patient to reframe their story by altering or even painting over certain aspects.6 Paul's art helped to connect the cancer to his life story while offering a buffer against intolerable feelings that his body, and thus he himself, had failed in some way.
Fig 2.

Fig 2.
The following week Paul was more confident in mixing colors, creating lines and shapes. The art making facilitated a freer dialogue between us as Paul continued to work through his feelings about going home in a wheelchair, even discussing the necessary accommodations for a return to work. The last painting Paul made that session was a simple one with different colored lines stretching across the page (Fig 3). The slick feeling of the paint as it drew out his unhurried lines offered him a moment of quiet contemplation. There did not seem to be any need to speak, and the need to get it right that I had seen in our earlier sessions was gone. Having these quieter, reflective moments with Paul emphasized the role of art therapy in providing freer, “breathing spaces” within the supportive care environment, benefits previously noted in the literature.2
Fig 3.
View larger version:
Fig 3.
A fearful anticipation built as the date of Paul's discharge came closer. On the penultimate day, Paul had an acute myocardial infarction. In the context of his advanced cancer, a decision was made that there would be no further escalation of therapy. At our ward round the next day Paul appeared traumatized by the utter failure of his body and a brush with death that the medical decision making seemed to accentuate. We were quite struck by the sudden change in his mood and loss of all vitality.
Over the following days he drifted in and out of consciousness. In more lucid moments I sat beside him drawing undulating lines on a pad as he spoke openly about death and afterlife without any trace of fear. I wondered how Paul's feelings about death, though not always verbalized, had colored his art therapy and how close they had sat to the surface. Yalom poignantly describes death as something that “whirs continuously beneath the membrane of life and exerts a vast influence on experience and conduct.”7(p29) I ended the session with my customary promise of another time next week, and his cryptic response of “I'll see you when I see you” stayed with me.
Paul died a few hours later from another myocardial infarction.
Two months later, a thank you card arrived from Paul's mother with a photograph of Paul sitting upright, dressed in a white shirt and a tie looking every bit the confident professional. After commenting on how different Paul looked in this photograph, we realized that we had interpreted his initial demeanor as defensive bluff rather than a true depiction of who he was. With this photograph in mind I now see a story in our work that mirrors and continues Paul's story. It begins with a feeling of insecurity about one's position in the world, and the need for a safe place in which to practice and learn from mistakes. A gradual sense of acceptance followed that recalled the early sporting achievements that cemented Paul's standing among his siblings and his peers. The focus on anxiety and coping within the hospital obscured a broader view of his life, and the photograph opened my eyes to this rich hinterland. Paul taught me at an early stage in my career that art therapy is a synergistic process that goes far beyond being “taught” to draw as requested on our first meeting. The rewards of this experience arose from the collaborative therapeutic connection we shared. I realized that that although he had never sketched the human body, together we had both worked to sketch his human experience.

Changes in Osteoblastic Activity in Patient Who Received Bortezomib as Second Line Treatment for Plasma Cell Myeloma: A Prospective Multicenter Study

 

KS Eom, SJ Kim, JJ Lee, C Suh, JS Kim, SS Yoon… - BioMed Research …, 2014
... pain in terms of total VAS after cycle 4, the proportion of patients who reported severe bone pain
(VAS ) decreased ... M. Kaiser, C. Müller et al., “Bortezomib increases osteoblast activity in myeloma
patients irrespective of response to treatment,” European Journal of Haematology ...

Friday, June 27, 2014

Modern mammography screening and breast cancer mortality: population study


BMJ 2014; 

  1. Harald Weedon-Fekjær, researcher123,
  2. Pål R Romundstad, professor of epidemiology1,
  3. Lars J Vatten, professor of epidemiology14
Author Affiliations
  1. Correspondence to: H Weedon-Fekjær harald.weedon-fekjar@medisin.uio.no
  • Accepted 19 May 2014

Abstract

Objective To evaluate the effectiveness of contemporary mammography screening using individual information about screening history and breast cancer mortality from public screening programmes.
Design Prospective cohort study of Norwegian women who were followed between 1986 and 2009. Within that period (1995-2005), a national mammography screening programme was gradually implemented, with biennial invitations sent to women aged 50-69 years.
Participants All Norwegian women aged 50-79 between 1986 and 2009.
Main outcome measures Multiple Poisson regression analysis was used to estimate breast cancer mortality rate ratios comparing women who were invited to screening (intention to screen) with women who were not invited, with a clear distinction between cases of breast cancer diagnosed before (without potential for screening effect) and after (with potential for screening effect) the first invitation for screening. We took competing causes of death into account by censoring women from further follow-up who died from other causes. Based on the observed mortality reduction combined with the all cause and breast cancer specific mortality in Norway in 2009, we used the CISNET (Cancer Intervention and Surveillance Modeling Network) Stanford simulation model to estimate how many women would need to be invited to biennial mammography screening in the age group 50-69 years to prevent one breast cancer death during their lifetime.
Results During 15 193 034 person years of observation (1986-2009), deaths from breast cancer occurred in 1175 women with a diagnosis after being invited to screening and 8996 women who had not been invited before diagnosis. After adjustment for age, birth cohort, county of residence, and national trends in deaths from breast cancer, the mortality rate ratio associated with being invited to mammography screening was 0.72 (95% confidence interval 0.64 to 0.79). To prevent one death from breast cancer, 368 (95% confidence interval 266 to 508) women would need to be invited to screening.
Conclusion Invitation to modern mammography screening may reduce deaths from breast cancer by about 28%.

Introduction

The efficacy of mammography screening was tested in randomised trials in the 1970s and 1980s.1 More than 10 years ago, an overview by the World Health Organization indicated that mammography screening may reduce mortality from breast cancer by 25%.2 However, the methods used by some of the original trials have been criticised, and a report from the Cochrane Collaboration considered the estimates of mortality benefit from many of those trials to be invalid.3 4 Recent advances in modern chemotherapy and adjuvant treatment have improved the survival of women with breast cancer,5 6 and progress in treatment has led some investigators to question the need for early detection of breast cancer by mammography screening.7

Updated studies are clearly needed, but new randomised trials are not realistic and evaluations of modern screening require accurate information about screening history compared with the timing of breast cancer diagnosis, as well as precise and long term follow-up of mortality. Many observational studies have assessed breast cancer mortality associated with mammography screening, but results have been inconsistent, ranging from no effect to improved mortality benefits than those obtained in the original screening trials.8 9 10 11 12 13 14 15 16 Norway provides an ideal setting to study the effects of mammography screening,17 18 but in two previous Norwegian studies that used an incidence based mortality approach, only fractions of the available and potentially important data were included in the analyses.8 11
We analysed data from all women in Norway who were aged 50 to 79 during 1986 to 2009, the period during which the Norwegian mammography screening programme was gradually implemented (1995-2005). We compared the rates of deaths from breast cancer among those who were invited to screening (with a potential for screening effect) with those who had not been invited to screening before breast cancer was diagnosed (without a potential screening effect).

Methods

The Norwegian breast cancer screening programme

The Norwegian breast cancer screening programme was initiated by the Norwegian government in 1995 and introduced in four counties in November of that year. The programme was gradually implemented in the remaining 15 counties, with complete national coverage achieved in 2005. The screening programme is administered by the Norwegian Cancer Registry, and all women aged 50-69 are invited to screening every two years. Two view screening mammograms are taken in breast diagnostic centres exclusively dedicated to the diagnosis and treatment of breast diseases. Two readers independently evaluate the mammograms, and women whose mammograms require further consideration are referred for diagnostic mammography, and, if necessary, for additional clinical evaluation. Attendance for screening has been relatively stable, at approximately 76%.
The reporting of cancer to the Norwegian cancer registry is mandatory, and diagnostic information is obtained separately from clinicians, pathologists, and death certificates, with 0.2% of all cancers ascertained only from death certificates.18 The unique 11 digit personal identification number of each citizen allows follow-up for cause specific mortality, which is provided by Statistics Norway. We used data used on individual dates of screening invitations, dates of breast cancer diagnoses, and dates of breast cancer deaths.

Study participants

We included all Norwegian women aged 50 to 79 years between 1986 and 2009. The dynamic nature of inclusions and exclusions to the cohort by age means that women contributed person years of observation from the age when they were eligible to be observed until they were censored from further observation, either because of death (from breast cancer or other causes), they had reached 80 years of age, or they had reached the end of follow-up (31 December 2009). The actual number of participating women in dynamic cohorts will vary for each given year, but in 2000 a total of 638 238 women were under observation, and the study included 15 193 034 person years of observation.
The first invitation to take part in the Norwegian mammography screening programme depended on the woman’s county of residence and her birth cohort, but from 1995 to 2005 all women in the country aged between 50 and 69 were gradually invited to participate. The supplementary figure shows the mortality rate of breast cancer in Norway (1986-2009) among women aged 50-79 and the period during which the mammography screening programme was implemented in Norwegian counties (1995-2005).

Statistical analysis

In the analysis, we regarded women with a diagnosis of breast cancer after the invitation date to mammography screening as being exposed to screening, and women with a diagnosis of breast cancer before the invitation date as being unexposed to screening. To assess the effect of invitation to screening we compared incidence based breast cancer mortality among women invited to screening (intention to screen) with those not invited, under the counterfactual assumption that if invited women had not been invited, their risk of death from breast cancer would be similar to that of women who had not (yet) been invited.
To account for differences in age and effects of birth cohort and calendar time, we used a multivariable Poisson regression model. To achieve optimal flexibility in the statistical adjustments, we used natural splines to allow for non-linear variations in age, period, and cohort effects (see R code in supplementary appendix d). In sensitivity analyses, we also tested the statistical models without smoothing of period and cohort effects, and we used age and period models without the birth cohort variable to limit the potential for colinearity. In addition because the rates for breast cancer mortality differed slightly between counties, we adjusted for county of residence. In the Poisson regression analysis we took competing causes of death into account by censoring from further follow-up those women who died from causes other than breast cancer.
The time interval from diagnosis until death from breast cancer varies from a few months to many years, and therefore we carefully separated breast cancers diagnosed in women before invitation to first screening from those diagnosed after invitation to first screening to avoid misclassification of breast cancer deaths according to exposure status (invited or not invited before diagnosis). At the beginning of the implementation period in each county almost all deaths from breast cancer occurred among women with a diagnosis before screening invitations started. Over time a gradually higher proportion of breast cancer deaths could be attributed to breast cancers diagnosed after women had been invited to screening. We accounted for this dynamic change by estimating the proportion of the observed breast cancer mortality that was expected to be due to cancers diagnosed after the first screening invitation, assuming that invitations to screening had no effect on breast cancer mortality. In the estimation we used the interval from diagnosis until death from breast cancer among women (in 10 year age groups) who had not yet been invited. Thus we avoided the lead time bias that would have occurred if we had used the interval from diagnosis until breast cancer death among invited women. As an offset in the statistical modelling we added to the model the estimated proportion of breast cancer deaths that was attributed to breast cancers diagnosed after screening invitation, thus adjusting the expected breast cancer mortality for each group according to invitation status (see supplementary appendix for formulas and implementation).
The individual data were precisely split according to exposure status, with separation of invited and not yet invited women within each age-period-county combination during the implementation period of mammography screening in each county. Thus the analysis compares two groups, using detailed information, with adjustment for differences by age, period, cohort, and county. Using this dynamic modelling approach we could utilise all the available individual data in the analysis, without the limitation of selected comparison groups, as in previous studies using data from Norway.8 11
To account for all random statistical uncertainty, we used bootstrap replications and calculated 95% confidence intervals for the estimated effects associated with invitation to mammography screening. To test the robustness of the results, we repeated the analyses under a broad range of statistical assumptions, including a pure age-period-county model, different smoothing of age and period effects, different choice of reference period and reference age groups, and varying the effect of screening invitation by calendar year.
Since screening effects are likely to vary by age and time since screening, these variables may not be balanced between comparison groups. In a separate sensitivity analysis we therefore weighted the screening variable based on the simulated screening effects by age and time since screening provided by the CISNET (Cancer Intervention and Surveillance Modeling Network) Stanford simulation model.19 20 21
We also calculated the number of women who need to be invited to screening to prevent one death from breast cancer. The number relates to Norwegian women in the age group 50-69 years in 2009. Firstly, we assumed an effect of screening invitations corresponding to the reduction in breast cancer mortality that we observed in our data. Secondly, we used the observed breast cancer mortality in Norway in 2009 and adjusted for the observed reduction in mortality associated with invitation to mammography screening. Thus we could estimate the likely breast cancer mortality in the absence of screening. Thirdly, we used the observed all cause mortality in Norway in 2009 and calculated the probability that women who were first invited at 50 years of age were alive at a given age (51, 52, 53, and so on up to 79 years of age). Effects of screening are likely to vary by age and by time since screening, but these effects are difficult to estimate empirically owing to a limited number of observations. Therefore we applied the CISNET Stanford model scaled to the observed Norwegian breast cancer mortality reduction to estimate the likely screening effects by age and time since screening. In the CISNET Stanford model, smaller tumour size and lower clinical stage at diagnosis resulting from an earlier diagnosis is assumed to explain potential reductions in breast cancer mortality. By combining the breast cancer mortality rates in Norway in 2009, the estimated reduction in breast cancer mortality, and the CISNET Stanford simulation model, we calculated the absolute reduction in breast cancer mortality that could be attributed to screening within each age group. After combining the estimated reduction in breast cancer mortality with the probability of reaching a certain age, given the observed all cause mortality in 2009, we could summarise the data and estimate the probability that one death from breast cancer could be avoided by being invited to mammography screening. Thus the inverse of that probability yielded the number of women aged 50-69 who need to be invited to screening to prevent one death from breast cancer during their lifetime. (See the spreadsheet in the supplementary appendix for further details.)
All statistical analyses were conducted using the R statistical package22 (see the supplementary appendix for details of the calculation).

Results

During 15 193 034 person years of observation, breast cancer deaths occurred in 1175 of the women invited to mammography screening and in 8996 of the women who were not invited. After adjustment for age, birth cohort, county of residence, and underlying national trends in breast cancer mortality, the mortality rate ratio associated with being invited to screening was 0.72 (95% confidence interval 0.64 to 0.79), indicating a 28% lower risk of death from breast cancer in women who were invited for screening compared with women who were not invited (table 1).


Mortality rate ratio of breast cancer among women aged 50-79 who were invited or not invited (reference) to the Norwegian mammography screening programme, 1986-2009
After the invitations to screening had ended (at 70 years of age), we found that the benefit for breast cancer mortality persisted (table 2), but with a possible gradual decline by time since screening (P for trend 0.35). Thus, between five and 10 years after the invitations to screening had ended, the adjusted mortality rate ratio was 0.79 (95% confidence interval 0.57 to 1.01).
Breast cancer mortality rate ratios associated with invitations to mammography screening programme in relation to screening period
To test the robustness of the findings we repeated the analyses under different statistical assumptions (sensitivity analyses), including leaving out the cohort effect, using non-smoothed period effects, and weighting the screening effect by age and time since screening (table 3). However, these additional procedures did not substantially influence the estimated effect and yielded mortality rate ratios ranging from 0.71 to 0.75. By introducing a period dependent screening effect, the results suggested a possible increasing reduction in breast cancer mortality by calendar year, but that analysis had limited statistical power (P=0.29).
Breast cancer mortality rate ratios associated with invitations to mammography screening programme in alternative (sensitivity) analyses under different statistical assumptions
We also estimated how many women between 50 and 69 years of age would need to be invited to mammography screening to prevent one death from breast cancer, based on the estimated effect on breast cancer mortality that we found in this study and the observed all cause and breast cancer specific mortality in Norway in 2009. Overall, 368 (95% confidence interval 266 to 508) women in the age group 50-69 years would need to be invited to biennial mammography screening to prevent one death from breast cancer during their lifetime (see supplementary appendix table for calculation).
Based on the estimated effect of screening invitations (table 1), we also estimated the effect of mammography screening among women who actually attended (approximately 76% of invited women). Thus attendance may be associated with a 37% reduction in breast cancer mortality (0.28/0.76=0.37), and 280 women would need to attend screening to prevent one death from breast cancer (368×0.76=280).

Discussion

In this study, based on more than 15 million person years of observation, we estimated that invitation to mammography screening was associated with a 28% reduced risk of death from breast cancer compared with not being invited to screening, and that 368 women need to be invited to screening to prevent one death from breast cancer. The screening effect persisted but seemed to be gradually reduced after invitations to screening had ended. The large population and long follow-up of mortality provided precise estimates and suggests that chance is unlikely to explain the main findings of the study.

Strengths and limitations of this study

Modern treatment has reduced the number of deaths from breast cancer,5 6 20 and in the analysis we took into account the effect of changes in nationwide treatment by adjusting for trends in national breast cancer mortality. To improve and standardise breast cancer treatment across Norway, clinical guidelines were implemented before mammography screening became established. Although some differences in treatment may remain, such differences are unlikely to be systematically related to mammography screening status (invited or not invited). However, breast diagnostic centres were established in parallel with the Norwegian mammography screening programme and resulted in centralisation of care for women with breast cancer. We cannot exclude the possibility that organisational aspects of care related to these centres may have contributed to some of the decrease in breast cancer mortality that we observed after invitations to screening.
Before the national screening programme, mammography screening was available at private radiology institutions, and many women had mammograms for clinical or screening purposes.23 Assuming that screening activity was highly frequent, an increase in breast cancer incidence and some increase in ductal carcinoma in situ would be expected to precede the implementation of the screening programme. However, in contrast with this expectation, no clear increase in incidence was observed before the national mammography screening programme was established.24 25 Therefore it seems unlikely that screening activity before the national programme could have substantially influenced and attenuated the results of the present study.

Comparison with other studies

In some studies, women who attended for mammography screening were compared with women who did not attend. In a review of studies that compared breast cancer mortality in women who did and did not attend for screening programmes in Europe, attendance was estimated to be associated with a breast cancer mortality benefit of 31%.12 In a recent Norwegian study, attendance was associated with a mortality benefit of 43%.26 Attendance does, however, imply an active choice, and women who choose to attend may differ from those who choose not to attend in ways that may lead to biased estimates of the screening effect.27 To prevent such a bias we analysed the data according to whether women were invited or not invited to screening (intention to screen).
Two previous prospective studies in Norway also used incidence based mortality to assess the potential benefits of mammography screening.8 11 In contrast with the present study, those studies restricted the analyses to selected comparison groups (birth cohorts or counties) and reported moderate mortality benefits (10% and 11%, respectively) with low precision (wide confidence intervals). In the study by Kalager and colleagues,8 the low precision was due to a short follow-up of mortality, which ended in 2005. Another limitation was that instead of using detailed information about the actual age of the women and date of screening invitations in each county, the investigators used broad categories that probably resulted in some misclassification of exposure (screening or not, in relation to diagnosis). Also, the investigators included breast cancer deaths based on time of diagnosis and not on the actual time of death. Therefore, women with an earlier diagnosis as a result of screening were more likely to be included as invited cases (deaths) than were unscreened women, whose diagnosis was not forwarded by the screening facility. As a consequence, the association of screening invitation with breast cancer mortality is likely to be diluted in that study. In a separate analysis, we limited our data to more closely match that of Kalager and colleagues’,8 and found a reduction in breast cancer mortality of 14% associated with an invitation to screening, which is slightly stronger than the effect reported by the investigators using even fewer detailed data. In the study by Olsen and colleagues,11 effects of mammography screening were only assessed for selected birth cohorts and only in the four counties where the screening programme was first introduced. Therefore the investigators missed any effect in the remaining birth cohorts, as well as in the other 15 Norwegian counties.
In a recent comprehensive review of European studies,13 two (from Denmark and Finland) that used incidence based mortality were identified as particularly reliable.9 28 According to those studies, the mammography screening programme in Copenhagen was associated with a 25% reduction in breast cancer mortality,8 and in Finland, a reduction of 24% was attributed to the recently established mammography screening programme. The Finnish study, however, was associated with substantial statistical uncertainty.28
It has been questioned whether the evidence from the original screening trials is still relevant within the context of modern treatment for breast cancer,5 6 and with generally greater awareness of the disease among women. Our findings, as well as the results from the Danish and Finnish studies,9 28 suggest that the relative effectiveness of mammography screening is comparable to the efficacy reported from some of the randomised screening trials.2 29
In our study the estimated benefit for breast cancer mortality (28%) associated with invitation to mammography screening indicates a substantial effect, but evolving improvements in treatment will probably lead to a gradual reduction in the absolute benefit of screening.5 20 30 Based on breast cancer mortality data from 1980, the Euroscreen Working Group estimated that 111 to 143 women would need to be screened to prevent one death from breast cancer.31 Using breast cancer mortality data from 2009, we estimated that 368 women in the age group 50-69 years would need to be invited to screening to prevent one death from breast cancer during their lifetime. Our higher number is partly attributable to different assumptions about the duration of the effect of screening and partly attributable to lower breast cancer mortality in the absence of screening. The secular decline in breast cancer mortality caused by progress in treatment is substantial, and one consequence of further improvements in treatment is that increasingly more women will need to be invited to mammography screening to prevent one death from breast cancer.
Instead of using individual screening information (incidence based analysis), other researchers have related the timing of introducing mammography screening to time trends in breast cancer mortality.10 12 In these studies, breast cancers that were diagnosed before screening cannot be reliably distinguished from screening detected cancers. In a separate analysis of our data, we disregarded individual information about the time of diagnosis, and similar to studies using mortality trend analysis, we also found no association of the time that mammography screening was implemented with breast cancer mortality (data not shown). This illustrates how important it is to properly separate breast cancers according to screening status at diagnosis, otherwise any effect of screening will be diluted and cannot be attributed to screening.32 Therefore, incidence based mortality and detailed screening status are necessary requirements for an appropriate assessment of the effectiveness of mammography screening.32