Monday, August 13, 2007

Radiation and CLL

Although ionizing radiation is a well known cause of leukemia, most papers alluding to the topic exclude chronic lymphocytic leukemia (CLL) from consideration since it is believed to be well-established that CLL is not caused by radiation [1]. Just how secure is this assumption?

The primary data come first from studies of atom bomb survivors at Hiroshima and Nagasaki [2-4]. Only ten cases of CLL were identified in survivors between 1945 and 1980, and of those ten, seven turned out to be acute T-cell leukemia/lymphoma (ATLL) when examined more closely. ATLL is endemic in the area around Nagasaki being associated with infection with the human T-cell lymphotropic virus type I (HTLV-1). These findings point out two of the hazards in interpreting the epidemiological data: CLL is an extremely rare diagnosis among those who were bombed (and indeed amongst the Japanese in general), and the definition of CLL has changed down the years. Many who would have been diagnosed as CLL in the past are now recognized as having different sorts of lymphoid malignancies, and since, even as recently as 1975, the diagnosis of CLL required a lymphocyte count of over 15 x 109/L [5], many low count cases would have gone unrecognized.

The second primary sources of data come from studies of patients treated with ionizing radiation for benign conditions. The initial study [6] of 14,000 British patients with ankylosing spondylitis treated with radiotherapy between 1935 and 1954 with an average bone marrow dose of 4,400 mSv showed an excess of acute leukemia and chronic myeloid leukemia in the first five years post-irradiation, but no excess of CLL. It is believed that CLL have a very long latent period, making a follow-up of less than two decades unacceptable, but later reports of this study in 1994 and 1995 [7, 8] found only seven deaths attributable to CLL, and while this was greater than expected, it was not significantly so. Similarly, a study of 12,955 women irradiated for benign gynecological disorders found no significant excess of CLL-related deaths [9].

These studies illustrate other difficulties in the epidemiological data. CLL is seldom recorded as a cause of death in patients who have been diagnosed with it. For many patients, especially those with mutated IgVH genes, it is a very trivial condition that never causes ill health. The traditional methods by which epidemiologists acquire cases – from death certificates and hospital admissions – are ineffective in CLL; many patients never require hospital admission and they die from causes unrelated to their CLL. In one series 75% of cases were diagnosed because they had a blood test for a different condition; presumably there are undiagnosed cases in the community who have not had blood tests.

A recent analysis of the Surveillance Epidemiology and End Results (SEER) database puts the annual incidence in the USA at 3.5 per 100,000 (males 5.0: females 2.5) [10]. However, the Leukaemia Research Fund Data Collection Study which gathered data from individual hematologists responsible for laboratories covering about one third of the population of England and Wales (rather than from death certificates and hospital admissions) found a higher incidence in the U.K. of 6.15 per 100,000, and even this concealed a variation between 1.3 and 13.7 per 100,000 in different health districts, largely dependent on how interested the local hematologist was in the disease. [11].

Although the US Energy Employees Occupational Illness Compensation Program refuses to acknowledge any claims that CLL is radiation induced [12], this establishment view has recently been challenged. Although they present no new data, Richardson et al [13] argue that the data are insufficiently compelling to make this assumption and that the molecular lesions in CLL are sufficiently similar to those in other leukemias, that the presumption should be that radiation can cause CLL unless there are convincing data to the contrary. They argue that the epidemiological studies are simply too weak to carry that burden. On the other hand it should be recognized that one of the co-authors of this paper is the Executive Secretary of the Preparatory Commission for the Comprehensive Nuclear-Test-Ban Treaty Organization and another is the recipient of the 2003 Nuclear-Free Future lifetime achievement award.

Relatively new data are available form a study of Czech uranium minors[14]. This study intended not to miss cases by looking at incidence rather than mortality, and ensuring that subjects had annual blood tests. An earlier abstract [15] from this group had claimed on the basis of 41 cases that the incidence among miners employed for at least one year underground was significantly greater than the general Czech polulation. But, then, the general Czech population does not have a blood test every year. This publication reports a higher incidence of CLL among those exposed to greatest quantity of radon. Unfortunately, the same study did not show a significant increase of myeloid leukemias asociated with a higher exposure to radon, which would have been more likely according to previous experience, nor a significant increase in cases of non-Hodkin’s lymphoma which would have fitted better with the hypothesis of Richardson et al [13].

In an upcoming issue of Leukemia Research Abramenko et al [16] report the first study of CLL in individuals exposed to radionuclides following the accident at the Chernobyl nuclear power plant. Previous published abstracts [17,18] have suggested CLL in Chernobyl clean-up workers occrred in younger patients and presented with more advanced symptoms, pursued a more aggressive course and was more resistant to standard agents than in patients not exposed to ionizing radiation. In this study 47 patients with CLL following exposure were compared with 141 patients without a history of exposure. The patients were examined more comprehensively than before and included the mutational status of IgVH genes among their investigations. Among the irradiated group 77.6% had unmutated IgVH genes, but surprisingly this was not significantly different from the non-irradiated group where the figure was 68.3%. Both were much higher than the figure of about 40% reported in most Western countries [19], and is probably explained by less assiduous screening in the control population and therefore the ommission of the more benign (and mutated) cases. In a sub-group among the clean-up workers who received the greatest dose of irradiation, all bar used germline IgVH genes and especially used the V1-69 and V3-21 genes that are associated with stereotypic B-cell receptors and poorer prognosis.

There was a significantly higher risk of second cancers and Richter’s syndrome among the irradiated group (as might be expected) and especially among those who received the highest dose of irradiation.

What do these new data amount to? They certainly do not establish that CLL may be caused or even made worse by ionizing radiation. On the other hand there is enough suspicion for the case to be sub-judice. Irradiation has been given a clean bill of health with respect to CLL with less than adequate evidence.

1. Zablotska LB, Ashmore JP, Howe GR. Analysis of mortality among Canadian nuclear power industry workers after chronic low-dose exposure to ionizing radiation. Radiat Res. 2004 ;161:633-41.

2. Finch SC, Hoshito T, Itoga T, Ichimaru M, Ingram Jr RH. Chronic lymphocytic leukemia in Hiroshima and Nagasaki, Japan. Blood 1969; 33: 79 – 86.

3. Preston DL, Kusumi S, Tomonaga M, Izumi S, Ron E, Kuramoto A. Cancer incidence in atomic bomb survivors. Part III. Leukemia, lymphoma and multiple myeloma, 1950-1987. Radiat Res 1994; 137: 68 – 97.
4. Ishimaru T, Hoshino T, Ichimaru M, Okada H, Tomiyasu T, Tsuchimoto T, et al. 1969. Leukemia in Atomic Bomb Survivors: Hiroshima and Nagasaki. TR-25-69. Hiroshima, Japan:Atomic Bomb Casualty Commission.
5. Rai KR, Sawitsky A, Cronkite ER, Chanana AD, Levy RN, Pasternack BS Clinical staging of chronic lymphocytic leukemia. Blood 1975;46:219-234.
6. Court-Brown W, Doll R. Mortality from cancer and other causes after radiotherapy for ankylosing spondylitis. Brit Med J 1965; 2:1327-32.
7. Weiss HA, Darby SC, Doll R. Cancer mortality following X-ray treatment for ankylosing spondylitis. Int J Cancer 1994; 59:327-38.
8. Weiss HA, Darby SC, Fearn T, Doll R. Leukemia mortality after X-ray treatment for ankylosing spondylitis. Radiat Res 1995; 142:1-11.
9. Inskip PD, Kleinerman RA, Stovall M, Cookfair DL, Hajimichael O, Moloney WC. Leukemia, lymphoma and multiple myeloma after pelvic tadiotherapy for benign disease. Radiat Res 1993; 135:108-24.
10. National Cancer Institute: SEER Cancer Statistics Review 1975-2001. Available at:
11. Cartwright RA, Bernard SM, Bird CC, Darwin CM, O´Brien C, Richards IC, Roberts B, McKinney PA. Chronic lymphocytic leukaemia: case control epidemiological study in Yorkshire. Brit. J. Haematol. 1987 56:79-82.
12. Department of Health and Human Services. $” CFR Parts 81 and 82. Guidelines for Determining the Probability of Causation and Methods for Radiation Dose Reconstruction Under the Employees Occupational Illness Compensation Program Act of 2000; Final Rules. Fed Reg 2002; 67:22295-314.
13. Richardson DB, Wing S, Schroeder J, Schmitz-Feurhake I, Hoffmann W. Ionizing radiation and chronic lymphocytic leukemia. Environ Health Perspect 2005; 113:1-5.
14. Rericha V, Kulich M, Reicha R, Shore DL, Sandler DP. Incidence of leukemia, lymphoma and multiple myeloma in Czech uranium miners: a case-cohort study. Environ Health Perspect 2006; 114:818-22.
15. Rericher V, Sandler DP, Shore DL, Solansky I, Hnizdo E Sram R. Non-lung cancer incidence in Czech uranium miners. [Abstract] Epidemiology 9:S99.
16. Abramenko IV, Bilous NI, Chumak AA, Davidova EI, Kryachok IA, Martina ZV, Nechaev SI, Dyagil IS, Bazyka DA, Bebeshko VG. Chronic lymphocytic leukemia patients exposed to ionizing radiation due to the Chernobyl NPP accident – with focus on immunoglobulin heavy chain gene analysis. Leuk Res 2008 (in press)
17. Klymenko V, Kryachok I, Dyagil I, Bazyka D, Bebeshko V. Some clinical and hematologic features of CLL in persons who suffered from the Chernobyl accident in Ukraine in 1986. CIII Int Workshop on CLL. Paris Oct 29-31 1999. Abstract book 1999:43.
18. Kryachok I, Polyshchuk O, Dyagil I, Abramenko I, Bazyka D, Bebeshko V. Comparative analysis of CLL in persons who suffered after Chernobyl accident and in unexposed CLL patients. Haematologica 2005; 90:454A
19. Montillo M, Hamblin T, Hallek M, Montserrat E, Morra E. Chronic lymphocytic leukemia: novel prognostic factors and their relevance for risk adapted therapeutic strategies. Haematologica 2005; 90:391-9.

1 comment:

Steve Madden said...

The conventional heteroskedasticity-robust (HR) variance matrix estimator for cross-sectional regression (with or without a degrees of freedom adjustment), applied to the fixed effects estimator for panel data with serially uncorrelated errors, is inconsistent if the number of time periods T is fixed (and greater than two) as the number of entities n increases.

Or to put it another way, we don't know :)