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Purpose: Protraction of radiation therapy courses can lead to lower cancer control and cancer-specific survival rates. The requirement for daily, consecutive radiation treatments coupled with the complexities of multimodality cancer care and quality assurance can occasionally lead to missed patient appointments or clinical inefficiency. To determine whether an automated text messaging (short message service [SMs]) platform could improve patient compliance with scheduled radiation therapy delivery, we created an automated SMS platform to send daily reminders of radiation therapy appointments., Methods and Materials: An automated SMS text messaging program was used from July 2016 to January 2017 to deliver daily appointment time reminders to patients on an elective basis. Automated text messages were sent 2 hours before treatment appointments with appointment-specific information. We analyzed for compliance with radiation therapy appointments for patients who elected to receive SMS reminders versus those who did not., Results: Multivariate analysis of >37,000 encounters involving ∼3400 patients demonstrated that of the factors considered, nonreceipt of SMS appointment reminders had a strong association with 15- to 60-minute tardiness (odds ratio [OR], 1.25; 95% confidence interval [CI], 1.13-1.38; P < .0001), >60-minute tardiness (OR, 1.56; 95% CI, 1.34-1.82; P < .0001) and no-shows (OR, 6.77; 95% CI, 5.45-8.41; P < .0001). Other demographic factors associated with decreased compliance included being early in a radiation therapy course, having an appointment earlier in the day, younger age, and male sex. Receipt of an SMS message did not correlate with overall treatment package time., Conclusions: Receipt of text messages correlates with compliance for radiation therapy appointments. Prospective randomized trials would be required to determine conclusively whether SMS is an effective intervention for improving compliance in populations at risk for being late to or missing radiation therapy appointments., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Current standard for locally advanced non-small cell lung cancer (NSCLC) is combined concurrent therapy with a platinum-based regimen. Preclinical synergistic activity of pemetrexed with radiation therapy (RT) and favorable toxicity profile has led to clinical trials evaluating pemetrexed in chemoradiation regimens. This literature search of concurrent pemetrexed and RT treatment of patients with stage III NSCLC included MEDLINE database, meeting abstracts, and the clinical trial registry database. Nineteen unique studies were represented across all databases including 11 phase I studies and eight phase II studies. Of the six phase II trials with mature data available, median overall survival ranged from 18.7 to 34 months. Esophagitis and pneumonitis occurred in 0-16% and 0-23% of patients, respectively. Of the ongoing trials, there is one phase III and four phase II trials with pemetrexed in locally advanced NSCLC. Pemetrexed can be administered safely at full systemic doses with either cisplatin or carboplatin concomitantly with radical doses of thoracic radiation therapy. While results from the ongoing phase III PROCLAIM trial are needed to address definitively the efficacy of pemetrexed-cisplatin plus RT in stage III NSCLC, available results from phase II trials suggest that this regimen has promising activity with an acceptable toxicity profile., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Locally advanced non-small cell lung cancer (LA-NSCLC) is a heterogeneous disease, encompassing stage IIIA, for which surgery in combination with chemotherapy and/or radiation therapy (RT) represents a potential treatment approach for select patients, and stage IIIB, for which chemoradiation represents the standard of care. Recent advances in systemic cytotoxic and molecularly targeted therapies coupled with technologic innovations in radiotherapy have the potential to improve outcomes for this patient population. Many ongoing clinical trials use specific genetic mutations or histologic status to determine the combination of targeted therapies and RT, as well as to determine the optimal chemoradiotherapy platforms. Additionally, use of modern RT techniques has improved outcomes for some patients with limited metastatic disease, thereby prompting further studies on how to best integrate aggressive management of oligometastases using RT with chemotherapeutic regimens., (Copyright © 2014 Elsevier Inc. All rights reserved.)

PurposeTo compare 2 stereotactic body radiation therapy (SBRT) schedules for medically inoperable early-stage lung cancer to determine which produces the lowest rate of grade ≥3 protocol-specified adverse events (psAEs) at 1 year.Methods and materialsPatients with biopsy-proven peripheral (≥2 cm from the central bronchial tree) T1 or T2, N0 (clinically node negative by positron emission tomography), M0 tumors were eligible. Patients were randomized to receive either 34 Gy in 1 fraction (arm 1) or 48 Gy in 4 consecutive daily fractions (arm 2). Rigorous central accreditation and quality assurance confirmed treatment per protocol guidelines. This study was designed to detect a psAEs rate >17% at a 10% significance level (1-sided) and 90% power. Secondary endpoints included rates of primary tumor control (PC), overall survival (OS), and disease-free survival (DFS) at 1 year. Designating the better of the 2 regimens was based on prespecified rules of psAEs and PC for each arm.ResultsNinety-four patients were accrued between September 2009 and March 2011. The median follow-up time was 30.2 months. Of 84 analyzable patients, 39 were in arm 1 and 45 in arm 2. Patient and tumor characteristics were balanced between arms. Four (10.3%) patients on arm 1 (95% confidence interval [CI] 2.9%-24.2%) and 6 (13.3%) patients on arm 2 (95% CI 5.1%-26.8%) experienced psAEs. The 2-year OS rate was 61.3% (95% CI 44.2%-74.6%) for arm 1 patients and 77.7% (95% CI 62.5%-87.3%) for arm 2. The 2-year DFS was 56.4% (95% CI 39.6%-70.2%) for arm 1 and 71.1% (95% CI 55.5%-82.1%) for arm 2. The 1-year PC rate was 97.0% (95% CI 84.2%-99.9%) for arm 1 and 92.7% (95% CI 80.1%-98.5%) for arm 2.Conclusions34 Gy in 1 fraction met the prespecified criteria and, of the 2 schedules, warrants further clinical research.

In this review, we attempt to make a case for the establishment of a limited number of heavy ion cancer research and treatment facilities in the United States. Based on the basic physics and biology research, conducted largely in Japan and Germany, and early phase clinical trials involving a relatively small number of patients, we believe that heavy ions have a considerably greater potential to enhance the therapeutic ratio for many cancer types compared to conventional X-ray and proton radiotherapy. Moreover, with ongoing technological developments and with research in physical, biological, immunological, and clinical aspects, it is quite plausible that cost effectiveness of radiotherapy with heavier ions can be substantially improved. [ABSTRACT FROM AUTHOR]

The article focuses on a study which evaluated the toxicity and efficacy of stereotactic body radiation therapy in a high-risk population of patients 18 years and older with early stage but medically inoperable lung cancer. The prescription dose of the radiation was 18 Gy per fraction x 3 fractions with entire treatment lasting between 1 1/2 and 2 weeks. The protocol-specified adverse events related to stereotactic body radiation therapy are cited, including hypocalcemia, hypoxia and pneumonitis. A survival rate of 55.8% at 3 years, high rates of local tumor control and moderate treatment-related morbidity were observed in the patients.

Simple Summary: Emerging evidence indicates that the immune system plays an important role in controlling tumors during radiotherapy, and radiation-induced immune toxicity such as lymphopenia is associated with poor survival. However, the immune system is not considered as a critical organ at risk in radiotherapy partially because the radiation dose to the immune system is difficult to compute. In this study, we developed a model to compute the radiation dose to the circulating blood, which contains the majority of active immune cells. We then validated this model by examining the correlations of the blood dose with treatment outcome for patients enrolled in the NRG/RTOG0617 phase III clinical trial. We demonstrated that the blood dose was significantly and independently associated with overall survival and local progression-free survival. This result suggests that radiation dose to circulating immune cells is critical for tumor control, and decreasing the dose to the immune system has the potential to improve survival. Background: We hypothesized that the Effective radiation Dose to the Immune Cells (EDIC) in circulating blood is a significant factor for the treatment outcome in patients with locally advanced non-small-cell lung cancer (NSCLC). Methods: This is a secondary study of a phase III trial, NRG/RTOG 0617, in patients with stage III NSCLC treated with radiation-based treatment. The EDIC was computed as equivalent uniform dose to the entire blood based on radiation doses to all blood-containing organs, with consideration of blood flow and fractionation effect. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS) and local progression-free survival (LPFS). The EDIC–survival relationship was analyzed with consideration of clinical significant factors. Results: A total of 456 patients were eligible. The median EDIC values were 5.6 Gy (range, 2.1–12.2 Gy) and 6.3 Gy (2.1–11.6 Gy) for the low- and high-dose groups, respectively. The EDIC was significantly associated with OS (hazard ratio [HR] = 1.12, p = 0.005) and LPFS (HR = 1.09, p = 0.02) but PFS (HR = 1.05, p = 0.17) after adjustment for tumor dose, gross tumor volume and other factors. OS decreased with an increasing EDIC in a non-linear pattern: the two-year OS decreased first with a slope of 8%/Gy when the EDIC < 6 Gy, remained relatively unchanged when the EDIC was 6–8 Gy, and followed by a further reduction with a slope of 12%/Gy when the EDIC > 8 Gy. Conclusions: The EDIC is a significant independent risk factor for poor OS and LPFS in RTOG 0617 patients with stage III NSCLC, suggesting that radiation dose to circulating immune cells is critical for tumor control. Organ at risk for the immune system should be considered during RT plan. [ABSTRACT FROM AUTHOR]

Purpose: SBRT is a new therapeutic paradigm using large dose per fraction treatments (aggressive hypofractionation). While SBRT has shown efficacy for treating patients with lung, liver and spine tumors, to our knowledge there have been no preclinical studies evaluating the efficacy of this treatment for prostate cancer. We investigated the dose-response characteristics of SBRT for treating human prostate cancer in a nude mouse model. Materials and Methods: Nude mice were injected subcutaneously into the right flank with C4-2 prostate cancer cells grown in culture. A dose escalation trial was performed to assess toxicity and response. Tumor bearing animals were radiated with 3 fractions (1 per week) for a total dose of 15 Gy in 11, 22.5 Gy in 9 and 45 Gy in 10, while 8 untreated animals served as controls. The mice were weighed, and tumor volume and PSA measurements were performed at baseline and weekly until 4 weeks after treatment. Results: There was no treatment related toxicity. There was a significant difference in the tumor response to higher radiation doses. In the 15 and 22.5 Gy groups mean tumor volume decreased to 58% and 90% of the original volume, respectively, but the rats experienced progressive tumor regrowth within 1 week after the completion of therapy. The 45 Gy group had a mean tumor volume and PSA decrease of greater than 90%, which was sustained 1 month after treatment in all except 2 mice. Conclusions: SBRT dose level treatments were able to significantly decrease tumor volume and PSA. However, using 15 and 22.5 Gy durable responses were not achieved except in a few mice. The 45 Gy group demonstrated sustained PSA and tumor volume decreases in most mice. These results clearly show an increasing dose-response relationship for a range of hypofractionated dose levels, as used in SBRT. [Copyright &y& Elsevier]

Purpose: To conduct a phase I study incorporating trastuzumab with paclitaxel, cisplatin, and radiation for adenocarcinoma of the esophagus.Methods and Materials: Patients with adenocarcinoma of the esophagus without distant organ metastases were eligible. All patients received cisplatin 25 mg/m2 and paclitaxel 50 mg/m2 weekly for 6 weeks with radiation 50.4 Gy. HER-2/neu-positive patients (2+/3+ by immunohistochemistry) received weekly trastuzumab at dose levels of 1, 1.5, or 2 mg/kg weekly for 5 weeks after an initial bolus of 2, 3, or 4 mg/kg, respectively. HER-2/neu-negative patients received the same chemoradiation without trastuzumab as a control for toxicity. Dose-limiting toxicities were defined as grade 3 esophageal, cardiac, or pulmonary toxicity.Results: Twelve of 36 screened patients (33%) overexpressed HER-2/neu by immunohistochemistry (seven 3+ and five 2+). Eight of 12 patients with HER-2/neu overexpression by IHC had an increase in the number of HER-2/neu genes, six from amplification of the HER-2/ neu gene and two were hypderdiploid for chromosome 17. Thirty patients were enrolled (12 HER-2/neu-positive and 18 HER-2/neu-negative controls). No increase in toxicity was seen with the addition of trastuzumab. One of 12 patients in the trastuzumab arm and 8 of 17 in the control arm had grade 3 esophagitis (p < or = .026). Mean left ventricular ejection fraction for the trastuzumab group was 57% before treatment and 56% after treatment.Conclusion: HER-2/neu is overexpressed in approximately one-third of esophageal adenocarcinomas. Trastuzumab can be added at full dose to cisplatin, paclitaxel, and radiation. Future studies of trastuzumab in esophageal adenocarcinoma are indicated. [ABSTRACT FROM AUTHOR]

Integration of hypofractionated body radiotherapy (H-RT) into immune checkpoint inhibitor (ICI) therapy may be a promising strategy to improve the outcomes of ICIs, although sufficient data is lacking regarding the safety and efficacy of this regimen. We, hereby, reviewed the safety and efficacy of this combination in 59 patients treated with H-RT during or within 8 weeks of ICI infusion and compared results with historical reports of ICI treatment alone. Most patients had RCC or melanoma. Median follow-up was 11 months. Most patients received either Nivolumab alone or with Ipilimumab; 83% received stereotactic RT and 17% received conformal H-RT. Any grade adverse events (AEs) were reported in 46 patients, and grade 3-4 in 12 patients without any treatment-related grade 5 toxicity. The most common grade 3 AEs were fatigue and pneumonitis. Grade 3-4 toxicities were higher with ICI combination and with simultaneous ICIs. Overall, most any-grade or grade ≥3 AE rates did not differ significantly from historically reported rates with single-agent or multi-agent ICIs. Toxicity did not correlate with H-RT site, dose, fraction number, tumor type, or ICI and H-RT sequencing. Median progression-free survival was 6.5 months. Objective response rate (ORR) was 26%; 10% had complete response (CR). Median duration of response was 9.4 ± 4.6 months. H-RT of lung lesions was more likely to achieve CR than other sites. H-RT of bone lesions had a lower ORR than non-bone H-RT. In conclusion, combining body H-RT with ICIs is safe and promising. Prospective validation is warranted. [ABSTRACT FROM AUTHOR]

Purpose: Radiation dose intensification improves outcome in men with high-risk prostate cancer (HR-PCa). A prospective trial was conducted to determine safety, feasibility, and maximal tolerated dose of multilevel magnetic resonance imaging (MRI)-based 5-fraction SABR in patients with HR-PCa.Methods and Materials: This phase I clinical trial enrolled patients with HR-PCa with grade group ≥4, prostate-specific antigen (PSA) ≥20 ng/mL, or radiographic ≥T3, and well-defined prostatic lesions on multiparametric MRI (mpMRI) into 4 dose-escalation cohorts. The initial cohort received 47.5 Gy to the prostate, 50 Gy to mpMRI-defined intraprostatic lesion(s), and 22.5 Gy to pelvic lymph nodes in 5 fractions. Radiation doses were escalated for pelvic nodes to 25 Gy and mpMRI lesion(s) to 52.5 Gy and then 55 Gy. Escalation was performed sequentially according to rule-based trial design with 7 to 15 patients per cohort and a 90-day observation period. All men received peri-rectal hydrogel spacer, intraprostatic fiducial placement, and 2 years of androgen deprivation. The primary endpoint was maximal tolerated dose according to a 90-day acute dose-limiting toxicity (DLT) rate <33%. DLT was defined as National Cancer Institute Common Toxicity Criteria for Adverse Events ≥grade 3 treatment-related toxicity. Secondary outcomes included acute and delayed gastrointestinal (GI)/genitourinary (GU) toxicity graded with Common Toxicity Criteria for Adverse Events.Results: Fifty-five of the 62 enrolled patients were included in the analysis. Dose was escalated through all 4 cohorts without observing any DLTs. Median overall follow-up was 18 months, with a median follow-up of 42, 24, 12, and 7.5 months for cohorts 1 to 4 respectively. Acute and late grade 2 GU toxicities were 25% and 20%, while GI were 13% and 7%, respectively. Late grade 3 GU and GI toxicities were 2% and 0%, respectively.Conclusions: SABR dose for HR-PCa was safely escalated with multilevel dose painting of 47.5 Gy to prostate, 55 Gy to mpMRI-defined intraprostatic lesions, and 25 Gy to pelvic nodal region in 5 fractions. Longer and ongoing follow-up will be required to assess late toxicity. [ABSTRACT FROM AUTHOR]

Purpose: To determine the pain response and prevention of vertebral compression fractures (VCFs) after single-fraction stereotactic ablative radiation therapy (SABR) in conjunction with immediate vertebroplasty for spine metastases.Methods and Materials: Patients with localized spine metastases free from VCF associated with loss of vertebral height with a pain score ≥4 using the visual analog scale were enrolled. Spine SABR was performed with 20 Gy delivered to the gross disease and 14 Gy to the contiguous bone marrow in a single fraction. Immediate, prophylactic vertebroplasty was performed within 1 month after spine SABR. The primary endpoint was pain response at 3 months compared to the historical control with external beam radiation therapy from Radiation Therapy Oncology Group study 9714. Secondary endpoints included pain response at 1 month, duration of pain response, vertebroplasty rate, VCF rate, local control, and overall survival.Results: Thirty-five patients were enrolled, of whom 29 were deemed eligible and underwent single-fraction spine SABR. Twenty-three of these patients subsequently underwent prophylactic vertebroplasty. The 3-month pain response was significantly improved compared to Radiation Therapy Oncology Group study 9714: 95% versus 51% (P < .0001). The local control with a median follow-up of 9.6 months was 92%. The freedom from VCF was 90% at 1 year. Spine SABR was well tolerated with no grade 2 or higher toxicities. A single patient with disease extending from the vertebral body into the spinal canal developed vertebroplasty-related myelopathy, which was corrected with surgery.Conclusions: Single-fraction SABR immediately followed by prophylactic vertebroplasty improves pain response compared with conventional radiation therapy while providing long-term pain control and structural stability of the treated spine. Vertebroplasty is well tolerated as a prophylactic measure in patients without loss of vertebral height after spine SABR. Pain response and VCF rates are similar to patients undergoing SABR alone. Thus, patients who would benefit most from the addition of vertebroplasty need to be further identified. [ABSTRACT FROM AUTHOR]

Background: The risk of subsequent primary cancers in patients with prostate cancer after treatment with photon radiotherapy is small in absolute numbers, but it is higher than that after surgical treatment. Carbon ion radiotherapy has a theoretically lower risk of inducing secondary malignancies than photon radiotherapy, but this risk has not been investigated in practice because of the low number of facilities offering such therapy worldwide and the limited data on long-term follow-up because the therapy has only been available since 1994. We aimed to analyse the risk of subsequent primary cancers after treatment with carbon ion radiotherapy in patients with localised prostate cancer and to compare it with that after photon radiotherapy or surgery in this setting.Methods: In this retrospective cohort study, we reviewed records of patients who received carbon ion radiotherapy for prostate cancer between June 27, 1995, and July 10, 2012, at the National Institute of Radiological Sciences (NIRS) in Japan. We also retrieved the records of patients diagnosed and treated for prostate cancer between Jan 1, 1994, and Dec 31, 2012, from the Osaka Cancer Registry. Eligible patients had histologically confirmed localised prostate cancer and a minimum follow-up of at least 3 months; no age restrictions were applied. We excluded patients with metastasis, node-positive disease, or locally invasive (T4 stage) prostate cancer, those with previous or synchronous malignancies, and those who received previous radiotherapy or chemotherapy. We did a multivariable analysis to estimate predictors of subsequent cancers after carbon ion radiotherapy treatment. We also used propensity score inverse probability weighting to retrospectively compare the incidence of subsequent cancers in patients with localised prostate cancer treated with carbon beams, photon radiotherapy, or surgery.Findings: Of 1580 patients who received carbon radiotherapy for prostate cancer at the NIRS, 1455 (92%) patients met the eligibility criteria. Of 38 594 patients with prostate cancer identified in the Osaka registry, 1983 (5%) patients treated with photon radiotherapy and 5948 (15%) treated with surgery were included. Median follow-up durations were 7·9 years (IQR 5·9-10·0) for patients who received carbon ion radiotherapy (after limiting the database to 10-year maximum follow-up), 5·7 years (4·5-6·4) for patients who received photon radiotherapy, and 6·0 years (5·0-8·6) for those who received surgery. 234 subsequent primary cancers were diagnosed in the carbon ion radiotherapy cohort; some patients developed several tumours. On multivariable analysis, age (p=0·0021 for 71-75 years vs ≤60 years; p=0·012 for >75 years vs ≤60 years) and smoking (p=0·0005) were associated with a higher risk of subsequent primary cancers in patients treated with carbon ion radiotherapy. In the propensity score-weighted analyses, carbon ion radiotherapy was associated with a lower risk of subsequent primary cancers than photon radiotherapy (hazard ratio [HR] 0·81 [95% CI 0·66-0·99]; p=0·038) or surgery (HR 0·80 [0·68-0·95]; p=0·0088), whereas photon radiotherapy was associated with a higher risk of subsequent primary cancers than surgery (HR 1·18 [1·02-1·36]; p=0·029).Interpretation: Our analysis suggests that patients with localised prostate cancer treated with carbon ion radiotherapy appear to have a lower risk of subsequent primary cancers than those treated with photon radiotherapy. Although prospective evaluation with longer follow-up is warranted to support these results, our data supports a wider adoption of carbon ion radiotherapy for patients with expected long-term overall survival or those with poor outcomes after receiving conventional treatments.Funding: Research Project for Heavy Ions at the National Institute of Radiological Sciences (Japan). [ABSTRACT FROM AUTHOR]

Purpose: To demonstrate the feasibility of a real-time whole-brain radiation therapy (WBRT) workflow, taking advantage of contemporary radiation therapy capabilities and seeking to optimize clinical workflow for WBRT.Methods and Materials: We developed a method incorporating the linear accelerator's on-board imaging system for patient simulation, used cone-beam computed tomography (CBCT) data for treatment planning, and delivered the first fraction of prescribed therapy, all during the patient's initial appointment. Simulation was performed in the linear accelerator vault. An acquired CBCT data set was used for scripted treatment planning protocol, providing inversely planned, automated treatment plan generation. The osseous boundaries of the brain were auto-contoured to create a target volume. Two parallel-opposed beams using field-in-field intensity modulate radiation therapy covered this target to the user-defined inferior level (C1 or C2). The method was commissioned using an anthropomorphic head phantom and verified using 100 clinically treated patients.Results: Whole-brain target heterogeneity was within 95%-107% of the prescription dose, and target coverage compared favorably to standard, manually created 3-dimensional plans. For the commissioning CBCT datasets, the secondary monitor unit verification and independent 3-dimensional dose distribution comparison for computed and delivered doses were within 2% agreement relative to the scripted auto-plans. On average, time needed to complete the entire process was 35.1 ± 10.3 minutes from CBCT start to last beam delivered.Conclusions: The real-time WBRT workflow using integrated on-site imaging, planning, quality assurance, and delivery was tested and deemed clinically feasible. The design necessitates a synchronized team consisting of physician, physicist, dosimetrist, and therapists. This work serves as a proof of concept of real-time planning and delivery for other treatment sites. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Stereotactic body radiation therapy (SBRT) is a new therapeutic paradigm that uses a very large dose per fraction treatments (ablative hypofractionation). We investigated the use of ablative hypofractionation in treating human renal cell carcinoma using a nude mouse model. Methods: Nude mice were injected subcutaneously with A498 human renal carcinoma cells. Tumour-bearing animals were radiated with three fractions (one per week) for a total dose of 48Gy (n =12), while untreated animals served as controls (n =7). The mice were weighed, and tumour volumes were measured at baseline and weekly until 7 weeks post-treatment. Results: Control animals demonstrated progressive tumour growth and were sacrificed because of either tumour size or ulceration. Tumours in the treatment group grew to three times their initial size over the 3 weeks of treatment but subsequently decreased progressively to less than 30% of their initial volume. All treated tumours exhibited marked cytologic changes. Tumours from mice sacrificed before post-treatment week 4 had a mitotic count of 1–4/10hpf. Tumours from mice sacrificed more than 4 weeks post-treatment (n =4) demonstrated no mitoses. Conclusions: Treatment with high-dose-per-fraction radiation to 48Gy resulted in a sustained decrease in tumour volume and marked cytologic changes. These results are preliminary—but promising—and encourage further research into this application of ablative hypofractionated radiation for kidney cancer. [Copyright &y& Elsevier]

Abstract: Background and purpose: In vitro studies have suggested that 9-nitro-20(s)-Camptothecin (9NC/Orathecin/Rubitecan) can enhance the effects of radiation. We conducted a phase I study to assess the toxicity and determine the maximum tolerated dose of 9NC when combined with radiation in patients with locally advanced adenocarcinoma of the pancreas. Patients and methods: Eleven patients with locally advanced adenocarcinoma of the pancreas received 9NC, orally during radiation. Radiation therapy consisted of 45Gy in 25 fractions given over 5 weeks. The starting dose of 9NC was 1mg/m2/day. Results: Eight patients received 9NC at a dose of 1mg/m2/day and three patients received a dose of 1.25mg/m2/day. Dose-limiting toxicity (DLT) was defined as ≥grade 3 non-hematologic toxicity and ≥grade 4 hematologic toxicity. Dose-limiting toxicity of grade 3 nausea/vomiting developed in one patient at the first dose level. At dose level 2, two of three patients developed DLT. Both developed grade 3 nausea, fatigue, and anorexia. Additionally, one of these patients had grade 3 dehydration and the other had grade 4 leukopenia, grade 3 vomiting, and grade 3 weakness. Conclusions: 9NC, 1mg/m2/day, can be given concurrently with radiation with acceptable toxicity. [Copyright &y& Elsevier]

Purpose: Fluorinated pyrimidines have been established as radiosensitizers in the combined modality therapy of esophageal cancer. UFT, an oral combination of a 5-fluorouracil pro-drug (uracil) and a dihydropyrimidine dehydrogenase inhibitor (ftorafur), may provide improvement in the ease of administration with equal efficacy. This Phase I study was designed to determine the maximal tolerated dose and dose-limiting toxicity of UFT, leucovorin, and cisplatin when given with radiotherapy in the neoadjuvant treatment of resectable esophageal cancer. Methods: Chemotherapy consisted of i.v. cisplatin 80 mg/m2 (Days 1 and 22) and UFT with leucovorin orally on Days 1–35. UFT was escalated in 50-mg/m2 increments, starting at 200 mg/m2/d. Radiotherapy consisted of 4500 cGy in 25 fractions. Patients underwent resection 4–6 weeks after chemoradiotherapy. Results: Ten patients with resectable esophageal cancer were enrolled. Of the 7 patients entered at dose level 1, 1 developed a dose-limiting toxicity of nausea. All 3 patients entered at dose level 2 developed dose-limiting toxicity. The maximal tolerated dose for UFT was the starting level, 200 mg/m2/d. Of the 10 patients enrolled, 8 underwent esophagectomy and 2 developed progressive disease and did not undergo surgery. The disease of 6 of the 8 patients was downstaged at surgery. Conclusion: The recommended UFT dose for Phase II studies is 200 mg/m2/d given orally in two divided doses when given with leucovorin, cisplatin, and radiotherapy. [Copyright &y& Elsevier]

: PurposeRecent studies have demonstrated radiosensitization by inhibiting receptor tyrosine kinases (RTKs). Irradiation activates RTKs and their downstream prosurvival molecule, Akt. In this study, we investigated the mechanism by which SU6668, an inhibitor of RTKs involved in angiogenic pathways, enhances effects of irradiation.: Methods and materialsWestern blots were used to determine Akt phosphorylation. Clonogenic assays were performed to determine endothelial survival after combination of SU6668 and irradiation. This combination therapy was also tested in mouse models with Lewis lung carcinoma or glioblastoma multiforme (GL261) for inhibition of tumor growth and tumor vasculature by examining tumor volume, tumor vascular window, and blood flow.: ResultsWe found that SU6668 inhibited the Akt activation inducible by irradiation. Clonogenic survival of endothelial cells was decreased after the combined therapy compared with radiotherapy alone. In vivo studies demonstrated reduction of tumor vasculature and blood flow. In addition, 21 Gy in 7 fractions given concurrently with SU6668 resulted in tumor growth delay compared to either treatment alone.: ConclusionThese data suggest that the combination therapy was more effective in destroying tumor vasculature than either treatment alone. SU6668 augments tumor-suppressive effects of radiotherapy in Lewis lung carcinoma and GL261 xenographs, possibly through reducing the survival of tumor endothelium. [Copyright &y& Elsevier]

Background and purpose: To evaluate a semisynthetic epothilone B, BMS-247550, as a potential radiosensitizer in vitro and in vivo.Materials and methods: Human NCI-H460 lung cancer cells were treated with either BMS-247550 or paclitaxel and in combination with radiation at multiple doses for different time periods. Surviving fractions were then analyzed using a clonogenic assay. Cell cycle redistribution by BMS-247550 was measured with propidium iodide and flow cytometry. Percent apoptosis was also measured using 7-amino-actinomycin D staining with flow cytometry. For in vivo studies, the H460 xenograft model was used in athymic nude mice. Tumors were treated with BMS-247550 (5 mg/kg) i.p. injection on days 0, 2, and 4 and/or radiation (2 Gy/day, days 0–4).Results: The in vitro radiation dose enhancement ratios (DER) of 1-h BMS-247550 and paclitaxel were 2.03 and 1.34, respectively. Treatment with BMS-247550 enhanced the G2/M block and induced apoptosis; whereas in combination with radiation, the induction of apoptosis was additive. BMS-247550 in combination with radiation in vivo enhanced the tumor growth delay when compared with either drug or radiation alone.Conclusions: These results demonstrated that BMS-247550 could enhance the effects of radiation in human lung cancer cells both in vitro and in vivo and that a G2/M block and increased apoptosis might be possible explanations for the enhancement. [Copyright &y& Elsevier]

Background and purpose: Tumor hypoxia and anemia have been linked to poor overall survival and local control in carcinomas of both the uterine cervix and the head and neck for patients undergoing radiotherapy. Little is known about the effect of these factors on the outcome of NSCLC patients with locally advanced disease undergoing chemoradiation therapy.Materials and methods: To examine the impact of anemia in stage III NSCLC patients undergoing combined modality therapy, we reviewed our database from three sequential trials of concurrent weekly paclitaxel +/− carboplatin and radiation therapy. 115 pts from 17 institutions were enrolled from 4/94 to 5/97. In this series, hemoglobin values were collected before treatment and weekly during radiotherapy. We correlated baseline Hb and Hb changes during chemoradiation treatment with overall survival. Results: Although pretreatment anemia was common (30% Hb=110–130 g/l, 16% Hb <110 g/l), log-rank analyses of presenting Hb, average Hb and minimum Hb during treatment were not statistically significantly predictive of survival. However in a Cox model, declining hemoglobin during chemoradiation had a statistically significant impact on survival.Conclusions: These analyses reveal that a decline in hemoglobin during chemoradiation for stage III NSCLC has a statistically significant correlation with overall survival. Strategies maximizing hemoglobin during combined modality therapy need further exploration in well-planned randomized trials. [Copyright &y& Elsevier]