Vorinostat enhances the cisplatin-mediated anticancer effects in small cell lung cancer cells.

BACKGROUND: Vorinostat, a histone deacetylase (HDAC) inhibitor, is a promising agent for cancer therapy. Combining vorinostat with cisplatin may relax the chromatin structure and facilitate the accessibility of cisplatin, thus enhancing its cytotoxicity. Studies have not yet investigated the effects of the combination of vorinostat and cisplatin on small cell lung cancer (SCLC). METHODS: We first assessed the efficacy of vorinostat with etoposide/cisplatin (EP; triple combination) and then investigated the effects of cotreatment with vorinostat and cisplatin on H209 and H146 SCLC cell lines. The anticancer effects of various combinations were determined in terms of cell viability, apoptosis, cell cycle distribution, and vorinostat-regulated proteins. We also evaluated the efficacy of vorinostat/cisplatin combination in H209 xenograft nude mice. RESULTS: Our data revealed that the triple combination engendered a significant reduction of cell viability and high apoptotic cell death. In addition, vorinostat combined with cisplatin enhanced cell growth inhibition, induced apoptosis, and promoted cell cycle arrest. We observed that the acetylation levels of histone H3 and α-tubulin were higher in combination treatments than in vorinostat treatment alone. Moreover, vorinostat reduced the expression of thymidylate synthase (TS), and TS remained inhibited after cotreament with cisplatin. Furthermore, an in vivo study revealed that the combination of vorinostat and cisplatin significantly inhibited tumor growth in xenograft nude mice (tumor growth inhibition T/C% = 20.5 %). CONCLUSIONS: Combined treatments with vorinostat promote the cytotoxicity of cisplatin and induce the expression of vorinostat-regulated acetyl proteins, eventually enhancing antitumor effects in SCLC cell lines. Triple combinations with a low dosage of cisplatin demonstrate similar therapeutic effects. Such triple combinations, if applied clinically, may reduce the undesired adverse effects of cisplatin. The effects of the combination of vorinostat and cisplatin should be evaluated further before conducting clinical trials for SCLC treatment.

Early results of CyberKnife image-guided robotic stereotactic radiosurgery for treatment of lung tumors.

OBJECTIVE: To determine if image-guided robotic stereotactic radiosurgery (IGR-SRS) by CyberKnife achieves acceptable local control in resectable but medically inoperable patients with non-small cell lung cancer (NSCLC) or pulmonary metastasis, and to evaluate control rates and toxicity. METHODS: Treatment details and outcomes were reviewed for 95 patients (age range 33-96 years) with 136 histologically proven cancers treated by IGR-SRS at the CyberKnife Center of Miami between March 2004 and March 2007. Tumor volumes ranged from 1.2 cc to 338 cc. Targeting was accomplished using combined skeletal alignment and real-time tracking via fiducials placed within the tumor. Total doses ranged from 15 to 67.5 Gy delivered in 1 to 5 fractions. RESULTS: Of the 95 patients treated, 78 (82%) are still alive at 1 to 36 months post-treatment. Nineteen patients have died, four from disease other than cancer progression. All patients but one achieved at least partial response to treatment and tolerated radiosurgery well. For the majority of our patients, fatigue had been the main side effect. CONCLUSIONS: The delivery of precisely targeted high radiation doses with surgical precision to lung tumors in a hypo-fractionated fashion is feasible and safe. Image-guided robotic stereotactic radiosurgery (IGR-SRS) of lung tumors with the CyberKnife achieves excellent rates of local disease control with limited toxicity to surrounding tissues, and in many cases may be curative for patients for whom surgery is not an option.

Curative radiotherapy for primary orbital lymphoma.

PURPOSE: To review our institutional experience with primary orbital lymphoma and determine the prognostic factors for survival, local control, and distant metastases. In addition, we also analyzed the risk factors for complications in the radiotherapeutic management of this tumor. METHODS AND MATERIALS: Between 1973 and 1998, 47 patients (29 women [62%] and 18 men [38%], median age 69 years, range 32-89) with Stage IAE orbital lymphoma were treated with curative intent at one department. Five had bilateral orbital involvement. The tumor was located in the eyelid and extraocular muscles in 23 (44%), conjunctiva in 17 (33%), and lacrimal apparatus in 12 (23%). The histologic features according to the World Heath Organization classification of lymphoid neoplasms was follicular lymphoma in 25, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type in 8, diffuse large B-cell lymphoma in 12, mantle cell lymphoma in 6, and peripheral T-cell lymphoma in 1. For the purposes of comparison with the existing literature on orbital lymphomas, the grading system according to the Working Formulation was also recorded. The histologic grade was low in 33 (63%), intermediate in 18 (35%), and high in 1 (2%). All patients were treated with primary radiotherapy alone. The median dose for low-grade tumors was 3000 cGy (range 2000-4020); the median dose for intermediate and high-grade tumors was 4000 cGy (range 3000-5100). A lens-sparing approach was used in 19 patients (37%). Late complications for the lens and cornea were scored according to the subjective, objective, management, and analytic (SOMA) scale of the Late Effects of Normal Tissue (LENT) scoring system. The median follow-up was 55 months (range 6-232). RESULTS: The local control rate was 100% in the 52 orbits treated. The 5-year overall survival and relapse-free survival rate was 73.6% and 65.5%, respectively. Tumor grade and location did not predict for overall survival or relapse-free survival. Seven patients (15%) developed distant recurrence (brain 2, extremity 2, mediastinum 1, liver 1, and retroperitoneum 1). One patient (2%) developed cervical node metastasis. The 5- and 10-year cataract-free survival rate was 56.7% and 32.9%, respectively. Of the 12 lens complications, 8 were LENT Grade 1 and 4 were Grade 3 toxicity. Only male gender predicted for an increased risk of cataract formation. Radiotherapy dose and technique did not predict for cataract formation; however, none of the patients who underwent the lens-sparing technique developed Grade 3 lens toxicity or required surgical correction. Of the nine corneal events, two were Grade 1, four Grade 2, and three were Grade 3 toxicity. Ten dry eyes were recorded; all were mild, and no patient had severe dry eye syndrome. Neovascular glaucoma was seen in 1 patient. No injury to the retina or optic nerve was reported. CONCLUSION: Radiotherapy alone is a highly effective modality in the curative management of primary orbital lymphoma. Most complications were minimal and did not require medical or surgical intervention. Although the use of the lens-sparing technique did not influence the incidence of cataractogenesis, we continue to recommend this approach whenever possible, because our experience indicates a higher grade of toxicity occurs and a higher incidence of corrective surgery is needed in patients treated without lens protection.

Intracranial ependymomas: an analysis of prognostic factors and patterns of failure.

From 1965 to 1997, 49 patients were diagnosed and treated for intracranial ependymoma at one institution. Tumor location was infratentorial in two thirds, and pathology was low grade in 38 patients (78%). Gross total resection of the primary tumor was achieved in 21 (43%). Thirty-six patients received adjuvant radiotherapy; the entire neuraxis was treated in 14, whole brain in 10, and local field only in 12. Median follow-up was 9.6 years (range, 2-33 years). The 5-, 10-, and 15-year overall survival rates were 71.4%, 63.5%, and 63.5% for craniospinal radiotherapy, 60.0%, 60.0%, and 40.0% for whole brain radiotherapy, and 80.8%, 64.6%, and 64.6% for local field radiotherapy (p = 0.88). The 5-, 10-, and 15-year local control rates were 60.3%, 54.4%, and 48.9%. The prognostic factors for a better local control rate were gross total resection (p = 0.021) and low grade histology (p = 0.031). Seventeen of 43 (39.5%) M0 patients did not respond to treatment; all had local failure and 4 also had a spinal relapse. Spinal relapse developed in 3 of 31 (10%) M0 patients who did not receive spinal radiotherapy, whereas 1 of 12 (8%) who had spinal radiotherapy did not respond to treatment in the spine. The results of this study indicate that local radiotherapy is sufficient for M0 patients with intracranial ependymoma.

Protracted radiotherapy treatment duration in medulloblastoma.

From 1970 to 1997, 63 patients with medulloblastoma were treated with craniospinal irradiation followed by a posterior fossa boost. There were 38 males and 25 females with a median age of 9 years (range, 8 months to 53 years). Stage was T1-T3a in 50 (79%) and M0 in 38 patients (60%) according to the Chang staging system. Gross total resection of the primary tumor was achieved in 33 (52%) and median posterior fossa dose was 54 Gy, with 55 (87%) receiving > or =50 Gy. Median radiotherapy treatment duration was 49 days (range, 30-104 days) with 35 patients (56%) completing radiotherapy in <50 days. The most common reasons for a protracted radiotherapy treatment duration > or =50 days were hematologic toxicity (46%) and use of <1.6 Gy fraction size per day (29%). Chemotherapy was used in 22 (35%). Median follow-up time was 10.8 years (range, 2-28.5 years). The 5- and 10-year freedom from progression rates were 58% +/- 13% and 50% +/- 13%, respectively, whereas the 5- and 10-year posterior fossa control rates were 61% +/- 12% and 54% +/- 13%, respectively. On multivariate analysis, age > or =3 years, M0 status, > or =50 Gy PFB dose, radiotherapy treatment duration <50 days, and use of chemotherapy correlated with better freedom from progression and posterior fossa control rates. The 5- and 10-year freedom from progression rates were 67% +/- 15% and 64% +/- 16%, respectively, for patients with radiotherapy treatment duration <50 days and were 42% +/- 20% and 29% +/- 18%, respectively, for duration > or =50 days ( p= 0.0026, log-rank test). The 5- and 10-year posterior fossa control rates were 70% +/- 15% and 70% +/- 15%, respectively, for radiotherapy treatment duration <50 days and 46% +/- 20% and 33% +/- 19%, respectively, for duration > or =50 days ( p= 0.0037, log-rank test). In addition to age > or =3 years, M0 stage, use of adjuvant chemotherapy, and posterior fossa dose > or =50 Gy, our findings also reveal that radiotherapy treatment duration <50 days has a favorable prognostic outcome in patients with medulloblastoma.

Dose response and local control using radiotherapy in non-metastatic Ewing sarcoma.

BACKGROUND: To determine prognostic factors for local control in the radiotherapeutic management of non-metastatic Ewing sarcoma. PROCEDURE: Forty patients with localized Ewing sarcoma (ES) were treated with primary site RT at one institution. Median RT dose was 55.8 Gy (range, 25.5-76 Gy). Chemotherapy was given to 34 patients (85%) with the most common regimen being vincristine, dactinomycin, cyclophosphamide, doxorubicin alternating with ifosfamide and etoposide (VACA + IE) in 10. Median follow-up for surviving patients was 12.3 years (range, 1.7-26.4 years). RESULTS: The 5- and 10-year local control rate was 78.2%. On multivariate analysis, RT dose was the only prognostic factor to impact on local control. The 5- and 10-year local control rate was 88.7% for RT dose >or=49 Gy and was 37.5% for <49 Gy (P = 0.0002, log-rank test). For tumors or=49 Gy and 50.0% for RT dose <49 Gy (P = 0.01, log-rank test). For tumors >8 cm, the 5- and 10-year local control rate was 85.7% for RT dose >or=54 Gy and 26.7% for RT dose <54 Gy (P = 0.006, log-rank test). CONCLUSIONS: Radiotherapy dose was found to influence local control in ES. In particular, patients who received RT doses >or=49 Gy for tumor size or=54 Gy for tumor size >8 cm had improved local control.

The value of postoperative radiotherapy in childhood nonrhabdomyosarcoma soft tissue sarcoma.

OBJECTIVE: To determine the value of postoperative radiotherapy (RT) in the management of nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) of childhood. PROCEDURE: From 1964 to 2000, 62 children with a median age of 14 years were seen at the University of Iowa and underwent a wide local excision for non-metastatic NRSTS. Tumors were high grade in 36 (58%) and >5 cm in 24 (39%). Margins of resection were negative (Group I) in 37 (60%) and positive (Group II) in 25 (40%). Postoperative RT was delivered to 20 patients (32%); eight of 37 (22%) Group I and 12 of 25 (48%) Group II children received postoperative RT. Chemotherapy was employed in 19 patients (31%). Median follow-up was 9.6 years. RESULTS: The 5- and 10-year overall survival rates for Group I were 69 and 63% and for Group II were 66 and 60%. The 5- and 10-year local control rate was 66%. On multivariate analysis, size of tumor (P < 0.001) and postoperative RT (P = 0.017) were prognostic factors for local control. All 13 Group I children with low grade,

Safety and efficacy of tiered limited-dose gamma knife stereotactic radiosurgery for unilateral acoustic neuroma.

Stereotactic radiosurgery has become a more widely employed modality of treatment for acoustic neuromas, but controversy still arises regarding the safety and efficacy of the technique. In general, radiation doses have been reduced over time. Since beginning treatments of acoustic neuromas with the Gamma Knife at the University of Miami/Jackson Memorial Medical Center in 1994, a dose regimen was adopted by the first author employing limited doses selected on the basis of tumor size with the anterior and medial regions of the prescription isodose surface kept just inside the gadolinium-enhanced limit of the tumor, in order to protect the facial nerve and brainstem. The records of patients treated for unilateral tumors were retrospectively reviewed. Fifty-two patients, aged 23-83 years, were treated with peripheral tumor doses of 10-14 Gy at the 45-70% isodoses. No patient developed new facial weakness or sensory loss; 3 patients had minor transient facial twitching within a few months of treatment. Of 34 patients followed more than 1 year (range 14-100 months, mean 43.4 months, median 37 months), 17 tumors reduced in size, 16 remained unchanged, and 1 increased in size. One patient, who had radiosurgery as planned postoperative adjuvant treatment after partial resection of a large tumor, developed an enlarging peritumoral arachnoid cyst that required surgical resection 79 months after radiosurgery. Patients with good pretreatment hearing retained approximately the same subjective level of hearing. Very good control of unilateral acoustic neuroma has been achieved by a limited-dose scheme that produces minimal complications, but due to the frequently indolent course of these tumors, continued long-term monitoring will be necessary.