Radiation dose and leukemia risk in patients treated for cancer of the cervix.

To quantify the risk of radiation-induced leukemia and provide further information on the nature of the relationship between dose and response, a case-control study was undertaken in a cohort of over 150,000 women with invasive cancer of the uterine cervix. The cases either were reported to one of 17 population-based cancer registries or were treated in any of 16 oncologic clinics in Canada, Europe, and the United States. Four controls were individually matched to each of 195 cases of leukemia on the basis of age and calendar year when diagnosed with cervical cancer and survival time. Leukemia diagnoses were verified by one hematologist. Radiation dose to active bone marrow was estimated by medical physicists on the basis of the original radiotherapy records of study subjects. The risk of chronic lymphocytic leukemia, one of the few malignancies without evidence for an association with ionizing radiation, was not increased [relative risk (RR) = 1.03; n = 52]. However, for all other forms of leukemia taken together (n = 143), a twofold risk was evident (RR = 2.0; 90% confidence interval = 1.0-4.2). Risk increased with increasing radiation dose until average doses of about 400 rad (4 Gy) were reached and then decreased at higher doses. This pattern is consistent with experimental data for which the down-turn in risk at high doses has been interpreted as due to killing of potentially leukemic cells. The dose-response information was modeled with various RR functions, accounting for the nonhomogeneous distribution of radiation dose during radiotherapy. The local radiation doses to each of 14 bone marrow compartments for each patient were incorporated in the models, and the corresponding risks were summed. A good fit to the observed data was obtained with a linear-exponential function, which included a positive linear induction term and a negative exponential term. The estimate of the excess RR per rad was 0.9%, and the estimated RR at 100 rad (1 Gy) was 1.7. The model proposed in this study of risk proportional to mass exposed and of risk to an individual given by the sum of incremental risks to anatomic sites appears to be applicable to a wide range of dose distributions. Furthermore, the pattern of leukemia incidence associated with different levels of radiation dose is consistent with a model postulating increasing risk with increasing exposure, modified at high doses by increased frequency of cell death, which reduces risk.

Radiation dose and second cancer risk in patients treated for cancer of the cervix.

The risk of cancer associated with a broad range of organ doses was estimated in an international study of women with cervical cancer. Among 150,000 patients reported to one of 19 population-based cancer registries or treated in any of 20 oncology clinics, 4188 women with second cancers and 6880 matched controls were selected for detailed study. Radiation doses for selected organs were reconstructed for each patient on the basis of her original radiotherapy records. Very high doses, on the order of several hundred gray, were found to increase the risk of cancers of the bladder [relative risk (RR) = 4.0], rectum (RR = 1.8), vagina (RR = 2.7), and possibly bone (RR = 1.3), uterine corpus (RR = 1.3), cecum (RR = 1.5), and non-Hodgkin's lymphoma (RR = 2.5). For all female genital cancers taken together, a sharp dose-response gradient was observed, reaching fivefold for doses more than 150 Gy. Several gray increased the risk of stomach cancer (RR = 2.1) and leukemia (RR = 2.0). Although cancer of the pancreas was elevated, there was no evidence of a dose-dependent risk. Cancer of the kidney was significantly increased among 15-year survivors. A nonsignificant twofold risk of radiogenic thyroid cancer was observed following an average dose of only 0.11 Gy. Breast cancer was not increased overall, despite an average dose of 0.31 Gy and 953 cases available for evaluation (RR = 0.9); there was, however, a weak suggestion of a dose response among women whose ovaries had been surgically removed. Doses greater than 6 Gy to the ovaries reduced breast cancer risk by 44%. A significant deficit of ovarian cancer was observed within 5 years of radiotherapy; in contrast, a dose response was suggested among 10-year survivors. Radiation was not found to increase the overall risk of cancers of the small intestine, colon, ovary, vulva, connective tissue, breast, Hodgkin's disease, multiple myeloma, or chronic lymphocytic leukemia. For most cancers associated with radiation, risks were highest among long-term survivors and appeared concentrated among women irradiated at relatively younger ages.

[Fractionation and protraction in the intracavitary local irradiation of gynecological tumors (author's transl)]. / Fraktionierung und Protrahierung bei der intrakavitären Lokalbestrahlung gynäkologischer Tumoren.

The difficulties of dosage and temporary adaptation of the short time afterloading therapy to an optimal healing result combined with a minimum of side-effects in radiotherapy of gynecological tumors aren't still solved yet. Only a therapy scheme which parts from the good results of the long term radium therapy in combination with an adequately dosed and distributed deep therapy has a chance to replace the radium therapy of gynecological tumors in the long run.

[Radiotherapy of cervical carcinoma]. / Die Strahlentherapie des Zervixkarzinoms.

Refering to the "Annual Report on the Results of Treatment in Gynecological Cancer" it is pointed out, that there is still no agreement concerning the kind of treatment of stage I and a part of stage II patients. In stage I patients most of the clinics use primarily operation. In stage II still an important number of the patients are operated, too. There is no certain difference in the 5-years figures between operation and radiation treatment. In stage III and IV patients mostly get radiation treatment. In the radiation treatment there is a trend to use afterloading instead of Radium. In external radiation more and more clinics use accelerators. Using these new application forms there is no evidence that the indication rather for primary operation or radiation treatment would have changed. There is still a slight increase of the 5-years figures but at the same time there is also a tendency for increase of the better stages.

[Experience with the conversion from radium therapy to an afterloading procedure with special reference to spatial dose distribution]. / Erfahrungen bei der Umstellung der Radiumtherapie auf ein Afterloadingverfahren unter besonderer Berücksichtigung der räumlichen Dosisverteilung.

In radium therapy, the spatial and temporal dose distribution have never been identical in the different hospitals. However, the healing results did not vary correspondingly despite the partly great methodical differences between German and foreign hospitals. Furthermore, the spatial and temporal dose distribution in radium therapy did not conform to theoretic considerations but were a result of the low specific activity of radium as well as of the technical standard of X-ray therapy units until the sixties. It is shown that all requirements valid for radium therapy are also fulfilled by the afterloading method using a linear ray emitter, if an adequate dosage and fractionation is chosen. Taking into account the radiation risk, we think that the radium must be replaced by an afterloading method using a less dangerous nuclide. In our opinion the high dose rate technique is the most favorable method.

[Value and importance of intracavitary therapy in cervix carcinoma]. / Wert und Wertigkeit der intrakavitären Therapie beim Kollumkarzinom.

The guiding topic of this report was "the value and importance of intracavitary therapy in uterine cervix carcinoma". This implies first of all the task to assess the importance of contact therapy within the scope of all therapeutic measures taken in case of uterine cervix carcinoma. Furthermore it was necessary to compare the importance of the different methods of contact therapy: conventional radium therapy as well as low dose rate and high dose rate afterloading techniques. As to surgical intervention, it is clear that only favorable stages can be taken into consideration for this treatment. It is shown by means of data taken from the Annual Report, Vol. 18, that a considerable number of patients with uterine cervix carcinoma I are irradiated even in hospitals whose field of activity lies preponderantly in surgery, and that by far most of the patients cured from uterine cervix cancer owe their recovery to contact therapy. The consideration of contact therapy methods shows clearly that radium should no longer be used in clinical practice. Psychological doubts often hinder the decision if long-term or short-term afterloading therapy is to be applied. It is therefore shown that the very different forms of radium therapy with their chronological and spatial dose distribution were due to the characteristics of radium (e.g. little specific activity) or to other compelling features and that they were not based on radiobiological aspects. The radium dose values obtained by empirical research and the resulting spatial and chronological dose distribution are therefore not imperative. So it is not inevitable to choose the low dose rate afterloading method. On the contrary, the high dose rate technique with an adequate fractionation is very probably the method of choice. To sum up it can be said that contact therapy is still the most important therapeutic method in uterine cervix cancer.

[Dose calculations for local irradiation of endometrial carcinoma]. / Dosisberechnungen bei der lokalen Bestrahlung des Endometriumkarzinoms.

A program for a personal computer has been developed to calculate and optimize dose distributions around a high dose intracavitary afterloading applicator having a single source. The problems of the local irradiation of the endometrium-carcinoma are emphasized in connection with the optimization criteria for an adequate irradiation planing. Exemplarily, the anisotropic proportions of absorption around a special type of applicator are calculated. In addition, an algorithm for optimization of dwell times of three-dimensional arranged source positions according to a prescribed dose distribution is theoretically presented. Further, an easy way of finding isodosis by given source positions and dwell times is introduced by taking into consideration the need to superimpose the dose distribution with external radiation fields. All calculations are tested in a water phantom.

[The influencing of rat-tail tumors with and without irradiation]. / Beeinflussung von Rattenschwanztumoren durch Antikoagulantien mit und ohne Bestrahlung

In a collective of 200 Wistar rats, the influence of anticoagulants upon the rat tail tumor (Walker 256 carcinosarcoma) was checked with and without irradiation. After implantation of the tumor and development of a certain definite tumor volume, the animals were divided into four different groups of 50 rats each. The first one was the control group without any manipulation, the second received an one-stage X-irradiation with 2500 R SD directed to the tail tumor, the third was treated with an oral dose of Phenprocoumon which was added to the daily drinking quantity (0.1 mg/kg body weight), and the fourth group was given an one-stage X-irradiation together with the oral Phenprocoumon treatment. The influence of these different treatments on the growth of the primary tumor, on the incidence of metastases and on the death rate was checked up. The best therapeutical effect was observed with combined radiation and Phenprocoumon treatment. The therapy resulted in an almost complete growth rate depression of the primary tumor, in an early tendency of remission of the primary tumor, a 42 per cent decrease of the incidence of metastases to the lung, and a 42 per cent increase of the survival rate. With regard to the frequency of metastases and to the survival rate, treatment with Phenprocoumon alone showed significantly better results as sole radiation treatment.

[Experience in peritoneography, for the prevention of the primary complications during intraperitoneal instillation of radiogold]. / Erfahrungen mit der Peritoneographie zur Vermeidung primärer Komplikationen bei der intraperitonealen Radiogoldinstillation

Prior to intraabdominal radiogold therapy of the ovarian carcinoma, at the gynecologic clinic of the university of Göttingen and at the gynecologic and obstetric center at Giessen a peritoneography is made. If the distribution of the contrast solution is homogeneous within the abdomen, a homogeneous distribution of activity can also be expected after the radiogold instillation. By means of the peritoneography it is possible to see incorrect punctures into the abdominal walls, into the intestine, into the retroperitoneal space, or into peritoneal conglutinations before the radiogold instillation. Peritoneography, therefore, contributes to a reduction of the early complications of the radiogold therapy. The method used in peritoneography at Göttingen and the method of Giessen are described. The first one (Göttingen) is more comfortable for the patient, as it necessitates less changes of position; the other (Giessen) is a little more economical. A suitable cannula for puncture is described.

Radiation dose and breast cancer risk in patients treated for cancer of the cervix.

The relationship between breast cancer and radiation treatment for cervical cancer was evaluated in an international study of 953 women who subsequently developed breast cancer and 1,806 matched controls. Radiation doses to the breast (average 0.31 Gy) and ovaries (average 32 Gy) were reconstructed for exposed subjects on the basis of their original radiotherapy records. Overall, 88% of the breast cancer cases and 89% of the controls received radiation treatment [relative risk (RR) = 0.88; 95% confidence interval (CI) = 0.7-1.2]. Among women with intact ovaries (561 cases, 1,037 controls), radiotherapy was linked to a significant 35% reduction in breast cancer risk, attributable in all likelihood to the cessation of ovarian function. Ovarian doses of 6 Gy were sufficient to reduce breast cancer risk but larger doses did not reduce risk further. This saturation-type response is probably due to the killing of a critical number of ovarian cells. Cervical cancer patients without ovaries (145 cases, 284 controls) were analyzed separately because such women are at especially low natural risk for breast cancer development. In theory, any effect of low-dose breast exposure, received incidentally during treatment for cervical cancer, should be more readily detectable. Among women without ovaries, there was a slight increase in breast cancer risk (RR = 1.07; 95% CI = 0.6-2.0), and a suggestion of a dose response with the RR being 1.0, 0.7, 1.5 and 3.1 for breast doses of 0, 0.01-0.24, 0.25-0.49 and 0.50+ Gy, respectively. However, this trend of increasing RR was not statistically significant. If low-dose radiation increases the risk of breast cancer among women over age 40 years, it appears that the risk is much lower than would be predicted from studies of younger women exposed to higher doses.