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Treatment regimens, platinum-sensitivity and BRCA status of ovarian and fallopian tube cancer patients.

Sites of disease and progression of all patients.

Quality of life (QoL) t-tests for all patients (A), GYN versus non-GYN patients (B) and patients who completed cycle 2 and those who did not (C).

Supplemental Figure Legend from A Phase I Study of Veliparib (ABT-888) in Combination with Low-Dose Fractionated Whole Abdominal Radiation Therapy in Patients with Advanced Solid Malignancies and Peritoneal Carcinomatosis

Purpose: The combination of low-dose radiotherapy with PARP inhibition has been shown to enhance antitumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with escalating doses of veliparib (ABT-888), a small-molecule PARP inhibitor, in patients with peritoneal carcinomatosis from advanced solid tumor malignancies.Experimental Design: Patients were treated with veliparib (80–320 mg daily) for a total of 3 cycles. LDFWAR consisted of 21.6 Gy in 36 fractions, 0.6 Gy twice daily on days 1 and 5 for weeks 1–3 of each cycle. Circulating tumor cells (CTC) were collected and evaluated for γ-H2AX. Quality of life (QoL) was assessed using the EORTC-QLQ-C30 questionnaire.Results: Twenty-two patients were treated. Treatment-related grade 3 and 4 toxicities included lymphopenia (68%), anemia (9%), thrombocytopenia (14%), neutropenia (4%), leukopenia (9%), ascites (4%), vomiting (4%), and dyspnea (4%). No objective responses were observed. Disease stabilization (≥24 weeks) was observed in 7 patients (33%). Median progression-free survival (mPFS) was 4.47 months and median overall survival (mOS) was 13.04 months. In the subset of 8 ovarian and fallopian cancers, mPFS was 6.77 months and mOS was 17.54 months compared with mPFS 2.71 months and mOS 13.01 months in others. Patients with ovarian and fallopian cancers had better QoL over time than those with other cancers. An increased percentage of γ-H2AX–positive CTCs was observed in a subset of patients (3/6 with >2 CTCs at baseline).Conclusions: Combined veliparib and LDFWAR is a well-tolerated regimen that resulted in prolonged disease stability for some patients with advanced solid tumors and carcinomatosis, particularly in the ovarian and fallopian cancer subpopulation. Clin Cancer Res; 21(1); 68–76. ©2014 AACR.

CTC number and ɣ-H2AX-positive CTC changes during treatment with radiotherapy and veliparib.

BackgroundSmall cell lung cancer (SCLC) represents approximately 15% of lung cancers, and approximately 70% are diagnosed as extensive-stage SCLC (ES-SCLC). Although ES-SCLC is highly responsive to chemotherapy, patients typically progress rapidly, and there is an urgent need for new therapies. Immune checkpoint inhibitors (ICIs) have recently been investigated in SCLC, and this review provides guidance on the use of these agents in ES-SCLC based on phase III evidence.MethodsPublished and presented literature on phase III data addressing use of ICIs in ES-SCLC was identified using the key search terms “small cell lung cancer” AND “checkpoint inhibitors” (OR respective aliases). Directed searches of eligible studies were periodically performed to ensure capture of the most recent data.ResultsSix phase III trials were identified, with four assessing the benefits of ICIs plus chemotherapy first-line, one evaluating ICIs as first-line therapy maintenance, and one assessing ICI monotherapy after progression on platinum-based chemotherapy. The addition of ipilimumab or tremelimumab to first-line treatment or as first-line maintenance did not improve survival. Two out of three studies combining PD-1/PD-L1 inhibitors with first-line platinum-based chemotherapy demonstrated significant long-lasting survival benefits and improved quality of life with no unexpected safety concerns. PD-1/PD-L1 inhibitors as first-line maintenance or in later lines of therapy did not improve survival. Biomarker research is ongoing as well as research into the role of ICIs in combination with radiation therapy in limited-stage SCLC.ConclusionThe addition of atezolizumab or durvalumab to first-line platinum-based chemotherapy for ES-SCLC prolongs survival and improves quality of life.Implications for PracticePlatinum-based chemotherapy has been standard of care for extensive-stage small cell lung cancer (ES-SCLC) for more than a decade. Six recent phase III trials investigating immune checkpoint inhibitors (ICIs) have clarified the role of these agents in this setting. Although ICIs were assessed first-line, as first-line maintenance, and in later lines of therapy, the additions of atezolizumab or durvalumab to first-line platinum-based chemotherapy were the only interventions that significantly improved overall survival and increased quality of life. These combinations should therefore be considered standard therapy for first-line ES-SCLC. Biomarker research and investigations into the role of ICIs for limited-stage disease are ongoing.

Background Stereotactic Body Radiation Therapy (SBRT) is a non-invasive ablative treatment for hepatocellular carcinoma (HCC). This report aimed to address the limited availability of long-term outcomes after SBRT for HCC from North America. Methods Localized HCC patients without vascular invasion, who were ineligible for other liver-directed therapies and treated with SBRT at the University of Toronto or University of Michigan, were pooled to determine overall survival (OS), cumulative recurrence rates, and ≥ grade-3 toxicity. Multivariable analysis determined factors affecting OS and local recurrence rates. Results In 297 patients with 436 HCCs (42% > 3 cm), one-, three- and five-year OS was 77·3%, 39·0% and 24·1%, respectively. On Cox proportional hazards regression analysis, liver transplant after SBRT, Child–Pugh A liver function, alpha-fetoprotein ≤ 10 ng/ml, and Eastern Co-operative Oncology Group performance status 0 significantly improved OS (hazard ratio [HR] = 0·06, 95% confidence interval [CI- 0·02–0·25; p Conclusions SBRT confers high local control and long-term survival in a substantial proportion of HCC patients unsuitable for, or refractory to standard loco-regional treatments. Liver transplant should be considered if appropriate downsizing occurs after SBRT.

Background The PACIFIC study established durvalumab as a standard of care for consolidation therapy in patients treated with radical intent chemoradiation for stage III inoperable non-small cell lung cancer. In clinical practice, many patients are not eligible for trials, yet radical intent chemoradiation may still be used. Methods A virtual anonymous tumour board Delphi-model was used in order to generate consensus on the use of durvalumab in six clinical situations where chemoradiation is used in clinical practice and recommended in guidelines, yet not PACIFIC eligible. Two anonymous iterations were sent and recommendations were circulated for approval and comment. Results are presented using a modified PICOT format (patients, intervention, control, outcomes, and ongoing trials). Results In three of the scenarios, consensus was reached and recommendations were for the use of consolidation durvalumab, but being respectful of potentially increased toxicity/reduced benefit in comparison to PACIFIC results (treatment of stage IIB inoperable, recurrent mediastinal disease, and residual gross disease post attempted surgical removal). There was a recommendation against using durvalumab in resected stage III disease with R1 or R0 margins, even if chemoradiation were considered. There was not consensus on the use of consolidation durvalumab in the setting of oligometastatic disease or in the setting of large cell neuroendocrine carcinoma or combined small cell carcinoma. Conclusion Treatment of ‘real-world’ lung cancer often involves chemoradiation in settings outside of stage III and eligible for the PACIFIC study. This paper offers recommendations in these scenarios based on a consensus approach.

Background Molecular testing in advanced lung cancer is standard in guiding treatment selection. However, population-wide implementation of testing remains a challenge. We developed a knowledge translation intervention to improve understanding among diagnostic specialists about molecular testing and appropriate diagnostic sampling in lung cancer. Methods Specialty-specific education programs were developed from existing literature and input from Canadian leaders in lung pathology, respirology, interventional radiology, thoracic surgery, radiation oncology, and medical oncology. The programs, including key messages, review of current data, existing guidelines, group discussion, and participant feedback, were administered at provincial and national specialty meetings. Participant knowledge was assessed before and after the intervention by using anonymous questionnaires. Molecular ( EGFR ) testing rates in Ontario were also evaluated before and after the intervention period. Results Ten programs were administered to diagnostic specialists, including respirologists, pathologists, thoracic surgeons, radiologists, radiation oncologists, and medical oncologists, with completion of 255 preintervention and 219 postintervention surveys. At baseline, 30% were unsure of tissue handling methods for molecular testing, 20% chose an incorrect technique, and half were unfamiliar with how to initiate testing. After intervention, specialist knowledge improved regarding tissue handling and appropriate fixation techniques and uncertainty decreased from 30% to 2% ( p EGFR ) testing requests in Ontario was observed over the intervention period ( p = 0.0032). Conclusions Significant knowledge gaps exist among diagnostic specialists regarding molecular testing and targeted therapy in lung cancer. This initiative significantly improved understanding of the importance and methods of successful molecular testing and correlated with increased testing rates.

// Ali Hosni 1 , Kathy Han 1 , Lisa W. Le 2 , Jolie Ringash 1 , James Brierley 1 , Rebecca Wong 1 , Robert Dinniwell 1 , Anthony Brade 1 , Laura A. Dawson 1 , Bernard J. Cummings 1 , Monika K. Krzyzanowska 3 , Eric X. Chen 3 , David Hedley 3 , Jennifer Knox 3 , Alexandra M. Easson 4 , Patricia Lindsay 1 , Tim Craig 1 and John Kim 1 1 Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada 2 Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada 3 Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada 4 Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada Correspondence to: John Kim, email: john.kim@rmp.uhn.ca Keywords: anal cancer; chemoradiotherapy; IMRT; pattern of failure; outcomes Received: November 11, 2017 Accepted: February 27, 2018 Published: April 17, 2018 ABSTRACT Purpose: Patterns of failure and long term outcomes were prospectively evaluated following tumor factors-stratified radiation dose for anal/perianal cancer. Methods: Between 2008–2013, patients with anal/perianal squamous cell carcinoma were accrued to an institutional REB-approved prospective study. All patients were treated with image-guided intensity-modulated radiation therapy (IG-IMRT). Radiation dose selection (27–36 Gy for elective target, and 45–63 Gy for gross target) was based on tumor clinico-pathologic features. Chemotherapy regimen was 5-fluorouracil/mitomycin-C (weeks 1&5). Local [LF], regional failure [RF], distant metastasis [DM], overall- [OS], disease-free [DFS], colostomy-free survival [CFS] and late toxicity were analyzed. Results: Overall, 101 patients were evaluated; median follow-up: 56.5 months; 49.5% male; 34.7% T3/4-category, and 35.6% N+. Median radiation dose was 63 Gy. The most common acute grade ≥3 toxicities were skin (41.6%) and hematological (30.7%). Five-year OS, DFS, CFS, LF, RF, DM rates were 83.4%, 75.7%, 74.7, 13.9%, 4.6% and 5% respectively. Five-year LF for patients with T1-2 and T3-4 disease were 0% and 39.2% respectively. All LF ( n = 14, after 63 Gy, in tumors ≥5 cm) were in the high dose volume except one marginal to the high dose volume. All RF ( n = 4) were within elective dose volume except one within the high dose volume. On multivariable analysis, T3/4-category predicted for poor DFS, CFS and OS. The overall late grade ≥3 toxicity was 36.2% (mainly anal [20%]). Conclusions: Individualized radiation dose selection using IG-IMRT resulted in good long term outcomes. However, central failures remain a problem for locally advanced tumors even with high dose radiation (63 Gy/7weeks).

Background The combination of low-dose radiation therapy with PARP inhibition enhances anti-tumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with ABT-888 in patients with peritoneal carcinomatosis with a dose escalation in ovarian and fallopian cancer patients (OV). Methods Patients were treated with veliparib, 40–400mg orally BID on days 1–21 of 3 28-day cycles on 6 dose levels. Dose levels 5 and 6 included only OV patients. LDFWAR consisted of 21.6Gy in 36 fractions, 0.6Gy twice daily on days 1 and 5 for weeks 1–3 of each cycle. Circulating tumor material and quality of life were serially assessed. Results 32pts were treated. Median follow-up was 45months (10–50). The most common treatment-related grade 3 and 4 toxicities were lymphopenia (59%), anemia (9%), thrombocytopenia (12%), neutropenia (6%), leukopenia (6%), nausea (6%), diarrhea (6%), anorexia (6%), vomiting (6%) and fatigue (6%). The maximum tolerated dose was determined to be 250mg PO BID. Median PFS was 3.6months and median OS was 9.1months. In OV patients, OS was longer for platinum-sensitive patients (10.9mo) compared to platinum-resistant patients (5.8mo). QoL decreased for all groups during treatment. Germline BRCA status was known for 14/18 patients with OV cancers, 5 of whom were BRCA mutation carriers. One objective response (3%) was observed. Conclusion ABT-888 plus LDFWAR is tolerable with gastrointestinal symptoms, fatigue and myelosuppression as the most common toxicities. The single observed objective response was in a germline BRCA mutated, platinum-sensitive patient.

For more than a decade, there has been no improvement in outcomes for patients with unresectable locally advanced (la) non-small-cell lung cancer (nsclc). The standard treatment in that setting is definitive concurrent chemotherapy and radiation (ccrt). Although the intent of treatment is curative, most patients rapidly progress, and their prognosis is poor, with a 5-year overall survival (os) rate in the 15%&ndash, 25% range. Those patients therefore represent a critical unmet need, warranting expedited approval of, and access to, new treatments that can improve outcomes. The pacific trial, which evaluated durvalumab consolidation therapy after ccrt in unresectable la nsclc, demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (pfs) and a significant improvement in os. Durvalumab thus fills a critical unmet need in the setting of unresectable la nsclc and provides a new option for patients treated with curative intent. Here, we review the treatment of unresectable la nsclc, with a focus on the effect of the clinical data for durvalumab.

While this quote is likely apocryphal and not, as is commonly attributed, a curse of Chinese origin (1), its ironic sentiment seems apt when one considers the rapidly shifting treatment landscape for patients with brain metastases.

Background Although molecular testing has become standard in managing advanced nonsquamous non-small-cell lung cancer (nsclc), most patients undergo minimally invasive procedures, and the diagnostic tumour specimens available for testing are usually limited. A knowledge translation initiative to educate diagnostic specialists about sampling techniques and laboratory processes was undertaken to improve the uptake and application of molecular testing in advanced lung cancer. Methods A multidisciplinary panel of physician experts including pathologists, respirologists, interventional thoracic radiologists, thoracic surgeons, medical oncologists, and radiation oncologists developed a specialty-specific education program, adapting international clinical guidelines to the local Ontario context. Expert recommendations from the program are reported here. Results Panel experts agreed that specialists procuring samples for lung cancer diagnosis should choose biopsy techniques that maximize tumour cellularity, and that conservation strategies to maximize tissue for molecular testing should be used in tissue processing. The timeliness of molecular reporting can be improved by pathologist-initiated reflex testing upon confirmation of nonsquamous nsclc and by prompt transportation of specimens to designated molecular diagnostic centres. To coordinate timely molecular testing and optimal treatment, collaboration and communication between all clinicians involved in diagnosing patients with advanced lung cancer are mandatory. Conclusions Knowledge transfer to diagnostic lung cancer specialists could potentially improve molecular testing and treatment for advanced lung cancer patients.

Introduction: There are limited treatment options for patients with prior pneumonectomy and a new lung malignancy. The safety and efficacy of stereotactic body radiotherapy in this subpopulation has not been well defined. Methods: Postpneumonectomy patients treated with lung SBRT were identified from a prospective single institution database. Treatment toxicity was recorded prospectively using the Common Terminology Criteria for Adverse Events version 3.0. Disease recurrences were categorized as local, regional, or distant metastatic disease. Overall survival was calculated using the Kaplan-Meier method. Results: Of 406 patients, 13 postpneumonectomy patients were identified and 14 tumors were treated with SBRT. Median age was 69 years. Three lesions were biopsy confirmed. The SBRT doses were 60 Gy/3 ( n = 1), 54 Gy/3 ( n = 1), 48 Gy/4 ( n = 7), 60 Gy/8 ( n = 2), and 50 Gy/10 ( n = 3). Median follow-up was 24 months. Two patients had grade 3 radiation pneumonitis 3 and 4 months post-SBRT; they died 3 and 1 months later, respectively, one of myocardial infarction and the other of progressive dyspnea thought to be related to congestive heart failure. There were no local failures, one regional failure, and three distant failures. Median survival was 29 months, 1 and 2 year overall survival were 69% (95% confidence interval: 48–100%) and 61% (95% confidence interval: 39–95%), respectively. Conclusions: SBRT in patients with prior pneumonectomy poses challenges because of limited lung reserve. However, local control and long-term survival can be achieved using SBRT in this inoperable population. Careful consideration must be given to radiation planning to minimize the risk of radiation pneumonitis.

Background and purpose To evaluate the tolerability and maximum tolerated dose (MTD) of sorafenib administered concurrently with palliative radiotherapy. Material and methods In patients with incurable cancer, sorafenib was escalated independently in three cohorts based on irradiation site: thorax, abdomen or pelvis. Sorafenib was administered days 1–28 and radiotherapy (30 Gy in 10 fractions) was delivered days 8–12 and 15–19. Dose-limiting toxicities (DLT) were acute grade 3+ toxicities attributable to radiotherapy. Results For the thorax, abdomen and pelvis cohorts, 14, 16 and 4 patients were recruited, and Dose Levels 3, 3 and 2 were reached, respectively. Sorafenib-related systemic toxicity led to significant sorafenib interruption in 10 patients. There were 3 DLTs in total, one per cohort: grade 3 oesophagitis (thoracic), transaminase elevation (abdominal) and grade 5 bowel perforation (pelvic; patient with tumour invading bowel). Grade 2 radiation dermatitis developed in 12 patients. The trial was terminated early as slow accrual and sorafenib-related systemic toxicity prevented efficient evaluation of RT-related DLTs. Conclusions The MTD of sorafenib when used with 30 Gy in 10 fractions was not established due to sorafenib-related systemic toxicity. Severe radiotherapy-related toxicities were also observed. These events suggest this concurrent combination does not warrant further study.

BACKGROUND: This study reports the adoption of prophylactic cranial irradiation (PCI) in patients with limited stage small cell lung carcinoma (LS-SCLC) at Princess Margaret Hospital (PMH) and the factors that impact PCI utilization. METHODS: A retrospective review was performed on all patients with LS-SCLC treated at PMH from 1997 to 2007. Clinical details including the rate of PCI utilization were determined and, for patients not receiving PCI, the documented reason was recorded. Brain failure free survival (FFS) and overall survival (OS) were estimated by the Kaplan-Meier method, comparing patients treated with or without PCI. Pearson chi-square test was used to determine factors associated with PCI use. RESULTS: Two hundred seven patients were treated for LS-SCLC and 61.4% (n = 127) of these patients received PCI. The most common documented reason for not receiving PCI was patient refusal, typically because of concerns about PCI toxicity. Patients older than 65 were significantly less likely to receive PCI. Brain FFS and OS rates were significantly higher in patients who received PCI. CONCLUSIONS: Not all eligible patients are receiving PCI, despite its significant effect on reducing brain metastases and improving OS. Emphasizing the benefits of PCI to patients, when discussing potential toxicities, may improve utilization.

In the world of evidence-based medicine, a dogmatic hierarchy of clinical trial design 1 has conditioned us to only change practice based on randomized data and to discount observational studies. Thus, defining treatment paradigms for rare cancers (or rare subsets of cancers) remains a challenge. If a randomized controlled trial (RCT) cannot be completed, how does one establish practice-changing results? In the article that accompanies this editorial, Tao et al 2 report a retrospective analysis of 79 patients and the impact of radiation dose on outcomes for inoperable, locally advanced intrahepatic cholangiocarcinoma (IHC).Tantalizingly,patientstreatedto higher than the median radiation dose (biologic equivalent dose 80.5 Gy, equivalent to approximately 58 Gy in 15 fractions) achieved remarkable levels of long-term local control, overall survival, and progression-free survival (78%, 58%, and 39%, respectively, at 3 years) with a surprisingly low incidenceoftoxicities.Ofnote,biologicequivalentdosewastheonly variable statistically associated with outcomes on multivariable analysis. The outcomes of these patients are within reported outcomes of patients with ICH in surgical series. In contrast, the expected outcome fromstandard of caretreatmentfor these patients can be estimated from the results of the randomized ABC-02 trial, 2 which treated a mix of inoperable patients (approximately 25% locally advanced and 75% metastatic) with systemic therapy alone, 3 achieving a 3-year survival rate that was close to zero.

Adjuvant hyperthermia can improve treatment outcome for locally recurrent breast cancer (LRBC). Previously, we demonstrated that infection of human breast cancer cells with a recombinant adenovirus expressing beta-galactosidase from the human hsp70b gene promoter (Ad.70b.betagal) results in 50- to 800-fold increases in reporter gene expression following heat treatment (30 minutes at 43 degrees C). Here, we describe a heat-directed suicide gene therapy strategy based on an adenoviral vector (Ad.70b.CDTK) in which expression of the dual prodrug-activating E. coli cytosine deaminase/herpes simplex virus thymidine kinase (CDTK) fusion gene is under the control of the hsp70b promoter. Treatment of T47D and MCF-7 breast cancer cells with mild hyperthermia (43 degrees C/30 minutes) and prodrugs (100 microg/ml 5-fluorocytosine and 10 microg/ml ganciclovir) following infection with Ad.70b.CDTK (10-100 PFU/cell) resulted in 30- to 60-fold decreases in clonogenic survival relative to control cultures treated with heat or prodrugs alone. Clonogenic survival declined even further (up to 240-fold) following heat treatment at 41.5 degrees C for 120 minutes. A decreased clonogenic survival was accompanied by tumor cell apoptosis. These results demonstrate that this combined treatment strategy can be highly effective against heat- and radiation-resistant breast tumor cells and supports the continued development of heat-directed CDTK suicide gene therapy strategies for LRBC.

Purpose: The combination of low-dose radiotherapy with PARP inhibition has been shown to enhance antitumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with escalating doses of veliparib (ABT-888), a small-molecule PARP inhibitor, in patients with peritoneal carcinomatosis from advanced solid tumor malignancies. Experimental Design: Patients were treated with veliparib (80–320 mg daily) for a total of 3 cycles. LDFWAR consisted of 21.6 Gy in 36 fractions, 0.6 Gy twice daily on days 1 and 5 for weeks 1–3 of each cycle. Circulating tumor cells (CTC) were collected and evaluated for γ-H2AX. Quality of life (QoL) was assessed using the EORTC-QLQ-C30 questionnaire. Results: Twenty-two patients were treated. Treatment-related grade 3 and 4 toxicities included lymphopenia (68%), anemia (9%), thrombocytopenia (14%), neutropenia (4%), leukopenia (9%), ascites (4%), vomiting (4%), and dyspnea (4%). No objective responses were observed. Disease stabilization (≥24 weeks) was observed in 7 patients (33%). Median progression-free survival (mPFS) was 4.47 months and median overall survival (mOS) was 13.04 months. In the subset of 8 ovarian and fallopian cancers, mPFS was 6.77 months and mOS was 17.54 months compared with mPFS 2.71 months and mOS 13.01 months in others. Patients with ovarian and fallopian cancers had better QoL over time than those with other cancers. An increased percentage of γ-H2AX–positive CTCs was observed in a subset of patients (3/6 with >2 CTCs at baseline). Conclusions: Combined veliparib and LDFWAR is a well-tolerated regimen that resulted in prolonged disease stability for some patients with advanced solid tumors and carcinomatosis, particularly in the ovarian and fallopian cancer subpopulation. Clin Cancer Res; 21(1); 68–76. ©2014 AACR.

Hepatocellular carcinoma (hcc) is a leading cause of cancer mortality, and its incidence is increasing in developed countries. Risk factors include cirrhosis from viral hepatitis or alcohol abuse. Metabolic syndrome is a newly recognized, but important, risk factor that is likely contributing to the increased incidence of hcc. Surgery is the therapy of choice for hcc, but local therapies are often contraindicated, usually because of advanced disease or comorbid conditions such as cardiac disease (which is associated with metabolic syndrome). Current radiation therapy techniques such as stereotactic body radiotherapy allow for treatment plans that highly conform to the target and provide excellent sparing of normal structures. Radiation therapy is emerging as a viable option in patients not eligible for surgery or other locoregional therapies. Here, we report a case of a large hcc presenting in a patient with metabolic syndrome without significant alcohol history or biochemical liver dysfunction. The patient was not a candidate for locoregional therapies because of cardiac and renal comorbidities typical of patients experiencing the long-term sequelae of metabolic syndrome. Treatment using an arc-based volumetric-modulated arc therapy technique allowed for the highest dose of radiation to be delivered to the tumour while the peripheral radiation dose was minimized. A complete local response was confirmed by computed tomography imaging 21 months after treatment completion.

Targeting therapeutic gene expression to tumor cells represents a major challenge for cancer gene therapy. The strong transcriptional response exhibited by heat shock genes, along with the beneficial therapeutic effects of hyperthermia have led us to develop a heat-directed gene-targeting strategy for cancer treatment. Heat shock gene expression is mediated in large part by the interaction of heat shock factor 1 with specific binding sites (heat shock elements; HSE) found in the promoters of heat-inducible genes. Here we present a quantitative analysis of heat-inducible gene expression mediated by the wild-type hsp70b gene promoter, as well as a modified hsp70b promoter containing additional HSE sequences. β-Galactosidase (β-gal) expression was induced between 50- and 800-fold in a panel of human breast cancer cell lines infected with an adenoviral vector containing the wild-type hsp70b promoter (Ad.70b.βg) following treatment at 43°C for 30 minutes. Infection with an adenoviral vector containing the modified hsp70b promoter (Ad.HSE.70b.βg) resulted in a 200- to 950-fold increase in β-gal expression under the same conditions, and also provided a 1–2°C decrease in the threshold of activation. Significant increases in the heat responsiveness of the Ad.HSE.70b.βg construct were observed in five of six tumor cell lines tested, as well as under thermotolerant conditions. Finally, we demonstrate that localized heating of a HeLa cell xenograft can effectively target β-gal gene expression following intratumoral injection of Ad.70b.βg. Adenoviral vectors incorporating heat-inducible therapeutic genes may provide useful adjuncts for clinical hyperthermia. Cancer Gene Therapy (2000) 7, 1566–1574.

The p53 tumor suppressor gene and members of the transforming growth factor-beta (TGF-beta) superfamily play central roles in signaling cell cycle arrest and apoptosis (programmed cell death) in normal development and differentiation, as well as in carcinogenesis. Here we describe a distantly related member of the TGF-beta superfamily, designated placental TGF-beta (PTGF-beta), that is up-regulated in response to both p53-dependent and -independent apoptotic signaling events arising from DNA damage in human breast cancer cells. PTGF-beta is normally expressed in placenta and at lower levels in kidney, lung, pancreas, and muscle but could not be detected in any tumor cell line studied. The PTGF-beta promoter is activated by p53 and contains two p53 binding site motifs. Functional studies demonstrated that one of these p53 binding sites is essential for p53-mediated PTGF-beta promoter induction and specifically binds recombinant p53 in gel mobility shift assays. PTGF-beta overexpression from a recombinant adenoviral vector (AdPTGF-beta) led to an 80% reduction in MDA-MB-468 breast cancer cell viability and a 50-60% reduction in other human breast cancer cell lines studied, including MCF-7 cells, which are resistant to growth inhibition by recombinant wild-type p53. Like p53, PTGF-beta overexpression was seen to induce both G(1) cell cycle arrest and apoptosis in breast tumor cells. These results provide the first evidence for a direct functional link between p53 and the TGF-beta superfamily and implicate PTGF-beta as an important intercellular mediator of p53 function and the cytostatic effects of radiation and chemotherapeutic cancer agents.

The gold standard treatment for early-stage non–small-cell lung cancer is surgical resection. Yet operative risk is prohibitive for many patients with this condition. Over half of patients who are given a diagnosis of lung cancer are 70 years of age or older. The prevalence of comorbidities in

The safety, pharmacokinetics, biodistribution and radiation dosimetry of (111)In-DTPA-hEGF, an Auger electron-emitting radiopharmaceutical, were evaluated in a first-in-human trial. Dose escalation was performed in patients with EGFR-positive metastatic breast cancer who had received ≥2 prior courses of systemic treatment. (111)In-DTPA-hEGF (0.25 mg) was administered once intravenously (i.v.). Blood was collected for biochemistry/hematology testing and pharmacokinetic and immunogenicity analyses at selected times post injection (p.i.). Whole body planar images were acquired at 1, 4-6, 24 and 72 h p.i. and SPECT images at 24 and/or 72 h p.i. Macrodosimetry (MIRD) for the whole body and organs was estimated using OLINDA. Correlative radiological imaging was obtained at baseline, 1 and 3 months and then 6 monthly. Toxicity was scored using Common Terminology Criteria for Adverse Events (CTCAE)v2.0. Sixteen patients, median age 47 yr (range, 35-59), received (111)In-DTPA-hEGF as follows: 357-434 MBq (7), 754-805 MBq (3), 1,241-1,527 MBq (3) and 2,030-2,290 MBq (3). Fifteen were evaluable for toxicity. The commonest adverse events (AE) were flushing, chills, nausea, and vomiting occurring during or immediately p.i. One patient experienced Grade 3 thrombocytopenia (attributed to bone marrow infiltration by cancer). There were no other Grade 3 or 4 AEs. Maximum tolerated dose was not reached. Clear accumulation of radiopharmaceutical in at least one known site of disease was observed in 47% of patients. (111)In-DTPA-hEGF was cleared biexponentially from the blood with α-phase T½ of 0.16 ± 0.03 h and β-phase T½ of 9.41 ± 1.93 h. (111)In-DTPA-hEGF was not immunogenic. The mean radiation dose estimates in mGy/MBq for whole body, liver, kidneys, spleen and thyroid were 0.08, 0.86, 0.74, 0.37 and 0.30, respectively. No objective antitumor responses were observed at the doses studied. In summary, administered amounts of up to 2,290 MBq (0.25 mg) of (111)In-DTPA-hEGF were well tolerated as a single i.v. injection.

Outcomes after treatment with accelerated hypofractionated radiotherapy in stage i medically inoperable non-small-cell lung cancer (nsclc) patients were determined. Our single-institution retrospective review looked at medically inoperable patients with T1&ndash, 2N0M0 nsclc treated with accelerated hypofractionated curative-intent radiotherapy between 1999 and 2009. Patients were staged mainly by computed tomography imaging of chest and abdomen, bone scan, and computed tomography/magnetic resonance imaging of brain. Positron-emission tomography (pet) staging was performed in 6 patients. Medical charts were reviewed to determine demographics, radiotherapy details, sites of failure, toxicity (as defined by the Common Terminology Criteria for Adverse Events, version 3.0) and vital status. The cumulative incidence of local and distant failure was calculated. Overall (os) and cause-specific (css) survival were estimated by the Kaplan&ndash, Meier method. In the 60 patients treated during the study period, the dose regimens were 50 Gy in 20 fractions (n = 6), 55 Gy in 20 fractions (n = 8), 60 Gy in 20 fractions (n = 42), and 60 Gy in 25 fractions (n = 4). All patients were treated once daily. The median follow-up was 27 months (range: 4&ndash, 94 months). The os rates at 2 and 5 years were 61% [95% confidence interval (ci): 50% to 75%] and 19% (95% ci: 10% to 34%) respectively. The css rates at 2 and 5 years were 79% (95% ci: 68% to 91%) and 39% (95% ci: 24% to 63%) respectively. The cumulative incidence of local failure was 20% at 5 years. The cumulative incidence of distant failure was 28% at 5 years. No patients experienced grade 3 or greater pneumonitis or esophagitis. Accelerated hypofractionated regimens are well tolerated and provide good local control in medically inoperable patients with stage i nsclc. Such regimens may be a reasonable treatment alternative when stereotactic body radiation therapy is not feasible.

Introduction: We have used respiratory-correlated cone beam computed tomography (rcCBCT) imaging to study the volumetric and positional changes that occur throughout the course of radical radiotherapy in non-small cell lung cancer (NSCLC). Methods: Tumor volumes and centers of mass were recorded and analyzed on weekly serial rcCBCT images of NSCLC patients treated with radical radiotherapy to a dose ≥45 Gy with concurrent chemotherapy. Results: Sixty patients with locally advanced NSCLC were included; in 31 patients, the primary tumor was peripheral and thus suitable for contouring. There was a mean percent decrease of 40.2% by fraction 15 and 51.1% by treatment completion. Among all 60 patients, 19 patients (32%) had more than 30% regression by fraction 15 and 25 patients (81%) by treatment completion. Statistically significant tumor migration in at least one direction between the first and the last 2 weeks was demonstrated in 14 of 27 patients. Clinically relevant changes (atelectasis and effusions) were noted in 11 of 29 visually assessed patients. Conclusions: Current rcCBCT image quality allows assessment of tumors located more peripherally. Significant tumor regression was documented in the majority of patients. In view of these observations, the suitability of adaptive radiotherapy in radical lung cancer treatment should be further investigated.

We have previously demonstrated that protein kinase B (PKB) is a mediator of heat-induced apoptosis for human breast cancer cells. To investigate the therapeutic potential of abrogating the function of this important survival protein, a novel replication-deficient adenovirus was constructed, wherein a mutant, kinase-inactive PKB gene (AAA) was inserted downstream of the CMV promoter. Two human breast cancer cell lines, MCF-7 and MDA-468, were treated, along with the MCF-10 serving as a "normal" mammary epithelial comparator. Apoptosis was increased with adv.AAA (25 PFU/cell) infection alone, but was significantly enhanced with the addition of heat exposure. Differential survival was observed with the MDA-468 cancer cells being more sensitive than the MCF-7 cells. The MCF-10 cells, in contrast, were most resistant to these treatments. Results from the clonogenic assay reflected the apoptosis data, with an apparent additive interaction between adv.AAA and hyperthermia treatments, again with greater differential sensitivity of the malignant, compared to the "normal" mammary epithelial cells. Heat or adv.beta-gal treatments led to phosphorylation of PKB and Forkhead, but this phosphorylation was reduced with adv.AAA therapy. In parallel, the combination of adv.AAA and heat treatment reduced PKB kinase activity more so than with either heat or adv.beta-gal alone. In conclusion, our results demonstrate that inhibition of the PKB-dependent survival pathway will promote apoptosis and thermosensitization in malignant breast cancer cells, with relative sparing of their normal counterpart, suggesting that a therapeutic gain could be achievable using this therapeutic strategy.

In previous studies we demonstrated that a modified human HSP70b promoter (HSE.70b) directs high levels of gene expression to tumor cells after mild hyperthermia treatment in the range of 41.5-44 degrees C. This transcriptional targeting system exhibits low basal activity at 37 degrees C, is highly induced (950-fold) after mild heat treatment (43 degrees C/30 min), and returns to basal activity levels within 12-24 hours of activation. Here we describe heat-directed targeting of an activated form of the Gibbon ape leukemia virus env protein (GALV FMG) to tumor cells. GALV FMG mediates cell-cell fusion, and when expressed in tumor cells can produce bystander effects of up to 1:200. Transient transfection of a HSE70b.GALV FMG minigene caused extensive syncytia formation in HeLa and HT-1080 cells following mild heat treatment (44 degrees C/30 min). Stable transfection into HT-1080 cells produced a cell line (HG5) that exhibits massive syncytia formation and a 60% reduction in viability relative to a vector-only control (CI1) following heat treatment in vitro. Mild hyperthermia also resulted in syncytia formation, necrosis, and complete macroscopic regression of HG5 xenograft tumors grown in the footpads of mice with severe combined immunodeficiency disorders (SCID). Median survival increased from 12.5 (in heated CI1 controls) to 52 days after a single heat treatment. Heat-directed tumor cell fusion may prove to be a highly beneficial adjunct to existing cancer treatment strategies that take advantage of the synergistic interaction between mild hyperthermia and radiation or chemotherapeutic drugs.

Background Veliparib, an oral PARP-1 and -2 inhibitor, potentiates the antitumor activity of DNA damaging agents including radiation therapy in vivo, and is shown to cross the blood-brain barrier. Updated data on safety and antitumor activity from an ongoing phase 1, dose-escalation study of veliparib with concurrent WBRT in pts with brain mets are presented here. Methods Pts with brain mets (including leptomeningeal) from primary non-CNS metastatic solid tumors (except germ cell cancer), adequate organ function, and Karnofsky performanace status (KPS) ≥70 were treated with WBRT (37.5 Gy in 15 fractions or 30 Gy in 10 fractions daily) and veliparib BID in escalating doses of 10–300 mg; the final WBRT fraction was followed by 1 extra day of veliparib. Safety and exploratory efficacy were assessed. Safety was evaluated in pts who received at least 1 dose of veliparib. Best brain tumor response (complete or partial per RECIST) rates were calculated for all pts who had at least 1 measureable lesion at baseline. Median survival time was estimated using Kaplan-Meier methodology for all dosed pts. Results To date, 66 pts (M/F, 23/43; median age 58 y) have been treated. Baseline KPS was 70, 80, 90, and 100 in 7.6, 31.8, 37.9, and 22.7% pts, respectively; primary tumor types were breast (n = 21), NSCLC (n = 23), melanoma (n = 10), colorectal (n = 3), renal (n = 1), and others (n = 8); 74.2% pts had multiple lesions, and 16.7% had prior brain stereotactic radiosurgery. Treatment-emergent dose-limiting toxicities were grade 3 hypokalemia and hyponatremia in 1 pt each at the 150 mg dose. Grade 3/4 treatment-emergent adverse events (≥4%) were fatigue (6.1%), dehydration (6.1%), anemia (4.5%), thrombocytopenia (4.5%), hyperglycemia (4.5%), and hyponatremia (4.5%). Best tumor response rate and median survival time were 36.8% and 6.6 months (m) for NSCLC, and 50% and 8.3 m for breast cancer. Conclusion Addition of veliparib up to 200 mg BID was well tolerated with concurrent standard WBRT and dose escalation is ongoing. These encouraging safety and preliminary efficacy data suggest that veliparib requires further evaluation as a radiosensitizer with WBRT in pts with NSCLC and brain mets in a randomized trial. Disclosure M.P. Mehta: Consultant: Abbott, BMS, Elekta, Merck, Novartis, Novocure, Tomotherapy, Vertex; Stock Options: Accuray, Pharmacyclics; DSMB: Apogenix; Protocol Data Review: Adnexus; Board of Directors: Pharmacyclics. W.J. Curran: Dr. Curran had served on the advisory board of Lilly, BMS, and Plexxikon. There are no conflicts. D. Wang: As a clinical investigator, and the principle investigator at Henry Ford Health System, I have conducted this clinical trial that is financially supported by Abbott Oncology. I have no other conflict of interest to be disclosed, otherwise. L. Kleinberg: I have received research funding from Abbott. J. Qian: Full-time Abbott employee and stockholder. T. Leahy: Full-time Abbott employee and stockholder. B. Desai: Full-time Abbott employee and stockholder. V.L. Giranda: Full-time Abbott employee and stockholder. All other authors have declared no conflicts of interest.