Subsequent Tumor Response Research Articles

Hyperpolarized 13C Metabolic MRI of Patients with Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related death in the United States. However, early response assessment using the current approach of measuring changes in tumor size on computed tomography (CT) or MRI is challenging. To investigate the feasibility of hyperpolarized (HP) [1-13C]pyruvate MRI to quantify metabolism in the normal appearing pancreas and PDA, and to assess changes in PDA metabolism following systemic chemotherapy. Prospective. Six patients (65.0 ± 7.6 years, 2 females) with locally advanced or metastatic PDA enrolled prior to starting a new line of systemic chemotherapy. 3-T, T1-weighted gradient echo, metabolite-selective 13C echoplanar imaging. Time-resolved HP [1-13C]pyruvate data were acquired before (N = 6) and 4-weeks after (N = 3) treatment initiation. Pyruvate metabolism, as quantified by pharmacokinetic modeling and metabolite area-under-the-curve ratios, was assessed in manually segmented PDA and normal appearing pancreas ROIs (N = 5). The change in tumor metabolism before and 4-weeks after treatment initiation was assessed in primary PDA (N = 2) and liver metastases (N = 1), and was compared to objective tumor response defined by response evaluation criteria in solid tumors (RECIST) on subsequent CTs. Descriptive tests (mean ± standard deviation), model fit error for pharmacokinetic rate constants. Primary PDA showed reduced alanine-to-lactate ratios when compared to normal pancreas, due to increased lactate-to-pyruvate or reduced alanine-to-pyruvate ratios. Of the three patients who received HP [1-13C]pyruvate MRI before and 4-weeks after treatment initiation, one patient had a primary tumor with early metabolic response (increase in alanine-to-lactate) and subsequent partial response according to RECIST, one patient had a primary tumor with relatively stable metabolism and subsequent stable disease by RECIST, and one patient had metastatic PDA with increase in lactate-to-pyruvate of the liver metastases and corresponding progressive disease according to RECIST. Altered pyruvate metabolism with increased lactate or reduced alanine was observed in the primary tumor. Early metabolic response assessed at 4-weeks after treatment initiation correlated with subsequent objective tumor response assessed using RECIST. 2 TECHNICAL EFFICACY: Stage 2.

SYST-24 PROPOFOL EXERTS ANTI-TUMOR EFFECTS IN GLIOMA AND THE TUMOR MICROENVIRONMENT VIA NON-CODING RNAS AND SECRETED EXOSOMES

Abstract BACKGROUND Glioblastoma (GBM), is the most common primary brain tumor. GBM contains a small subpopulation of glioma stem cells (GSCs) that are implicated in tumor recurrence and treatment resistance and therefore represent important therapeutic targets. Recent clinical studies suggest propofol impacts subsequent tumor response to treatments and patient prognosis. The effects of propofol on patient derived GSCs alone and in combination with radiation and temozolomide, (TMZ) have not been reported. Objectives: The molecular mechanisms underlying propofol’s anti-tumor effects on GSCs and its effect on cellular communication with microglia was studied. Using GSC spheroids, differentiated glioma and tumor cells on a microfluid chip, effects of propofol alone and together with radiation and TMZ on the self-renewal and stemness of GSCs, their mesenchymal transit and the proliferation and apoptosis of differentiated glioma cells was analyzed. Using transwell plates, the effects of propofol on the cross-talk of GSCs with human microglia cells was examined. RESULTS Propofol exerted a dose-dependent inhibitory effect on the self-renewal, expression of mesenchymal markers and migration of GSCs and sensitized them to both temozolomide (TMZ) and radiation. At higher concentrations propofol induced a large degree of cell death as demonstrated using microfluid chip. Propofol increased the expression of the lncRNA BDNF-AS, which acts as a tumor suppressor in GBM and silencing of this lncRNA partially abrogated propofol’s anti-tumor effects. Propofol also inhibited the pro-tumorigenic GSC-microglia cross talk via extracellular vesicles (EVs) and delivery of BDNF-AS. CONCLUSIONS Propofol exerted anti-tumor effects on GSCs and differentiated glioma cells by inhibiting cell renewal, proliferation, and mesenchymal transition and by inducing cell death at higher concentration. Propofol also sensitized GSCs to radiation and TMZ. Propofol, which is widely used in GBM surgeries, should be further explored as a potential repurposed drug during resection and an effective adjunct to radiation and TMZ.

Propofol Inhibits Glioma Stem Cell Growth and Migration and Their Interaction with Microglia via BDNF-AS and Extracellular Vesicles.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. GBM contains a small subpopulation of glioma stem cells (GSCs) that are implicated in treatment resistance, tumor infiltration, and recurrence, and are thereby considered important therapeutic targets. Recent clinical studies have suggested that the choice of general anesthetic (GA), particularly propofol, during tumor resection, affects subsequent tumor response to treatments and patient prognosis. In this study, we investigated the molecular mechanisms underlying propofol's anti-tumor effects on GSCs and their interaction with microglia cells. Propofol exerted a dose-dependent inhibitory effect on the self-renewal, expression of mesenchymal markers, and migration of GSCs and sensitized them to both temozolomide (TMZ) and radiation. At higher concentrations, propofol induced a large degree of cell death, as demonstrated using microfluid chip technology. Propofol increased the expression of the lncRNA BDNF-AS, which acts as a tumor suppressor in GBM, and silencing of this lncRNA partially abrogated propofol's effects. Propofol also inhibited the pro-tumorigenic GSC-microglia crosstalk via extracellular vesicles (EVs) and delivery of BDNF-AS. In conclusion, propofol exerted anti-tumor effects on GSCs, sensitized these cells to radiation and TMZ, and inhibited their pro-tumorigenic interactions with microglia via transfer of BDNF-AS by EVs.

Retrospective Multicenter Analysis of the Outcome of a Re-Induction with Immune Checkpoint Inhibitors in Advanced Merkel Cell Carcinoma

Significant progress has been made in the treatment of advanced Merkel cell carcinoma (MCC) by establishing immune checkpoint inhibitors (ICI). Tumor progression, durable response, or adverse events may lead to ICI discontinuation in MCC patients. If in these patients tumor progression occurs, the question remains if re-induction with ICI achieves renewed tumor response. This retrospective multicenter study evaluated patients in with re-induction of anti-PD-1/anti-PD-L1 therapy for advanced MCC. Clinical data were extracted at treatment initiation, tumor response, treatment cessation, and subsequent tumor response to re-induction. Eight patients from seven centers (mean age 67.8 years) were included. The median duration of initial therapy with anti-PD-1/anti-PD-L1 was 9.6 months (2–21 months). Two patients achieved complete response (CR), four patients partial response (PR), one patient stable disease (SD), while in one patient progressive disease (PD) occurred as best overall response (BOR) to ICI. Reason for discontinuation of ICI was PD in three patients and severe adverse events in five patients. Following a median anti-PD-1/anti-PD-L1 therapy-free interval of 9.5 months (3–18 months), re-induction with ICI therapy was initiated. Five of eight patients (62.5%) achieved an objective response upon re-induction, while in three patients, no response could be observed. Notably, adverse events, which had led to the discontinuation of the first ICI treatment line, were not observed upon re-induction. The initial response to immune checkpoint inhibitors seems to be an important marker for successful re-induction. Interestingly, adverse events leading to treatment discontinuation were not observed during re-induction.

Pressure-enabled delivery of gemcitabine in an orthotopic pancreatic cancer mouse model

BackgroundWe describe the use of pancreatic retrograde venous infusion in an orthotopic murine model of pancreatic ductal adenocarcinoma and hypothesize that pancreatic retrograde venous infusion delivery of gemcitabine will increase concentrations of gemcitabine in the tumor and the subsequent tumor response to treatment. MethodsMurine pancreatic ductal adenocarcinoma (KPC4580P) was transplanted onto the pancreatic tail of C57BL/6J mice. Groups (n = 15) of mice were assigned to sham laparotomy and 100 mg/kg intraperitoneal infusion of gemcitabine (systemic gemcitabine), pancreatic venous isolation with pancreatic retrograde venous infusion of 100 mg/kg gemcitabine, or pancreatic retrograde venous infusion with saline infusion. Tumor pressures were recorded during pancreatic retrograde venous infusion. Mice were killed at 1 hour or 7 days after infusion. ResultsBaseline tumor pressures were 45 ± 8 mm Hg, and pancreatic retrograde venous infusion increased tumor pressures by 29 ± 6 mm Hg (P < .01). Pancreatic retrograde venous infusion gemcitabine mice had greater tumor gemcitabine concentrations compared with systemic gemcitabine (127 vs 19 ng/mg; P < .01) and lesser tumor volumes compared with both systemic gem and pancreatic retrograde venous infusion with saline (274 vs 857 vs 629 mm3; P < .01). ConclusionPancreatic retrograde venous infusion increased tumor pressures greater than baseline, improved gemcitabine delivery, and increased the treatment response. These findings suggest that pressurized, regional delivery overcomes the increased pressure barrier in pancreatic ductal adenocarcinoma. Additional preclinical studies with cytotoxic and immunotherapeutic agents and clinical trials using pressure-enabled drug delivery with pancreatic retrograde venous infusion devices are underway.

Calcium carbonate nanoparticles stimulate tumor metabolic reprogramming and modulate tumor metastasis.

CaCO3 nanoparticles (nano-CaCO3) can neutralize the acidic pHe of solid tumors, but the lack of intrinsic imaging signal precludes noninvasive monitoring of pH-perturbation in tumor microenvironment. We aim to develop a theranostic version of nano-CaCO3 to noninvasively monitor pH modulation and subsequent tumor response. We synthesized ferromagnetic core coated with CaCO3 (magnetite CaCO3). Magnetic resonance imaging (MRI) was used to determine the biodistribution and pH modulation using murine fibrosarcoma and breast cancer models. Magnetite CaCO3-MRI imaging showed that nano-CaCO3 rapidly raised tumor pHe, followed by excessive tumor-associated acid production after its clearance. Continuous nano-CaCO3 infusion could inhibit metastasis. Nano-CaCO3 exposure induces tumor metabolic reprogramming that could account for the failure of previous intermittent pH-modulation strategies to achieve sustainable therapeutic effect.

Clinical outcomes and emergent circulating tumor (ct)DNA RAS mutations and allele fraction for patients with metastatic colorectal cancer (mCRC) treated with panitumumab from the ASPECCT study.

3584 Background: ASPECCT was a phase III clinical trial performed in the chemotherapy-refractory third-line mCRC setting (N = 1010). This analysis explores the relationship between circulating levels of mutations and clinical outcomes for panitumumab-treated subjects using univariate and multivariate models that treat total mutational load as a continuous measure. Methods: 238 subjects treated with panitumumab had paired plasma samples at baseline and post-treatment (PT). Samples were analyzed for mutations using the Plasma Select-R™ 63-gene panel (0.1% limit of detection). The fraction of mutant RAS reads was evaluated for association with tumor response (by RECIST) and overall survival using univariate and multivariate Cox proportional hazards models. Results: 52% of the subjects who were RAS wild-type by plasma at baseline never developed a RAS mutation. For those with mutant RAS ctDNA ( KRAS+ NRAS) detected at baseline or PT, there was an overall increase in RAS mutant DNA fraction at PT compared to baseline. By non-parametric analysis, there was no difference in the distribution of baseline mutant RAS fraction between those who achieved stable disease (SD) or those with progression ( P = 0.09). There was also no difference in the increase in mutant RAS fraction on therapy between subjects with SD or progressive disease (PD). In addition, RAS mutation was not required for progression: 48% of subjects with PD had no RAS mutant DNA detected. Conclusions: In this exploratory analysis, baseline plasma mutant RAS fraction is an unreliable predictor of subsequent tumor response. Subjects with objective response or SD may have stable or rising levels of mutant RAS DNA. Subjects without any detectable RAS mutation still experience PD. These findings suggest that detectable plasma ctDNA RAS mutations do not necessarily predict response to panitumumab and should be interpreted with caution. Further work is needed to establish clinically relevant and validated thresholds. Clinical trial information: NCT01001377.

Intravoxel Incoherent Motion-derived Histogram Metrics for Assessment of Response after Combined Chemotherapy and Radiation Therapy in Rectal Cancer: Initial Experience and Comparison between Single-Section and Volumetric Analyses.

Purpose To determine the diagnostic performance of intravoxel incoherent motion (IVIM) parameters and apparent diffusion coefficient (ADC) to assess response to combined chemotherapy and radiation therapy (CRT) in patients with rectal cancer by using histogram analysis derived from whole-tumor volumes and single-section regions of interest (ROIs). Materials and Methods The institutional review board approved this retrospective study of 31 patients with rectal cancer who underwent magnetic resonance (MR) imaging before and after CRT, including diffusion-weighted imaging with 34 b values prior to surgery. Patient consent was not required. ADC, perfusion-related diffusion fraction (f), slow diffusion coefficient (D), and fast diffusion coefficient (D*) were calculated on MR images acquired before and after CRT by using biexponential fitting. ADC and IVIM histogram metrics and median values were obtained by using whole-tumor volume and single-section ROI analyses. All ADC and IVIM parameters obtained before and after CRT were compared with histopathologic findings by using t tests with Holm-Sidak correction. Receiver operating characteristic curves were generated to evaluate the diagnostic performance of IVIM parameters derived from whole-tumor volume and single-section ROIs for prediction of histopathologic response. Results Extreme values aside, results of histogram analysis of ADC and IVIM were equivalent to median values for tumor response assessment (P > .06). Prior to CRT, none of the median ADC and IVIM diffusion metrics correlated with subsequent tumor response (P > .36). Median D and ADC values derived from either whole-volume or single-section analysis increased significantly after CRT (P ≤ .01) and were significantly higher in good versus poor responders (P ≤ .02). Median IVIM f and D* values did not significantly change after CRT and were not associated with tumor response to CRT (P > .36). Interobserver agreement was excellent for whole-tumor volume analysis (range, 0.91-0.95) but was only moderate for single-section ROI analysis (range, 0.50-0.63). Conclusion Median D and ADC values obtained after CRT were useful for discrimination between good and poor responders. Histogram metrics did not add to the median values for assessment of tumor response. Volumetric analysis demonstrated better interobserver reproducibility when compared with single-section ROI analysis. (©) RSNA, 2016 Online supplemental material is available for this article.

OT2-05-03: ACRIN 6688 Phase II Study of Fluorine-18 3′-Deoxy-3′ Fluorothymidine (FLT) in Invasive Breast Cancer.

Abstract Background Neoadjuvant chemotherapy (NAC) prior to surgery provides enhanced options for locoregional management and has become an integral component of primary breast cancer management. Initial tumor response in patients receiving NAC is generally determined at therapy completion. This evaluation is determined by either the presence/absence of palpable tumor as a clinical response and/or presence/absence of invasive tumor cells in the breast and nodes as a pathological response. The ability to evaluate the effectiveness of neoadjuvant therapy early during treatment would be of significant importance. FDG PET imaging has been shown to be predictive of subsequent tumor response, but the tendency of FDG to accumulate in inflammatory tissues can complicate image interpretation. MRI changes have also been touted as predictors of response. Preliminary data suggest that early FLT PET is better able to predict response to therapy, as FLT uptake has been shown to correlate with cellular proliferation, and does not significantly accumulate in inflammatory tissue (Kenny et al, Eur J Nucl Med Mol Imaging 2007:1339–1347). The analysis of these data may provide a better understanding of early treatment response and improve the clinical management of breast cancer in the future. Trial design and eligibility: In this phase II multi-institutional study, breast cancer patients with locally advanced disease with a tumor size ≥2cm (measured on imaging or estimated by physical exam) are eligible. Participants will receive standard of care NAC at their respective institutions. Participants will have 3 FLT imaging sessions to evaluate therapy response: at baseline, early-treatment (5-10 days after initiating treatment), and post-treatment prior to surgery. Specific aims: The primary objective is to correlate the percentage change in the standardized uptake value between baseline and early therapy FLT in the primary tumor with pathologic response. Correlatively, FLT PET parameters will be compared with proliferative indices from the initial biopsy and residual tumor surgical samples using Ki-67 staining, mitotic index, and residual cancer burden. Potential safety issues and the physiologic effects associated with FLT administration will also be evaluated. Statistical methods: To evaluate the relationship between an uptake parameter and pathologic complete response, a ROC curve will be estimated and the area under the curve, along with its 95% confidence interval, will be determined. Accrual: Currently, 45/67 patients have accrued to the study. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-05-03.

ACRIN 6688 phase II study of fluorine-18 3′-deoxy-3′ fluorothymidine (FLT) in invasive breast cancer.

TPS125 Background: Neoadjuvant chemotherapy (NAC) prior to surgery provides enhanced options for locoregional management and has become an integral component of primary breast cancer management. Initial tumor response in patients receiving NAC is generally determined at therapy completion. This evaluation is determined by either the presence/absence of palpable tumor as a clinical response and/or presence/absence of invasive tumor cells in the breast and nodes as a pathological response. The ability to evaluate the effectiveness of neoadjuvant therapy early during treatment would be of significant importance. FDG PET imaging has been shown to be predictive of subsequent tumor response, but the tendency of FDG to accumulate in inflammatory tissues can complicate image interpretation. MRI changes have also been touted as predictors of response. Preliminary data suggest that early FLT PET is better able to predict response to therapy, as FLT uptake has been shown to correlate with cellular proliferation, and does not significantly accumulate in inflammatory tissue (Kenny et al, Eur J Nucl Med Mol Imaging 2007:1339-1347). Methods: In this phase II multi-institutional study, breast cancer patients with locally advanced disease with a tumor size ≥2cm (measured on imaging or estimated by physical exam) are eligible. Participants will receive standard of care NAC at their respective institutions. Participants will have 3 FLT imaging sessions to evaluate therapy response: at baseline, early-treatment (5-10 days after initiating treatment), and post-treatment. The primary objective is to correlate the percentage change in the standardized uptake value between baseline and early therapy FLT in the primary tumor with pathologic response. Correlatively, FLT PET parameters will be compared with proliferative indices from the initial biopsy and residual tumor surgical samples using Ki-67 staining, mitotic index, and residual cancer burden. Potential safety issues and the physiologic effects associated with FLT administration will also be evaluated. The analysis of these data may provide a better understanding of early treatment response and improve the clinical management of breast cancer in the future.

Costimulated, Tumor-Derived Donor Lymphocyte (TDL) Infusion for B-Cell Tumor Relapse After Allogeneic Hematopoietic Stem Cell Transplantation

AbstractAbstract 683Donor lymphocyte infusion (DLI) is the primary treatment for relapse after allogeneic hematopoietic stem cell transplantation (allotransplant), but is effective in less than half of patients and is associated with significant graft-vs-host disease (GVHD). Furthermore, DLI is not available for cord-blood or many unrelated-donor recipients. We theorized that tumor from patients relapsing post-allotransplant would contain infiltrating donor T- lymphocytes with tumor-specificity. If such cells had been “primed”, but inadequately costimulated for tumor cell killing, costimulation ex-vivo could generate a donor lymphocyte product with increased graft-vs-tumor (GVT) potency. Preclinical feasibility was demonstrated in tumor biopsies from patients with tumor progression after allotransplant. Ex-vivo CD3/CD28 costimulation of tumor-infiltrating lymphocytes with antibody-coated magnetic beads yielded donor products, predominently consisting of effector T-cells; tumor specimens of greater than 1 cm reliably produced donor T cell expansions that would permit clinically relevant cell dosing. Based on these preclinical results, we conducted a Phase 1 study of tumor-derived donor lymphocyte (TDL) therapy in allotransplant recipients with B-lymphoid tumor progression despite full-donor T cell chimerism and DLI, or for which DLI was not available. The primary objectives of (1) feasibility of ex-vivo costimulation of lymphocytes from surgically harvested tumor to generate a TDL product and (2) safety of TDL infusion (TDLI) in patients with relapse after allotransplant were met within the first 7 of 15 planned subjects. All 7 patients had chemotherapy-refractory relapse after allotransplant (diffuse large-B cell lymphoma (DLBCL) = 2; Hodgkin's Lymphoma (HL) = 4; chronic lymphocytic leukemia (CLL) = 1). Tumor was surgically resected. Lymphocytes were released from tumor tissue through mechanical dispersion and cultured with CD3/CD28 antibody-coated magnetic beads in media supplemented with IL-2 (100 IU/ml) for a median of 12 days (range: 7– 42 days). T cells comprised from 0.5 – 63.4% of tumor cell suspensions (culture inocula) and 82 – 99% of expanded products (22- to 144-fold expansion). PCR-based chimerism assessment of products demonstrated that the TDL were of donor origin (median 99% donor). During TDL expansion, markers of activation and effector function increased (CD4: CD40L; CD8: CD137, perforin, NKG2D). Percentages of FoxP3+ Treg cells declined and TBet+ Th1/Tc1 effectors increased in the costimulated TDL product. Expression of CD27 and CD28 has been associated with long-term persistence of infused effector T cells; although these markers declined in culture, expression was retained in a significant proportion of cells from the 5 products that were cultured for less than 14 days. TDL products meeting release criteria for tumor contamination (<5%) and sterility were generated for all subjects. TDL were administered to all subjects, with a median of 2.63 × 107 cells/kg (range: 0.93 – 10 × 107 cells/kg) infused. No acute toxicities were seen during 24 hours of observation post-infusion, and there was no evidence of GVHD over a minimum follow-up of 4 weeks. Three subjects succumbed to their cancer prior to disease restaging (2 DLBCL and 1 HL). In 2 of 4 evaluable subjects, tumor-specific effects were observed following TDLI: in the first (HL), FDG-PET uptake by tumor declined at 4 and at 8 weeks after TDLI; in the second (HL), peri-tumoral pulmonary infiltrates developed 4 weeks after TDLI, with a subsequent tumor response upon initiation of systemic steroids. The remaining 2 subjects demonstrated mixed responses, with transient overall disease stabilization. We have demonstrated the feasibility and safety of TDL therapy, with suggestive evidence of tumor-directed biologic effects and potential GVT activity. Incorporating host immune depletion prior to TDLI, as has been required for efficacy in autologous adoptive cellular therapy, may permit more potent and sustainable GVT responses. TDL may provide a therapeutic option for patients without a source of DLI, e.g., cord-blood recipients, or for those whose tumors do not respond to standard DLI. Disclosures:June:N/A: Inventor, Government-held Patent.

Pancreatic Cancer: Utility of Dynamic Contrast-enhanced MR Imaging in Assessment of Antiangiogenic Therapy

To prospectively evaluate the utility of dynamic contrast material-enhanced magnetic resonance (MR) imaging in predicting the response of locally advanced pancreatic cancer to combined chemotherapy and antiangiogenic therapy. This prospective, institutional review board-approved, HIPAA-compliant study with informed consent assessed dynamic contrast-enhanced MR imaging in 11 patients (mean age, 54.3 years; six men and five women) with locally invasive pancreatic cancer before and 28 days after combined chemotherapy and antiangiogenic therapy. Axial perfusion images were obtained after injection of 0.1 mmol gadopentetate dimeglumine per kilogram of body weight. Sagittal images of the upper abdominal aorta were obtained for arterial input function calculation. A two-compartment kinetic model was used to calculate the perfusion parameters K(trans) (the rate constant that represents transfer of contrast agent from the arterial blood into the extravascular extracellular space), K(ep) (the rate constant that represents transfer of contrast agent from the extravascular extracellular space to the blood plasma), and volume of distribution (v(e)). Semiquantitative measurements, peak tissue gadolinium concentration (C(peak)), maximum slope of gadolinium increase (slope), and area under the gadolinium curve at 60 seconds (AUC(60)) were also calculated. Perfusion parameters and tumor size changes were correlated with carbohydrate antigen 19-9 levels. Comparisons between pre- and posttreatment studies were performed by using the Wilcoxon signed rank test, and comparisons between responders and nonresponders were performed by using the Mann-Whitney test. After therapy, K(trans), v(e), C(peak), slope, and AUC(60) decreased significantly (P = .02, .001, .002, .007, and .01, respectively). Tumor size and K(ep) were not significantly changed. Pretreatment K(trans) and K(ep) were significantly higher (P = .02 and .006, respectively) in tumors that showed marker response than in those that did not. A pretreatment K(trans) value (milliliters of blood per milliliter of tissue times minutes) of more than 0.78 mL/mL . min was 100% sensitive and 71% specific for subsequent tumor response. Semiquantative parameters and tumor size were not different between the groups. Pretreatment K(trans) measurement in pancreatic tumors can predict response to antiangiogenic therapy. All perfusion parameters showed substantial reduction after 28 days of combined chemotherapy and antiangiogenic therapy.

Efficacy of cetuximab-based second-line therapy in patients with metastatic head and neck squamous cell carcinoma (HNSCC) which progressed on gefitinib-based first-line therapy

6075 Background: The pathobiology of HNSCC depends, in part, on the epidermal growth factor receptor (EGFR). In HNSCC cell lines and xenograft models, tyrosine kinase (TKI) and monoclonal antibody inhibitors of EGFR had additive and apparent independent effects in controlling the proliferation of HNSCC. Cetuximab and gefitinib each have anti-tumor activity in pts with HNSCC; however, it is not known if tumor resistance to a TKI EGFR inhibitor conveys cross-resistance to a monoclonal antibody EGFR inhibitor. Methods: In a retrospective study of pts with metastatic HNSCC, we sought to determine the tumor response (by RECIST criteria) rate to a second line regimen of cetuximab (400 mg/m2 loading dose then 250 mg/m2/wk) and carboplatin (AUC 5 q3wks) in pts whose disease had progressed on gefitinib (250 mg orally daily) and docetaxel on ECOG protocol 1302. Results: Of the 22 pts enrolled at this institution onto ECOG 1302 protocol from 2/05–7/07, we identified 5 treated with cetuximab and carboplatin as second line therapy after disease progression on gefitinib and docetaxel. Best tumor response to gefitinib and docetaxel was partial (PR) in 2, stable (SD) in 1, and progression (PROG) in 2. Best tumor response to second line therapy with cetuximab and carboplatin was PR in 1, SD in 1, and PROG in 3. Relationship of tumor response to therapies is shown below (Table). Conclusions: This limited data set suggests: 1) Prior tumor progression on gefitinib/docetaxel does not predict for failure to respond to second line therapy with cetuximab/carboplatin, and 2) A potential favorable effect of prior tumor response to an oral EGFR TKI in predicting subsequent tumor response to a monoclonal antibody EGFR inhibitor. Expected tumor response rate to single agent carboplatin is 10% suggesting that the response rate (2 of 6) to cetuximab/carboplatin seen in our patients was at least in part due to cetuximab. Relationship of Tumor Response to Therapies Patient Best Tumor Response to First Line Therapy (Gefitinib/Docetaxel) Best Tumor Response to Second Line Therapy (Cetuximab/Carboplatin) 1 PR SD 2 PR PR 3 SD PROG 4 PROG PROG 5 PROG PROG Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Abraxis, Bristol-Myers Squibb, Cytogen, ImClone, sanofi-aventis Abraxis

Influence of the organic anion-transporting polypeptide 1B1 ( OATP1B1) polymorphisms on irinotecan-pharmacokinetics and clinical outcome of patients with advanced non-small cell lung cancer

To investigate whether the OATP1B1 polymorphisms affect irinotecan-pharmacokinetics and subsequent toxicity and tumor response of patients with advanced NSCLC. A total of 81 Korean NSCLC patients enrolled in a phase II study of irinotecan and cisplatin chemotherapy were genotyped for OATP1B1 -11187G>A, 388A>G and 521T>C variants. The 521TC or CC and -11187AA genotypes were associated with higher AUC(SN-38) (p=0.016 and 0.030, respectively). When haplotypes were assigned, patients with *15 haplotype showed significantly higher AUC(SN-38) than *1a or *1b haplotypes (p=0.006). Grade 4 neutropenia was associated with the 521TC or CC genotypes, whereas, grade 3 diarrhea was associated with 388GG genotype (p=0.046). Of the 81 patients enrolled, 77 were assessable for response and 36 (47%) patients achieved partial responses (PR). However, no statistical significance was observed between genotype and response. These findings suggest that OATP1B1 variants are involved in SN-38 disposition and highly predictive for severe toxicity of NSCLC patients treated with irinotecan-based chemotherapy.

Quantitative Fluoroestradiol Positron Emission Tomography Imaging Predicts Response to Endocrine Treatment in Breast Cancer

In breast cancer, [(18)F]fluoroestradiol (FES) positron emission tomography (PET) correlates with estrogen receptors (ER) expression and predicts response to tamoxifen. We tested the ability of FES-PET imaging to predict response to salvage hormonal treatment in heavily pretreated metastatic breast cancer patients, predominantly treated with aromatase inhibitors. Initial FES uptake measurements in 47 patients with ER-positive tumors were correlated with subsequent tumor response to 6 months of hormonal treatment. Most patients had bone dominant disease and prior tamoxifen exposure. Response was compared to initial FES-PET uptake, measured qualitatively and quantitatively using standardized uptake value (SUV) and estradiol-binding flux. Eleven of 47 patients (23%) had an objective response. While no patients with absent FES uptake had a response to treatment, the association between qualitative FES-PET results and response was not significant (P = .14). However, quantitative FES uptake and response were significantly associated; zero of 15 patients with initial SUV less than 1.5 responded to hormonal therapy, compared with 11 of 32 patients (34%) with SUV higher than 1.5 (P < .01). In the subset of patients whose tumors did not overexpress HER2/neu, 11 of 24 patients (46%) with SUV higher than 1.5 responded. Quantitative FES-PET can predict response to hormonal therapy and may help guide treatment selection. Treatment selection using quantitative FES-PET in our patient series would have increased the rate of response from 23% to 34% overall, and from 29% to 46% in the subset of patients lacking HER2/neu overexpression. A multi-institutional collaborative trial would permit definitive assessment of the value of FES-PET for therapeutic decision making.

Acute Tumor Response to ZD6126 Assessed by Intrinsic Susceptibility Magnetic Resonance Imaging

The effective magnetic resonance imaging (MRI) transverse relaxation rate R2* was investigated as an early acute marker of the response of rat GH3 prolactinomas to the vascular-targeting agent, ZD6126. Multigradient echo (MGRE) MRI was used to quantify R2*, which is sensitive to tissue deoxyhemoglobin levels. Tumor R2* was measured prior to, and either immediately for up to 35 minutes, or 24 hours following administration of 50 mg/kg ZD6126. Following MRI, tumor perfusion was assessed by Hoechst 33342 uptake. Tumor R2* significantly increased to 116 ± 4% of baseline 35 minutes after challenge, consistent with an ischemic insult induced by vascular collapse. A strong positive correlation between baseline R2* and the subsequent increase in R2* measured 35 minutes after treatment was obtained, suggesting that the baseline R2* is prognostic for the subsequent tumor response to ZD6126. In contrast, a significant decrease in tumor R2* was found 24 hours after administration of ZD6126. Both the 35-minute and 24-hour R2* responses to ZD6126 were associated with a decrease in Hoechst 33342 uptake. Interpretation of the R2* response is complex, yet changes in tumor R2* may provide a convenient and early MRI biomarker for detecting the antitumor activity of vascular-targeting agents.

Functional diffusion map: A noninvasive MRI biomarker for early stratification of clinical brain tumor response

Assessment of radiation and chemotherapy efficacy for brain cancer patients is traditionally accomplished by measuring changes in tumor size several months after therapy has been administered. The ability to use noninvasive imaging during the early stages of fractionated therapy to determine whether a particular treatment will be effective would provide an opportunity to optimize individual patient management and avoid unnecessary systemic toxicity, expense, and treatment delays. We investigated whether changes in the Brownian motion of water within tumor tissue as quantified by using diffusion MRI could be used as a biomarker for early prediction of treatment response in brain cancer patients. Twenty brain tumor patients were examined by standard and diffusion MRI before initiation of treatment. Additional images were acquired 3 weeks after initiation of chemo- and/or radiotherapy. Images were coregistered to pretreatment scans, and changes in tumor water diffusion values were calculated and displayed as a functional diffusion map (fDM) for correlation with clinical response. Of the 20 patients imaged during the course of therapy, 6 were classified as having a partial response, 6 as stable disease, and 8 as progressive disease. The fDMs were found to predict patient response at 3 weeks from the start of treatment, revealing that early changes in tumor diffusion values could be used as a prognostic indicator of subsequent volumetric tumor response. Overall, fDM analysis provided an early biomarker for predicting treatment response in brain tumor patients.

FDG–PET in staging and restaging non-small cell lung cancer after neoadjuvant chemoradiotherapy: correlation with histopathology

This study was performed to investigate the utility of FDG–PET for: (1) initial staging, and (2) restaging of the primary and mediastinal nodal lesions 2 weeks after the completion of preoperative chemoradiotherapy in patients with stage III non-small cell lung cancer (NSCLC). Twenty-six patients with histologically confirmed stage III NSCLC were accrued to this study from April 1993 to July 1998. They included 21 with stage IIIA (N2) NSCLC who were enrolled into an institutional phase II study, and 5 patients with a highly selected subset of stage IIIB disease characterized by the presence of microscopic metastatic disease in contralateral mediastinal lymph nodes who were also treated with preoperative chemoradiotherapy; N3 lesions ( n=3) and minimal T4 lesions. Demographic characteristics included median age 62 years (a range from 47 to 73) and gender ratio of male 15 to female 11. Histologic types of tumor consisted of squamous cell carcinoma 6, adenocarcinoma 11, large cell carcinoma 5, and non-small cell carcinoma 4. All patients had FDG–PET imaging of the chest before the initiation and 2 weeks after completion of preoperative therapy. The FDG–PET images were evaluated qualitatively for uptake at the primary tumor sites and mediastinal lymph nodes. Standard uptake values (SUVs) were also calculated for the primary tumors and all PET findings were correlated with surgical histopathologic data. Preoperative chemoradiotherapy resulted in complete pathologic response in 8 of 26 primary lesions. By qualitative analysis, 96% of these tumors showed level 3 or 4 uptake before preoperative chemoradiotherapy. After chemoradiotherapy, 57% (15/26) of patients showed at least a one level decrease in uptake, and the sensitivity and specificity of FDG–PET for differentiating residual tumor from pathologic complete response were 67% (12/18) and 63% (5/8). Mean SUV was 14.87±7.11 at baseline and decreased to 5.72±3.35 after chemoradiotherapy ( n=21, P<0.00001). When a value of 3.0 was used as the SUV cut-off, sensitivity and specificity were 88 and 67%, respectively. The mean values of visual intensity were 3.87±0.35 and 3.8±0.51 for patients who achieved pathologic complete response ( n=8) and for those who showed residual cancer after the preoperative therapy ( n=18), respectively. The mean SUVs were 16.97±8.52 and 14.03±6.61 for patients who achieved pathologic complete response ( n=6) and for those who showed residual cancer ( n=15) after the preoperative therapy, respectively. Therefore, the degree of FDG uptake before preoperative chemoradiotherapy did not provide predictive value for subsequent tumor response. For mediastinal initial staging, the sensitivity and specificity of FDG–PET were 75 and 90.5%. The sensitivity and specificity of FDG–PET for mediastinal restaging were 58.0 and 93.0%. These results indicate that FDG–PET is useful for monitoring the therapeutic effect of neoadjuvant chemoradiotherapy in patients with stage III NSCLC. For the primary lesions, SUV based analysis has high sensitivity but limited specificity for detecting residual tumor. In contrast, for restaging of mediastinal lymph nodes, FDG–PET is highly specific, but has limited sensitivity.

185 Our treatment protocol in nasopharyngeal carcinoma

Nasopharynx cancers are classified differently from other types of head and neck cancers by their extensive lymphatic spread and frequent distant metastasis. In most cases RT is the only treatment modality because of the localization. Neoadjuvant chemotherapy studies are held to have better results in the local-regional advanced disease. 39 was treated in our clinic between August 91–June 94. Thirty of the 39 cases were treated according to the NF cancer treatment protocol of Dokuz Eylül University Head and Neck Cancer Group. Our treatment protocol for Stage I–III disease is curative RT and for Stage IV disease both neoadjuvant CT (CDDP + Bleomycin + Methotrexate) and RT. This protocol is activated in October 1992. Twenty-six cases were Stage IV, 3 cases Stage III, 1 case Stage II. Fifteen cases were treated by RT and CT and 15 cases were treated with RT alone. The applied RT technique and total doses are standard in all cases. Each case is irradiated with 50 Gy to the supraclavicular and cervical areas without lymphatic involvement and with 70 Gy irradiation to the primary tumor and to involved cervical lymph node areas. Neoadjuvant CT is applied two courses every 21 days and after and after subsequent tumor response evaluation, RT was started. Median follow-up period is 22 month (3–40 months). Three cases with distant metastases died. Local recurrence is detected in two cases and second series of RT was applied. A case with regional recurrence was treated with CT alone. Two cases were lost in follow up (one having a pulmonary metastasis). The rest of the patients are disease free.

Clinical correlates of MDR1 (P-glycoprotein) gene expression in ovarian and small-cell lung carcinomas.

Expression of the MDR1 (P-glycoprotein) gene causes resistance to several classes of lipophilic anti-cancer drugs, but MDR1 expression in untreated ovarian and lung carcinomas is rarely detectable by standard assays. This study was designed to measure the MDR1 messenger RNA (mRNA) content of ovarian and lung carcinomas and to analyze clinical correlations of MDR1 expression in these tumors. A sensitive assay based on the polymerase chain reaction (PCR) was used in a retrospective study to measure MDR1 mRNA in biopsy samples of 100 solid tumors, including 60 ovarian and 32 lung carcinomas. The levels of MDR1 mRNA were correlated with history of chemotherapeutic treatment for all tumors; for ovarian and small-cell lung carcinomas (SCLCs), these levels were also correlated with subsequent tumor response to chemotherapy. Among previously untreated patients, MDR1 mRNA was expressed in 68% (50 of 74) of all tumors. Among patients pretreated with chemotherapy regimens that included at least one P-glycoprotein-transported drug (MDR regimens), 95% (20 of 21) of all tumors expressed MDR1 mRNA though the incidence of high-level MDR1 expression was decreased among the treated tumors. MDR1 mRNA was expressed in only one of five tumors treated with regimens that included no P-glycoprotein substrates (non-MDR regimens). Subsequent tumor response to chemotherapy was evaluated in 35 patients with ovarian carcinoma and seven patients with SCLC. The presence of even very low levels of MDR1 mRNA correlated with the lack of response to MDR regimens in these tumor types (P < .035 for ovarian carcinomas, P < .029 for SCLCs, and P < .0005 for both tumor types; Fisher's Exact Test). Low-level expression of MDR1 mRNA correlates with clinical resistance to combination chemotherapy in ovarian cancer and SCLC. We hypothesize that MDR1 is expressed in a subpopulation of more malignant tumor cells possessing multiple mechanisms of drug resistance. The presence of MDR1-expressing tumor cells may be useful as a predictive marker for clinical resistance to combination chemotherapy in ovarian cancer and SCLC. Prospective studies are needed to confirm this hypothesis.