Cancer Risk. Klaus-Rüdiger Trott Università degli Studi di Pavia And University College London Cancer Isntitue and Technische Universität München

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1 Cancer Risk Klaus-Rüdiger Trott Università degli Studi di Pavia And University College London Cancer Isntitue and Technische Universität München

2 The aims of Radiation Protection The aims of Radiation Protection are not To protect radiation To protect radiation protection experts To protect human beings from radiation but To protect human beings from morbidities potentially elicited by radiation exposures

3 The morbidities potentially caused by radiation exposures Cancer and leukaemia Cardiovascular and other vascular diseases Neurocognitive disorders and intellectual deficits Immunological disorders Hormonal disorders Cataracts and other eye diseases And many others

4 Morbidities depend on locally absorbed radiation doses The Frequency of cancer and leukaemia The Severity of all other morbidities, however, by setting thresholds of relevant severity, a dose dependency of incidence can be derived. Yet The threshold of frequency depends entirely on the arbitrary threshold of severity, see cataract)

5 Volume dependence of radiation risks The development of organ specific morbidities does not depend on dose in volumes but on dose in specific sensitive organ structures. This means: Mean organ doses are meaningless in the evaluation of most potential radiation morbidities

6 The abuse of effective dose in radiation protection The effective dose concept has been developed as a criterium for the planning of radiation protection procedures in populations. I is also used in the reporting of population to exposures from medical radiations ICRP has been warning again and again against using effective dose for the purpose of calculating individual radiation risks.

7 Are all cancers the same? After radiation exposures, different organs differ dramatically in their radiosensitivity towards cancer induction. The organ specific risk of radiation-induced cancer is completely different from the spontaneous risk. Example: spontaneous risk radiation risk Prostate very high very small Breast very high very high

8 Cancer risks of particular organs differ dramatically depending on Gender Life style factors Age at exposure Attained age Race

9 In the RERF Study on radiation-induced excess solid cancer cases in 55 years among >100,000 A-bomb survivors Total: 853 cases (10.7%) Total Deaths from radiationinduced cancers and non-cancer diseases up to 2003: solid cancers (60%) 353 non cancer diseases (40%)

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12 Preston et al.: LSS cancer incidence

13 Preston et al.: LSS cancer incidence

14 Preston et al.: LSS cancer incidence

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16 Besides the Life Span Study and the Adult Health Study, dedicated follow-up studies on patients who were treated with ionising radiation for benign and malignant diseases provide important additional information on organ specific cancer and non-cancer risks. Studies which aim at direct determination of risks from specific diagnostic procedures are unlikely to provide any new information because of uncertain dosimetry and unsystematic follow-up

17 Follow-up studies of patients treated for benign diseases Ankylosing spondylitis, mean dose 3Gy, leukaemia, lung ca, colon ca., stomach ca Peptic ulcer, mean dose to heart up to 3Gy, lung ca, heart diseases Tinea capitis, mean thyroid dose <0.5Gy, thyroid ca, neurocognitive disorders Haemangiomas doses ranging from 0.1-several Gy, cancers, in particular breast ca

18 The most comprehensive review: Second primary cancers and cardiovascular disease after radiotherapy. Report Nr 170 NCRP 2011 The report describes on more than 400 pages the radiation biology, the radiation physics and dose reconstruction and the epidemiological evidence for these late complications of radiotherapy. A short version has been published as: Second malignant neoplasms and cardiovascular disease following radiotherapy L.B.Travis et al. J.Natl.Cancer Inst. 2012; 104:

19 Second malignant neoplasms and cardiovascular disease following radiotherapy L.B.Travis et al. J.Natl.Cancer Inst. 2012; 104: The problem: 1. The 5-year survival rate for all cancers combined reached 66% for patients diagnosed during As of 2007, there were approximately 12 million men and women in the US, 3.5% of the US population with a history of cancer. 3. Multiple primary cancer now account for approximately one in six incident cancers.

20 Second cancers after radiotherapy of malignant diseases If a patient who had been cured from malignant disease by radiotherapy, several years later developed a second cancer which clearly is not a late metastasis or loco-regional recurrence, this could be from the following causes: spontaneous, independent new cancer. Since the cumulative risk of cancer in the general population is high ( 30%) the probability of having two independent cancers is not negligible and increases strongly with age although the probability decreases if the interval between first and second cancer is short. the first and the second cancer are the consequences of the same carcinogen: e.g. smoking (lung, bladder, head and neck) genetic predisposition, e.g. due to mutations such as BRCA (breast and ovary), endocrine cancer syndrome, RB (retinoblastoma and osteosarcoma) radiation-induced ( or induced by chemotherapy plus radiotherapy )

21 Incidence per people AVERAGE ANNUAL CANCER INCIDENCE IN UK BY AGE GROUP male female Age group

22 age related spontaneous cancer incidence risk of patients treated at given age diagnosed within the a follow-up period of 5 years (data from UK, England and Wales ) age at treatment cancer risk within the next 5 years males females % 2 % % 2.7 % 60 5 % 3.6 % 65 7 % 4.6 % % 5.4 % % 6.3 %

23 Second cancers after radiotherapy of malignant diseases Studies on the risk of second cancers after radiotherapy of malignant diseases can be performed if: the first cancer has a high probability of cure and if there is a comparison group of patients with the same cancer but without or with very low doses of radiotherapy. Comparison with the cancer rates in the normal population are not suited and are likely to be biased ( e.g. studies on second cancers after radiotherapy of Hodgkin s disease ) Methods which can be used: case control study cohort study The types of first malignancies where this has been studied: o Cancer of the cervix o Prostate cancer o Breast cancer

24 Second cancers after radiotherapy of prostate cancer Brenner et al., Cancer 88: (2000) Study design: cohort study on 122,123 patients with prostate cancer registered in the SEER programme (The National Cancer Institute s Surveillance, Epidemiology and End Results Programme) who were either operated or irradiated. operated irradiated number of patients 70,539 51, 584 person-years at risk 312, ,341 mean survival time 4.4 years 4.2 years mean age at therapy 71.4 years 70.3 years mean age at second cancer 77 years 75.3 years % of persons at risk after 5 10 years 35.8% 33.5% > 10 years 10.8% 9.8%

25 Second cancers after radiotherapy of prostate cancer Brenner et al., Cancer 88: (2000) operated irradiated second malignancies at all times after treatment after > 5 years after > 10 years Relative Risk after > 5 years after > 10 years all second cancers 1.11 p< p<0.002 bladder 1.55 p< p<0.01 rectum 1.35 p< p<0.03 Leukaemia in the first 10 years (ten years being the mean life expectancy of a cured prostate cancer patient) operated patients irradiated patients 39 in person-years 25 in person-years O/E = 2 (p<0.05) the absolute risk of radiation-induced leukaemia is 0.1%

26 Second cancers after radiotherapy of prostate cancer Brenner et al., Cancer 88: (2000) Out of the approximately 17,000 prostate cancer patients who survived more than five years after curative radiotherapy, developed a second primary cancer. More than 1,000 of those second cancers are due to cure from the first cancer and the subsequent increased life span of the cancer patients. Approximately 120 to 150 of those second cancers among 51,584 prostate cancer patients are related to radiotherapy, i.e.: approximately 50 cases of bladder cancer approximately 15 cases of cancer of the rectum approximately 50 cases of lung cancer approximately 12 cases of leukaemia

27 Second cancers after postoperative radiotherapy of breast cancer Darby, S.C. et al. Lancet oncology 6: (2005) Study design: cohort study using 308,861 women included in the US surveillance, epidemiology and end results (SEER) programme who were treated for breast cancer between 1973 and ,165 (37%) had received radiotherapy as part of primary treatment. 1,459 women later developed lung cancer for which laterality was clearly defined in the records. The main endpoint was the laterality of second lung cancer in relation to the laterality of breast cancer. Results: 1,064 cases of lung cancer occurred in women who did not receive radiotherapy, 512 were ipsilateral, 534 were contralateral. 431 cases of lung cancer occurred in women who received radiotherapy, of these were 262 cases ipsilateral and 169 contralateral. The proportion of ipsilateral second lung cancers in women who had received radiotherapy increased with increasing follow-up time: follow-up time second cancers lung cancer mortality years ipsilateral contralateral ratio < >

28 Dose to the contralateral breast from radiotherapy and risk of second primary breast cancer in the WECARE study Marilyn Stovall et al. Int.J.Radiat.Oncol.Biol.Phys. 72: (2008) Case control study on 708 cases (women with asynchronous bilateral breast cancer) and 1399 controls, all < 55 years old at treatment of 1st ca. Doses to quadrants of the contralateral breasts calculated. Results: Women <40 years who received a radiation dose >1Gy to the contralateral breast had an elevated long term risk of developing a second primary breast cancer. Relative Risk 2.5! No increase in women >40 years.

29 The proportion of second cancers attributable to radiotherapy treatment in adults: a prospective cohort study in the US SEER cancer registries Amy Berrrington de Gonzales et al. Lancet Oncology 2011: The largest and most important study on the second cancer risk from radiotherapy in adult patients: Cohort study in five year adult survivors, with second cancers. Question: in which first cancers is this risk particularly high?

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31 Second primary cancers after adjuvant radiotherapy in early breast cancer patients: Danish Breast Cancer Cooperative Group Trine Grantzau et al., Radiother.Oncol 106:42-49 (2013) A Danish Cancer Registry based cohort study on 46,176 breast cancer patients treated with/without postoperative radiotherapy according so sequential national protocols between 1982 and Second cancers (excluding second breast cancers) were identified in the Danish Cancer Registry Study was part of the EU ALLEGRO Project) Results: yes Radiotherapy no Patients 23,627 22,549 Median Latency so SPM 6 years 7 years All second cancers 2,595 Second cancers on potentially Irradiated sites 1,148 SIRs after different follow-up were calculated

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33 Second primary cancers after adjuvant radiotherapy in early breast cancer patients: Danish Breast Cancer Cooperative Group Trine Grantzau et al., Radiother.Oncol 106:42-49 (2013) Conclusion: In absolute numbers, the risk of developing a radiationinduced second lung cancer remains relatively low and is equivalent to one radiation-induced cancer for every 200 women treated with radiotherapy. A similar number is also estimated for radiationinduced fatal cardiac disease after treatment of breast cancer.

34 Stem cell biology with respect to Carcinogenesis ICRP draft report for consultation July 2014 Summary: The target cells for carcinogenesis continue to be considered primarily the tissue stem cells. In haematopoietic tissue, colonic mucosa and epidermis, there is some evidence for progenitor cells being target cells as well. The microenvironmental niche is an important regulator of stem cell maintenance and a modifyer of stem cell response. Carcinogenesis depends primarily on three factors: (1) the number and sensitivity of stem cells to radiation-induced mutation, (2) the rentention of mutated stem cells in a tissue, (3) the population size of stem cells with a sufficient number of predisposing mutations.

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36 Risk of second primary lung cancer in women after radiotherapy for breast cancer T.Grantzau et al., Radiother.Oncol. 111: (2014) A case-control study nested in the population-based cohort of early breast cancer patients. Cases were 151 cases of second primary lung cancer Compared with 443 individually matched controls Individual dose reconstructions were performed and the dose delivered to the centre of the second lung cancer determined (and the same location in controls). Relative risk of second lung cancer increased by 8.5% per Gy.

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38 The risk of therapy-induced second cancers is critically high after treatment of children

39 Second malignant neoplasms and cardiovascular disease following radiotherapy L.B.Travis et al. J.Natl.Cancer Inst. 2012; 104: The cumulative incidence of all subsequent neoplasms at 30 years after diagnosis of childhood cancer was 20% among 5-year survivors and was higher for those who received radiotherapy than for those who did not (25% versus 10%) Patients who developed a second neoplasm had a cumulative incidence of developing yet another primary cancer by 20 years after the SMN of 46%. The highest absolute excess risk (excess cases per personyears) were observed for bone (22) thyroid (18) and breast (17).

40 The Childhood Cancer Survivor Study Neglia J.S. et al., J. National Cancer Institute 93: (2001) Retrospective cohort of 13,581 children, treated for cancer and surviving more than 5 years. Mean age at treatment 8 years. 298 patients developed new second cancer. Mean interval to second cancer 13 years. Standard incidence ratio 6.4. The largest excess was for bone cancers (SIR 20) and breast cancer (SIR 16) Twenty years after the childhood cancer diagnosis, the cumulative estimated cancer incidence was 3.2 %. Relationship to radiotherapy not studied but significant effect of chemotherapy using alkylating agents.

41 French English Childhood Cancer Survivor Study De Vathaire et al. Brit.J.Cancer 79: (1999) Cohort study on 4,400 three years survivors of childhood cancer treated before ,949 received chemotherapy 3,109 received radiotherapy (in full dose reconstruction!) 1,056 received radiotherapy only 880 received chemotherapy only Mean age at first treatment 6 years Mean follow-up 15 years (3-48 years) Lost to follow-up 532 (12%) Died 578 (13%) Follow-up >20 years 1,062

42 French English Childhood Cancer Survivor Study De Vathaire et al. Brit.J.Cancer 79: (1999) All second solid tumours 113 Time since treatment relative risk excess absolute risk 3 9 years per 10,000 PY years years 6 27 Types of second cancers Sarcomas 55 mainly after combined RT/CT Thyroid 14 after RT and CT Breast 13 after RT and CT Brain 12 after RT and CT

43 French English Childhood Cancer Survivor Study New Analysis 2011 Tukenova M, and 11 others, senior author de Vathaire. Int J Radiation Oncology Biology Physics 80: , (2011) Types of fatal cancers: Carcinomas: cumulative mortality steadily increasing with follow-up, 45 years from diagnosis of first cancer 4.5% Sarcomas: death rates increase in the first 20 years and then plateau.

44 French English Childhood Cancer Survivor Study Diallo, I. and 10 other authors, senior author F.de Vathaire, International Journal of Radiation Oncology Biology Physics 74: (2009) Location of second cancers in relation to dose Fatal second cancers Location in beam border distant all (115) sarcomas (52) breast ca (13) CNS (10) thyroid (17)

45 US Childhood Hodgkin Survivor Study Constine L and 13 other authors. Int.J.Radiat.Oncol.Biol.Phys. 72:24-33 (2008) 930 children (mean age 13 years) treated for Hodgkin s disease between 1960 and Mean follow-up 17 years. 43% received radiotherapy alone, 48% radiotherapy plus chemotherapy Second cancers occurred in 102 patients, expected number based on national statistics 7 cases. 15 years actuarial survival incidence rate 19 %.

46 US Childhood Hodgkin Survivor Study Constine L and 13 other authors. Int.J.Radiat.Oncol.Biol.Phys. 72:24-33 (2008) Types of second cancer Females Males (398) (532) All Breast Thyroid Gastrointestinal Leukaemia Lymphoma Sarcoma

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48 G. Schellong et al. (2014): Brustkrebs bei jungen Frauen nach Therapie eines Hodgkin Lymphoms im Kindes- und Jugendalter. Deutsches Ärzteblatt 111: 3-9 Long-term follow-up of 590 female patients treated in childhood or adolescence for Hodgkin s disease within 5 consecutive randomized clinical trials between 1975 and Median follow-up 17.8 years, maximal follow-up 33.7 years 26 primary breast cancers diagnosed, between 14 and 31 years after radiotherapy. 25/26 were located in the treatment field which received between 20 and 45 Gy. The cumulative incidence of breast cancer at an attained age of 40 years was 10%, the standard incidence ratio was 25. The risk in women developing breast cancer after radiotherapy for Hodgkin s disease is similar to the risk of women carrying a BRCA-1 mutation.

49 G. Schellong et al. (2014) Reported cumulative incidences for secondary breast cancers from studies on childhood cancer. Deutsches Ärzteblatt 111: 3-9

50 G. Schellong et al. (2014) Reported cumulative incidences for secondary breast cancers from studies on childhood cancer. Deutsches Ärzteblatt 111: 3-9 The influence of age at irradiation on the risk of developing radiation associated breast cancer: 480 children were between 9 and 16 years old when irradiated. All breast cancers occurred in this group 74 children were less than 9 years old at irradiation. No breast cancer was found (so far). Hypothesis: the age period of 9 to 16 years covers the time of puberty which is characterized by pronounced proliferation and spreading of mammary gland cells making the developing breast particularly sensitive to the carcinogeneic action of radiations.

51 G. Schellong et al. (2014) Reported cumulative incidences for secondary breast cancers from studies on childhood cancer. Deutsches Ärzteblatt 111: 3-9 A multimodal screening programme after chest wall irradiation for pediatric cancers in women was established for these patients: Starting at the attained age of 25 years Clinical examination of the breasts and ultrasonography every 6 months MRI of the breast every year In cases of doubtful findings, mammography after the age of 40 years Transfer to the routine mammography screening programme at the attained age of 50 years A similar programme was tested by M. Terenziani et al. In Milano and evaluated in Int.J.Radiat.Oncol.Biol.Phys. (2013) 85: 35-39

52 conclusions After treatment of childhood cancers today, more patients die from therapy-induced second malignancies than from the treated primary cancer. Radiotherapy is a major contributor to the high risk of second cancers in cured patients. The risk appears to be related to the dose distribution in the patient. Question: Are protons the solution to this problem or are they part of the problem?

53 Evidence for radiation-induced malignant diseases after exposure in utero Studies of medical exposure to diagnostic x-rays during pregnancy are important because of the possibility that the developing fetus may be more susceptible to the carcinogenic effects of ionizing radiaation than the adult or the young child. The Oxford survey of childhood cancers was the first (published in 1958) and is still the largest study to find an association between obstetric x-rays and childhood cancer. Results were last thoroughly evaluated by R. Mole, Brit. J. Cancer 62: (1990)

54 The Oxford Survey of Childhood Cancer Study design Each child known to have died with cancer in England, Wales and Scotland is linked with another living child of the same sex, the matched control, born in the same civil administrative district in which the death occurred and with a closely similar birth date. Using a standard questionnaire the same person interviews both mothers (e.g. whether and when she had been X-rayed during pregnancy), validated through hospital records. The recorded X-rayings are diagnostic examinations involving abdominal or pelvic exposures.

55 No evidence for radiation-induced malignant diseases after exposure in utero in A-bomb survivors In the A-bomb survivors exposed in utero to on average 0.2 Sv no increase in childhood cancer was observed. It is noteworthy that excess relative risks after in utero exosure have only been found in case-control studies, not in cohort studies. Averaged over the first 35 years of follow-up ( ), the life span study mortality data suggest that the excess relative risks per Sievert in survivors of the atomic bombings who were less than 10 years old when exposed are appoximately 17 for leukaemia and 2 for other cancers.

56 The risk of radiation-induced malignant diseases after exposure in utero Studies of in utero exposure have given a wide range of risk estimates. Since there is no biological reason to assume that the embryo or fetus is resistant to the effects of ionizing radiation, and in particular to leukaemogenesis, the finding of a positive risk after appreciable dosis is to be expected. However, on the basis of present data, the exact quantification of the risk is subject to much uncertainty.

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