NOCEBO EFFECT: WORDS AND PAINS

WHEN PREDICTION RHYMES WITH CURSE

By Annette Lexa, PhD Toxicology
Regulatory Toxicologist-Environmental Health Risk Assessor Expert (Eurotox)

A medicine that neglects the link between body and mind

Modern medicine maintains the idea that it is a rational, objective practice, resulting from a scientific approach, in constant progress and in which belief does not enter into account. It relies more and more on state-of-the-art technical tools, on computers, on statistics... It is based on the reductionist postulate that therapeutic activity is purely a molecular pharmacological activity, targeted on the diseased area (by replacing, preventing, regulating or stimulating the synthesis or release of an endogenous molecule).

Medication or therapeutic act is administered to a biological body that is supposed to be "inert", and ignores patient's living body, much like adding oil to an engine or tightening a bolt. It relies on measurement of biological parameters, using standardized anatomical-pathological criteria to diagnose or evaluate effectiveness of a treatment. And it often only addresses an effect, a consequence, but rarely the root cause.

This system of thought has made possible to make great discoveries and achieve major advances (pain, infections, surgery...). But it has also distanced us from common sense, pragmatism and the obvious. Our long dualistic tradition, inherited from Descartes, has separated body and mind and this separation maintains confusion: emotions, thoughts would have no consistency, no biological reality (if it is not by the trace of a nervous influx passage) and no influence on biological body.

This conception of the body suggests that the "spirit" would be an entity separate from the body and would have no connection with the body. This is one of the paradoxes of scientism.

Yet it is science itself that has confirmed what we have always known, that body and mind are intimately intertwined, with mind influencing body and body influencing mind, in a constant back and forth.

The placebo effect conveys hope

Medicine has introduced the placebo effect in clinical trials to evaluate therapeutic efficacy, but continues to largely ignore and underestimate this effect for ethical, dogmatic and economic reasons.

The placebo effect, which has been known for a long time, has often been ridiculed. It remains insufficiently studied for its therapeutic potential. All we know is that it acts by influencing physiological defense mechanisms of the body (pain, depression, Parkinson's disease...), brain secreting endogenous substances which in turn are capable of influencing pain circuits for example. It can even cause release of dopamine in Parkinson's patients with a dopaminergic deficit.

 But to this day, the initial mechanism (belief, emotion) that led to triggering the biochemical pathway, that ultimately results in the production of dopamine, remains a mystery to science.

And if the placebo effect, whose origin is still poorly known, is that of an object that conveys hope, the nocebo effect is even more mysterious.

 When prediction rhymes with curse 

The definition of the nocebo effect is what causes the disease by anticipation of the disease in a favorable emotional context. The subject expects a well-defined negative event via social, media, professional, popular messages, etc., and this event will occur. Of course, not everyone is sensitive to this nocebo effect. It will depend on mental state, the person's inner world, his or her way of being in the world, beliefs, capacity for self-analysis, time and social context in which this person lives.

 This is the case of voodoo death described by the first anthropologists, or closer to our societies, collective hysteria or categorization of pathologies (you are pre-menopausal, bipolar, pre-hypertensive, your child is dyslexic, he has an attention disorder with hyperactivity ...).

The nocebo effect is based on 3 main mechanisms of the mind:

  • a suggestion: negative messages and attitudes from caregivers, autosuggestion,
  •  conditioning and belief,
  •  symbolic representation: white coat effect, collective symbolic representations.

I believe, you believe, we believe... 

We have forgotten how much we are symbolic animals. Animals because we are gifted with reflexive learning abilities, symbolic because we need strong representations and signs that make sense.

We are capable of autosuggestion and suggestion (Coué method, hypnosis...), capable of mental manipulation (Mesmer's tub and magnetism, voodoo death...) and we neglect to what extent medical visit, white coat and red or blue pill, imaging devices have replaced these curious rituals which seem to us to come from another time and seem ridiculous. We have forgotten how reality is constructed by our minds and that we all need to believe and convince ourselves.

The American philosopher Charles Sanders Peirce helps us to understand how our beliefs, such as the belief that "the earlier a cancer is caught, the better the chance of a cure:

  • by tenacity (repetition) which allows us to avoid wasting time, even if it means persisting in bad faith,
  • by the a priori (it's likely so it must be true, even if it is not demonstrable), this method dispenses with any effort,
  • through the use of authority argument (intellectual manipulation, emotional extortion, physical coercion) which allows to organize crowds by discharging them from doubt and reflection,
  • by scientific approach, which is more demanding but allows for criticism of method and results.

The play "Doctor Knock or the triumph of medicine" by Jules Romain is a perfect example of the effect of convictions on health. He denounces the manipulation of a medicine that has become so powerful that it transforms all healthy people into patients who ignore themselves. Yet this dated comedy is totally modern, since today we are witnessing the creation of diseases and pre-diseases everywhere (disease mongering) and everyone wins... except the healthy individual surrounded on all sides (and still amazed to be alive in the face of so many diseases) and the real patient that an overwhelmed medicine ends up not being able to treat properly, because of an inflation of non-patients and pre-diseases cluttering up the waiting rooms.

The response to physiological stress: a possible explanation of nocebo effect

Faced with an anxiety-provoking situation, we have three options: suffer, flee or fight. If we cannot flee, we can fight. If we cannot fight, we are doomed to suffer. During stressful situations that we cannot avoid either by fleeing or by fighting (moral harassment for example), our body secretes chemical messengers, such as cortisol, which end up causing pathologies: immune system overload, heart attack, hypertension, psychic disorders (memory loss, fatigue, insomnia, anxiety, depression), infections and cancers due to immune system collapse, suicide, death.

The role of cholecystokinin (a neuropeptide secreted by the duodenum but also by the brain) is evoked: it provokes a reaction of pain in a person who is afraid (as well as nausea). The deactivation of the endogenous dopamine and opiate systems are also involved in pain.

A poorly known and largely underestimated effect

A search of the PubMed database in 2011 revealed that the keyword "nocebo" was indexed to 151 publications. In comparison, more than 150,000 were linked to the keyword "placebo". 2200 studies were related to the placebo effect while only 151 publications were related to the nocebo effect of which 20% were empirical studies, the rest being letters to the editor, comments, editorials and reviews.

Main tool for verifying the effectiveness of a therapy is a randomized, double-blind clinical trial. Two cohorts of patients are randomly selected (matched by age or other criteria), with the patient and the physician not knowing whether the therapy is placebo or active ingredient. It is easy to understand that it is ethically impossible for medicine to do harm (primum non nocere) and that the nocebo effect cannot be studied in a case of randomized clinical trials.

However, nocebo effect has been observed when switching from drugs to generics. And it was studied because there were economic stakes. The content of excipients changes, appearance of capsule and its color change, engraving, size, taste, speed of dissolution under the tongue ... Yet active ingredient remains unchanged. And yet  reporting rate of adverse reactions explodes.

I will harm myself, you will harm me, we will harm each other... 

There is no need to look for someone else to take responsibility for your own actions to harm yourself sometimes:

  • Narcissistic injury, humiliation, resentment, feeling of uselessness...
  •  Unconscious family loyalty
  • Birthday syndrome
  •  " Programmed " death
  •  Habit to obey, to be assisted, lack of audacity, of courage…

Medical profession bears its share of responsibility, often unconsciously or negligently, for certain words, silences, acts or gestures:

  • Diagnosis or prognosis (self-fulfilling prophecy) announced by the physician (aggravated by the obsession with the right to know enshrined in law)
  • Named, catalogued condition,
  • A caregiver's abrupt and clumsy verbal suggestion ("If you don't take my treatment, by Christmas, you're dead"),
  • Reading summaries of 'product characteristics' provided to patients (adverse reactions),
  • Wild decoding of conflicts by inexperienced therapists generating perverse and iatrogenic effects (theory of Doctor Hamer, known as "New Germanic Medicine"),
  • Routine practices, harmful relational interactions between patients and caregivers in hospital (lack of sensorial and emotional interactions, negative thinking).

Finally, at collective level, nocebo effect is well known:

  • Voodoo death, collective hysteria
  •  Hospital institutions: denial of suffering, hyperactivity to avoid patient relationship, mind/body cleavage, excessive security seeking, routine, mothering, regression
  • Risk of a nocebo effect on healthy ("ignorant" patients) and their descendants, a risk linked to personalized predictive medicine, "disease mongering" (creation of diseases), vaccine obsession, obsession with normality, screening for cancer, incurable Alzheimer's disease, etc.

Nocebo effect and breast cancer screening 

Systematic breast cancer screening, which is performed on a massive number of women in Western countries, most of whom will never die of breast cancer, poses an ethical dilemma for medical profession and community: by trying too hard to "do well", to "save lives", are we not doing the opposite?

Should the taboo that surrounds the panic fear of a de-spiritualized society, that has nothing left to offer other than over-medicalization to calm existential anxieties, continue to hold normative categories of populations hostage (such as women between 50 and 74 years of age for example)? Should economic criteria lead medical profession to betray one of its main precepts, primum non nocere?

How can a truly targeted and effective screening be carried out, while avoiding inducing a long-term nocebo effect on healthy women who may be over-diagnosed and over-treated (30% over-diagnosis, or even 50% in the case of ductal cancers in situ) and on their descendants? This is the question that professionals in healthcare system should be asking themselves today.

Because the impact of early detection of breast cancer on overall quality of life of women concerned (their well-being) is underestimated, denied and not studied at all in risk-benefit balances. And yet...

  • Chronic stress of "terror of cancer" maintained by medical profession relayed by media,
  •  Painful exams, anxiety-provoking, anxious expectations of exams and results every 2 years, misdiagnosis and diagnostic escalation,
  • Physical and psychic impacts of "preventive" breast removal, radiotherapy sessions and chemotherapy practiced in excess,
  •  Complications of surgical procedures and invasive diagnostics, nosocomial diseases,
  •  Secondary cancers induced by repeated exposure to ionizing radiation from mammograms and radiotherapy,
  • Transgenerational nocebo effect on daughters and granddaughters of women who have had breast cancer in their family.

All these consequences are not taken into account in what should be a global benefit-risk assessment in terms not only of mortality reduction, but also in terms of quality of life.

He who makes the angel makes the beast

Well-being (physical and mental) is at center of all concerns. The smallest psychological unit is set up in case of more or less traumatic events. Except apparently when it is a question of enlisting entire female populations, without any special care or precautions, in organized breast cancer screening.

This repeated examination generates chronic discomfort for a certain number of women, a discomfort that is denied and underestimated by social and medical institutions, which nevertheless try to "play it down" and trivialize it, even though it carries within itself potentially devastating individual and intimate consequences. It is somewhat as if society accepted such a price to pay, such sacrifices in name of medical progress.

We live in an anxious society, creating pathologies and spending crazy energy to repair the diseases and pollutions it has created itself (so-called diseases of civilization including diabetes, cardiovascular diseases, autoimmune diseases, cancers ...) and while our fundamental knowledge on development (and regression) of cancers by an organism is still at a standstill.

Words are a powerful tool at the disposal of modern medicine. But words are double-edged weapons that can cure but they can also kill. And medical personnel are neither prepared nor encouraged to use this formidable therapeutic tool.

Medicine, through its managerial and judicial obsession (Kouchner's law) has entered into a vicious circle that is aggressive, regressive, generating anguish and fear by creating pathologies through excessive interventionism. However, it could find its way back to the path of common sense and pragmatism, and this in interest of real patients who should be able to benefit from all the attention.

To do so, medicine could :

  • Treat both pathology and 'lived' body of patient.
  • Reclaiming a place for symbolic meaning, the word that heals and the representations of illness experienced in care practices.
  •  Ensuring symbolic effectiveness throughout diagnostic and care pathway
  • Recovering the benefits of lying (the right not to know)
  •  Avoid creating diseases by obsession with the norm
  • Discreetly practice predictive medicine based on genetic determinism, underestimating the role of epigenetics, environment and chance in the development of a pathology.
  • Above all, being pragmatic, regaining common sense (it is true what succeeds).

Finally, women, who are too docile and submissive to medical profession, should take care to reconnect with their intelligence and intuition and not rush into the spiral of screening, not to submit to it without first serenely weighing personal, intimate advantages and disadvantages that it represents for themselves.

Finally, medicine and society should ask themselves questions about meaning of life and death other than through techno-scientific answer: recognize the place of medicine, which does not make it absolute master of life and death of individuals, find meaning elsewhere without waiting, and ask medicine for more than it can give.

Beyond capture of the topic by "experts", the limits of screening open us all to exciting reflections on our fears, our fragilities, our limits, our weaknesses, our freedoms. On the meaning of our life and death. In reality, a beautiful challenge.

Bibliography 

Nocebo, la toxicité symbolique, ouvrage collectif, Collection Thériaka, remèdes et rationnalités, Jacques André Editeur, 2010, 231p.

Thierry Janssen, La maladie a-t-elle un sens, Ed Fayard, 2008, 351p.

Disease mongering ou stratégie de knock

http://docteurdu16.blogspot.fr/2009/02/disease-mongering-ou-la-strategie-de.html

The patient paradox. Why sexed-up medicine is bad for your health. Margaret McCartney.

http://docteurdu16.blogspot.fr/2015/12/the-patient-paradox-why-sexed-up.html

Raul de la Fuente-Fernandez et al. , Expectation and Dopamine Release: Mechanism of the Placebo Effect in Parkinson’s Disease, Science 10 August 2001 ,Vol. 293 no. 5532 pp. 1164-1166

Winfried Häuser et al, Nocebo Phenomena in Medicine, Their Relevance in Everyday Clinical Practice, Dtsch Arztebl Int. Jun 2012; 109(26): 459–46

Annette Lexa, Le dépistage du cancer du sein, dernier avatar de la misogynie médicale 

http://cancer-rose.fr/qui-fait-quoi/le-depistage-du-cancer-du-sein-dernier-avatar-de-la-misogynie-medicale/

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Breast cancer, night work and gender inequality in the workplace

Annette LEXA

Doctor in Toxicology EUROTOX

The topic of breast cancer risk in workplace is a neglected subject

While, according to European statistics, approximately 7% of employees in the EU work at night (7.2% in France in 2010), studies on the risk of breast cancer in the workplace receive little attention. There is little scientific literature on this subject. This lack of interest is all the more paradoxical since early detection of breast cancer in women has been the subject of extreme - even meticulous - attention by technocrats and their battalions of territorial health officials since ministerial order of 2006 .

In France, primary prevention in the workplace, improvement of working conditions, occupational medicine monitoring of women at risk (night work, flight attendants) are not part of the cancer plan or the 2006 order 3 .

However, since 2008, night shift work (with irregularly alternating periods of day and night work) has been classified by the International Agency for Research on Cancer (IARC) as a probable human carcinogen. The IARC relied on animal models and epidemiological studies of jetlagged night nurses and flight attendants. These studies show an increased risk of developing breast cancer among these women compared to those who work in conventional workplaces. Night work is thought to disrupt the internal biological clock that regulates the alternation of sleep and wakefulness. In the long term, night-time exposure to light blocks the synthesis of melatonin (sleep hormone) and this leads to a decrease of immune defenses.

It is also thought that this exposure to light could alter the expression of certain genes that can lead to formation of cancer cells. The role of melatonin on estrogens is thought to explain the excess risk of breast cancer 1 and 6. On the other hand, the role of occupational exposures in the development of breast cancer in men (the male individual) has been known for a long time (solvents, ionizing radiation).

Sociologist Marie Ménoret goes further: "Zeneca Pharmaceutical, the world's largest seller of anti-cancer drugs for breast cancer, thanks to its patent for Tamoxifen, is also a producer of pesticides and other deleterious products, known to be carcinogenic. »

According to a study conducted by the Breast Cancer Fund in 2015, the risk of developing breast cancer is increased by 50% among nurses. It is multiplied by 5 in hairdressers and beauticians as well as in the food industry. It is multiplied by 5 among dry cleaning and laundry workers and by 4 among workers in the paper and graphic arts industry as well as in the production of rubber and plastic products. The risk factors are multiple and can be added to each other: job stress is pointed out, night work and frequent time differences, ionizing radiation and chemical substances such as benzene, organic solvents, polycyclic aromatic hydrocarbons, pesticides and many endocrine disruptors poorly or not at all identified by regulations.

A professional prevention for women on the cheap 

In France 2, 61% of employees report being familiar with the CHSCT ( Committee for Safety, Hygiene and Working Conditions) but 62.7% of men compared to only 59% of women. Women are therefore less well informed. Only 35% of male employees are aware of the existence of the risk assessment document, compared with 24% of female employees. This figure must be much lower when it comes to knowledge of the individual exposure form, even though it is mandatory. Worse, being a woman doubles the probability of being overlooked by occupational medicine (probably because it considers that women consult more easily in private practice). And this situation of denial makes the recognition of breast cancer as an occupational disease even more complicated - if not impossible.

"Think Breast Cancer Politically".

The invisibility of specific risks of breast cancer for women in the workplace is a glaring demonstration of the gender inequality of occupational risk prevention policies, while millions of women in Europe, often employed in small, poorly informed and inadequately monitored workplaces, are exposed to chemicals, night shifts, ionising radiation (including in medical diagnosis) and the stress of the double day 5 , which is all the more distressing for women in single-parent families.

To paraphrase Marie Ménoret, breast cancer is definitely a political issue that feminists have totally forgotten to address. The lives of women themselves are at stake. It is urgent that the younger generations take control of it.

References

1/ Travailleurs de nuit : des travailleurs en rupture, HESA Mag n°5 , 1er semestre 2012, 31-35

2/ « Chausser les lunettes du genre » pour comprendre les conditions de travail, Laurent Vigel, HESA mag,N°12, 2e semestre 2015, 12-17

3/ Arrêté du 29 septembre 2006 relatif aux programmes de dépistage des cancers

4/ Ménoret M., 2006, « Prévention du cancer du sein : cachez ce politique que je ne saurais voir », Nouvelles questions féministes, 25(2), 32-47.

5)The average working week for women is 64 hours compared to 53.4% for men. The difference comes from unpaid domestic work (26.4 hours for women compared to 8.8 hours for men).

6/ Document pdf « Travail posté de nuit et cancers » par  M. Druet-Cabanac, Y. Aubert, D. Dumont, Consultation de Pathologies Professionnelles, CHU de Limoges

Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

Mass screening for breast cancer disregards ethical values and fundamental principles of radiation protection system

By ANNETTE LEXA, Toxicologist PhD

OCTOBER 20, 2019

Mass screening for breast cancer is a technocratic monster inscribed in the law by ministerial order.

It is supposed to be based on the 9 pillars of public health policies. In its wording itself, it flouts the principle of knowledge [1] according to which objectives and actions must take into account the best available knowledge and, conversely, knowledge must meet the need for information to enlighten decisions. However, to date no study has confirmed the effectiveness of screening, based exclusively on the dogma "the earlier a cancer is detected, the better it is cured", which has not been validated in reality as mortality has not decreased since the system was introduced more than 25 years ago.

But it is even worse. The ministerial decree strongly encourages healthy women aged 50 and over to be regularly exposed to ionizing radiation from medical imaging (mammography and synthetic tomography).

The International Commission on Radiological Protection (ICRP) has established principles and values of radiation protection in order to protect populations and individuals [2]. These major principles and values are based on the regulatory use of the linear no-threshold model, which remains a conservative but contested basis [3] in view of recent discoveries in radiobiology. This probabilistic model is based on the dose-response relationship, which postulates that the number of radiation-induced cancers varies linearly with the dose received in an irreversible and cumulative manner and "without threshold" below which an exposure could be considered as having no effect.

Each ionizing particle passing through an organism has a certain probability of hitting the DNA; each impact causes a mutation that has a probability of moving to a stage leading to the initiation of cancerous proliferation. Therefore, overall probability of observing a cancer can only increase linearly with the dose received. Today we know that there is a fundamental inequality between individuals. Each individual has his or her own specific threshold of tolerance to ionizing radiation. Delivering the same dose to all while a non-negligible fraction (5 to 20%) of population has a risk of radiation-induced cancer 10 times higher than the norm is not acceptable. [4]

What are the currently recommended doses?

The recommended doses were enacted in 1991 by the International Commission on Radiological Protection (ICRP). They are valid for entire human population and do not take into account invidual susceptibilities. The commission estimates natural irradiation (radon, telluric, cosmic) at 2.5 mSv/year, average medical irradiation at 1.2 to 2 mSv/year and civil nuclear at 0.2 mSv/year.

Not everyone is equal because there are radon regions and others are not, with radon alone representing 1.2 mSv/year.

In addition, the consumption of medical imaging procedures is exploding with 70 million procedures in France per year (3), and, again for France, the annual dose received for medical diagnosis is 1 mSv/ inhabitant/year on average but can reach 20 mSv/year according to the Academy of Medicine itself, which does not hide its concern [5]. Women undergo more than men, due to the societal obsession with the breast, an accessible but sensitive organ. In the context of breast cancer screening, a woman who is not ill and is still young can also receive a much more radiant tomosynthesis exam, in a doctor's office without being warned of the risk involved. And many women are exposed from the age of 25-30 years by careless practitioners.

For the population, the dose is limited to 5 mSv per year, the maximum tolerable lifetime dose is 70 mSv.

However, doses received during medical imaging exams can lead to an excess of this limit, without taking into account individual susceptibility. For example, the monitoring of scoliosis in young girls in the past generated a dose of 0.11 Sv to the mammary gland.

Perez A-F, et al. Low radiation doses: towards a new reading of risk assessment? Bull Cancer (2015), http://dx.doi.org/10.1016/j.bulcan.2015.03.019

Mammography generates 2 x 2 mGy images spaced 3 minutes apart. Double-strand breaks (DSB) - a source of gene instability leading to the development of cancer - appear as early as 1mGy and the effect is significant around 100-300 mGy. Radiosusceptible individuals with delayed transit of the ATM repair protein simply cannot repair or poorly repair these DSBs in less than 3 minutes, and thus DSBs accumulate during mammography. The risk is all the higher the younger woman is, the more she is unaware of her radiosusceptibility status, and the more the examination is repeated every year or every 2 years. 6] (see the bibliography of Nicolas FORAY's work).

THREE MAIN PRINCIPLES OF THE RADIATION PROTECTION SYSTEM

- The rationale that states that any decision to subject a person to even the weakest possible source of ionizing radiation should do more good than harm. A sufficient benefit must be obtained to offset any costs or negative consequences. Ionizing radiation sources should not be used if there are other alternatives (e.g., no radiography if similar results are obtained with an ultrasound, it is up to physician and radiologist to make the trade-off between benefit and risk, the benefit a person receives from examination must outweigh radiological risk). Practitioners remain primarily responsible for justifying procedures they request or perform.

- The optimization of exposures to these radiations which must be at the lowest possible level;

- The limitation stating that individual exposures must not exceed dose limits recommended by the ICRP in order to avoid occurrence of stochastic (= random) effects. Each country defines regulatory limits based on ICRP recommendations.

ESSENTIAL ETHICAL VALUES UNDERLYING THE RADIATION PROTECTION SYSTEM (2) [7] [7]

Beneficence and non-maleficence 

Beneficence means doing good, and non-maleficence means not doing harm. These two related ethical values have a long history in moral philosophy, going back to the Hippocratic Oath, which requires a physician to do good and avoid harm. The use of radiation, although coupled with certain risks, can undoubtedly have desirable consequences, such as improved diagnosis and cancer therapy in medicine. But these must be weighed against harmful consequences. One of the main challenges in beneficence and non-maleficence is how to measure  benefits versus harm and risks involved. Moreover, such an assessment must be done in a transparent manner.

Prudence

Prudence is the ability to make informed and carefully considered choices in full knowledge of the implications and consequences of actions. It is also the ability to choose and act on what is in our power to do and not do.

Justice 

Justice is generally defined as fairness in distribution of advantages and disadvantages: fair compensation for losses (reparation), fairness of rules and procedures in decision-making processes. First, the principle of fairness in situations reflects personal circumstances in which individuals are involved. This is the role of regulatory dose limits, of compliance with protocols in order to reduce exposures in individuals subjected to the same radiation exposure (see the Toul irradiated persons case).

Inequality can also be seen as the inequity between the doses received by screened non-sick women, especially the youngest, compared to non-sick and unscreened women who are therefore less irradiated.

Dignity

Dignity is an attribute of human condition. It means that every individual deserves unconditional respect, regardless of age, gender, health, social status, ethnic origin, and/or religion. It is the principle of the Universal Declaration of Human Rights which states that all people are born free and equal in dignity and rights.

Personal autonomy is a corollary of human dignity: individuals have the capacity to act freely in order to be able to make informed decisions. This principle is found in "informed consent" in medicine, a principle that states that a person has the right to accept risk voluntarily and has an equal right not to accept it. This informed consent is of paramount importance when it comes to patients who are not seriously ill but are still young and healthy and who are being incited to be screened for cancer and the likelihood of  being affected is very low.

PROCEDURAL VALUES OF THE RADIATION PROTECTION SYSTEM

- Responsibility: individuals responsible for making decisions are accountable for their actions to all those who may be affected by these actions. In terms of governance, this means the obligation of individuals or organizations to account for their activities, to take responsibility and to be prepared to be accountable.

==> The sponsors of the MyPebs study, which aims to recruit women aged 40 and over to compare mass screening with a personalized form of screening, will be accountable in terms of radiation protection and will assume their responsibility when the time comes (and we will make sure they do).

- Transparency means "openness to decisions and activities that affect society, economy, and environment and willingness to communicate them clearly, precisely, quickly, honestly".

Transparency does not simply mean communication or consultation, it means accessibility to information about activities, deliberations and decisions involved and honesty with which this information is conveyed. This transparency implies that all relevant information is provided to persons concerned.

Thus, informed consent has been developed in the context of medical ethics. The prerequisites of informed consent include :

- information (which should be appropriate and sufficient)

- understanding

- volunteering (avoid undue influence)

- all of this associated with the right of refusal and withdrawal (without any prejudice such as the idea that had germinated in the sick brains of a few in the 90s, to withdraw the social rights of women who would not get screened).

For vulnerable people with limited or diminished abilities (people with disabilities, in prison, interned in psychiatric hospitals, etc.), for weak people under the influence of extorting or threatening doctors, for pregnant women, additional protection both in terms of consent and strict evaluation of the benefit/risk ratio is doubly necessary.

However, the 2006 Order [8] (7) went so far as to incite territorial officials to recruit, without information on the radio risk involved, women living in the Guyanese forest, handicapped, in prison, in order to increase the percentage of participation in mass screening for breast cancer, which is an obvious abuse of weakness.

==> By not communicating with women concerned in an honest and transparent manner about the radiation-induced risk and the intrinsic inequality of associated individual risk, mass screening for breast cancer does not respect this ethical value.

Worse, the My Pebs study (https://cancer-rose.fr/my-pebs/), funded by public money at the European level, does not respect this elementary ethical value, since it is to date impossible to freely dispose of the protocol and  women recruited are not informed of the radio-induced individual risk, all the more so as they are younger (inclusion planned from the age of 40).

-Inclusivity 

This is stakeholder participation, which involves all parties concerned in the decision-making processes related to radiation protection.

==> The 2016 citizens' consultation obviously did not respect this fundamental value of radiation protection.

CONCLUSION

By exposing women who are not ill, to ionizing radiation (mammography, tomosynthesis...), mass screening flouts the principles of justification, optimization and limitation of the radiation protection system as they currently exist, i.e. without taking into account individual inequality.

So obsessed with the promise of a fantasized benefit, screening has become blind to the inconsiderate risk it poses to non-ill women by subjecting them to unnecessary examinations, dangerous technologies (tomosynthesis) and without taking into account other possible doses received during the year.

Mass screening - and its uncontrolled extension to young women - flouts the fundamental ethical values of the radiation protection system, which are non-maleficence, prudence, justice (individual inequality in relation to radiation), transparency (lack of communication about individual risk) and inclusiveness in the participation processes.

The same is true of the My Pebs study, which intends to recruit 85,000 so-called "volunteer" women without informing them faithfully of the radiation risk involved, in defiance of the most elementary values of the radiation protection system.

  - But why so much malevolence and so little ethics, we can ask?

    - Because nature hates emptiness,

    - Because idea of doing nothing is unbearable in our mercantile society,

    - Because France hates the idea of citizens having  ability to act freely in order to make informed decisions,

    - Because  lure of gain ignores the principle of non-maleficence, prudence, dignity and equality regarding radio-induced risk.

    - Because there are lobbies (Europa Donna, etc.)

    - Because women have a propensity to subordinate themselves to medical authority from which they are struggling to emancipate themselves, and the market knows it.

Bibliography

[1] Plaidoyer pour l’abrogation de l’arrêté ministériel du 29 septembre 2006 encadrant le dépistage du cancer du sein , Annette LEXA, 2016.

[2] ICRP, 201X. Ethical foundations of the system of 37 radiological protection. ICRP Publication 1XX. Ann. ICRP XX(X), 1–XX.

http://www.icrp.org/docs/TG94%20Draft%20for%20Public%20Consultation%20(20April2017).pdf

[3] https://fr.wikipedia.org/wiki/Lin%C3%A9aire_sans_seuil

   - Argument in favor of the linear no-threshold model: Epidemiological studies have shown an increased risk of cancer at doses of 10 mGy. The carcinogenic effect of doses of the order of 10 mSv is proven in humans. From 10 mGy, the linear no-threshold relationship correctly reflects the dose-response relationship in the Hiroshima and Nagasaki cohort. At doses below 10 mSv, the irradiated cells are crossed by only one trajectory and the effect of each trajectory is an independent stochastic event. The nature of the lesions thus caused and the probability of repair and elimination of the damaged cells do not depend on the dose or the flow rate. The probability that an initiated cell will give rise to cancer is not influenced by lesions in neighboring cells or adjacent tissues.

- Some of the arguments in its favour have lost some of their value, in particular due to numerous results from radiobiology laboratories: Even if ionizations are independent, there may be group effects via cellular communication mechanisms; The efficiency of chromosomal damage repair is directly dependent on the dose rate, with the possibility of hypersensitivity to very low rate radiation; The development of cancer depends not only on an isolated cell but also on the surrounding tissues, which may contribute to its evasion of the immune system; The effects of one irradiation at a given time may depend on previous irradiations (adaptive response).

To these arguments against, we must now add individual susceptibility (genetic and epigenetic) leading a non-negligible part of the population (about 20%) to a risk of radio-induced cancer according to its own tolerance threshold, previously neglected in studies mixing radio-induced and spontaneous cancer with age.

[4] MODULE NATIONAL D'ENSEIGNEMENT DE RADIOPROTECTION DU DES DE RADIOLOGIE, Principes et mise en œuvre de la radioprotection, Drs J.F. Chateil, H. Ducou Le Pointe et D. Sirinelli, 2010. http://www.sfrnet.org/data/upload/files/10_objectifs_et_principes.pdf

[5] De l’usage des Rayons X en radiologie (diagnostique et interventionnelle), à l’exclusion de la radiothérapie. Rapport et recommandations. Dubousset J., Académie Nationale de Médecine, 2016. http://www.academie-medecine.fr/de-lusage-des-rayons-x-en-radiologie-diagnostique-et-interventionnelle-a-lexclusion-de-la-radiotherapie-rapport-et-recommandations/

[6] https://cancer-rose.fr/en/2020/12/29/predictive-test-for-radiotherapy-reactions-women-at-high-risk/

[7] https://cancer-rose.fr/en/2020/12/15/radiotoxicity-and-breast-cancer-screening-caution-caution-caution/

[8] Arrêté du 29 septembre 2006 relatif aux programmes de dépistage des cancers

https://www.legifrance.gouv.fr/affichTexte.do?cidTexte=JORFTEXT000000460656

Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

Secondary hematological cancers after treated breast cancer

September 19, 2019

Article from January 2019, Summary by Cécile Bour, MD

Evaluation of the Incidence of Hematologic Malignant Neoplasms Among Breast Cancer Survivors in France

JAMA Network Open. 2019;2(1):e187147. doi:10.1001/jamanetworkopen.2018.7147

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484549/

download PDF 

Authors :

Marie Joelle Jabagi, PharmD, MPH; Norbert Vey, MD, PhD; Anthony Goncalves, MD, PhD; Thien Le Tri, MSc; Mahmoud Zureik, MD, PhD; Rosemary Dray-Spira, MD, PhD

About this study

This is a cohort study. All French women between the ages of 20 and 85 years who were diagnosed with breast cancer and did not die (referred to as "survivors"), between 2006 and 2015, were included and were followed up until the onset of hematological cancer, or until death, or until loss of follow-up, as the case may be. Comparisons were made with all French women in general population enrolled in general health insurance plan each year from 2007 to 2016. Data from the SNDS (containing data from the PMSI and the CepiDC) were analyzed.

Results

The different types of hematological neoplasia considered were acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative neoplasms, multiple myeloma, Hodgkin's lymphoma or non-Hodgkin's lymphoma, acute lymphoblastic leukemia, lymphocytic lymphoma. The incidence (number of new cases) of these different types was estimated and compared to the incidence in women in general population.

In this study of 439,704 French women, women with a diagnosis of breast cancer who had not died from it, had a statistically standardized higher incidence of acute myeloid leukemia and myelodysplastic syndrome compared to women in general population. There was a slight increase in the incidence of multiple myeloma and acute lymphoblastic leukemia.

French women participating in the study who had breast cancer in the last decade were 3X more likely to develop acute myeloid leukemia and five times more likely to develop myelodysplastic syndrome than women in  general population. Several previous studies have linked these pathologies to chemotherapeutic agents, radiotherapy, and taxotere therapy (adjuvant treatment of breast cancer, see HAS 2015 advisory). (See studies [1])

It cannot be ignored that hematological risk of malignant neoplasm reaches peaks within specific time frames after breast cancer.

The annual incidence of acute myeloid leukemia in these patients from this study, increased during the first few years following diagnosis of breast cancer, with an early peak around year three and a subsequent peak around year eight. This finding is consistent with previous studies indicating the presence of 2 types of acute lymphocytic leukemia associated with treatment.

The authors suggest that the latency of onset may depend on the age of the patient at diagnosis, type of therapy and dosage regimen, and also on the limited time of follow-up in the study (even later cases may occur that have not been reported here).

The majority of secondary leukemias are of the myeloid type, but it is estimated that acute secondary lymphoblastic leukemias account for 10% to 12% of all secondary leukemias, with breast cancer being the most common cancer causing these secondary pathologies. In this study, there was a two-fold increase in the incidence of acute lymphocytic leukemia in breast cancer "survivors". Some studies showed that irradiation and chemotherapy were associated with pathogenesis [2], while other studies suggested that prior therapy plays a less important role in secondary acute lymphocytic leukemia than genetic predisposition [3].

A 50% increase in the incidence of multiple myeloma was observed in breast cancer survivors in this study. This slight increase has not been reported and needs to be further investigated, particularly the role of susceptibility due to heredity in BCRA1 and BCRA2 mutation carriers. [4]

Conclusion

This study reveals that acute myeloid leukemia, myelodysplastic syndrome and acute lymphoblastic leukemia are more common in treated women who do not die from breast cancer than in women in the general population; this is of concern and according to the authors, ongoing surveillance of hematological malignancies and further research into the underlying mechanisms of these diseases is needed.

This study is intended to better inform practicing oncologists; patients with a history of breast cancer should be informed of the increased risk of developing certain hematologic malignancies after their first cancer diagnosis.

Recent discovery of genetic signatures that guide treatment decisions in early stages of breast cancer could reduce the number of patients exposed to cytotoxic chemotherapy and its complications, including hematological cancers[5].

It is therefore necessary to continue monitoring trends in the occurrence of hematological cancers, especially as approaches to cancer treatment are evolving rapidly. Further research is also needed to evaluate  treatment modality in cases of genetic predisposition to secondary malignancies.

Comments :

(EDITOR'S NOTE)

Concerns about overdiagnosis are all the more justified because women, some of whom are at high risk and unaware of it [6], may be receiving radiation therapy that they would not have needed, and are being precipitated by screening for a disease they would not have had in its absence, with potential risks inherent in treatment, including secondary hematological diseases.

This has been shown in studies that suggest that risks of treatment may outweigh the expected benefit of screening. [7]

As our dotted poster on the home page of the site (bottom of the page, "poster") shows, the benefit/risk balance in screened women is far from being in favor of benefit, due to overdiagnosis, radiation-induced cancers, radiation-induced coronaritis, surgical and anesthetic accidents, post-treatment thromboembolism, and secondary hematopathies.

The Cancer Rose Collective regrets that these elements are not explicitly detailed in the information brochure given to women who are part of the new study on personalized screening, the MyPebs study. Overdiagnosis is minimized at rates that are currently obsolete, overtreatment, a tangible consequence resulting from overdiagnosis for women, is not stated, and consequences of treatment are not mentioned[8].

References

[1] Studies about relation between breast cancer treatment and Hematologic Malignant Neoplasms:

  • SmithRE,BryantJ,DeCillisA,AndersonS;National Surgical Adjuvant Breast and Bowel Project Experience. Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National Surgical Adjuvant Breast and Bowel Project Experience. J Clin Oncol. 2003;21 (7):1195-1204. doi:1200/JCO.2003.03.114
  • PragaC,BerghJ,BlissJ,etal.Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: correlation with doses of epirubicin and cyclophosphamide. J Clin Oncol. 2005;23(18):4179-4191. doi:1200/JCO.2005.05.029
  • BeadleG,BaadeP,FritschiL.Acute myeloid leukemia after breast cancer:a population-based comparison with hematological malignancies and other cancers. Ann Oncol. 2009;20(1):103-109. doi:1093/annonc/mdn530
  • Le Deley M-C, Suzan F, Cutuli B, et al. Anthracyclines, mitoxantrone, radiotherapy, and granulocyte colony- stimulating factor: risk factors for leukemia and myelodysplastic syndrome after breast cancer. J Clin Oncol. 2007; 25(3):292-300. doi:1200/JCO.2006.05.9048
  • Galper S, Gelman R, Recht A, et al. Second non breast malignancies after conservative surgery and radiation therapy for early-stage breast cancer. Int J Radiat Oncol Biol Phys. 2002;52(2):406-414. doi:1016/S0360-3016 (01)02661-X
  • RenellaR,VerkooijenHM,FiorettaG,etal.Increased risk of acute myeloid leukaemia after treatment for breast cancer. Breast. 2006;15(5):614-619. doi:1016/j.breast.2005.11.007
  • CurtisRE,BoiceJDJr,StovallM,FlanneryJT,MoloneyWC.Leukemia risk following radiotherapy for breast cancer. J Clin Oncol. 1989;7(1):21-29. doi:1200/JCO.1989.7.1.21

[2]

  • HsuW-L,PrestonDL,SodaM,etal.The incidence of leukemia,lymphoma and multiple myeloma among atomic bomb survivors: 1950-2001. Radiat Res. 2013;179(3):361-382. doi:1667/RR2892.1
  • AndersenMK,ChristiansenDH,JensenBA,ErnstP,HaugeG,Pedersen-BjergaardJ.Therapy-related acute lymphoblastic leukaemia with MLL rearrangements following DNA topoisomerase II inhibitors, an increasing problem: report on two new cases and review of the literature since 1992. Br J Haematol. 2001;114(3):539-543. doi:1046/j.1365-2141.2001.03000.x

[3] GanzelC,DevlinS,DouerD,RoweJM,SteinEM,TallmanMS.Secondary acute lymphoblastic leukaemiais

constitutional and probably not related to prior therapy. Br J Haematol. 2015;170(1):50-55. doi:10.1111/bjh.13386

[4] StruewingJP,HartgeP,WacholderS,etal.The risk of cancer associated with specific mutations of BRCA1and

BRCA2 among Ashkenazi Jews. N Engl J Med. 1997;336(20):1401-1408. doi:10.1056/NEJM199705153362001

[5]

  • CardosoF,van’tVeerLJ,BogaertsJ,etal;MINDACTInvestigators.70-Gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med. 2016;375(8):717-729. doi:1056/NEJMoa1602253
  • SparanoJA,GrayRJ,MakowerDF,etal.Adjuvant chemotherapy guided by a21-gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111-121. doi:1056/NEJMoa1804710

[6]

[7] https://cancer-rose.fr/en/2020/12/29/excess-mortality-due-to-treatment-outweighs-the-benefit-of-breast-cancer-screening-synthesis-of-several-studies/

[8] https://cancer-rose.fr/my-pebs/wp-content/uploads/2019/02/Formulaire-consentement-dorigine.pdf

Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

Predictive test for radiotherapy induced reactions: women at high risk

Dr. Annette LEXA (PhD Toxicology)

November 20, 2017

While mainstream media give the impression of discovering a hot scoop and a possible polemic [1] , the French[2] and international biomedical community is now perfectly aware of the limits of breast cancer screening and its burden (limited benefits, imperfect sensitivity and specificity [3], over-diagnosis, "preventive" surgery, morbidity and mortality by radiotherapy) but does not communicate this fact to the general public.

Cancer Rose with FORMINDEP (french non profit organization for independent medical education and information), with several independent general practitioners on social networks (Jean Claude Grange, Claudina Michal-Teitelbaum, JB Blanc, Dominique Dupagne, Jaddo, etc.) and several women (Martine Bronner, Rachel Campergue, etc.) have simply relayed - voluntarily, independently and free of charge - the scientific information available to the first concerned, work which should normally have been done by professionals and which has not been done for 2 main reasons : some have severe cognitive biases, others are very afraid of the "feelings" of women who might lose "confidence" in screening, which must therefore be improved as soon as possible. This probably explains this first Pink October 2017, which is strangely silent.

Regarding the risk associated with radiotherapy, Cancer Rose had already alerted women to the risk [4]. However, it continues to be largely underestimated [2]. Following an e-mail sent to us by an anxious woman on October 4, we looked for an update on the predictive tissue radiosensitivity tests available in France [5]. And what we discovered is not very pleasant, we should say again.

Radiosensitivity is a real public health problem

60% of the 380,000 new cases of cancer in France are treated by radiotherapy. Patients receive sessions of the order of 2 Gy [6], repeated daily. Even with state-of-the-art equipment, the risk of irradiating healthy connective tissue [7] is unavoidable.

 Among patients treated by radiotherapy, 5 to 20% may show adverse reactions such as dermatitis, fibrosis, rectitis (this is called tissue radiosensitivity), secondary radiation-induced cancers [8] (between 5 and 12%) (this is called cancer radio-susceptibility).  At present, no personalized medicine currently takes into account the individual risk of radiosensitivity or radiosusceptibility. Moreover, international radiation protection rules (e.g. Sievert[6] still consider individuals as being all radioresistant for these two concepts. Even nowadays, people are exposed to the same dose of radiation that can lead either to a cure without side effects, a cure with more or less serious to fatal side effects in the case of coronary artery disease, or even death in 100% of exceptional cases of well-characterized rare genetic diseases. All treatment parameters are set without taking into account individual variations. Therefore, a person who will have a 10 times higher risk of developing cancer, will still receive the same dose as a person repairing his DNA lesions well and is unlikely to develop secondary cancer.

Indeed, the biggest problem is the double-strand breakage of the DNA (which we will call DSB, it is the most serious lesion that can be suffered by the DNA because both copies are affected). Normally the repair of DSB is initiated by a cytoplasmic protein called ATM. For about fifteen years, the Radiobiology Group of UMR 1052 INSERM (Lyon) has been working to understand this mechanism and to develop an individual predictive test.

This protein is activated for any oxidative stress producing DSBs and passes into the nucleus to trigger DNA repair. This group of researchers has identified 3 groups of humans:

- Group I = radioresistant, low-risk cancer patients who quickly and correctly repair DSBs, which represent about 75-85% of the population.

- Group II = moderate radiosensitive, and radiosusceptible (high risk of cancer), who repair late and with errors even at low radiation doses. Individuals in Group II would represent 20% of the general population. When these individuals are subjected to radiotherapy sessions, they can more easily trigger radiation-induced cancers, but also dermatitis, rectitis, coronaritis, etc.

- Group III = hyper-radiosensitive individuals who do not repair the DSB and are highly radiosusceptible, these present rare genetic syndromes diagnosed early in life (ataxia telangiectasia) and represent 1 person/100,000 but 0.5 to 5% of individuals worldwide would be carriers of a mutation of the ATM gene.

This classification also exists for tumor cells, independently of the group of healthy tissues (e.g., a group II patient may show group I, II or III tumors).

Finally, there is the problem of the repetition of low doses that can overwhelm the restorative capacity of the irradiated cells. This risk must be taken into account for young patients at high family risk. It is also known today that people with the BRCA1 or BRCA2 mutation have a risk associated with a certain radiosusceptibility, as well as people carrying mutations on p53 or ATM.

In addition to the risk associated with radiotherapy, the risk associated with radiodiagnosis should not be overlooked.  It accounts for the majority of medical exposures, usually to healthy individuals. If the exposure dose is 100 to 1000 times lower than in radiotherapy, the average exposure is constantly increasing : it is justified to question the safety of low doses of irradiation in group II patients, and in particular in young patients carrying the mutation ATM (1% incidence), or BRCA1 (1/1000 incidence) and BRCA2 (1/2000), the latter mutations presenting for the carrier an excess risk of breast cancer by a factor of 5 to 10 (this represents nearly 1% of the general population which has, for women, a risk of breast cancer 5 to 10 times higher than normal). Mammography generates 2 x 2 mGy images, spaced 3 minutes apart. Repeated doses induce CDBs and may induce additional DSBs during repair, thus increasing the effect of low doses. Studies have shown a risk of radiation-induced breast cancer for cumulative doses of 100 mGy. This is one of the reasons why mammograms should not be cumulated too much before the age of 50 and especially not before the age of 30 for women in group II.

Radiosensitivity tests: ATM transit test and apoptosis test 

In order to be truly predictive, a test must meet 3 criteria:

- It must be founded on a solid scientific basis

- it must have been tested on a large number of individuals of different radiosensitivity

- it must show the highest possible statistical power, independent of the dose, the nature of the tissue response and the location of the tumor.

Experience has shown that the more rapid the test, the less powerful it is.

Generally based on non-irradiated cells, proteomic and genomic approaches are currently not convincing and currently no genetic marker or gene expression can claim to predict radiosensitivity.

The ATM transit test

However, a simple test exists today to analyze the activity of the ATM protein in the nucleus during a 2 Gy irradiation of skin fibroblasts taken from the person. This test was developed by the radiobiology group of UMR1052 INSERM (French National Institute of Health and Medical Research) in Lyon. The test is based on the principle that the slower the transit of the ATM protein in the nucleus, the more radiosensitive the patient is. This test can distinguish 5 clinical grades of severity of tissue reactions (equivalent to degrees of burn), its sensitivity is 100% and its specificity 92%.

The development of the ATM test was carried out as part of a larger research project called the COPERNIC project [9]. Two tests will be marketed at the beginning of 2018 by NEOLYS DIAGNOSTICS[10] in several forms: a rapid test[11] (performed in an anti-cancer center, results in 4 to 5 hours) called "first sorting" from a rapid skin or blood sample for a few hundred euros, and a complete test* from a cutaneous sampling (3 weeks). The radiobiology group of the UMR1052 Inserm and the company NEOLYS DIAGNOSTICS collaborate, within a framework set by the Inserm deontology commission, to better define the regulations and ethics regarding radiosensitivity issues in order to give a clear legal framework to the use of these tests, which are always prescribed by doctors.

ATM transit theory also finds applications for toxicity related to non-radiative agents such as metals or pesticides: tests are being developed in this direction, which requires absolute rigor in the management of information and the implementation of alternatives when they would prove to be positive.

*In fact the price of the characterization test has not yet been finalized. It should be around 2,000€ (instead of 1,500€ as indicated) for the 3 weeks required for this test in a specialized medical analysis laboratory (excluding the anti-cancer center). Thanks to Mr. Gilles Devillers - pharmacist - president of Neolys Diagnostics, for the clarifications made.

The apoptosis test

There is another test model based on the apoptosis[12] of lymphocytes circulating in the blood, irradiated at 8 Gy. But this model is only valid for lymphocytes (which have been shown not to be the best candidates to represent breast connective tissue) and, moreover, the dose is higher (remember that a radiotherapy session exposes to a dose of 2 Gy). Originally, this test is only valid for delayed tissue reactions (such as those observed in some prostate cancers). It is based on the premise that more apoptosis means more radioresistance, which is contrary to the consensus observation that the more radio-induced death is observed, the more radiosensitive the cells are.

In addition, this test is based on the premise that lymphocyte death can predict the death of other types of tissue, such as conjunctive tissue, which rarely apoptoses.

The apoptosis criterion is all the more problematic as the test uses a high dose of 8 Gy (there is systematically a rapid apoptosis in 24 to 48 hours at this high dose).

At 2 Gy, there is less apoptosis and moreover it is observed at this dose that the more extensive the apoptosis, the more radiosensitive the patients are (Baijer et al, 2016 ). The figures put forward suggest that the test based on lymphocyte apoptosis shows lower statistical performance than the ATM test. Finally, the recruitment of patients for the development of the test can be problematic: the prospective aspect [13] of the trials favors rather radioresistant subjects and the performance of the test to detect radiosensitive patients is therefore based on a few dozen patients, which can introduce an undiscussed bias.

 This test is currently being developed by the company NOVAGRAY [14]. On its website, the company proposes to adapt the dose and the sequence of the sessions "to the woman patient's profile" when the patient has agreed to pay 1500 euros for this test. Evoking "a woman patient" leaves one wondering: since the test was initially developed for prostate cancer, the breast not being explicitly mentioned, is the woman more willing to buy a test than a man patient? This is all the more surprising since the site states that tests for prostate and lung cancer are in development. This suggests that the test currently available at NOVAGRAY is not specific for breast cancer.

CONCLUSION

There is little clear and accessible information on this type of personalized medicine for women facing breast cancer screening and treatment. And yet, it is vital for them. Patients already weakened by the announcement of the disease and the care pathway to be undertaken cannot alone assume the choice of a radiosensitivity test. Does the doctor prescribing this non-reimbursed test provide them with balanced and up-to-date information?

How can they discern between apoptosis and ATM testing for a comparable price? Should cheaper first-sort tests be favored? Moreover, while radiosusceptibility tests could be developed through the ATM transit theory, apoptosis (and therefore cell death) tests do not meet patients' expectations regarding mammographic exposure.

We are facing an extremely serious inequality of access to information and innovation, while lives are at risk. Despite the very complex mechanisms of individual response to radiation, there is now an urgent need for the authorities to take into account and better frame all issues related to individual radiosensitivity and radiosusceptibility.

BIBLIOGRAPHIE :

- Influence of Nucleoshuttling of the ATM Protein in the Healthy Tissues Response to Radiation Therapy: Toward a Molecular Classification of Human Radiosensitivity , The COPERNIC project investigators,
 Int J Radiation Oncol Biol Phys, Vol. 94, No. 3, pp. 450- 460, 2016

- The Henri Mondor Procedure of Morbidity and Mortality Review Meetings: Prospective Registration of Clinical, Dosimetric, and Individual Radiosensitivity Data of Patients With Severe Radiation Toxicity , Yazid Belkacemi et col. , Int J Radiation Oncol Biol Phys, Vol. 96, No. 3, pp. 629-636, 2016

- TNFSF10/TRAIL regulates human T4 effector memory lymphocyte radiosensitivity and predicts radiation-induced acute and subacute dermatitis, Baijer et col., Oncotarget. 2016 Apr 19;7(16):21416-27

- Radiation-induced CD8 T-lymphocyte Apoptosis as a Predictor of Breast Fibrosis After Radiotherapy: Results of the Prospective Multicenter French Trial, David Azria et col. , EBioMedicine,  December 2015 Volume 2, Issue 12, Pages 1965–1973

 - Low radiation doses: towards a new reading of risk assessment? Anne-Fleur Perez, Clément Devic, Catherine Colin, Nicolas Foray , Bull Cancer 2015

- Individual radio sensitivity: an old notion and its future , Conclusions of the December 16, 2013 seminar organized by the ASN , 2014

- Radiosensitivity Evidence of an individual factor, Nicolas Foray, Catherine Colin and Michel Bourguignon, Medicine/Science 2013; 29: 397-403

- 100 years of individual Radiosensitivity: How We Have Forgotten the Evidence, Nicolas Foray, PhDCatherine Colin, MD, PhD Michel Bourguignon, Radiology: Volume 264: Number 3—September 2012

- DNA double-strand breaks induced by mammographic screening procedures in human mammary epithelial cells , Catherine Colin et col. , Int J Radiat Biol. 2011 Nov;87(11):1103-12.

 [1]Breast cancer: the relevance of screening in question, Catherine Ducruet, Les Echos.fr, 07/10/17 - https://www.lesechos.fr/industrie-services/pharmacie-sante/030668058097-cancer-du-sein-la-pertinence-du-depistage-en-question-2120226.php#FFEP5i8Gtd07a53G.99

[2] Delaloge S, et al. Breast cancer screening: on the way to the future. Bull Cancer (2016), http://dx.doi.org/ 10.1016/j.bulcan.2016.06.005

[3] The sensitivity of a test is its ability to detect as many " ill people " as possible (false negatives are avoided). Specificity is its capacity to detect only ill people (avoid false positives).

 [4] Mammograms and radiosensitivity, Annette LEXA , https://www.cancer-rose.fr/mammographies-et-radiosensiblite

[5]  "Being very anxious about the effects of radiotherapy, I discovered a company (Novagray) that markets a radiosensitivity test. In April 2017 this test was not reimbursed and costs 1500 euros. I finally did not accept this test for financial reasons but also because in case of non-radiosensitivity the number of sessions is decreased and the dose increased, which did not seem reassuring to me. Do you know this test and can you give me your opinion? My radiotherapy sessions are over but I refuse the control mammogram, considering that there is no consideration of all the accumulated radiation. »

[6]  The sievert (Sv) is an international unit used to give an assessment of the biological impact of radiation on humans. The Gray (Gy) is the absolute dose of radiation received/Sievert. A dose of 2 Gy is about 1000 times the dose received for a mammogram image.

[7] Connective tissue is the supporting tissue (collagen fiber, fat tissue, dermis, etc.) but also blood cells (macrophages, leukocytes, etc.). These are tissues that have the same embryonic origin. However, not all scientific authorities consider blood or lymph as connective tissue. The breast is an organ that contains mainly connective tissue.

[8]  For a 50-year-old woman with small breast cancer, the absolute benefit expected from radiotherapy is a reduction in breast cancer mortality of about 2-5%. For non-smokers, the absolute risk of developing lung cancer or cardiotoxic risk 10 years after breast cancer radiation therapy appears to be less than 1%. For smokers, the absolute risk is 4%.

Estimation des risques de la radiothérapie du cancer du sein : Evidence From Modern Radiation Doses to the Lungs and Heart and From Previous Randomized Trials, Taylor C. et al, J Clin Oncol. 2017 20 mai ; 35(15):1641-1649).

This lack of benefit on overall mortality is also noted in a report in French of 2015, Evaluation of intraoperative radiotherapy in breast cancer, October 2015, Note de cadrage, HAS, October 2015. http://www.has-sante.fr/portail/upload/docs/application/pdf/2015-10/cadrage_rtpo.pdf)

[9] The COPERNIC project: http://www.radiobiologie.fr/index.php?tg=articles&idx=More&topics=6&article=37

[10] SAS NEOLYS (http://www.neolysdiagnostics.com/fr/ ) was founded by the founders Gilles Devillers, Nicolas Foray, Julien Gillet-Daubin. It is based on the 15 years of work of the Radiobiology Group of UMR 1052 INSERM.

[11] This rapid test was recently accepted in Int J radiat Biol Oncol Phys

[12] Apoptosis is one of the forms of cell death by self-destruction (a kind of cell suicide), genetically programmed.

 [13] A prospective study consists of comparing the occurrence of a pathology in groups defined according to their exposure to a factor presumed to be responsible for the pathology.

[14] SAS NOVAGRAY is directed by Clémence Franc who co-founded NOVAGRAY with Prof. David Azria in 2015.  Pr AZRIA is head of the Oncologic Radiotherapy Department at the Cancer Institute of Montpellier (ICM) and radiobiology project leader in the team "Immunociblage et radiobiologie en oncologie" directed by André Pélerin at the head of the INSERM U1194 unit at the Cancer Research Institute of Montpellier (IRCM).

Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

Radiotoxicity and breast cancer screening: caution, caution, caution…

 Dr Annette LEXA (PhD Toxicology)

July 2, 2019

In October 2017, I published on this site, an informative article on the risk associated to radiotoxicity[1] explaining that 15 years of research performed by the Radiobiology Community UMR 1052 INSERM (a joint research unit within the National Institute for Health and Medical Research, Lyon) demonstrated that we are not equal when exposed to radiation. Moreover, this issue is not a new one in authorized environments, as the ASN (Nuclear Safety Authority) had already been concerned about it in 2003, calling for study and protection of populations at risk “through the evolution of medical practices with regard to ionizing radiation and an eventual evolution of regulations”.
We are now in 2019, the data is accumulating and nothing is moving. The main reason for this is the lack of disciplinary transversality: while radiotherapists and radiophysicists are regular collaborators, radiobiologists are rare and less involved in therapeutic choices.
Although radiotherapists point out problems with the physical doses received, biological factors are the ones that explain the dramatic reactions of patients, causing them to interrupt the radiotherapy, which is nevertheless necessary.

It should be mentioned that the current regulatory context[2] resulting from the amendments to the Labor Code and the Public Health Code introduced in 2002-2003, is based, in particular, on the monitoring of the 120,000 survivors of Hiroshima-Nagasaki. We are now facing a paradigm shift that is changing our view of radiation-induced events. Advocates of hubris around early cancer screening have not thought for a moment about this paradigm shift: early screening will induce even more medical imaging, overdiagnosis, overtreatment, and radiation-induced cancers in young and healthy women.

It is absolutely necessary that this new paradigm be implemented into legislation, good medical practice, population screening campaigns as well as all in clinical and epidemiological studies (such as the vast European study My PEBs, which enlists women as young as 40 years of age without the slightest precaution, without information or informed consent on this subject[3]). It's no longer a matter of the precautionary principle, it's a matter of prevention, because we can no longer say "we didn't know."

Mechanisms involved

Radiation induces chromosomal effects resulting in well-known anomalies (micronucleus, translocation, insertion) which are the manifestation of double-strand breaks (DSB) of poorly repaired DNA. Poor repair of DSBs is the most serious event that the double helix of DNA can undergo.

For the same dose of absorbed radiation, our cells undergo 40 DSB / Gy (Gray is the unit of measurement used in medicine to quantify irradiation). However, DBSs are already occurring at 1mGy and the effect is significant at around 100-300 mGy, so we talk about hyper-radiosensitivity to low doses. It is the persistence of unrepaired lesions that counts and it is on the signalling and repairing of our DNA that we are not all equal face to radiation.

In humans, there are two ways to repair DSBs: end-joining (predominant) and recombination. This is the model of a perforated sock, explained by Nicolas Foray: either we place the two pieces together and join them together (end joining) or we make a patch when the hole is too large, as our grandmothers used to do (recombination).The end-joining repair model is a source of error that can result in a high radiosensitivity and severe immunodeficiency. Recombination repair pattern necessarily causes breaks in other regions of DNA, as a piece of DNA has to be removed to repair the first break, resulting in DNA chain damage.

There is a distinct category of proteins known as 'tumour suppressors' which are involved in DNA signaling and repair. They function well in homozygous individuals [4] for these proteins such as BRCA1, BRC12, p53, Rb…

  • Heterozygous BRCA1+/- mutations in the BRCA1 protein, responsible for the majority of familial breast and ovarian cancers, increase the risk of cancer by a factor of 6 to 10. BRCA1 is closely related to the ATM[5] protein involved in the signaling of DSBs and would be indispensable for the action of the Rad51[6] protein involved in the repair by recombinant DNA.
  • The heterozygous BRCA2 +/- mutations are implicated in ovarian and male breast cancer. The BRCA2 protein interacts with the RAD51 protein for DNA repair.
  • Overexpression of the Rad51 protein induces hyper-recombinations, a source of high genetic instability leading to tumour processes. We are now aware that radio- sensitive individuals overexpress hyper-recombinations leading to radio-induced cancers.

The research carried out by the Radiobiology Group identified three population groups according to their resistance to radiation:

  • Radioresistant (Group I)75-85% of the population: ATM cytoplasmic protein in dimeric form, very good recognition of DBSs, no predisposition to cancer.
  • Moderate radiosensitivity (Group II) 5-20% of the population: delayed transit of the ATM protein in the nucleus, poor recognition of DBSs, poor repair, moderate radiosensitivity, high risk of cancer.
  • Hyper radiosensitivity (Group III) >1% of the population: mutation of the ATM protein, poor recognition of DBSs, poor repair, hyper-radiosensitivity, high risk of cancer.

Radiosensitivity of DNA to low doses of ionising radiation

We already know that the breast is a radiosensitive organ. Mammography, by performing successive images, results in a repetition of low doses of 2 mGy sent at 3 minutes intervals. These radiations will induce a tissue reaction in some women: cellular apoptosis [7], double-stranded DNA (DSB) breaks with late repair defects which can induce either secondary cancer from improperly repaired cells or cell death. When the control mechanisms are efficient, cell death is more likely than its transformation into an immortal cancer cell line.

This radiosensitivity has been known for a long time in radiotherapy, its late, long-lasting and very difficult to treat expected effects (burns, necrosis, fibrosis, apoptosis) affect 5-15% of patients treated for cancer (8,000-25,000 people per year).

Extreme radiosensitivity exists in several rare genetic deficiency syndromes (ataxia telangiectasia, progeria, xeroderma pigmentosum, Huntington's chorea, Fanconi anaemia, Li-Fraumeni syndrome, etc.): patients who are homozygous for the genes involved are unable to tolerate the doses used in medical imaging. Although these cases are rare but detectable, it is possible that in the general population a large number of heterozygotes may be observed, a source of genomic instability for these carriers and causing problems during repeated radiotherapy and medical imaging.

Radiosusceptibility signs a predisposition to radiation-induced cancers even at low doses

The effect is random, probabilistic and will concern 5% of patients who have received radiotherapy. They are likely to develop with a high probability a secondary radiation-induced cancer, knowing that these patients affected by cancer are already more radiosensitive than the majority of the population.
This radiosusceptibility is increased in mammographic conditions (images delivering 2+2 mGy at intervals of 3 minutes with immediate repetition, preventing the mutated genomes from setting up signalling and successful repair). Women at high family risk of breast cancer (15% of breast cancer cases) have defects in signalling and repairing of their DNA: this is the case of the BRCA1 protein, which is at the heart of the complexes formed to repair the DNA DBSs. But women carrying a mutation of this gene which has thus become defective, and who are therefore more likely to develop cancers because their DNA has not been properly repaired, are encouraged to undergo close monitoring at an early stage, with a combination of mammograms and even tomograms. Some doctors - who do not know anything about radiosusceptibility - require them to undergo examinations every 6 months or every year, while the greatest caution should be applied: spacing of at least ½h at 1 hour from the x-rays (50% of DBSs are normally repaired within 50 minutes), avoid contrast products and x-rays.

Time for conclusion

This knowledge implies a new screening strategy for women at high family risk (such as taking a single mammogram, proposing MRIs and ultrasounds that do not emit ionising radiation). It also calls into question the continuation of organised screening such as outlined in Law 2004-806 of 9 August 2004 on public health policy, consolidated version as of 16 April 2019. No one has ever thought of questioning French radiobiology specialists on this "point of detail".
Work is currently underway to validate predictive tests for radiosensitivity before any radiotherapy.

While awaiting the availability and reimbursement of easy and inexpensive predictive tests for all the tens of millions of women, young and not so young, but above all healthy women, enrolled in mammographic screening, this knowledge of the biological causes of radiosensitivity and radiosusceptibility requires, on the basis of the precautionary principle, that the project of extending mammographic surveillance of young women should be stopped. Radiologists, gynecologists and oncologists must be informed of the risks of radiation-induced cancers to that they are exposing their patients with this regrettable "life-saving screening". Don't we say that hell is paved with good intentions? Don't we also say that "error is human, stubbornness (by arrogance) is diabolical? ».

Read also, in the news :

  1. The Academy of Medicine warns that the risk linked to imaging examinations must be offset against the risks of the disease itself. http://www.academie-medecine.fr/wp-content/uploads/2016/12/16.11.15-DUBOUSSET-rapport-v-16.12.8-AK.pdf page 8 and 9

The incidence of cancer (breast and endometrial) is multiplied by 5 for adolescents treated for scoliosis 25 years earlier (with an average of 16 x-rays per case) in a Danish study in 2016 (26). This work led to the recommendation to take these images with a postero-anterior incidence rather than the reverse, in order to expose less the mammary gland. The new systems, which are unfortunately not widespread enough (EOS)(15), allow a reduction in dose by a factor of 6 to 40 compared with conventional radiographs. Complete monitoring of scoliosis can therefore be carried out for the equivalent of a single conventional radiography. Once the diagnosis has been specified on the initial radiography, the best protection is to monitor this scoliosis using non-irradiating means such as the scoliometer, or surface topography systems (27), with an X-ray check being carried out only if a significant change in surface topography is found.
c) The incidence of cancer in adulthood would be increased. Some populations have a particular radiosensitivity linked to DNA repair disorders (30,31). Obviously, the risk associated with imaging examinations must be weighed against the risks of the disease itself (e.g. mucoviscidosis) and the use of non-irradiating techniques (MRI, ultrasound) should be systematically favoured if possible.

2. https://www.francebleu.fr/infos/sante-sciences/les-nouveaux-cas-de-cancers-en-hausse-surtout-chez-les-femmes-1562060451
https://www.lemonde.fr/sciences/article/2019/07/02/les-nouveaux-cas-de-cancer-en-forte-hausse-en-france_5484200_1650684.html
No reduction in breast cancer despite screening, increase in lung cancer in women. We wonder about the proportion of lung cancers in women attributable to over-diagnosis and thus secondary to over-treatment by unnecessary radiotherapy.

Bibliography

Radiosensibilité et irradiation mammaire, Toxicité des polluants et cancers du sein , Nicolas Foray, Unité UA8 Radiations Défense, Santé et Environnement, Groupement de Recherche sur les Radiations de Lyon (GRRAL) , 2019, Communication personnelle à Cancer Rose
https://its.aviesan.fr/getlibrarypublicfile.php/cd704e89988a4e3bcf2e1217566876cf/inserm/_/collection_library/201800012/0001/J1-098ITS-2017.foray.lyon.ITMO.TS..21.nov.2017.pdf.pdf

La susceptibilité individuelle aux rayonnements ionisants, Pr. Michel Bourguignon Commissaire ASN, 2014
https://www.irsn.fr/GT-CIPR/Documents/15-05-2014/GT-CIPR_15-05-2014_3-Bourguignon.pdf

La radio-susceptibilité individuelle: 3 défis et une vision pour la radioprotection, Pr Michel Bourguignon, ASN, 2015
http://reseau-ramip.fr/wa_files/06-TOULOUSE_20RaMiP_20RSI_20-_204_20Dec_202015_20__5BMode_20de_20compatibilit_C3_A9_5D.pdf

Impact du transit cytonucléaire de la protéine ATM en réponse aux radiations ionisantes : notions de pro- et anti-episkévie, Melanie Ferlazzo, Thèse de doctorat de l’Université de lyon, 2017
https://tel.archives-ouvertes.fr/tel-01588173/file/TH2017FERLAZZOMELANIE.pdf

[1]Test prédictif des réactions à la radiothérapie : des femmes en grand danger, Annette LExa, 2017 .
https://www.cancer-rose.fr/test-predictif-des-reactions-a-la-radiotherapie-des-femmes-en-grand-danger/
[2] La Directive 2013/59/Euratom du Conseil du 5 décembre 2013 fixe les normes de base relatives à la protection sanitaire contre les dangers résultant de l’exposition aux rayonnements ionisants. Une directive regroupe les directives de 1989 à 2003

[3]https://cancer-rose.fr/my-pebs/2019/06/13/argument-english/


4] Homozygotes have 2 functional parental alleles such as BRCA1 +/+ for example. Heterozygous BRCA +/- carriers have a deficient mutated allele resulting in poorer break signalling and therefore poorer repair.

5] The cytoplasmic protein ATM, is a dimer with a signaling function to stimulate DNA repair - See the importance of the transit of this protein in the signalling mechanism for double-stranded breakage repair: https://www.cancer-rose.fr/test-predictif-des-reactions-a-la-radiotherapie-des-femmes-en-grand-danger/

6] In humans, the RAD51 protein plays an essential role in recombination during DNA repair following double-strand breaks.

7] Apoptosis, or programmed cell death, is the process by which cells trigger their self-destruction in response to a signal

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