Arvin S. Glicksman

Comparison of maintenance treatment regimens for first central nervous system relapse in children with acute lymphocytic leukemia. A pediatric oncology group study

Eighty‐seven children with central nervous system (CNS) leukemia were randomized to receive either induction intrathecal chemotherapy (ITC) and cranial irradiation (CRT) plus maintenance ITC, or induction ITC and craniospinal irradiation (CSpRT) with no maintenance ITC. Induction ITC consisted of six weekly injections of methotrexate, hydrocortisone, and arabinosylcytosine. Also, intensification of systemic induction and maintenance chemotherapy was given. CRT + ITC was given as CRT, 2400 rad in 12 fractions followed by ITC maintenance bimonthly for 2 years. Craniospinal irradiation consisted of CRT + 1400 rad in ten fractions to the spine. Randomization was stratified according to whether CNS leukemia occurred at initial diagnosis of acute lymphocytic leukemia (ALL) (Stratum I, 15 patients), during first bone marrow (BM) remission (Stratum II, 49 patients), simultaneous with first BM relapse (Stratum III, 12 patients), or during second BM remission (Stratum IV, 11 patients). The median follow‐up for patients who remain at risk is 15 + months. Eight children (seven on CRT + ITC, one on CSpRT) developed presumed therapy related encephalopathy. In Stratum II, 16 of 29 (55%) patients receiving CRT + ITC experienced adverse events: 3 deaths during continuous complete remission (CCR) and 13 relapses (2 CNS, 1 CNS + BM, 7 BM, 1 BM + testes, and 2 testes) as compared with only 5 relapses in 20 (25%) patients on CSpRT (1 CNS, 1 CNS + BM, 1 BM, and 2 testes). The children on both regimens were comparable for sex, race, age at initial ALL diagnosis, time from ALL diagnosis to first episode of CNS leukemia, systemic therapy both before and after CNS relapse, and number of blasts in the spinal fluid at diagnosis of CNS leukemia. The conclusion is that children with isolated CNS leukemia can achieve prolonged survival with aggressive therapy, and that CSpRT is possibly less toxic and more likely than is CRT + ITC to prevent subsequent BM and testicular relapse (P < 0.02), but not subsequent CNS relapse (P = 0.7). A possible systemic therapy effect of spinal irradiation is postulated to explain the superiority of CSpRT.

Computerized tomography scan findings in children with acute lymphocytic leukemia treated with three different methods of central nervous system prophylaxis.

Computerized tomography (CT) scans of the head were done on 93 children with acute lymphocytic leukemia in continuous complete remission who had been randomly assigned to three different methods of central nervous system (CNS) prophylaxis. Twenty‐nine children had received six doses of intrathecal methotrexate, 30 had received six doses of intrathecal methotrexate plus 2400 rad of cranial irradiation, and 34 had received six doses of intrathecal methotrexate plus three courses of intermediate‐dose intravenous methotrexate. The overall incidence of abnormal scans was 35%, of which 91% were felt to represent minimal abnormalities. CT scan abnormalities were noted in 30% of the children receiving intrathecal methotrexate only, in 40% of those receiving intrathecal methotrexate plus cranial irradiation, and in 35% of those receiving intrathecal methotrexate plus intermediate dose methotrexate. These differences were not statistically significant. None of the three methods of CNS prophylaxis resulted in significant CT scan abnormalities. However, the few moderately or markedly abnormal scans evaluated were restricted to patients who received intrathecal methotrexate plus cranial irradiation. The clinical significance of CT scan abnormalities in leukemic children receiving these treatments remains unclear.

Radiation myelopathy in the rat: an interpretation of dose effect relationships

Abstract Data were collected on the production of overt paralysis in the rat after low linear energy transfer (LET) ionizing radiation exposure of different regions of the spinal cord. Data from both single and multiple radiation exposure schedules were interpreted using the ED 50 value (estimated dose needed to produce 50% paralysis in a group of irradiated animals) as the isoeffect comparison dose. Plots were made of the reciprocal of the ED 50 total dose versus the size of the dose per fraction used. The use of multifractionation data in such a way allows implications to be made about the nature of the in vivo response curve. These reciprocal dose plots indicate that the spinal cord normal tissue system shows two responses that may be specifically characterized by the ration of the intercept (α) of the linear regression fit of the reciprocal total dose versus dose per fraction curve to the slope (β) of the curve (α/β). For rat spinal cord, this value is about 3.8 ± 0.4 (standard error) for the thoraco-lumbar region and about 2.0 ± 0.3 (standard error) for the cervical region. While absolute dose response data vary somewhat among investigators, all of the data on production of paralysis in rats show similar trends with respect to the (α/β). ratio. We feel that this ratio may uniquely characterize this (and other) normal tissue systems. Knowledge of this parameter and how it varies after different treatments (e.g., high LET radiation exposure) may be important.

Selective modification of the X ray survival response of two mouse mammary adenocarcinoma sublines by N,N-dimethylformamide

Abstract The modification of the X ray survival response of two mammary adenocarcinoma tumor cell sublines by the polar solvent N,N-dimethylformamide (DMF) has been studied. The sublines (termed lines 66 and 67) differ significantly in their single dose survival responses to x-irradiation. Survival responses were fitted to the single-hit, multi-target, and linear-quadratic equations. For non-DMF treated cells, line 67 radiation parameters were: D 0 ( Gy ) = 1.41, D q ( Gy ) = 1.41, n (extrapolation number) = 2.73, α (10 −1 Gy −1 ) = 2.83, and β (10 −2 Gy −2 ) = 4.17. For line 66, these values were D 0 = 1.63, D g = 3.01, n = 6.4, α = 0.45, and β = 4.28. For investigation of DMF effects, cells were seeded at 1 x 10 4 per 25 cm 2 tissue culture flask in a DMF concentration of 0.8 % (0.10 M) and allowed to multiply for 4 days. For line 67, this increased the cell culture doubling time by about 27 %, and for line 66, by about 22 %. Cells were still in exponential growth at the time of irradiation. Immediately prior to irradiation, the media was removed, fresh media added and flasks were exposed to 100 kVp X rays. After exposure, cells were removed by trypsinization, counted and replated at appropriate dilution in fresh media. The survival parameters for line 67 (the radiosensitive line) then became D 0) = 1.56, D q = 0.89, n = 1.77 , α = 3.39, and β = 3.49. For line 66 (the radioresistant line), the survival parameters were D 0 = 1.56, D q , = 0.94, n = 1.83, α = 4.14, and β = 2.41. These results indicate that DMF may have the potential for modifying the low dose “shoulder” region of survival, particularly for cell lines that possess large shoulders.

Augmented therapy of extensive hodgkin’s disease: radiation to known disease or prolongation of induction chemotherapy did not improve survival—results of a cancer and leukemia group B study

PURPOSE This prospective randomized trial in extensive untreated Hodgkins disease was undertaken to assess the potential benefit of augmented therapy (12 months chemotherapy or radiation to known disease) compared to standard 6 months chemotherapy. PATIENT AND METHODS A total of 258 patients, mostly Stage IV, were randomized to four treatment regimens consisting of six cycles of CCNU, vinblastine, procarbazine, and prednisone (CVPP); 12 cycles of CVPP; six cycles of CVPP followed by 25 Gy radiotherapy; or three cycles CVPP, 25 Gy radiotherapy, and three cycles CVPP. RESULTS Complete remissions were achieved in 65% of all patients. A 58% overall 5-year survival rate was obtained. Relapses in irradiated areas of known disease occurred in only 6% of responding patients. There was, however, no statistical difference in response frequency, disease-free survival, or overall survival among the four regimens. Elderly patients responded less frequently. CONCLUSION While radiotherapy provided control of local (known) disease, no impact on overall survival was apparent. Likewise, doubling the duration of chemotherapy did not improve response or survival. Augmentation of therapy with either radiotherapy or more chemotherapy in this study was of no benefit compared to the standard 6 months of treatment.

Polar solvent modification of X ray induced potentially lethal damage in heterogeneous human colon tumor cells in vitro

Two subpopulations of tumor cells (clones A and D) obtained from a human colon adenocarcinoma were examined for their sensitivities to x-irradiation as unfed, early plateau phase cultures. Both the single dose survival curves and the kinetics of potentially lethal damage recovery (PLDR) were determined for the two tumor lines. Also, possible modification of PLDR by N,N-dimethylformamide (DMF), which has previously been shown to enhance the radiosensitivity of exponentially growing tumor cells, was investigated by adding DMF (0.8% v/v) to plateau phase cultures immediately after irradiation, and determining effects on the extent of PLDR. For non-DMF treated cells, the survival curve parameters of the diploid (clone D) and aneuploid (clone A) lines were very similar. The single-hit, multitarget values for n, Do (Gy), and Dq (Gy) were: 7.9, 0.82, and 1.70 for clone D; and 10.6, 0.83, and 1.96 for clone A. Using initial survival levels of 3.5% (clone D) or 5.5% (clone A) to investigate PLDR, it was found that the increase in survival (surviving fraction ratio or SFR) for clone D was 2.2, while the SFR for clone A was 1.6. DMF did not change either the kinetics or extent of PLDR in these two tumor lines when added to cultures immediately after irradiation. Our results indicate that significant heterogeneity in PLDR exists between these closely related tumor subpopulations.

Modification of the response of mouse skin to X-irradiation by a polar solvent, N,N-dimethylformamide

The modification of the response of mouse skin to either single or split (24 hrs) graded doses of X rays by topically applied N,N-dimethylformamide (DMF) was investigated. DMF was applied daily for 5 days prior to irradiation. At a radiation dose level producing dry desquamation, DMF enhanced the X ray response by a factor of 1.3. Also, at the same level of response, the fraction of X ray dose repaired in 24 hours was 0.57, whereas for the DMF-treated and irradiated skin, this factor was 0.41, indicating a reduction of about 28% in subeffective damage repair. The times of maximal involvement of the skin reactions were not different in the X ray plus DMF treated mice versus mice receiving x-irradiation only. The data indicate that DMF is able to modify intrinsic radiation sensitivity of mouse skin epithelial cells, possibly through a reduction in the magnitude of the shoulder region of the survival curve.

Formation of iron clusters in a mucus‐like medium

In a recent paper based upon repeated magnetization studies done on the lungs of smokers and non‐smokers who have inhaled small quantities of iron oxide power, Cohen et al. claim that the dust clearance ability of the cigarette smoker’s lung is markedly impaired. A re‐interpretation of this data which casts doubt on the logic of Cohen’s conclusion was suggested by Sterling and is based upon the hypothesis that during the magnetization phase of Cohen’s experiment, iron oxide ’’clusters’’ were preferentially formed in the highly mucus‐filled environment of the smoker’s lung. In order to test the plausibility of this hypothesis, in‐vitro experiments have been performed to measure the mean ’’cluster’’ diameter of iron oxide powder in a mucus‐like liquid medium (methylcellulose) during and after magnetization as functions of the solution viscosity. Results of these measurements will be presented.

Modification of the Effects of Ionizing Radiation by Differentiation-Inductiona

The use of differentiation-inducing agents (DIAs) has been proposed as a possible means of altering the phenotypic expression of neoplastic cells; such alterations might then have an impact on the choice of therapeutic strategy.’ We have investigated the effects of two types of such agents (sodium butyrate: NAB; N,N-dimethylformamide or N-methylformamide: DMF or NMF) on the responses of both rodent and human tumor cells to X-irradiation, both in vitro and in v~vo.~-’ These agents do possess significant activity with regard to modification of cellular radiation sensitivity (TABLE 1) . The most important effect in vitro of both NAB and DMF/NMF is the decrease produced in the D, value of the tumor survival curve.’ Since radiotherapy is given in multiple small doses (e.g., 30 fractions), this increased sensitivity is precisely in the right dose region. If such increased killing were carried throughout a clinical treatment, even a small enhancement (e.g., 5 % ) could produce marked effects (about four logarithmic units increase in the number of cells killed). In vivo, an important result has been the observation that chronic administration of NAB or NMF results in essentially complete removal of hypoxic cells.’ Electrode measurements in vitro of NAB-adapted tumor cells suggest that the NAB treatment may be reducing metabolism; this reduction could then lead to effective “ reoxygenation” in vivo (J. Leith, unpublished data). In summary, the increased radiosentization, decreased proliferation, and altered hypoxic cell physiology observed in tumor cells treated with DIAs indicate that continued preclinical research into the combinations of DIAs with conventional cytotoxic agents is worth pursuing. Still, DIAs must be well characterized, as it is likely that individual agents will have unique properties. For example, DMF and NMF produce reductions of intracellular glutathione: while NAB produces a marked increase in such levels5 As glutathione metabolism may be an important factor in the extent of multi-drug resistance which occurs,9 this difference may have clinically important implications for strategies of therapy.

Portal film duplication using instant photography.

Abstract The duplication of radiographic images by conventional instant photography is widespread in diagnostic radiology. A similar technique has been devised for use in radiotherapy to produce good quality copies of localization and portal films. These copies have proven extremely helpful for maintaining quality control within the radiotherapy department and within the Cancer and Leukemia Group B (CALGB).