John F. Deeken

Fractionated Stereotactic Radiosurgery for Reirradiation of Head-and-Neck Cancer

PURPOSEnStereotactic radiosurgery (SRS) is an appealing treatment option after previous radiotherapy because of its precision, conformality, and reduced treatment duration. We report our experience with reirradiation using fractionated SRS for head-and-neck cancer.nnnMETHODS AND MATERIALSnFrom 2002 to 2008, 65 patients received SRS to the oropharynx (n = 13), hypopharynx (n = 8), nasopharynx (n = 7), paranasal sinus (n = 7), neck (n = 7), and other sites (n = 23). Thirty-eight patients were treated definitively and 27 patients with metastatic disease and/or untreated local disease were treated palliatively. Nine patients underwent complete macroscopic resection before SRS. Thirty-three patients received concurrent chemoradiation. The median initial radiation dose was 67 Gy, and the median reirradiation SRS dose was 30 Gy (21-35 Gy) in 2-5 fractions.nnnRESULTSnMedian follow-up for surviving patients was 16 months. Fifty-six patients were evaluable for response: 30 (54%) had complete, 15 (27%) had partial, and 11 (20%) had no response. Median overall survival (OS) for all patients was 12 months. For definitively treated patients, the 2-year OS and locoregional control (LRC) rates were 41% and 30%, respectively. Multivariate analysis demonstrated that higher total dose, surgical resection, and nasopharynx site were significantly associated with improved LRC; surgical resection and nonsquamous histology were associated with improved OS. Seven patients (11%) experienced severe reirradiation-related toxicity, including one treatment-attributed death.nnnCONCLUSIONnSRS reirradiation for head-and-neck cancer is feasible. This study demonstrates encouraging response rates with acceptable toxicity. Fractionated SRS reirradiation with concurrent chemotherapy in select patients warrants further study.

Identification of Compounds that Correlate with ABCG2 Transporter Function in the National Cancer Institute Anticancer Drug Screen

ABCG2 is an ATP-binding cassette transporter that counts multiple anticancer compounds among its substrates and is believed to regulate oral bioavailability as well as serve a protective role in the blood-brain barrier, the maternal-fetal barrier, and hematopoietic stem cells. We sought to determine whether novel compounds that interact with the transporter could be identified through analysis of cytotoxicity profiles recorded in the NCI Anticancer Drug Screen database. A flow cytometric assay was used to measure ABCG2 function in the 60 cell lines and generate a molecular profile for COMPARE analysis. This strategy identified >70 compounds with Pearson correlation coefficients (PCCs) >0.4, where reduced drug sensitivity correlated with ABCG2 expression, as well as >120 compounds with PCCs < −0.4, indicating compounds to which ABCG2 expression conferred greater sensitivity. Despite identification of known single nucleotide polymorphisms in the ABCG2 gene in a number of the cell lines, omission of these lines from the COMPARE analysis did not affect PCCs. Available compounds were subjected to validation studies to confirm interaction with the transporter, including flow cytometry, [125I]IAAP binding, and cytotoxicity assays, and interaction was documented in 20 of the 27 compounds studied. Although known substrates of ABCG2 such as mitoxantrone or topotecan were not identified, we characterized three novel substrates—5-hydroxypicolinaldehyde thiosemicarbazone (NSC107392), (E)-N-(1-decylsulfanyl-3-hydroxypropan-2-yl)-3-(6-methyl-2,4-dioxo-1H-pyrimidin-5-yl)prop-2-enamide (NSC265473), and 1,2,3,4,7-pentahydroxy-1,3,4,4a,5,11b-hexahydro[1,3]dioxolo[4,5-j]phenanthridin-6(2H)-one [NSC349156 (pancratistatin)]—and four compounds that inhibited transporter function—2-[methyl(2-pyridin-2-ylethyl)-amino]fluoren-9-one hydroiodide (NSC24048), 5-amino-6-(7-amino-5,8-dihydro-6-methoxy-5,8-dioxo-2-quinolinyl)-4-(2-hydroxy-3,4-dimethoxyphenyl)-3-methyl-2-pyridinecarboxylic acid, methyl ester (NSC45384), (17β)-2,4-dibromo-estra-1,3,5(10)-triene-3,17-diol (NSC103054), and methyl N-(pyridine-4-carbonylamino)carbamodithioate (NSC636795). In summary, COMPARE analysis of the NCI drug screen database using the ABCG2 functional profile was able to identify novel substrates and transporter-interacting compounds.

Safety and efficacy of hypofractionated stereotactic body reirradiation in head and neck cancer: Long-term follow-up of a large series.

The purpose of this study was to report long‐term outcomes for a large cohort of patients with head and neck squamous cell carcinoma (HNSCC) who underwent stereotactic body radiotherapy (SBRT) reirradiation.

Effect of multimodality treatment on overall survival for patients with metastatic or recurrent HPV-positive head and neck squamous cell carcinoma.

The optimal treatment for patients with recurrent human papillomavirus (HPV)‐positive head and neck cancer is poorly understood.

Reirradiation of recurrent salivary gland malignancies with fractionated stereotactic body radiation therapy.

PurposeThe purpose of this study was to review a single-institution experience with the reirradiation of recurrent salivary gland tumors using fractionated stereotactic radiosurgery (SBRT).MethodsBetween 2003 and 2011, 18 patients diagnosed with recurrent, previously irradiated, salivary gland carcinomas were treated with SBRT reirradiation. Median age was 68 for all patients with most tumors being of major salivary gland origin. Most patients did not undergo surgical resection, and among those that did, all had positive margins. Only seven patients received chemotherapy, and the median SBRT dose was 30xa0Gy given in five fractions with a median cumulative dose of 91.1xa0Gy.ResultsThe median overall survival (OS), progression-free survival (PFS), and local control (LRC) were 11.5, 3.5, and 5.5xa0months, respectively. The 2-year OS, PFS, and LRC rates were 39%, 24%, and 53%, respectively. Statistical analysis identified presence of gross disease and interval to reirradiation as negative predictors of survival outcomes on both univariate and multivariate analyses (pxa0<xa00.05). On multivariate analysis, tumor volume was a negative predictor of survival outcomes (pxa0<xa00.05). Long-term toxicity analysis revealed four patients in the reirradiated group with soft tissue necrosis, which correlated with the cumulative dose (pxa0=xa00.01).ConclusionOur data suggest that SBRT is a reasonable treatment option for reirradiation of salivary gland tumors, but further studies are warranted.

Survival Outcomes of Patients Treated with Hypofractionated Stereotactic Body Radiation Therapy for Parotid Gland Tumors: a Retrospective Analysis

Background: to review a single-institution experience with the management of parotid malignancies treated by fractionated stereotactic body radiosurgery (SBRT). Findings: Between 2003 and 2011, 13 patients diagnosed with parotid malignancies were treated with adjuvant or definitive SBRT to a median dose of 33u2009Gy (range 25–40u2009Gy). There were 11 male and two female patients with a median age of 80. Ten patients declined conventional radiation treatment and three patients had received prior unrelated radiation therapy to neighboring structures with unavailable radiation records. Six patients were treated with definitive intent while seven patients were treated adjuvantly for adverse surgical or pathologic features. Five patients had clinical or pathologic evidence of lymph node disease. Conclusion: at a median follow-up of 14u2009months only one patient failed locally, and four failed distantly. The actuarial 2-year overall survival, progression-free survival, and local-regional control rates were 46, 84, and 47%, respectively. Statistical analysis revealed surgery as a positive predictor of overall survival while presence of gross disease was a negatively correlated factor (pu2009<u20090.05).

A phase 1/PK study of Sunitinib with highly active antiretroviral therapy (HAART) in HIV+ patients with solid tumors: AIDS malignancy consortium study 061

Background In developed counties the rates of non-AIDS defining cancers (NADCs) now exceed those of AIDS-defining cancers in HIV-positive patients. Drug-drug interactions between HAART and chemotherapy may complicate the treatment of patients with NADCs. In order to determine the proper dosing of new targeted chemotherapies in patients with NADCs who are also on HAART, the AMC is performing a series of phase I/pharmacokinetic (PK) studies to determine the proper dosing of these agents in HIV+ cancer patients. We present the results of the first such study which investigated sunitinib, an oral multiple tyrosine kinase inhibitor.

Abstract A128: A phase I study of liposomal‐encapsulated docetaxel (LE‐DT) in patients with advanced solid tumor malignancies

Background: Docetaxel is a semi‐synthetic microtubule disrupting antineoplastic drug indicated for the treatment of a wide variety of solid tumor malignancies. Past clinical trials have shown a dose‐response correlation when used in the treatment of prostate and breast cancer. Common dose limiting toxicities are myelosuppression and neuropathy. Liposomes are versatile drug carriers that may increase drug solubility, serve as sustained release systems, provide protection from drug degradation and drug related toxicities, and help overcome multidrug resistance mediated by P‐glycoprotein or similar resistant efflux mechanisms. The aims of this phase I study were to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), pharmacokinetics (pK), and clinical response of LE‐DT in patients with advanced solid tumor malignancies. Methods: LE‐DT was administered using a standard 3+3 dose escalation schema with dose levels of 50, 65, 85, 110, and 132 mg/m 2 . Drug was infused over 1 hour. Premedication with dexamethasone was not required as it is with standard docetaxel therapy. In patients who experienced infusionrelated reactions pre‐medication with steroids, antihistamines, and antipyretics were provided in subsequent cycles. Toxicities were recorded using NCI‐CTCAE 3.0, and response was assessed using RECIST criteria. PK samples were drawn during C1 and analyzed using Win NonLin. Results: Twenty‐four patients were treated in total. The total number of cycles each patient received ranged from 1 to 21 (median = 4). Dose escalation proceeded until DLTs were experienced by 2 out of 2 patients at the 132mg/m 2 dose level (both Grade 4 neutropenia). When additional patients were treated at the 110 mg/m 2 dose, 2 patients experienced Grade 4 neutropenia. The dose level was reduced to 85mg/m 2 , with one patient experiencing Grade 4 neutropenia at this level. The protocol was amended to allow G‐CSF growth factor support and dose re‐escalation. An additional 4 patients were treated at 110mg/m 2 and none of these patients experienced Grade 4 neutropenia. At this dose level, two patients experiencing Grade 3 fatigue. No patient experienced Grade 3/4 neuropathy, even in two patients treated for 10 and 21 cycles. Two patients experienced Grade 2 neuropathy. Additional toxicities included Grade 3 anemia in three patients. Drug pharmacokinetics followed a two‐compartment elimination pattern. Cmax and AUC inf were proportional to dose through the 110mg/m 2 dose level with a mean clearance of 28.5L/hr/m 2 . At the 132mg/m 2 dose Cl was 45.4 L/hr/m 2 . Serum half‐lives at the differing dose levels ranged from 15.1 to 22.4 hr. There was no correlation between pK measures and toxicity. One patient had a confirmed partial response (PR) and another had an unconfirmed PR (8%). Eight patients (33%) had prolonged stable disease lasting more than 3 months. One patient continues to have stable disease after 21 cycles. Conclusion: LE‐DT was tolerable with expected toxicities of neutropenia, anemia, and fatigue, but without water retention (edema). Importantly, in this heavily pretreated population no patient experienced clinically significant neuropathy. Clinical benefit (SD+PR) was observed in 41% of the patients. The recommended phase II dose of LE‐DT is 110mg/m 2 with growth factor support. Phase II studies of LE‐DT in prostate and pancreatic cancers are planned. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A128.