Seymour H. Levitt

Radiation-induced vascular damage in tumors: implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS).

We have reviewed the studies on radiation-induced vascular changes in human and experimental tumors reported in the last several decades. Although the reported results are inconsistent, they can be generalized as follows. In the human tumors treated with conventional fractionated radiotherapy, the morphological and functional status of the vasculature is preserved, if not improved, during the early part of a treatment course and then decreases toward the end of treatment. Irradiation of human tumor xenografts or rodent tumors with 5–10 Gy in a single dose causes relatively mild vascular damages, but increasing the radiation dose to higher than 10 Gy/fraction induces severe vascular damage resulting in reduced blood perfusion. Little is known about the vascular changes in human tumors treated with high-dose hypofractionated radiation such as stereotactic body radiotherapy (SBRT) or stereotactic radiosurgery (SRS). However, the results for experimental tumors strongly indicate that SBRT or SRS of human tumors with doses higher than about 10 Gy/fraction is likely to induce considerable vascular damages and thereby damages the intratumor microenvironment, leading to indirect tumor cell death. Vascular damage may play an important role in the response of human tumors to high-dose hypofractionated SBRT or SRS.

Prognostic significance of mediastinal involvement in Hodgkin's disease treated with curative radiotherapy

We evaluated the prognostic significance of mediastinal involvement in Hodgkins disease in 79 consecutive newly diagnosed patients treated with curative‐intent, nodal radiotherapy. Mediastinal masses were classified large or small depending on whether the ratio of the largest transverse diameter of the mass to the transverse diameter of the thorax at T5–6 was >.35. Forty‐eight patients had mediastinal disease; 20 had large masses, and 28 small masses. Complete remissions were achieved in 19 patients with large masses, 26 with small masses and all patients with no mediastinal masses. Relapses have occurred in 74% of patients with large masses but in only 27% with small masses and 19% without masses (P < .001). This high recurrence rate among patients with large masses could not be explained by other known adverse prognostic factors. Survival was adversely influenced by mediastinal mass size (P = .03). We conclude that curative‐intent, nodal irradiation is inadequate therapy for patients with large mediastinal masses. Controlled studies are needed to determine if survival can be improved by the addition of chemotherapy or whole lung irradiation.

IMPACT OF DELAY IN DIAGNOSIS ON CLINICAL STAGE OF TESTICULAR CANCER

Abstract Of 335 patients with germ-cell testicular cancer, 87·5% of the patients had symptoms related to the testis. Only 40% of the patients saw a physician within 2 weeks. Similarly, testicular signs were present in more than 90% of patients, but in only 61% of patients was a correct diagnosis made within 2 weeks of the initial physician visit. The length of the patient-related and physician-related delay was directly related to the clinical stage of the cancer at diagnosis. The median patient-plus-physician delay for stage I was 75 days, for stage II, 101 days, and for stage III, 134 days (p=0·017). Education programmes for the public and for physicians are needed to reduce delay in diagnosing testicular cancer.

Long-term cardiac mortality following radiation therapy for Hodgkin's disease: analysis with the relative seriality model☆

PURPOSE (a) To assess the increased risk of death due to ischemic heart disease (IHD) in a group of patients treated for Hodgkins disease (HD) with radiation therapy (RT) as the primary treatment. (b) To quantify the dose response of IHD using a biophysical model. MATERIALS AND METHODS Patient material consisted of 157 patients diagnosed for HD between 1972 and 1985 who received RT as the primary treatment at Radiumhemmet, Karolinska Hospital. The general population formed the control group. The RT treatments were reconstructed based on the individual treatment data and simulator films. Individual clinical and dosimetrical data were analyzed with the relative seriality model. The material was also analyzed grouping the material according to dose-volume constraints. RESULTS Of the 157 patients, 13 (8.3%) died due to IHD. The standardized mortality ratio (SMR) was 5.0 (95% CI, 2.7-8.6). Analysis of dose-volume histograms (DVH) showed an increasing risk with increasing dose to a larger volume fraction. The observed individual clinical complication data could not be modeled unambiguously. The group analysis resulted in the dose-response parameters: D(50)=71 Gy, gamma=0.96 and s=1.0. CONCLUSIONS A significantly increased risk of death due to IHD following RT for HD was found. The risk was found to increase with higher dose and larger volume fraction irradiated.

EXTRAMEDULLARY INVOLVEMENT OF THE TESTES IN CHILDHOOD LEUKEMIA

Thirteen out of 163 male children with acute leukemia developed extramedullary involvement of the testes. This represented an incidence of 8.0%. These 13 children experienced 19 separate episodes of enlargement. All episodes were treated with radiotherapy. The enlargement was unilateral in 9 episodes and bilateral in 10. The bone marrow (BM) was in complete remission in 13 episodes. In 8 of 13 patients the testis was the first site of relapse since the initial BM remission. Of the males with a WBC less than 20,000/mm3 on initial diagnosis of leukemia, 4.3% developed this testicular complication, as compared to 17.0% of those with a WBC equal to or greater than 20,000/mm3. The median time interval to testicular involvement was 13 months; to death, 9 months. Relapse at other sites usually followed testicular involvement. Autopsy findings did not appear to be dose‐related. Radiotherapy was clinically successful when a total dose in the range of 1200 rads was used, and is the treatment of choice for this complication.

Technological Basis of Radiation Therapy: Practical Clinical Applications

Intended for radiation oncologists and therapy technicians, this book reflects advances in the technology and practice of both diagnostic and therapeutic radiology. Approaches to the treatment of cancer have been modified utilizing multiple modalities as well as combinations of external beam and brachytherapy. Chapters new to this edition include discussions of diagnostic techniques in determining tumour size and location, soft tissue sarcomas and simulation. The importance of accurate localization, adequate dosage and reproducability of the daily treatment fields as essential to quality radiation therapy is stressed.

Radiobiology of stereotactic body radiation therapy/stereotactic radiosurgery and the linear-quadratic model

Received Feb 26, 2013, and in revised form Mar 11, 2013. Accepted for publication Mar 12, 2013The validity of the linear-quadratic (LQ) model for calculatingisoeffect doses in radiation therapy has been intensivelydebated in recent issues of the International Journal of Radi-ation Oncology, Biology, Physics (1-3).TheLQmodelissimple and convenient, and by far it has been the most usefulmeans for isodose calculation in treating tumors with conven-tional fractionated radiation therapy (2-4). The LQ modelsolely depends on the expected incidence of direct interactionsof radiation with specific cellular targets (ie, DNA strands).Because the LQ survival curve continuously bends downwardwith increasing radiation dose, many assume that the LQcalculation will inherently overestimate cell death caused byhigh-dose-per-fraction radiation therapy. Interestingly, however,clinical results have shown that the LQ model actually under-estimates tumor control by stereotactic body radiation therapy(SBRT) or stereotactic radiosurgery (SRS) (5), indicating thatmechanism(s) in addition to DNA strand breaks and/or chro-mosome aberrations may be involved in response of tumors toSBRT or SRS. Therefore, it has been hypothesized that SBRTor SRS may cause significant vascular damage in tumors,leading to indirect cell death (5, 6). We have recently reviewedprevious studies on the radiation-induced vascular damage intumors and pointed out the potentially important role of indi-rect/necrotic cell death due to the vascular damage in tumorcontrol with SBRT and SRS (7). We further discussed theradiobiological principles of SBRT and SRS in relation toradiation-induced vascular damage and resultant indirect celldeath (8). Interestingly, some 35 years ago we (C.W.S. andS.H.L.) realized that irradiation of rodent tumors with 10-20Gy in a single dose caused severe vascular injury, leading tonecrotic cell death in significant fractions of tumor cells 2 to 3days after the treatment (9, 10). Figure 1 summarizes theobservations we made on the effects of 10 Gy (1000 rads) ofx-rays in a single dose on the clonogenic surviving cells inWalker 256 rat tumors (10). The surviving cell fraction, asmeasured with an in vivoein vitro excision method, wasapproximately 2.6 10

Pineal and ectopic pineal tumors: The role of radiation therapy

Seventeen patients with pineal tumors and one ectopic (suprasellar) germinoma were treated with radiation therapy. Surgery was restricted to decompression in 16 patients, and only two patients had resection of the tumor. Thirteen of 18 patients are alive without evidence for disease with a ten‐year survival rate of 88%. The tumor dose ranged from 4000 rads to 6000 rads. No age or dose dependence in survival was noted, but patients with whole brain irradiation or generous volume to include ventricular system had better survival. No case of spinal metastasis was noted. The possibility of increased incidence of meningeal seeding following surgical intervention is considered. From their data, the authors feel that radiation therapy with or without surgical decompression should be the primary treatment for pinealoma. Surgery can be used for diagnosis and/or treatment of patients who show delayed response to radiation. Recommendation is made for the use of whole brain irradiation to 4000 rads followed by a boost to the tumor area to 5000 rads.

Radiobiological basis of total body irradiation with different dose rate and fractionation: Repair capacity of hemopoietic cells

Abstract Total body irradiation (TBI) followed by bone marrow transplantation is being used in the treatment of malignant or non-malignant hemopoietic disorders. It has been believed that the ability of hemopoietic cells to repair sublethal radiation damage is negligible. Therefore, several school of investigators suggested that TBI in a single exposure at extremely low dose rate (5 rad/min) over several hours, or in several fractions in 2–3 days, should yield a higher therapeutic gain, as compared with a single exposure at a high dose rate (26 rad/min). We reviewed the existing data in the literature, in particular, the response of hemopoietic cells to fractionated doses of irradiation and found that the repair capacity of both malignant and non-malignant hemopoietic cells might be greather than has been thought. It is concluded that we should not underestimate the ability of hemopoietic cells to repair sublethal radiation damage in using TBI.

Second neoplasms following megavoltage radiation in a pediatric population

Previous reports of radiation‐related neoplasia have relied primarily upon patients treated by orthovoltage to low doses for benign disease. This survey is believed to be the first to assess the incidence of second neoplasms following megavoltage therapy. The source was the records of all long‐term pediatric survivors (88 patients) who were treated with megavoltage radiation (cobalt 60) at the University of Minnesota. There was an average follow‐up period of 14 years during which 7 second neoplasms were discovered (8%). Five were not associated with prior radiation. Both radiation‐related neoplasms were associated with low doses and one was without significant morbidity. Two of the seven neoplasms were malignant; one was not associated with radiation while the other was associated with prolonged chemotherapy and low dose radiation (1%). The only fatal second neoplasm was not associated with radiation but developed 5 years after prolonged chlorambucil treatment. This review reveals the tendency of childhood cancer victims to develop other neoplasms regardless of radiation. The finding of neoplasia induction only at low radiation doses supports the Gray hypothesis of decreased tumor induction at high doses through increased cell killing.