Radiation-Related Toxicities Using Organ Sparing Total Marrow Irradiation Transplant Conditioning Regimens.

PURPOSE: Toxicities after organ sparing myeloablative total marrow irradiation (TMI) conditioning regimens have not been well characterized. The purpose of this study is to report pulmonary, renal, thyroid, and cataract toxicities from a prospective trial monitoring patients up to 8 years after TMI. METHODS AND MATERIALS: A total of 142 patients with primarily multiple myeloma or acute leukemia undergoing hematopoietic cell transplantation were evaluated. Follow-up included pulmonary function tests, serum creatinine, glomerular filtration rate, thyroid panel, and ophthalmologic examinations performed at 100 days, 6 months, and annually. Median TMI dose was 14 Gy (10-19 Gy) delivered at 1.5 to 2.0 Gy twice per day at a dose-rate of 200 cGy/min. RESULTS: Median age was 52 years (range 9-70). Median follow-up (range) for all patients was 2 years (0-8) and for patients alive at the time of last follow-up (n = 50), 5.5 years (0-8). Mean organ doses in Gy were lung 7.0, kidneys 7.1, thyroid 6.7, and lens 2.8. The crude incidence of radiation pneumonitis (RP) was 1 of 142 (0.7%). The cumulative incidence of infection and RP (I/RP) was 22.7% at 2 years post-TMI. Mean lung dose ≤8 Gy predicted for significantly lower rates of I/RP (2-year cumulative incidence 20.8% vs 31.8%, P = .012). No radiation-induced renal toxicity was noted. Hypothyroidism occurred in 6.0% and cataract formation in 7.0% of patients. CONCLUSIONS: TMI delivered with intensity modulated radiation therapy results in lower organ doses and was associated with fewer toxicities compared with historical cohorts treated with conventional total body irradiation. Keeping the mean lung dose to 8 Gy or less was associated with lower pulmonary complications. Further evaluation in clinical trials of intensity modulated radiation therapy to deliver TMI, total marrow and lymphoid irradiation, and organ sparing conformal total body irradiation is warranted.

Suberoylanilide hydroxamic acid induces hypersensitivity to radiation therapy in acute myelogenous leukemia cells expressing constitutively active FLT3 mutants.

Histone deacetylase inhibitors (HDIs) have shown promise as candidate radiosensitizer for many types of cancers. However, the mechanisms of action are not well understood, and whether they could have clinical impact on radiotherapy for leukemia is unclear. In this study, we demonstrate that suberoylanilide hydroxamic acid (SAHA) can increase radiosensitivity of acute myeloid leukemia (AML) cells through posttranslational modification of Rad51 protein responses and selective inhibition of the homology-directed repair (HDR) pathway. Our data also showed that AML cells with mutant, constitutively active FMS-like tyrosine kinase-3 (FLT3) were more radiation sensitive, caused by compromised non-homologous end joining (NHEJ) repair. Furthermore, SAHA-induced radiosensitization were enhanced in AML cells with expression of these FLT3 mutants. The results of this study suggest that SAHA, a recently approved HDI in clinical trials, may act as a candidate component for novel conditioning regimens to improve efficacy for AML patients undergoing radiotherapy and chemotherapy.

Clinical outcomes of patients treated with a second course of stereotactic radiosurgery for locally or regionally recurrent brain metastases after prior stereotactic radiosurgery.

Patients with metastatic disease are living longer and may be confronted with locally or regionally recurrent brain metastases (BM) after prior stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT). This study analyzes outcomes in patients without prior whole brain radiotherapy (WBRT) who were treated with a second course of SRS/FSRT for locally or regionally recurrent BM. We identified 32 patients at our institution who were treated with a second course of SRS/FSRT after initial SRS/FSRT for newly diagnosed BM. We report clinical outcomes including local control, survival, and toxicities. Control rates and survival were calculated using Kaplan-Meier analysis and the multivariate proportional hazards model. The Kaplan-Meier estimate of local control at 6 months was 77 % for targets treated by a second course of SRS/FSRT with 11/71 (15 %) targets experiencing local failure. Multivariate analysis shows that upon re-treatment, local recurrences were more likely to fail than regional recurrences (OR 8.8, p = 0.02). Median survival for all patients from first SRS/FSRT was 14.6 months (5.3-72.2 months) and 7.9 months (0.7-61.1 months) from second SRS/FSRT. Thirty-eight percent of patients ultimately received WBRT as salvage therapy after the second SRS/FSRT. Seventy-one percent of patients died without active neurologic symptoms. The present study demonstrates that the majority of patients who progress after SRS/FSRT for newly diagnosed BM are candidates for salvage SRS/FSRT. By reserving WBRT for later salvage, we believe that a significant proportion of patients can avoid WBRT all together, thus putting fewer patients at risk for neurocognitive toxicity.

Suberoylanilide hydroxamic acid as a radiosensitizer through modulation of RAD51 protein and inhibition of homology-directed repair in multiple myeloma.

Histone deacetylase inhibitors (HDI) have shown promise as candidate radiosensitizers for many types of cancers. However, the mechanisms of action are not well understood, and whether they could sensitize multiple myeloma (MM) to radiation therapy is unclear. In this study, we show that suberoylanilide hydroxamic acid (SAHA) at low concentrations has minimal cytotoxic effects, yet can significantly increase radiosensitivity of MM cells. SAHA seems to block RAD51 protein response to ionizing radiation, consistent with an inhibitory effect on the formation of RAD51 focus in irradiated MM cells. These effects of SAHA on RAD51 focus are independent of cell-cycle distribution changes. Furthermore, we show that SAHA selectively inhibits the homology-directed repair (HDR) pathway. The results of this study suggest that SAHA, a recently approved HDI in clinical trials for malignancies, at lower concentrations may act as a radiosensitizer via disruption of the RAD51-dependent HDR pathway.

Low-dose valproic acid enhances radiosensitivity of prostate cancer through acetylated p53-dependent modulation of mitochondrial membrane potential and apoptosis.

Histone deacetylase inhibitors (HDI) have shown promise as candidate radiosensitizers for many types of cancers, including prostate cancer. However, the mechanisms of action are not well understood. In this study, we show in prostate cancer cells that valproic acid (VPA) at low concentrations has minimal cytotoxic effects yet can significantly increase radiation-induced apoptosis. VPA seems to stabilize a specific acetyl modification (lysine 120) of the p53 tumor suppressor protein, resulting in an increase in its proapoptotic function at the mitochondrial membrane. These effects of VPA are independent of any action of the p53 protein as a transcription factor in the nucleus, since these effects were also observed in native and engineered prostate cancer cells containing mutant forms of p53 protein having no transcription factor activity. Transcription levels of p53-related or Bcl-2 family member proapoptotic proteins were not affected by VPA exposure. The results of this study suggest that, in addition to nuclear-based pathways previously reported, HDIs may also result in radiosensitization at lower concentrations via a specific p53 acetylation and its mitochondrial-based pathway(s).

Pitch, roll, and yaw variations in patient positioning.

PURPOSE: To use pretreatment megavoltage-computed tomography (MVCT) scans to evaluate positioning variations in pitch, roll, and yaw for patients treated with helical tomotherapy. METHODS AND MATERIALS: Twenty prostate and 15 head-and-neck cancer patients were selected. Pretreatment MVCT scans were performed before every treatment fraction and automatically registered to planning kilovoltage CT (KVCT) scans by bony landmarks. Image registration data were used to adjust patient setups before treatment. Corrections for pitch, roll, and yaw were recorded after bone registration, and data from fractions 1-5 and 16-20 were used to analyze mean rotational corrections. RESULTS: For prostate patients, the means and standard deviations (in degrees) for pitch, roll, and yaw corrections were -0.60 +/- 1.42, 0.66 +/- 1.22, and -0.33 +/- 0.83. In head-and-neck patients, the means and standard deviations (in degrees) were -0.24 +/- 1.19, -0.12 +/- 1.53, and 0.25 +/- 1.42 for pitch, roll, and yaw, respectively. No significant difference in rotational variations was observed between Weeks 1 and 4 of treatment. Head-and-neck patients had significantly smaller pitch variation, but significantly larger yaw variation, than prostate patients. No difference was found in roll corrections between the two groups. Overall, 96.6% of the rotational corrections were less than 4 degrees. CONCLUSIONS: The initial rotational setup errors for prostate and head-and-neck patients were all small in magnitude, statistically significant, but did not vary considerably during the course of radiotherapy. The data are relevant to couch hardware design for correcting rotational setup variations. There should be no theoretical difference between these data and data collected using cone beam KVCT on conventional linacs.

Development of an in vitro chemo-radiation response assay for cervical carcinoma.

PURPOSE: To determine if synergistic effects of radiation (RT) and chemotherapy (chemo) on human cervical carcinoma cell lines and fresh tumor explants could be determined using an in vitro assay. EXPERIMENTAL DESIGN: In vitro radiation response was determined for 4 cell lines and 26 fresh tumor explants in an agar-based assay. Cells were exposed to increasing doses of RT with or without cisplatin (CDDP), carmustine (BCNU), buthionine sulfoximine (BSO), or paclitaxel (Tax). Cell suspensions were cultured for 5 days, with [(3)H]thymidine added on day 3 and proliferation was measured. Results were reported as the fraction of proliferation compared to control (FC). For each combination of irradiation and drug, synergy was tested using the Chou analysis, where a combination index (CI) <1 indicated synergistic interaction. In simple correlation analysis, an R value of >0.7 indicated cross-resistance. RESULTS: RT dose-dependent proliferation inhibition was observed for 2 of the 4 cell lines, and for all but 1 of the fresh specimens. Significant heterogeneity of tumor response to RT was seen. Four specimens that were 1 standard deviation below the median FC response after exposure to 300 cGy were classified as extremely radiation resistant. Twenty-one tumors were evaluated for synergistic response using the combination of chemo and RT with a median FC of 0.27 (+/-0.27) for 6.0 Gy of RT alone, 0.22 (+/-0.21) for CDDP alone, and 0.05 (+/-0.08) for the combination. A CI of 0.35 and an R value of 0.09 demonstrated synergy between chemo and RT without cross-resistance. Similar synergy without cross-resistance was found for RT in combination with BCNU, BSO, and TAX. CONCLUSIONS: Heterogeneous RT dose-response relationships in the in vitro assay were demonstrated. Explants were more sensitive to RT than cell lines. Unlike cell lines, fresh tumor cells consistently displayed synergy with RT and chemo. The synergy between RT and BSO suggests that glutathione depletion may enhance the effect of RT. The assay was feasible for examining fresh tumors and may be an important tool for studying RT or drug resistance. Clinical trials to evaluate this assay are indicated.