Susan L. Tucker

Radiation Dose–Volume Effects in Radiation-Induced Rectal Injury

The available dose/volume/outcome data for rectal injury were reviewed. The volume of rectum receiving >or=60 Gy is consistently associated with the risk of Grade >or=2 rectal toxicity or rectal bleeding. Parameters for the Lyman-Kutcher-Burman normal tissue complication probability model from four clinical series are remarkably consistent, suggesting that high doses are predominant in determining the risk of toxicity. The best overall estimates (95% confidence interval) of the Lyman-Kutcher-Burman model parameters are n = 0.09 (0.04-0.14); m = 0.13 (0.10-0.17); and TD(50) = 76.9 (73.7-80.1) Gy. Most of the models of late radiation toxicity come from three-dimensional conformal radiotherapy dose-escalation studies of early-stage prostate cancer. It is possible that intensity-modulated radiotherapy or proton beam dose distributions require modification of these models because of the inherent differences in low and intermediate dose distributions.

Histone Deacetylase Inhibitors Radiosensitize Human Melanoma Cells by Suppressing DNA Repair Activity

Purpose: Histone deacetylase (HDAC) inhibitors have emerged recently as promising anticancer agents. They arrest cells in the cell cycle and induce differentiation and cell death. The antitumor activity of HDAC inhibitors has been linked to their ability to induce gene expression through acetylation of histone and nonhistone proteins. However, it has recently been suggested that HDAC inhibitors may also enhance the activity of other cancer therapeutics, including radiotherapy. The purpose of this study was to evaluate the ability of HDAC inhibitors to radiosensitize human melanoma cells in vitro. Experimental Design: A panel of HDAC inhibitors that included sodium butyrate (NaB), phenylbutyrate, tributyrin, and trichostatin A were tested for their ability to radiosensitize two human melanoma cell lines (A375 and MeWo) using clonogenic cell survival assays. Apoptosis and DNA repair were measured by standard assays. Results: NaB induced hyperacetylation of histone H4 in the two melanoma cell lines and the normal human fibroblasts. NaB radiosensitized both the A375 and MeWo melanoma cell lines, substantially reducing the surviving fraction at 2 Gy (SF2), whereas it had no effect on the normal human fibroblasts. The other HDAC inhibitors, phenylbutyrate, tributyrin, and trichostatin A had significant radiosensitizing effects on both melanoma cell lines tested. NaB modestly enhanced radiation-induced apoptosis that did not correlate with survival but did correlate with functional impairment of DNA repair as determined based on the host cell reactivation assay. Moreover, NaB significantly reduced the expression of the repair-related genes Ku70 and Ku86 and DNA-dependent protein kinase catalytic subunit in melanoma cells at the protein and mRNA levels. Normal human fibroblasts showed no change in DNA repair capacity or levels of DNA repair proteins following NaB treatment. We also examined γ-H2AX phosphorylation as a marker of radiation response to NaB and observed that compared with controls, γ-H2AX foci persisted long after ionizing exposure in the NaB-treated cells. Conclusions: HDAC inhibitors radiosensitize human tumor cells by affecting their ability to repair the DNA damage induced by ionizing radiation and that γ-H2AX phosphorylation can be used as a predictive marker of radioresponse.

Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of local and regional control.

PURPOSE This retrospective study was conducted to review the results of treatment and to identify prognostic factors for local and regional control in a population of 378 patients with nasopharyngeal carcinomas treated in a single institution by radiation therapy alone. METHODS AND MATERIAL All patients were treated at The University of Texas M. D. Anderson Cancer Center between 1954 and 1992 following a consistent treatment philosophy but with evolving technique. There were 286 males and 92 females with a median age of 52 years (range: 16-86 years). The majority of the patients were Caucasian (282 patients, 75%). Thirty-two patients (8%) had one or more cranial nerve deficits. Three-fourths of the patients presented with AJCC Stage IV disease (T4, N0-3, 118 patients; T1-3, N2-3 164 patients). Histologically, 193 tumors (51%) were squamous cell carcinomas, 154 (41%) lymphoepitheliomas, and 31 (8%) unclassified carcinomas. Average total dose varied with T-stage and ranged from 60.2 to 72.0 Gy. Median follow-up time was 10 years. RESULTS For the entire population the 5-, 10-, and 20-year actuarial survival rates were 48, 34, and 18%, respectively, with 184 patients (49%) dying of nasopharyngeal cancer. Actuarial control rates at 5, 10, and 20 years were 71, 66, and 66% for the primary site and 84, 83, and 83% for the neck. A total of 100 patients (26%) had local failures and 51 patients (13%) had regional failures with a median time to recurrence of 8.2 months and 13 months, respectively. Advanced T-stage, squamous histology, and presence of cranial nerve deficits were poor prognostic factors for local control in both univariate and multivariate analyses. N-stage and tumor histology were significant factors for neck control. Treatment year, total dose within the ranges used, and duration of treatment did not have any significant effect on local or regional control. The actuarial incidence of Grade 3-5 late complications was 16, 19, and 29% at 5, 10, and 20 years, respectively. Twelve patients (3%) died of treatment-related complications; all but one fatal complication occurred before 1971 and the other in 1976. CONCLUSIONS This study shows very good long-term local and regional control rates for nasopharyngeal carcinomas after definitive radiotherapy and establishes a benchmark for newer treatment strategies. Improvements in treatment technique over the years have dramatically reduced the frequency of severe late complications. Patients with advanced stage tumors and differentiated squamous histology have a relatively poor prognosis when treated with conventional radiotherapy and are candidates for dose escalation or combined modality studies.

Respiratory-driven lung tumor motion is independent of tumor size, tumor location, and pulmonary function

PURPOSE To determine whether superior-inferior lung tumor motion is predictable by tumor size or location, or pulmonary function test results. METHODS AND MATERIALS Superior-inferior tumor motion was measured on orthogonal radiographs taken during simulation of 22 patients with inoperable lung cancer diagnosed by orthogonal radiographs. RESULTS The tumor size averaged 5.5 +/- 3.1 cm (range 1.5-12 cm). Seven of 11 central tumors demonstrated some motion compared with 5 of 11 peripheral tumors. Four of 5 upper lobe tumors moved compared with 8 of 17 tumors that were either middle or lower lobe lesions. The mean fourth rib motion was 7.3 +/- 3.2 mm (range 2-15). The mean FeV(1) was 1.8 +/- 1.2 (range 0.55-5.33. The mean diffusing capacity of the lung for carbon monoxide was 14.0 +/- 6.5 (range 7.8-21.9). The mean total lung capacity was 6.5 +/- 1.2 (range 3.3-8.4). None of these parameters correlated with tumor motion. Although lateral tumor motion could not be consistently determined, 1 tumor moved 10 mm anterior-posteriorly. CONCLUSIONS Lung tumors often move significantly during respiration. Tumor motion is not predictable by tumor size or location, or pulmonary function test results. Therefore, tumor motion must be measured in all patients. Measurement in three dimensions will likely be necessary to maximize the irradiated lung volumes or choose beam arrangements parallel to the major axis of motion.

Influence of technologic advances on outcomes in patients with unresectable, locally advanced non-small-cell lung cancer receiving concomitant chemoradiotherapy.

PURPOSE In 2004, our institution began using four-dimensional computed tomography (4DCT) simulation and then intensity-modulated radiotherapy (IMRT) (4DCT/IMRT) instead of three-dimensional conformal radiotherapy (3DCRT) for the standard treatment of non-small-cell lung cancer (NSCLC). This retrospective study compares disease outcomes and toxicity in patients treated with concomitant chemotherapy and either 4DCT/IMRT or 3DCRT. METHODS AND MATERIALS A total of 496 NSCLC patients have been treated at M. D. Anderson Cancer Center between 1999 and 2006 with concomitant chemoradiotherapy. Among these, 318 were treated with CT/3DCRT and 91 with 4DCT/IMRT. Both groups received a median dose of 63 Gy. Disease end points were locoregional progression (LRP), distant metastasis (DM), and overall survival (OS). Disease covariates were gross tumor volume (GTV), nodal status, and histology. The toxicity end point was Grade >or=3 radiation pneumonitis; toxicity covariates were GTV, smoking status, and dosimetric factors. Data were analyzed using Cox proportional hazards models. RESULTS Mean follow-up times in the 4DCT/IMRT and CT/3DCRT groups were 1.3 (range, 0.1-3.2) and 2.1 (range, 0.1-7.9) years, respectively. The hazard ratios for 4DCT/IMRT were <1 for all disease end points; the difference was significant only for OS. The toxicity rate was significantly lower in the IMRT/4DCT group than in the CT/3DCRT group. V20 was significantly higher in the 3DCRT group and was a significant factor in determining toxicity. Freedom from DM was nearly identical in both groups. CONCLUSIONS Treatment with 4DCT/IMRT was at least as good as that with 3DCRT in terms of the rates of freedom from LRP and DM. There was a significant reduction in toxicity and a significant improvement in OS.

Postmastectomy Radiation Improves Local-Regional Control and Survival for Selected Patients With Locally Advanced Breast Cancer Treated With Neoadjuvant Chemotherapy and Mastectomy

PURPOSE To evaluate the efficacy of radiation in patients treated with neoadjuvant chemotherapy and mastectomy. PATIENTS AND METHODS We retrospectively analyzed the outcomes of 542 patients treated on six consecutive institutional prospective trials with neoadjuvant chemotherapy, mastectomy, and radiation. These data were compared to those of 134 patients who received similar treatment in these same trials but without radiation. RESULTS Irradiated patients had a lower rate of local-regional recurrence (LRR) (10-year rates: 11% v 22%, P = .0001). Radiation reduced LRR for patients with clinical T3 or T4 tumors, stage > or = IIB disease (AJCC 1988), pathological tumor size >2 cm, or four or more positive nodes (P < or = .002 for all comparisons). Patients who presented with clinically advanced stage III or IV disease but subsequently achieved a pathological complete response to neoadjuvant chemotherapy still had a high rate of LRR, which was significantly reduced with radiation (10-year rates: 33% v 3%, P = .006). Radiation improved cause-specific survival (CSS) in the following subsets: stage > or = IIIB disease, clinical T4 tumors, and four or more positive nodes (P < or = .007 for all comparisons). On multivariate analyses of LRR and CSS, the hazard ratios for lack of radiation were 4.7 (95% CI, 2.7 to 8.1; P < .0001) and 2.0 (95% CI, 1.4 to 2.9; P < .0001), respectively. CONCLUSION After neoadjuvant chemotherapy and mastectomy, comprehensive radiation was found to benefit both local control and survival for patients presenting with clinical T3 tumors or stage III-IV (ipsilateral supraclavicular nodal) disease and for patients with four or more positive nodes. Radiation should be considered for these patients regardless of their response to initial chemotherapy.

Prognostic factors for response and survival after high-dose cyclophosphamide, carmustine, and etoposide with autologous bone marrow transplantation for relapsed Hodgkin's disease.

Sixty-one patients with relapsed Hodgkins disease who had failed a mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)- and a doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)-like regimen were treated with a high-dose combination chemotherapy containing cyclophosphamide, carmustine, and etoposide (CBV) and autologous bone marrow transplantation (ABMT). Fifty-nine patients were treated in relapse and two were intensified early in third remission. Following therapy, 29 patients (47%) were in complete remission (CR), 18 patients (30%) achieved a partial response (PR), and 14 patients (23%) had progressive disease (PD). Among the partial responders, six patients achieved a CR following addition of local radiation therapy to sites of residual nodal disease. For a minimum follow-up of 2 years, 23 patients (38%) are alive and free of disease. High-dose CBV therapy produced severe myelosuppression, and there were four (7%) treatment-related deaths. A multivariate analysis identified failure of more than two prior chemotherapy treatments and poor performance status as important adverse risk factors for survival. Patients who had no adverse risk factor and/or were intensified with CBV while Hodgkins disease was still responding to conventional chemotherapy, had a CR rate of 63%, with 77% projected 3-year survival; whereas, all other patients had a CR rate of 31%, and a projected 3-year survival of only 18%. Our results demonstrated that CBV and ABMT can induce remission duration of 2 years or greater in a significant proportion of patients with relapsed Hodgkins disease.

Vorinostat, a histone deacetylase inhibitor, enhances the response of human tumor cells to ionizing radiation through prolongation of γ-H2AX foci

Vorinostat (suberoylanilide hydroxamic acid) is the prototype of a family of hybrid polar compounds that can induce growth arrest in transformed cells and shows promise for the treatment of cancer. Vorinostat specifically binds to and inhibits the activity of histone deacetylases resulting in acetylation of nucleosomal histones and an activation of gene transcription. Because histone deacetylases modulate chromatin structure and gene expression, both of which can influence radioresponse, this study was designed to examine the capacity of Vorinostat to influence radiation response in human tumor cells and investigate the mechanism underlying these interactions. Vorinostat induced hyperacetylation of histone H4 in a dose-dependent manner. We tested its ability to radiosensitize three human tumor cell lines (A375, MeWo, and A549) using clonogenic cell survival assays. Clonogenic cell survival assay showed that Vorinostat significantly radiosensitized all three tumor cell lines, substantially reducing the surviving fraction at 2 Gy. We examined potential mechanisms that may contribute to the enhanced radiation response induced by Vorinostat. Vorinostat and radiation alone did not induce apoptosis in the melanoma cell line. However, enhanced apoptosis was observed when cells were exposed to both Vorinostat and radiation, suggesting that Vorinostat renders tumor cells more susceptible to radiation-induced apoptosis. Results from DNA damage repair analysis in cultured A375 cells showed that Vorinostat had a strong inhibitory effect on the nonhomologous end joining pathway after radiation. A detailed examination of the involvement of the DNA repair pathway following Vorinostat treatment showed that Vorinostat reduced the expression of the repair-related genes Ku70, Ku80, and Rad50 in A375 cells as detected by Western blot analysis. We also examined γ-H2AX phosphorylation as a predictive marker of radiotherapy response to Vorinostat and observed that the combination of Vorinostat and radiation caused a prolongation of expression of DNA repair proteins such as γ-H2AX. Overall, we conclude that Vorinostat enhances tumor radioresponse by multiple mechanisms that may involve antiproliferative growth inhibition and effects on DNA repair after exposure to radiation. [Mol Cancer Ther 2006;5(8):1967–74]

Evidence for individual differences in the radiosensitivity of human skin

Previously published clinical data have been re-analysed to investigate individual differences in the radiosensitivity of human skin. In the clinical studies, acute and late skin reactions were recorded for 254 breast cancer patients receiving radiotherapy to the internal mammary nodes following simple or modified radical mastectomy. Each patient was treated bilaterally with different fractionation schedules to the right and left fields. Patients were assigned prospectively to 10 different treatment groups of 11-35 patients each, with all patients in a group receiving the same pair of fractionation schedules to the right and left fields. In the present study, correlations between the skin reactions in the two treatment fields per patient were investigated. For each of three different endpoints--peak reflectance measure of erythema, peak acute skin reaction score, and a ranking measure of the progression rate of telangiectasia--significant correlations were found between the levels of skin injury to the right and left treatment fields of the patients in most treatment groups. Although there were correlations between the absorbed doses in the right and left fields, statistical analyses indicated that dose effects were not sufficient to explain fully the patient-to-patient differences in skin response. Thus, these data provide evidence for the existence of individual differences in the radiation response of human skin, both for early and late effects. Whether these differences are dominated by heterogeneity in intrinsic cell radiosensitivity or by other factors has yet to be determined. However, there was no clear evidence of a correlation between the acute and late endpoints, suggesting that the individual differences in radiosensitivity are not dominated by a common genetic component expressed equally in all cells.

Radiation-induced injury to the visual pathway

Radiation-induced injury to the visual pathway was reviewed in a cohort of patients treated for various cancers of the nasal cavity and paranasal sinuses between 1969 and 1985. The study subjects consisted of 219 patients, 137 men and 82 women, in whom detailed records were available on the extent of orbital shielding, treatment plan for estimating doses delivered to various optic structures, and visual acuity follow-up information. There was a wide range in doses administered to various optic structures because patients with different primary lesion types were included and the radiotherapy techniques used varied during this era. The endpoint of the study was visual acuity < 20/100. The Cox proportional hazard model was used to assess the influence of various factors on the latent time to visual impairment and to fit the LQ model to the failure-time data. Actuarial curves showing the proportion of patients with visual impairment as a function of dose and time were generated. Corneal injury occurred in 24 of the 49 patients treated with the 3-field technique without any orbital shielding; variables affecting the incidence of cornea injury were total radiation dose and chemotherapy. Symptomatic retinopathy was diagnosed in 7 of 77 patients who received irradiation to a relatively large retinal surface, but no variables were found to correlate with this complication. Eight patients developed ipsilateral blindness due to optic neuropathy and 11 patients had bilateral visual impairment secondary to chiasm injury. The total radiation dose was identified as the predominant determinant. None of patients receiving a dose of < 50 Gy developed optic neuropathy or chiasm injury.(ABSTRACT TRUNCATED AT 250 WORDS)