Timothy E. Schultheiss

Radiation response of the central nervous system

This report reviews the anatomical, pathophysiological, and clinical aspects of radiation injury to the central nervous system (CNS). Despite the lack of pathognomonic characteristics for CNS radiation lesions, demyelination and malacia are consistently the dominant morphological features of radiation myelopathy. In addition, cerebral atrophy is commonly observed in patients with neurological deficits related to chemotherapy and radiation, and neurocognitive deficits are associated with diffuse white matter changes. Clinical and experimental dose-response information have been evaluated and summarized into specific recommendations for the spinal cord and brain. The common spinal cord dose limit of 45 Gy in 22 to 25 fractions is conservative and can be relaxed if respecting this limit materially reduces the probability of tumor control. It is suggested that the 5% incidence of radiation myelopathy probably lies between 57 and 61 Gy to the spinal cord in the absence of dose modifying chemotherapy. A clinically detectable length effect for the spinal cord has not been observed. The effects of chemotherapy and altered fractionation are also discussed. Brain necrosis in adults is rarely noted below 60 Gy in conventional fractionation, with imaging and clinical changes being observed generally only above 50 Gy. However, neurocognitive effects are observed at lower doses, especially in children. A more pronounced volume effect is believed to exist in the brain than in the spinal cord. Tumor progression may be hard to distinguish from radiation and chemotherapy effects. Diffuse white matter injury can be attributed to radiation and associated with neurological deficits, but leukoencephalopathy is rarely observed in the absence of chemotherapy. Subjective, objective, management, and analytic (SOMA) parameters related to radiation spinal cord and brain injury have been developed and presented on ordinal scales.

DOSE ESCALATION WITH 3D CONFORMAL TREATMENT: FIVE YEAR OUTCOMES, TREATMENT OPTIMIZATION, AND FUTURE DIRECTIONS

PURPOSE To report the 5-year outcomes of dose escalation with 3D conformal treatment (3DCRT) of prostate cancer. METHODS AND MATERIALS Two hundred thirty-two consecutive patients were treated with 3DCRT alone between 6/89 and 10/92 with ICRU reporting point dose that increased from 63 to 79 Gy. The median follow-up was 60 months, and any patient free of clinical or biochemical evidence of disease was termed bNED. Biochemical failure was defined as prostate-specific antigen (PSA) rising on two consecutive recordings and exceeding 1.5 ng/ml. Morbidity was reported by the Radiation Therapy Oncology Group (RTOG) scale, the Late Effects Normal Tissue (LENT) scale, and a Fox Chase modification of the latter (FC-LENT). All patients were treated with a four-field technique with a 1 cm clinical target volume (CTV) to planning target volume (PTV) margin to the prostate or prostate boost; the CTV and gross tumor volume (GTV) were the same. Actuarial rates of outcome were calculated by Kaplan-Meier and cumulative incidence methods and compared using the log rank and Grays test statistic, respectively. Cox regression models were used to establish prognostic factors predictive of the various measures of outcome. Five-year Kaplan-Meier bNED rates were utilized by dose group to estimate logit response models for bNED and late morbidity. RESULTS PSA <10 ng/ml: No dose response was demonstrated using estimated bNED rates or by analysis of PSA nadir vs. dose. PSA 10-19.9 ng/ml: A bNED dose response was demonstrated (p = 0.02) using the log rank test. The logit response model showed 5-year bNED rates of 35% at 70 Gy and 75% at 76 Gy (p = 0.0049) and illustrated the relative ineffectiveness of conventional dose treatment. PSA 20+ ng/ml: A bNED dose response was demonstrated (p = 0.02) using the log rank test. The logit response model indicated a 5-year bNED rate of 10% at 70 Gy and 32% at 76 Gy (p = 0.10). Morbidity: Dose response was demonstrated for FC-LENT grade 2 and grade 3,4 GI morbidity and for LENT grade 2 GU sequelae. RTOG grade 3,4 GI morbidity at 5 years was <1%. Factors associated with bNED, cause-specific survival, and metastasis were studied using Cox multivariate analysis. Pretreatment PSA (p = 0.0001), Gleason score 7-10 (p = 0.0001), and dose (p = 0.017) were significantly predictive of bNED. For each 1 Gy increase in dose, the hazard of bNED failure decreased by 8%. Palpation stage was associated with cause-specific survival (p = 0.002) and distant metastasis (p = 0.0004). Gleason score was also predictive of distant metastasis (p = 0.02). CONCLUSIONS A dose response was observed for patients with pretreatment PSA >10 ng/ml based on 5-year bNED results. No dose response was observed for patients with pretreatment PSA < 10 ng/ml. Dose response was observed for FC-LENT grade 2 and grade 3,4 GI sequelae and for LENT grade 2 GU sequelae. Optimization of treatment was made possible by the results in this report. The improvement in 5-year bNED rates for patients with PSA levels > 10 ng/ml strongly suggests that clinical trials employing radiation should investigate the use of 3DCRT and prostate doses of 76-80 Gy.

Late GI and GU complications in the treatment of prostate cancer

PURPOSE To assess the factors that predict late GI and GU morbidity in radiation treatment of the prostate. METHODS AND MATERIALS Seven hundred twelve consecutive prostate cancer patients treated at this institution between 1986 and 1994 (inclusive) with conformal or conventional techniques were included in the analysis. Patients had at least 3 months follow-up and received at least 65 Gy. Late GI Grade 3 morbidity was rectal bleeding (requiring three or more procedures) or proctitis. Late Grade 3 GU morbidity was cystitis or stricture. Multivariate analysis (MVA) was used to assess factors related to the complication-free survival. The factors assessed were age, occurrence of side effects > or = Grade 2 during treatment, irradiated volume parameters (use of pelvic fields, treatment of seminal vesicles to full dose or 57 Gy, and use of additional rectal shielding), dose, comorbidities, and other treatments (hormonal manipulation, TURP). RESULTS Acute GI and GU side effects (Grade 2 or higher) were noted in 246 and 201 patients, respectively; 67 of these patients exhibited both. GI side effects were not correlated with GU side effects acutely. Late and acute morbidities were correlated (both GI and GU). Fifteen of the 712 patients expressed Grade 3 or 4 GI injuries 3 to 32 months after the end of treatment, with a mean of 14.3 months. One hundred fifteen patients expressed Grade 2 or higher GI morbidity (mean: 13.7 months). The 43 Grade 2 or higher GU morbidities occurred significantly later (mean: 22.7 months). Central axis dose was the only independent variable significantly related to the incidence of late GI morbidity on MVA. No treatment volume parameters were significant for Grade 3. The following parameters were significantly related (by MVA) to Grade 2 GI morbidity: central axis dose, use of the increased rectal shielding, androgen deprivation therapy starting before RT. Acute and late GI morbidities were highly correlated. History of diabetes, treatment of pelvic nodes, and age less than 60 years were significantly related to acute GI side effects. The parameters significantly related to late Grade 2 or higher GU morbidity were central axis dose, androgen deprivation therapy (Zoladex or Lupron) prior to radiation therapy (RT), history of obstructive symptoms, and acute GU side effects. There were too few late Grade 3 GU morbidities to perform multivariate analysis. Acute GU side effects were highly correlated with late GU injury. The following were correlated with acute GU side effects: history of diabetes (+), treatment with conformal fields (-), TURP before RT (-), presentation with urinary obstructive symptoms. CONCLUSION Both late GI and GU morbidity demonstrate a dose dependence, but only the volume dependence observed is a reduction in late Grade 2-4 GI morbidity by increasing the rectal shielding in the lateral fields for the final 10 Gy. Moreover, both late GI and GU morbidity was increased in patients treated with hormone manipulation prior to RT. GI and GU injuries were correlated with their corresponding acute side effects. GI and GU complications must not be combined for analysis to determine the factors related to their occurrence.

RADIATION DOSE-VOLUME EFFECTS IN THE SPINAL CORD

Dose-volume data for myelopathy in humans treated with radiotherapy (RT) to the spine is reviewed, along with pertinent preclinical data. Using conventional fractionation of 1.8-2 Gy/fraction to the full-thickness cord, the estimated risk of myelopathy is <1% and <10% at 54 Gy and 61 Gy, respectively, with a calculated strong dependence on dose/fraction (alpha/beta = 0.87 Gy.) Reirradiation data in animals and humans suggest partial repair of RT-induced subclinical damage becoming evident about 6 months post-RT and increasing over the next 2 years. Reports of myelopathy from stereotactic radiosurgery to spinal lesions appear rare (<1%) when the maximum spinal cord dose is limited to the equivalent of 13 Gy in a single fraction or 20 Gy in three fractions. However, long-term data are insufficient to calculate a dose-volume relationship for myelopathy when the partial cord is treated with a hypofractionated regimen.

A comparison of daily CT localization to a daily ultrasound-based system in prostate cancer.

PURPOSE Daily CT localization has been demonstrated to be a precise method of correcting radiation field placement by reducing setup and organ motion variations to facilitate dose escalation in prostate carcinoma. The purpose of this study was to evaluate the feasibility and accuracy of daily ultrasound-guided localization utilizing daily CT as a standard. The relatively simple computer-assisted ultrasound-based system is designed to be an efficient means of achieving daily accuracy. METHODS AND MATERIALS After five weeks of conformal external beam radiation therapy, 23 patients underwent a second CT simulation. Prostate-only fields based on this scan were created with no PTV margin. On each of the final conedown treatment days, a repeat CT simulation and isocenter comparison was performed. Ten of the above patients also underwent prostate localization with a newly developed ultrasound-based system (BAT) that is designed to facilitate patient positioning at the treatment machine. The portable system, which electronically imports the CT simulation target contours and isocenter, is situated adjacent to the treatment couch. Transverse and sagittal suprapubic ultrasound images are captured, and the system overlays the corresponding CT contours relative to the machine isocenter. The CT contours are maneuvered in three dimensions by a touch screen menu to match the ultrasound images. The system then displays the 3-D couch shifts required to produce field alignment. RESULTS The BAT ultrasound system produced good quality images with minimal operator training required. The localization process was completed in less than 5 min. The absolute magnitude difference between CT and ultrasound was small (A/P range 0 to 5.9 mm, mean 3 mm +/- 1.8; Lat. range 0 to 7.9 mm, mean 2.4 mm +/- 1.8; S/I range 0 to 9 mm, mean 4.6 mm +/- 2.8). Analysis confirmed a significant correlation of isocenter shifts (A/P r = 0.66, p < 0.0001; Lat. r = 0.58, p < 0.003; S/I r = 0.78, p < 0.0001) in all dimensions, and linear regression confirmed the equivalence of the two modalities. CONCLUSIONS Daily CT localization is a precise method to improve daily target localization in prostate carcinoma. However, it requires significant human and technical resources that limit its widespread applicability. Conversely, localization with the BAT ultrasound system is simple and expeditious by virtue of its ability to image the prostate at the treatment machine in the treatment position. Our initial evaluation revealed ultrasound targeting to be functionally equivalent to CT. This ultrasound technology is promising and warrants further investigation in more patients and at other anatomical sites.

Phase I/II 90Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) radioimmunotherapy dosimetry results in relapsed or refractory non-Hodgkin's lymphoma.

Abstract.Dosimetry studies in patients with non-Hodgkin’s lymphoma were performed to estimate the radiation absorbed dose to normal organs and bone marrow from 90Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) treatment in this phase I/II, multicenter trial. The trial was designed to determine the dose of Rituximab (chimeric anti-CD20, Rituxan, IDEC-C2B8, MabThera), the unlabeled antibody given prior to the radioconjugate to clear peripheral blood B cells and optimize distribution, and to determine the maximum tolerated dose of 90Y-Zevalin [7.4, 11, or 15 MBq/kg (0.2, 0.3, or 0.4 mCi/kg)]. Patients received 111In-Zevalin (indium-111 ibritumomab tiuxetan, IDEC-In2B8 ) on day 0 followed by a therapeutic dose of 90Y-Zevalin on day 7. Both doses were preceded by an infusion of the chimeric, unlabeled antibody Rituximab. Following administration of 111In-Zevalin, serial anterior/posterior whole-body scans were acquired. Major-organ radioactivity versus time estimates were calculated using regions of interest. Residence times were computed and entered into the MIRDOSE3 computer software program to calculate estimated radiation absorbed dose to each organ. Initial analyses of estimated radiation absorbed dose were completed at the clinical site. An additional, centralized dosimetry analysis was performed subsequently to provide a consistent analysis of data collected from the seven clinical sites. In all patients with dosimetry data (n=56), normal organ and red marrow radiation absorbed doses were estimated to be well under the protocol-defined upper limit of 20 Gy and 3 Gy, respectively. Median estimated radiation absorbed dose was 3.4 Gy to liver (range 1.2–7.8 Gy), 2.6 Gy to lungs (range 0.72–4.4 Gy), and 0.38 Gy to kidneys (range 0.07–0.61 Gy). Median estimated tumor radiation absorbed dose was 17 Gy (range 5.8–67 Gy). No correlation was noted between hematologic toxicity and the following variables: red marrow radiation absorbed dose, blood T1/2, blood AUC, plasma T1/2, and plasma AUC. It is concluded that 90Y-Zevalin administered at nonmyeloablative maximum tolerated doses results in acceptable radiation absorbed doses to normal organs. The only toxicity of note is hematologic and is not correlated to red marrow radiation absorbed dose estimates or T1/2, reflecting that hematologic toxicity is dependent on bone marrow reserve in this heavily pretreated population.

Apoptosis in irradiated murine tumors

Early radiation responses of transplantable murine ovarian (OCaI) and hepatocellular (HCaI) carcinomas were examined at 6, 24, 48, 96, and 144 h after single photon doses of 25, 35, or 45 Gy. Previous studies using tumor growth delay and tumor radiocurability assays had shown OCaI tumors to be relatively radiosensitive and HCaI tumors to be radioresistant. At 6 h, approximately 20% of nuclei in OCaI tumors showed aberrations characteristic of cell death by apoptosis. This contrasted to an incidence of 3% in HCaI tumors. Mitotic activity was eliminated in OCaI tumors but was only transiently suppressed in HCaI tumors. At 24-96 h, OCaI tumors continued to display apoptosis and progressive necrosis, whereas HCaI tumors responded by exhibiting marked pleomorphism. Factors other than mitotic activity may influence tumor radiosensitivity, and one of these may be susceptibility to induction of apoptosis (programmed cell death), because this was a prominent early radiation response by the radiosensitive OCaI tumors.

Lateral rectal shielding reduces late rectal morbidity following high dose three-dimensional conformal radiation therapy for clinically localized prostate cancer: Further evidence for a significant dose effect

PURPOSE Using conventional treatment methods for the treatment of clinically localized prostate cancer central axis doses must be limited to 65-70 Gray (Gy) to prevent significant damage to nearby normal tissues. A fundamental hypothesis of three-dimensional conformal radiation therapy (3DCRT) is that, by defining the target organ(s) accurately in three dimensions, it is possible to deliver higher doses to the target without a significant increase in normal tissue complications. This study examines whether this hypothesis holds true and whether a simple modification of treatment technique can reduce the incidence of late rectal morbidity in patients with prostate cancer treated with 3DCRT to minimum planning target volume (PTV) doses of 71-75 Gy. METHODS AND MATERIALS The 257 patients with clinically localized prostate cancer who completed 3DCRT by December 31, 1993 and received a minimum PTV dose of 71-75 Gy are included in this report. The median follow-up time was 22 months (range: 4-67 months); 98% of patients had follow-up of longer than 12 months. The calculated dose at the center of the prostate was < 74 Gy in 19 patients, 74-76 Gy in 206 patients, and > 76 Gy in 32 patients. Late rectal morbidity was graded according to the Late Effects Normal Tissue (LENT) scoring system. Eighty-eight consecutive patients were treated with a rectal block added to the lateral fields. In these patients the posterior margin from the prostate to the block edge was reduced from the standard 15 to 5 mm for the final 10 Gy, which reduced the dose to portions of the anterior rectal wall by approximately 4-5 Gy. Estimates of rates for rectal morbidity were determined by Kaplan-Meier actuarial analysis. Differences in morbidity percentages were evaluated by the Pearson chi-square test. RESULTS Grade 2-3 rectal morbidity developed in 46 out of 257 patients (18%) and in the majority of cases consisted of rectal bleeding. No patient has developed Grade 4 or 5 rectal morbidity. The actuarial rate of Grade 2-3 morbidity is 23% at 24 months and the median time to the development of Grade 2-3 complications is 15 months. A statistically significant dose effect is evident. The incidence of Grade 2-3 rectal morbidity increased as the dose at the center of the prostate increased (p = 0.05). In patients receiving minimum PTV doses of < or = 76 Gy the use of a rectal block significantly reduced the incidence of Grade 2-3 toxicity; 6 out of 88 (7%) with a block vs. 30 out of 137 (22%) without a block, (p = 0.003). CONCLUSION The incidence of late rectal morbidity with 3DCRT to minimum PTV doses of 71-75 Gy is acceptable and to date no Grade 4-5 rectal morbidities have been observed. In our experience, higher doses to the center of the prostate are associated with an increased likelihood of developing Grade 2-3 rectal morbidity but treatment techniques that reduce the total dose to the anterior rectal wall have reduced the incidence of late rectal morbidity. If clinical studies indicate improved tumor control with minimum PTV doses above 71 Gy, then dose escalation above 76 Gy to the center of the prostate should be pursued cautiously with treatment techniques that limit the total dose to the anterior rectal wall.

OPTIMIZATION OF CONFORMAL RADIATION TREATMENT OF PROSTATE CANCER: REPORT OF A DOSE ESCALATION STUDY

PURPOSE The development of conformal radiation technique including improved patient immobilization has allowed us to test the value of dose escalation in optimizing the radiation treatment of prostate cancer. METHODS AND MATERIALS Outcome is reported for 233 consecutive patients treated with conformal technique between March 1989 and October 1992. Dose was escalated from 68 Gy to 79 Gy. Patient status is reported at 3 years follow-up, which is available in all alive patients. Pretreatment and serial posttreatment prostate specific antigen (PSA) values are available for all patients. Biochemical freedom of disease (bNED) defines failure as PSA > 1.5 ngm/ml and rising on two consecutive measures. Dose response for bNED control of cancer and late morbidity are represented by logit response models fitted to the data. Kaplan-Meier methods, the log rank test, and Cox Regression models are also used. RESULTS No dose response is observed for bNED survival for patients with pretreatment PSA <10 ngm/ml comparing patients treated above or below 71.5 Gy or on multivariate analysis. Dose response is observed for bNED survival for pretreatment PSA groups of 10-19.9 ngm/ml and 20+ ngm/ml. The dose associated with 50% bNED survival at 3 years is 64 Gy and 76 Gy, respectively. The slope of the dose responses are 13 and 9%, respectively. Dose response is demonstrated for Grade 2 gastrointestinal (GI), Grade 2 genitourinary (GU), and Grade 3,4 combined GI and GU late morbidity. The slopes of the morbidity responses are steeper than for cancer control (19 to 21%). CONCLUSIONS Patients with pretreatment PSA < 10 ngm/ml do not benefit from dose escalation, and the serious late morbidity of conformal radiation at 70 Gy is < 3%. Patients with PSA values 10-19.9 ngm/ml and 20+ ngm/ml benefit from dose escalation beyond 70 Gy. Treatment beyond 75 Gy results in > 10% serious morbidity unless special precautions are taken to protect the rectal mucosa. All levels of severity of radiation morbidity show a dose response and combined with the dose response for bNED survival these data allow the optimization of treatment.

Initial clinical assessment of CT-MRI image fusion software in localization of the prostate for 3D conformal radiation therapy☆

PURPOSE To assess the utility of image fusion software and compare MRI prostate localization with CT localization in patients undergoing 3D conformal radiation therapy of prostate cancer. MATERIALS AND METHODS After a phantom study was performed to ensure the accuracy of image fusion procedure, 22 prostate cancer patients had CT and MRI studies before the start of radiotherapy. Immobilization casts used during radiation treatment were also used for both imaging studies. After the clinical target volume (CTV) (prostate or prostate + seminal vesicles) was defined on CT, slices from the MRI study were reconstructed to precisely match the CT slices by identifying three common bony landmarks on each study. The CTV was separately defined on the matched MRI slices. Data related to the size and location of the prostate were compared between CT and MRI. The spatial relationship between the tip of urethrogram cone on CT and prostate apex seen on MRI was also estimated. RESULTS The phantom study showed the registration discrepancies between CT and MRI smaller than 1.0 mm in any pair in comparison. The patient study showed a mean image registration error of 0.9 (+/- 0.6) mm. The average prostate volume was 63.0 (+/- 25.8) cm3 and 50.9 (+/- 22.9) cm3 determined by CT and MRI, respectively. The difference in prostate location with the two studies usually differed at the base and at the apex of the prostate. On the transverse MRI, the prostate apex was situated 7.1 (+/- 4.5) mm dorsal and 15.1 (+/- 4.0) mm cephalad to the tip of urethrogram cone. CONCLUSIONS CT-MRI image fusion study made it possible to compare the two modalities directly. MRI localization of the prostate is more accurate than CT, and indicates the distance from cone to apex is 15 mm. CT-MRI image fusion technique provides valuable supplements to CT technology for more precise targeting of the prostate cancer.