p16INK4a Status and Response to Induction Low-Dose Fractionated Radiation in Advanced Head and Neck Cancer.

OBJECTIVE: To evaluate the impact of p16INK4a (p16) expression on clinical efficacy of induction low-dose fractionated radiation therapy (LDFRT) with concurrent chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). STUDY DESIGN: Historical cohort study. SETTING: Tertiary medical center. METHODS: A total of 66 Patients with locally advanced SCCHN were enrolled in 2 clinical trials using paclitaxel, carboplatin, and concurrent LDFRT induction therapy. Patients were evaluated for response to induction by a multidisciplinary team and then were given definitive treatment. Adequate tissue samples from the pretreatment biopsies of 42 individuals were identified and analyzed for p16 expression. Expression was correlated with clinical outcomes. RESULTS: Of 42 tumors, 15 (35.7%) were positive for p16. Patients with p16-positive tumors had improved response to induction, but this was not statistically significant (P = .06). Five-year overall survival was 80% in p16-positive patients and 58% in p16-negative patients (P = .025). CONCLUSIONS: p16 Expression affects treatment response in patients treated with induction LDFRT with concurrent chemotherapy. This is similar to results reported for standard induction chemotherapy.

A feasibility study using TomoDirect for craniospinal irradiation.

The feasibility of delivering craniospinal irradiation (CSI) with TomoDirect is investigated. A method is proposed to generate TomoDirect plans using standard three-dimensional (3D) beam arrangements on Tomotherapy with junctioning of these fields to minimize hot or cold spots at the cranial/spinal junction. These plans are evaluated and compared to a helical Tomotherapy and a three-dimensional conformal therapy (3D CRT) plan delivered on a conventional linear accelerator (linac) for CSI. The comparison shows that a TomoDirect plan with an overlap between the cranial and spinal fields might be preferable over Tomotherapy plans because of decreased low dose to large volumes of normal tissues outside of the planning target volume (PTV). Although the TomoDirect plans were not dosimetrically superior to a 3D CRT linac plan, the patient can be easily treated in the supine position, which is often more comfortable and efficient from an anesthesia standpoint. TomoDirect plans also have only one setup position which obviates the need for matching of fields and feathering of junctions, two issues encountered with conventional 3D CRT plans. TomoDirect plans can be delivered with comparable treatment times to conventional 3D plans and in shorter times than a Tomotherapy plan. In this paper, a method is proposed for creating TomoDirect craniospinal plans, and the dosimetric consequences for choosing different planning parameters are discussed.

Age-related disparities in the use of radiotherapy for treatment of localized soft tissue sarcoma.

BACKGROUND: Many elderly patients with cancer experience increased cancer-related morbidity and mortality compared with younger patients. In soft tissue sarcoma, adjuvant radiotherapy is an integral part of definitive therapy for limb preservation. The authors of this report hypothesized that age-related disparities exist in the use of radiation. METHODS: Surveillance, Epidemiology, and End Results (SEER) data were used to conduct a retrospective cohort study among patients aged ≥ 25 years who were diagnosed from 1998 to 2004 with nonmetastatic, biopsy-proven, high-grade soft tissue sarcoma of the extremities and underwent a limb-sparing procedure. Patients were stratified according to age (ages < 50 years, 50-70 years, and > 70 years). Logistic regression was used to determine the association between age and the receipt of radiotherapy adjusting for histology, tumor location, tumor size, surgery, sex, race, and marital status. A Cox proportional hazards model was used to compare disease-specific and all-cause mortality. RESULTS: Among 1354 eligible patients; 37.1% were aged > 70 years, 44.3% were women, and 84.4% were Caucasian. Although 73.8% of the cohort received radiotherapy, receipt decreased from 78.2% among patients aged < 50 years to 69.6% among patients aged >70 years (test for trend; P = .006). After adjusting for demographic and tumor factors, older patients remained less likely to receive radiotherapy (odds ratio, 0.66; 95% confidence interval, 0.47-0.92) and more likely to experience disease-specific death (hazard ratio, 2.4; 95% confidence interval, 1.4-4.1) compared with the youngest group. CONCLUSIONS: Older adults appeared to be less likely to receive definitive therapy for soft tissue sarcoma of the extremities. In the absence of clinical trials and treatment guidelines tailored to this population, under treatment may disadvantage elderly patients, who have increased cancer-related morbidity and mortality.

Effects of Multileaf Collimator Design and Function When Using an Optimized Dynamic Conformal Arc Approach for Stereotactic Radiosurgery Treatment of Multiple Brain Metastases With a Single Isocenter: A Planning Study.

Background Stereotactic radiosurgery (SRS) or fractionated SRS (fSRS) are effective options for the treatment of brain metastases. When treating multiple metastases with a linear accelerator-based approach, a single isocenter allows for efficient treatment delivery. In this study, we present our findings comparing dosimetric parameters of Brainlab (Munich, Germany) Elements™ Multiple Brain Mets SRS (MME) software (version 1.5 versus version 2.0) for a variety of scenarios and patients. The impact of multileaf collimator design and function on plan quality within the software was also evaluated. Materials and methods Twenty previously treated patients with a total of 58 lesions (from one to seven lesions each) were replanned with an updated version of the multiple brain Mets software solution. For each plan, the mean conformity index (CI), mean gradient index (GI), the volume of normal brain receiving 12 Gy (V12), and mean brain dose were evaluated. Additionally, all v2.0 plans were further evaluated with jaw tracking for by Elekta (Stockholm, Sweden) and HD120™ multileaf collimator by Varian Medical Systems (Palo Alto, USA). Results The new software version demonstrated improvements for CI, GI and V12 (p <0.01). For the Elekta Agility™ multileaf collimator, jaw tracking improved all dosimetric parameters except for CI (p =0.178) and mean brain dose (p =0.93). For the Varian with HD120 multileaf collimator, all parameters improved. Conclusions The software enhancements in v2.0 of the software provided improvements in planning efficiency and dosimetric parameters. Differences in multileaf collimator design may provide an additional incremental benefit in a subset of clinical scenarios.

Symptom clusters in patients with newly-diagnosed brain tumors.

A symptom cluster comprises three or more concurrent symptoms. There is a paucity of symptom cluster research in cancer patients. Data from a previously conducted clinical trial were analyzed to search for symptom clusters. This phase III, placebo-controlled, double-blind, prospective, randomized clinical trial of 66 patients assessed the effect of prophylactic d-threo-methylphenidate (d-MPH) on quality of life (QOL) in newly diagnosed brain tumor patients receiving brain radiation therapy. Patients received 5-15 mg of d-MPH or placebo twice daily starting on week 1 of radiation therapy and continuing for 8 weeks post radiotherapy. QOL data were collected at baseline; the end of radiation therapy; and 4, 8, and 12 weeks following radiation therapy using the Functional Assessment of Cancer Therapy (FACT), the FACT-Brain subscale, and the Center for Epidemiologic Studies Depression Scale. Exploratory factor analysis, multidimensional scaling (MDS), and cluster analysis were used to search for symptom clusters. The trial failed to show a treatment effect; patients receiving d-MPH or placebo were analyzed together to search for clusters. Two symptom clusters were identified using exploratory factor analysis--a language cluster including difficulty reading, writing, and finding the right words and a mood cluster including feelings of sadness, anxiety, and depressed mood; these clusters were supported by MDS and cluster analysis. Our results suggest that interventions that target both cognitive function and mood should be considered in this patient population. Further research on symptom clusters in brain tumor patients is needed.

Using low-dose radiation to potentiate the effect of induction chemotherapy in head and neck cancer: Results of a prospective phase 2 trial.

PURPOSE: Low-dose fractionated radiation therapy (LDFRT) induces effective cell killing through hyperradiation sensitivity and potentiates effects of chemotherapy. We report our second investigation of LDFRT as a potentiator of the chemotherapeutic effect of induction carboplatin and paclitaxel in locally advanced squamous cell cancer of the head and neck (SCCHN). EXPERIMENTAL DESIGN: Two cycles of induction therapy were given every 21 days: paclitaxel (75 mg/m2) on days 1, 8, and 15; carboplatin (area under the curve 6) day 1; and LDFRT 50 cGy fractions (2 each on days 1, 2, 8, and 15). Objectives included primary site complete response rate; secondary included overall survival, progression-free survival (PFS), disease-specific survival, and toxicity. RESULTS: A total of 24 evaluable patients were enrolled. Primary sites included oropharynx (62.5%), larynx (20.8%), oral cavity (8.3%), and hypopharynx (8.3%). Grade 3/4 toxicities included neutropenia (20%), leukopenia (32%), dehydration/hypotension (8%), anemia (4%), infection (4%), pulmonary/allergic rhinitis (4%), and diarrhea (4%). Primary site response rate was 23/24 (95.8%): 15/24 (62.5%) complete response, 8/24 (33.3%) partial response, and 1/24 (4.2%) stable disease. With median follow-up of 7.75 years, 9-year rates for overall survival were 49.4% (95% confidence interval [CI], 30.5-79.9), PFS was 72.2% (CI, 55.3-94.3), and disease-specific survival was 65.4% (44.3-96.4). CONCLUSION: Chemopotentiating LDFRT combined with paclitaxel and carboplatin is effective in SCCHN and provided an excellent median overall survival of 107.2 months, with median PFS not yet reached in this locally advanced SCCHN cohort. This compares favorably to prior investigations and caused fewer grade 3 and 4 toxicities than more intensive, 3-drug induction regimens. This trial demonstrates the innovative use of LDFRT as a potentiator of chemotherapy.

Low-dose fractionated radiation with induction chemotherapy for locally advanced head and neck cancer: 5 year results of a prospective phase II trial.

OBJECTIVE: This study aims to report the long-term outcomes of a novel treatment approach utilizing induction low-dose fractionated radiation therapy (LDFRT) and chemotherapy for locally advanced squamous cell carcinoma of head and neck (SCCHN). METHODS: We prospectively enrolled 40 patients with locally advanced SCCHN (77 % stage IV) on a phase II clinical trial and treated with induction paclitaxel (225 mg/m2), carboplatin (AUC 6), and LDFRT (80 cGy BID on days 1 and 2) every 21 days for two cycles. RESULTS: Forty patients enrolled; 39 were evaluable. The acute toxicity and response data have been previously reported; overall response rate (RR) was 82 %. After induction, definitive therapy was concurrent chemoradiation (CRT) in 51 %, XRT alone in 39 %, surgery in 5 %, and surgery and XRT in 5 %. The long-term outcomes are now reported with a median follow-up of 83 months. Locoregional control (LRC) is 80 % and distant control (DC) is 77 %. Five-year overall survival (OS), disease-specific survival, and progression-free survival (PFS) are 62 %, 66 %, and 58 %, respectively. CONCLUSION: Induction chemotherapy with LDFRT has a high initial RR, comparable toxicity to two-drug induction regimens, but adds a third novel and effective agent, LDFRT. Five-year follow-up shows favorable outcomes compared to historical controls and excellent compliance with definitive therapy. This novel treatment approach is now planned for phase 3 trial evaluation.

Inhibition of cyclin A kinase activity in E2F-1 chemogene therapy of colon cancer.

Adenoviral-mediated gene transfer of the apoptotic gene E2F-1 has been shown to induce apoptosis in a variety of tumor cells and acts in an additive or cooperative fashion with several specific chemotherapeutic agents to induce tumor cell death. The apoptotic function of E2F-1 is dependent on its ability to bind DNA; cyclin A kinase activity has been shown to negatively regulate the DNA-binding capacity of E2F-1. In the present study, we sought to determine whether cyclin A kinase activity is involved in mediating the interaction between E2F-1 and chemotherapeutic agents in colon cancer cells. Therefore, human colon adenocarcinoma (SW620) cells were treated with an adenovirus expressing E2F-1 (Ad-E2F-1, multiplicity of infection 20). Immediately following infection, a panel of conventional chemotherapeutic agents with varying modes of cytotoxic action were administered at LD(25 )doses. Three days following treatment, viability and growth inhibition were determined by trypan blue exclusion assay. Apoptosis was confirmed using cellular morphology, poly (ADP-ribose) polymerase cleavage, and flow-cytometric analysis. E2F-1 overexpression and cyclin A protein expression were monitored by immunoblot, and cyclin A kinase activity was determined by kinase assay. Vincristine (VIN), camptothecin (CPT), and actinomycin D were found to have a cooperative (>38% over the additive single therapy values) effect on E2F-1-mediated apoptosis. Etoposide, cisplatin (CIS), and 5-fluorouracil (5-FU) showed the least cooperation ( 0.1) compared to Ad-E2F-1 treatment alone. Combination of Ad-LacZ/5-FU and Ad-LacZ/actinomycin D significantly inhibited cyclin A kinase activity compared to Ad-LacZ treatment alone (p < 0.005). No other Ad-LacZ/drug combinations significantly affected cyclin A kinase activity (p > 0.05). In conclusion, combinations of E2F-1 adenovirus and VIN, CPT, or actinomycin D at LD(25 )had significant cooperative effects on colon cancer apoptotic cell death in vitro. Although inhibition of cyclin A kinase activity was observed in most Ad-E2F-1/drug combination treatments compared to Ad-E2F-1 treatment alone, there was no consistent correlation between degree of inhibition of cyclin A kinase activity and the cooperative effect. Nonetheless, inhibition of cyclin A kinase activity may be an important mechanism by which the chemogene therapy effects involving E2F-1 are modulated.