Initial Tumor Burden Research Articles

‘Deepness of Response' Is Associated with Overall Survival in Standard Systemic Chemotherapy for Metastatic Colorectal Cancer

Background: The identification of responders is an important issue in chemotherapy for metastatic colorectal cancer (mCRC). ‘Deepness of response' (DpR), defined as the maximum rate of reduction from the initial tumor burden, was recently proposed as a novel hypothetical parameter associated with overall survival (OS) in first-line chemotherapy plus cetuximab for mCRC. We determined whether this concept was universally applicable to diverse standard chemotherapeutic regimens for mCRC. Methods: We reviewed mCRC patients who received the first-line systemic chemotherapy regimens FOLFOX, CapeOX or FOLFIRI (with biologics) at our department between June 2005 and March 2015. Data such as clinicopathological parameters, metastasized organs, chemotherapeutic regimens, the best response by RECIST v1.1, progression-free survival (PFS) and OS were retrospectively retrieved for patients who exhibited tumor shrinkage. DpR was calculated as the uni-dimensional maximum reduction rate of measurable tumors. We addressed the association between DpR and survival. Results: Of the 156 patients receiving first-line chemotherapy regimens, tumor shrinkage was observed in 63 (41 of whom were men; median age 62 years). Complete remission was achieved in 6 patients, partial remission in 42 and stable disease in 15. The median DpR was 44.2% and was employed as the cutoff, in line with previous reports. DpR ≥45% (31 patients) was correlated with longer PFS (median 16.4 vs. 8.1 months for DpR <45%, p = 0.006) and OS (median 58.6 vs. 30.9 months for DpR <45%, p = 0.041). There was basically no difference in the subsequent chemotherapy between the DpR ≥45% and DpR <45% groups. Conclusion: DpR correlated with OS in various first-line systemic upfront chemotherapy regimens for mCRC.

VI. FDG-PET as a biomarker in lymphoma: from qualitative to quantitative analysis.

VI. FDG-PET as a biomarker in lymphoma: from qualitative to quantitative analysis.

Predictive Significance of Serum Beta 2-Microglobulin Levels and M-Protein Velocity for Symptomatic Progression of Smoldering Multiple Myeloma

Background: Smoldering multiple myeloma (SMM) has been defined as precursor state to symptomatic multiple myeloma (MM). Mayo Clinic demonstrated that the presence of bone marrow plasma cells (BMPC) ≥ 10% and M protein levels ≥ 3 g/dL significantly associated with early progression to symptomatic MM and the serum free-light chain (FLC) ratio of < 0.125 or 8 < was an important additional predictors of progression. PETHEMA showed that the proportion of aberrant plasma cells (aPCs) within the BMPC > 95% as assessed by flow cytometry was another important variable for progression. However, NIH demonstrated the discordance of these two risk models. The aim of this project is to develop the method to predict the symptomatic progression more definitely by simple parameters, usually available at medical practice.Methods: We employed the nation-wide retrospective study. The clinical data of SMM patients were collected from 61 medical centers in Japan and risk predictors of progression to symptomatic MM were analyzed. The diagnosis of SMM is made by the presence of the ratio of bone marrow plasma cells (BMPCs) ≥ 10% or serum M-protein levels ≥ 3 g/dL, and the absence of any myeloma derived end-organ damage. Eligible patients were aged 18 to 90 years, previously untreated, and diagnosed between 2000 and 2012. This study was approved by the institutional review board at all participating institutions.Results: Total 301 patients fulfilled the inclusion criteria. The median age was 67 years (rang 27 to 90). IgG is the major (80%) compared to IgA (15%) or Bence Jones protein (3%). Total 145 patients developed to symptomatic MM. The symptoms consisted of anemia in 66%, lytic bone lesions in 43%, and renal impairment in 10%. Both anemia and lytic bone lesions were seen in 16%. The median time to progression was 4.3 years. The cumulative incidence of progression was 30.7% at 2 years, 50.0% at 4 years, 59.8% at 6 years, and 68.6% at 8 years. Based on multivariate analysis, we firstly identify the serum beta 2-microglobulin (B2MG) levels ≥ 2.5 mg/L as a predictor for the early progression (HR 1.59; 95% CI, 1.11 to 2.29, p = 0.01), as well as the known factors: presence of both BMPC ≥ 10% and M protein levels ≥ 3 g/dL (HR 1.89; 95% CI, 1.31 to 2.73, p = 0.0007), IgA or Bence Jones type (HR:1.61; 95%CI, 1.04 to 2.49, p = 0.03), and immunoparesis (HR:1.88; 95%CI, 1.14 to 3.08, p = 0.01). FLC ratio was examined in 52 patients. A significant association with high risk of progression was observed in patients with FLC ratio of < 0.0625 or 16 < (P = 0.04), but not in those with the ratio of < 0.125 or 8 < (P = 0.09). Cytogenetic abnormality was examined with FISH in 82 patients. The cumulative incidence of progression in patients with either t(4;14), t(14;16), or del(17p) was not significantly different from those without such chromosomal aberration (P = 0.4). Notably, we firstly focused on the rate of rise of the M-protein levels over time which is referred to as the "M-protein velocity". We employed the linear regression analysis to estimate the gradient to assess the M-protein velocity of each patient. The receiver operating characteristics curve analysis showed that the M-protein velocity of 1.035 mg/dL/day was a risk-stratification cut-off point with a high specificity of 0.96 and with a moderate sensitivity of 0.60. Based on the landmark analysis, the serum B2MG levels ≥ 2.5 mg/L at diagnosis (HR 2.76; 95% CI, 1.69 to 4.51, P = 5 x 10–5) and the M-protein velocity > 1 mg/dL/day before the 18-month landmark point (HR 2.27; 95% CI, 1.30 to 3.95, P = 4 x 10–3) had independently correlated with subsequent progression to symptomatic MM. The cumulative incidence of progression of the patients with both the serum B2MG levels ≥ 2.5 mg/L at diagnosis and the M-protein velocity > 1 mg/dL/day showed 67.5% at 2 years, 75.6% at 3 years and 100% at 6.3 years after the landmark point.Conclusions: We identify the novel risk factors consisted of serum B2MG levels ≥ 2.5 mg/L and the M-protein velocity > 1 mg/dL/day for subsequent symptomatic progression. Theoretically, it is possible to emphasis that the serum B2MG levels represent the initial tumor burden of SMM and the M-protein velocity reflects the the growth rate of tumor cells. These results also suggest that the quantification of time-dependent change of measured values should be taken into consideration for the precise prediction of symptomatic progression.This study is supported by the National Cancer Center Research and Development Fund in Japan. DisclosuresNo relevant conflicts of interest to declare.

Metabolic Tumor Volume (MTV) Is a Predictor of Survival in Borderline Pancreatic Cancers Treated With Neoadjuvant Therapy

Purpose/Objective(s): A higher initial metabolic tumor burden is associated with lower median survival in locally advanced pancreatic cancer (LAPC), yet the prognostic utility of PET/CT is not defined in the setting of borderline resectable pancreatic cancer (BRPC). Materials/Methods: We performed a retrospective review of our institutional experience treating BRPC. Initial staging included endoscopic ultrasound as well as pancreas protocol CT and PET/CT scans. All patients underwent neoadjuvant gemcitabine-based chemotherapy and radiation therapy (RT). We limited the study to those patients receiving stereotactic body radiation therapy (SBRT) in 5 fractions. Restaging CT and PET/CT scans were obtained approximately 4 weeks following RT completion. The PET/CT scans were imported into a second program where the region of interest (ROI) was delineated over the pancreas primary tumor so that the MTV could be autocontoured. We measured the significance of the pretreatment and post-treatment SUV maximum and metabolic tumor volume (MTV) 2.5 to 5.0, which was defined as the MTVabove a threshold SUVof 2.5, 3.0, 4.0, and 5.0. Cox regression models were used to evaluate the significance between these parameters and disease free survival (DFS) and overall survival (OS). Results: We evaluated a total of 77 BRPC patients. Median follow-up was 9.2 months with a median dose of 35 Gy to the primary tumor/vessel interface. Sixty-two patients (80.5%) received induction chemotherapy with gemcitabine, docetaxel and capecitabine (GTX). Sixty-three (81.8%) underwent surgical resection. Significant predictors for OS included pretreatment MTV2.5 (p Z 0.017), mean SUV in pre-treatment MTV4.0 (p Z 0.034), mean SUV in pre-treatment MTV5.0 (p Z 0.021), post-treatment MTV3.0 (p Z 0.038), mean SUV in post-treatment MTV3.0 (p Z 0.034), post-treatment MTV4.0 (p Z 0.011), mean SUV in post-treatment MTV4.0 (p Z 0.009), post-treatment MTV5.0 (p Z 0.002), and mean SUV in posttreatment MTV5.0 (p Z 0.018). Differential SUV and MTV were not predictive. Conclusions: Our data suggests that preand post-neoadjuvant metabolic tumor volumes are prognostic for survival in BRPC. Author Disclosure: K. Latifi: None. A. Cruz: None. E. Mellon: None. T. Strom: None. J. Freilich: None. G. Springett: None. R. Kim: None. M. Malafa: None. R. Shridhar: None. S. Hoffe: None.

The role of surgical resection following imatinib treatment in patients with recurrent or metastatic gastrointestinal stromal tumors: results of propensity score analyses.

Although benefits of surgical resection of residual gastrointestinal stromal tumors (GISTs) after imatinib therapy have been suggested, those benefits over imatinib alone have not been proven. We compared the clinical outcomes of surgical resection of residual lesions after imatinib treatment (S group) with imatinib treatment alone (NS group) in patients with recurrent or metastatic GISTs. A total of 134 patients (42 in the S group, 92 in the NS group) with recurrent or metastatic GIST who had stable disease for more than 6 months after responding to imatinib were included. There were no statistically significant differences in the baseline characteristics of the S and NS groups except for age and number of peritoneal metastases. The median follow-up period was 58.9 months. Progression-free survival (PFS) and overall survival (OS) were significantly longer in the S group compared with the NS group (median PFS: 87.7 vs. 42.8 months, p = 0.001; median OS: not reached vs. 88.8 months, p = 0.001). Multivariate analysis revealed that S group, female sex, KIT exon 11 mutations, and low initial tumor burden were associated with longer PFS, and S group and low initial tumor burden were associated with a longer OS. Even after applying inverse probability of treatment weighting adjustment, the S group demonstrated significantly better outcomes in terms of PFS (HR 2.326; 95 % confidence interval [CI] 1.034-5.236; p = 0.0412) and OS (HR 5.464; 95 % CI 1.460-20.408; p = 0.0117). Surgical resection of residual lesions after disease control with imatinib is likely to be beneficial to patients with recurrent or metastatic GISTs.

Impact of tumor burden on tyrosine kinase inhibitors (TKI) efficacy in advanced non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations (EGFRm) and ALK rearrangement (ALK+).

e19021 Background: EGFRm and ALK+ are eligible to TKI. Predictive factors of response to TKI are poorly known, in particular the impact of the initial tumor burden. The objective of this study is t...

Radiobiological Modeling Based on 18F-Fluorodeoxyglucose Positron Emission Tomography Data for Esophageal Cancer.

BackgroundWe investigated the relationship of standardized uptake values (SUVs) to radiobiological parameters, such a 25 s tumor control probability (TCP), to allow for quantitative prediction of tumor response based on SUVs from 18F fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) before and after treatment for esophageal cancer.MethodsWe analyzed data from 20 esophageal cancer patients treated with chemoradiotherapy (CRT) followed by surgery. Tumor pathologic response to CRT was assessed in surgical specimens. Patients underwent 18F-FDG PET imaging before and after CRT. Rigid image registration was performed between both images. Because TCP in a heterogeneous tumor is a function of average cell survival, we modeled TCP as a function of <SUVR>, a possible surrogate for average cell survival (<SUVR>=<SUVafter/SUVbefore>). TCP was represented by a sigmoid function with two parameters: SUVR50, the <SUVR> at which TCP=0.5, and γ50, the slope of the curve at SUVR50. The two parameters and their confidence intervals (CIs) were estimated using the maximum-likelihood method. The correlation between SUV before CRT and SUV change <SUVbefore – SUVafter> was also studied.ResultsA TCP model as a function of SUV before and after treatment was developed for esophageal cancer patients. The maximum-likelihood estimate of SUVR50 was 0.47 (90% CI, 0.30-0.61) and for γ50 was 1.62 (90% CI, 0-4.2). High initial SUV and larger metabolic response (larger <SUVbefore –SUVafter>) were correlated, and this correlation was stronger among responders.ConclusionsOur TCP model indicates that <SUVafter/SUVbefore> is a possible surrogate for cell survival in esophageal cancer patients. Although CIs are large as a result of the small patient sample, parameters for a TCP curve can be derived and an individualized TCP can be calculated for future patients. Initial SUV does not predict response, whereas a correlation is found between surrogates for initial tumor burden and cell kill during therapy.

Phenotypic and Genomic Analysis Of Multiple Myeloma (MM) Minimal Residual Disease (MRD) Clonal Plasma Cells (PCs)

MRD monitoring is emerging as a powerful prognostic biomarker in MM. In addition to its utility to redefine the depth of response achieved after therapy, the MRD clone represents, from a biological point of view, a very small fraction of tumor cells that are truly chemoresistant, potentially quiescent (not producing M-protein), and able to recapitulate the initial tumor burden at relapse. Thus, the MRD clone represents a unique model to understand chemoresistance (in otherwise serological responding patients) and the characteristics of eventual MM clonogenic cells; however, the MRD clone has never been characterized at the biological level. Here, we compared the immunophenotypic and genomic profiles of paired baseline vs MRD clonal PCs from a total of 40 newly-diagnosed elderly MM patients enrolled in the GEM2010 trial: sequential VMP (9 cycles) followed by Rd (9 cycles) vs alternating VMP with Rd (18 cycles). MRD monitoring was performed by multidimensional flow cytometry (MFC) at cycles 9 and 18.First, we focused on the immunophenotypic expression profiling (iPEP) of patient-paired baseline vs MRD clonal PCs through 23-color MFC, combining backbone markers for the identification of clonal PCs with additional integrins, adhesion, activation and maturation molecules. Our results show that the iPEP from MRD clonal PCs at cycle 9 differed from paired baseline tumor cells by significantly (P<.05) increased MFI of CD11c, CD29, CD44, CD49d CD49e, CD54, and CD138, indicating that among the initial tumor bulk, the few chemoresistant cells were those with stronger expression of integrin and adhesion molecules. This phenomenon was particularly evident in patients randomized to the sequential arm; in fact, only after VMP there was a specific selection of CD117+chemoresistant clonal PCs (P=.03). Moreover, MRD clonal PCs showed significantly increased MFI of CD28 (a pro-survival mediator through dendritic cell interaction) and HLADR.Using patient-specific aberrant phenotypes, we then sorted clonal PCs (purity ≥97%) by FACS for subsequent genomic studies. Patient-specific paired comparison of baseline vs MRD clonal PCs (n=11) genomic profile was performed by high density Cytoscan750K array. The pattern of copy number abnormalities (CNA; only those with minimum of 25 consecutive imbalanced markers/segment and minimum 100 Kb length were considered) significantly varied from baseline to the chemoresistant MRD PC clone (accounting for whole chromosome, chromosomal arm or interstitial imbalances). Individual patient analysis showed one case in which both PC clones showed exactly the same 25 CNA; a second case in which MRD cells showed +1p36.21, -9p23, -17q11.2 and +17q25.3 in addition to 10 CNAs already present at baseline; 4 cases in which MRD cells maintained initial chromosomal imbalances but lacked specific CNA (range: 1-34) present at diagnosis; and 5 patients in which MRD cells displayed none of the CNA (range: 7-20) detected at baseline. It should be noted that markedly subclonal heterogeneity was detected at diagnosis. Accordingly, in one out of the 5 latter cases baseline but not MRD clonal PCs had 1q+ and 13q- which were further confirmed by FISH (in 85% and 58% of clonal PCs, respectively); this suggests that MRD PCs were present at the baseline state as a minor sublclone with respect to the initial tumor bulk. On the other hand, copy number neutral loss of heterozygosity (larger than 3Mb) was slightly more frequent in MRD as compared to patient paired baseline clonal PCs (13 vs 8, respectively).Only in 5/40 patients sufficient RNA was extracted from baseline and paired MRD FACS-sorted clonal PCs to perform gene expression profiling (GEP; HumanGene 1.0ST). Although the numbers are small, it should be noted that GEP of baseline vs. patient-paired MRD clonal PCs mostly overlapped, with only 19 genes found to be down-regulated after chemotherapy (SAM Excel add-in with a FDR q-value<10-5). Interestingly, 4 of those genes were connected to the glucocorticoid receptor signaling pathway and receptor gene NR3C1, a mediator of glucocorticoids activity in MM cells.In summary, this integrated phenotypic and genomic analysis suggests that from the baseline MM tumor bulk, primarily chemoresistant MRD PCs may be those potentially closer to the BM niche (with initial increased expression of integrins and adhesion molecules), as well as a more ancestral subclone (with less CNA) in a significant proportion of patients. Disclosures:No relevant conflicts of interest to declare.

Association between Absolute Tumor Burden and Serum Bone‐Specific Alkaline Phosphatase in Canine Appendicular Osteosarcoma

In dogs with appendicular osteosarcoma (OSA), increased pretreatment serum bone-specific alkaline phosphatase (BALP) activity is a negative prognostic factor, associated with shorter disease-free intervals and survival times, but a biologic basis for observed differential serum BALP activities in canine OSA patients remains incompletely defined. Serum BALP activity will correlate with absolute tumor burden in dogs with OSA. This study included 96 client-owned dogs with appendicular OSA. In canine OSA cell lines, the expression and membranous release of BALP was evaluated in vitro. The correlation between serum BALP activity and radiographic primary tumor size was evaluated in OSA-bearing dogs. In dogs developing visceral OSA metastases, serial changes in serum BALP activities were evaluated in relation to progression of macroscopic metastases, and visceral metastatic OSA cells were evaluated for BALP expression. In vitro, BALP expression was not associated with either tumorigenic or metastatic phenotype, rather the quantity of membranous BALP released was proportional with cell density. In dogs devoid of macroscopic metastases, there was a positive correlation between serum BALP activity and absolute primary tumor size. In dogs with progressive OSA metastases, serum BALP activity increased and coincided with the development of macroscopic metastases. OSA cells derived from visceral metastatic lesions retained BALP expression. Tumor burden is a determinant of serum BALP activity in dogs with appendicular OSA. The association between increased pretreatment BALP activity and negative clinical prognosis may simply be attributed to greater initial tumor burden, and consequently more advanced tumor stage.

The role of surgical resection following imatinib treatment in patients with metastatic or recurrent GIST.

10550 Background: Several retrospective studies have suggested that surgical resection of residual lesions could be beneficial if resection was done after disease control (partial response or stable disease) with imatinib in patients with metastatic or recurrent GIST. However, the benefit of surgical resection has not been proven yet compared to imatinib alone. Therefore, we compared the outcomes of surgical resection of residual lesions after imatinib (SI group) with those of imatinib alone (IM group) in patients with metastatic or recurrent GIST controlled with imatinib treatment. Methods: A total of 134 patients with metastatic or recurrent GIST who showed at least 6 months of disease stabilization or response to imatinib were included in this retrospective analysis. Patients were categorized into SI (n=42) or IM (n=92) group. To reduce the selection bias, propensity scores and inverse-probability-weighting (IPTW) adjustment were used in the outcome analysis. Results: Patient and tumor characteristics were statistically similar between SI and IM groups, except median age (51 in SI, 58 in IM, p=0.002), and metastases to peritoneum (12 in SI, 56 in IM, p=0.001). The patients in SI group underwent surgery of residual disease after a median 19.1 months of imatinib treatment (range, 7.2-87.0). With a median follow-up of 58.9 months (range, 15.4-129.1), progression-free survival (PFS) and overall survival (OS) were significantly longer in SI group than in IM group (PFS, 87.7 vs 42.8 months, p=0,001; OS, not reached vs 88.8 months, p=0.001). Multivariate analysis revealed SI group as well as female sex, KIT exon 11 mutation, and low initial tumor burden were associated with longer PFS, and SI group and low initial tumor burden were associated with longer OS. Even after applying IPTW adjustment, SI group showed significantly better outcome in terms of PFS (hazard ratio [HR], 2.326; 95% CI, 1.034-5.236; p=0.0412) and OS (HR, 5.464; 95% CI, 1.460-20.408; p=0.0117). Conclusions: This study strongly suggests that surgical resection of the residual lesions after disease control with imatinib may be beneficial in patients with metastatic or recurrent GIST.

Abstract 5508: Antitumor activity of cabazitaxel in pediatric patient-derived tumor xenografts (PDX).

Abstract Background: Cabazitaxel (Jevtana®), a semi-synthetic taxane, was approved for patients with metastatic hormone-refractory prostate cancer previously treated with docetaxel-based therapy. Cabazitaxel, which stabilizes microtubules as efficiently as docetaxel, has a better antiproliferative activity than docetaxel against chemotherapy resistant tumor cell lines, a broad spectrum of in vivo antitumor activity in docetaxel-sensitive tumors and in tumor models in which docetaxel was either poorly active or inactive. Unlike docetaxel, cabazitaxel is able to cross the blood-brain barrier and is active in intracranial human glioblastomas (AACR 2000). The preclinical combination of cabazitaxel and cisplatin exhibits therapeutic synergism (AACR 2011). Finally, cabazitaxel demonstrates greater activity than docetaxel in 3 pediatric tumor xenografts, 1 rhabdomyosarcoma and 2 Ewing's sarcomas (AACR 2012). Methods: The anti-tumor activity of cabazitaxel was further evaluated in comparison to docetaxel in 3 pediatric patient-derived tumor xenografts (PDX): 2 osteosarcomas derived from lung metastases of a 19 year old male (DM77) and a 3 year old female (DM113) patient; 1 Ewing's sarcoma taken from the bone of a 17 year old male patient (DM101). Cabazitaxel and docetaxel were dosed IV at 5.8, 9.3, 15 or 24.2 mg/kg, every 4 days for a total of 3 doses (initial tumor burden = 125 - 250 mm3). Results: Both cabazitaxel and docetaxel demonstrated antitumor activity in these 3 PDX. In DM113, cabazitaxel is significantly more active than docetaxel at 9.3, 15 and 24.2 mg/kg. Additionally, when comparing the numbers of partial regressions (PR ≥ 50 % initial tumor size for at least 7days), cabazitaxel is more potent than docetaxel at 15 (4/10 PR versus 0/10 PR, respectively) and at 24.2 mg/kg (5/10 PR versus 1/10 PR, respectively). Using body weight loss as a gross indicator of toxicity, docetaxel appears to more toxic than cabazitaxel in the 2 other PDX studies. In DM101, cabazitaxel at 15 or 24.2 mg/kg doses was significantly more active than docetaxel at the same dose or at the equitoxic dose (9.3 or 15 mg/kg, respectively). In addition, cabazitaxel induces more complete regressions (CR = no palpable tumors for at least 7days) and tumor free animals on day 60 (TF) than docetaxel (9/9 CR and 7/9 TF for cabazitaxel versus 4/9 CR and 1/9 TF for docetaxel at 15 mg/kg; 9/9 CR and 8/9 TF for cabazitaxel versus 3/9 CR and 2/9 TFS for docetaxel at 24.2 mg/kg). Finally, in DM77, cabazitaxel at 15 and 9.3 mg/kg is also more active than docetaxel at an equivalent dose or a toxicity adjusted dose (9.3 or 5.8 mg/kg, respectively). Conclusion: Both cabazitaxel and docetaxel are active in these 3 human pediatric PDX; however, cabazitaxel demonstrates greater activity than docetaxel. Taken together, preclinical data with cabazitaxel including activity in brain tumors and therapeutic synergism with cisplatin, support its development in pediatric indications. Citation Format: Patricia Vrignaud. Antitumor activity of cabazitaxel in pediatric patient-derived tumor xenografts (PDX). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5508. doi:10.1158/1538-7445.AM2013-5508

Pretreatment metabolic tumor volume (MTV) as a predictor of survival in borderline resectable pancreatic cancers treated with neoadjuvant therapy.

310 Background: A higher initial metabolic tumor burden is associated with lower median survival in locally advanced pancreatic cancer (LAPC), yet the prognostic utility of PET/CT is not defined in the setting of borderline resectable pancreatic cancer (BRPC). Methods: We performed a retrospectivereview of our institutional experience treating BRPC. Initial staging included endoscopic ultrasound as well as pancreatic protocol CT and PET/CT scans. All patients underwent neoadjuvant gemcitabine-based chemotherapy and radiation therapy (RT). RT was delivered using standard fractionation intensity modulated radiation therapy (IMRT) or stereotactic body radiation therapy (SBRT). Restaging CT and PET/CT scans were obtained approximately 4 weeks following RT completion. We measured the significance of the pre-treatment and post-treatment SUV maximum and metabolic tumor volume (MTV) 2.5 to 5.0, which was defined as the MTV above a threshold SUV of 2.5, 3.0, 4.0 and 5.0. Cox regression models were used to evaluate the significance between these parameters and disease free survival (DFS) and overall survival (OS). Results: We evaluated a total of 72 BRPC patients. Median follow up was 12.7 months. 56 patients (77%) received induction chemotherapy with gemcitabine, docetaxel and capecitabine (GTX). 43 (59.7 %) underwent surgical resection. Significant predictors for OS in the whole cohort included pre-treatment SUV maximum (p=0.0042), post-treatment SUV maximum (p=0.0183), pre-treatment MTV 2.5 (p=0.0016) and pre-treatment MTV 4.0 (p=0.0111). In addition, the difference between the MTV 4.0 pre-treatment and post-treatment was significant (p=0.0285). In patients who underwent surgical resection, there was a significant correlation between OS with pre-treatment SUV max (p=0.0229) and post-treatment SUV maximum (p=0.0325) but not pre-treatment MTV 2.5 (p=0.0654) nor MTV 4.0 (p=0.0928) nor the differences between each variable pre (0.1482) or post-treatment (0.0959). Conclusions: This is the first study to suggest that pre and post treatment PET activity is prognostic for BRPC.

The role of surgical resection following imatinib treatment in patients with metastatic or recurrent GIST.

62 Background: Several retrospective studies have suggested that surgical resection of residual lesions could be beneficial if resection was done after disease control (partial response or stable disease) with imatinib in patients with metastatic or recurrent GIST. However, the benefit of surgical resection has not been proven yet compared to imatinib alone. Therefore, we compared the outcomes of surgical resection of residual lesions after imatinib (SI group) with those of imatinib alone (IM group) in patients with metastatic or recurrent GIST controlled with imatinib treatment. Methods: A total of 134 patients with metastatic or recurrent GIST who showed at least 6 months of disease stabilization or response to imatinib were included in this retrospective analysis. Patients were categorized into SI (n=42) or IM (n=92) group. To reduce the selection bias, propensity scores and inverse-probability-weighting (IPTW) adjustment were used in the outcome analysis. Results: Patient and tumor characteristics were statistically similar between SI and IM groups, except median age (51 in SI, 58 in IM, p=0.002), and metastases to peritoneum (12 in SI, 56 in IM, p=0.001). The patients in SI group underwent surgery of residual disease after a median 19.1 months of imatinib treatment (range, 7.2-87.0). With a median follow-up of 58.9 months (range, 15.4-129.1), progression-free survival (PFS) and overall survival (OS) were significantly longer in SI group than in IM group (PFS, 87.7 vs 42.8 months, p=0,001; OS, not reached vs 88.8 months, p=0.001). Multivariate analysis revealed SI group as well as female sex, KIT exon 11 mutation, and low initial tumor burden were associated with longer PFS, and SI group and low initial tumor burden were associated with longer OS. Even after applying IPTW adjustment, SI group showed significantly better outcome in terms of PFS (hazard ratio [HR], 2.326; 95% CI, 1.034-5.236; p=0.0412) and OS (HR, 5.464; 95% CI, 1.460-20.408; p=0.0117). Conclusions: This study strongly suggests that surgical resection of the residual lesions after disease control with imatinib may be beneficial in patients with metastatic or recurrent GIST.

Successful selective internal radiotherapy (SIRT) in a patient with a malignant solid pseudopapillary pancreatic neoplasm (SPN)

Solid pseudopapillary neoplasms of the pancreas (SPNs, Gruber-Frantz-Tumor) are a rare entity representing 1–5% of all exocrine pancreatic tumors. The pseudocystic lesions preferentially affect young females <30 years, are mostly benign (∼90%) and normally present with unspecific symptoms.We describe the case of a 16-years-old Asian woman that was initially diagnosed with an SPN in the pancreatic head with mesenterial and hepatic metastases. After diagnosis, an extensive tumor resection was performed including pyloric-preserving pancreatic head resection followed by sequential resection of all hepatic metastases. After the patient was diagnosed with a hepatic recurrence and high intrahepatic tumor load, we chose a multimodal procedure and performed a selective internal radiotherapy (SIRT). Four years after SIRT and 10 years after initial diagnosis of metastatic SPN, the patient is in a good condition without any evidence for hepatic recurrence.This case represents a rare clinical course of a malignant and invasive SPN with an exceptionally long survival despite of high initial tumor burden. The selective internal radiotherapy is a suitable approach for inducing long-term remissions of the strongly vascularized liver metastases.

P3.01 A Decision Tool for the Design of Optimal Personalised Chemotherapy Protocols for the Treatment of Acute Myeloid Leukaemia (AML)

ABSTRACT AML is an aggressive cancer of the blood and bone marrow requiring intensive chemotherapy which, although effective for debulking tumour burden, is also highly destructive to normal tissues, often to a life-threatening extent. In current clinical practice only few patient-specific factors are taken into consideration and choice of treatment often depends on the treating physician's experience. However, there is a need for a systematic design of optimal protocols that account for both disease and patient characteristics. Towards this end, a framework is presented ( fig. 1 ) for the derivation of a Personalised-Chemotherapy Advisor (PC-Advisor) tool. The central part of this tool is a mathematical model that will enable the capture of patient behaviour under chemotherapy for a provided set of individual and disease parameters. In this work, a model is derived by combining the actions on the cell cycle, (drug target), with pharmacokinetic and pharmacodynamic aspects. Simulation and optimisation results are presented using this model for two patient case studies. The studied patients are of same sex, age and body mass index characteristics. However, their initial tumour burden and cell cycle times differ. They are both treated with the same treatment protocol in the model as they would be in clinical practice (a combination of cytarabine and daunorubicin). At completion of the first chemotherapy cycle one patient displays a bone marrow which contains a higher number of normal cells, whilst the other exhibits a higher number of AML cells. An optimisation problem is formulated thereafter for the latter patient resulting in the normal cell population incrementing enough to allow for normal bone marrow tissue recovery prior to the next chemotherapy cycle to further decrease AML cells. Model analysis results reveal the potential future applicability of the proposed tool and indicate the need for an interdisciplinary approach between clinicians, experimental- and model-based experts to collaborate in enabling personalised schedules for chemotherapy delivery in cancers such as AML. Download : Download full-size image Fig. 1 . Framework for the design of optimal personalised chemotherapy protocols.

Prognostic value of metabolic tumor volume on PET / CT in primary gastrointestinal diffuse large B cell lymphoma

Primary gastrointestinal (PGI) diffuse large B cell lymphoma (DLBCL) is a relatively common disease. Recent studies indicate that measurement of maximum standardized uptake value (SUV(max)) on pretreatment for (18)F-fluorodeoxyglucose PET is an important prognostic factor in PGI DLBCL. However, there is still an association between initial tumor burden and prognosis. Thus, in the present study, we investigated whether tumor volume by PET could have a potential prognostic value to predict the outcome. From 2006 to 2009, 165 Stage I E/II E PGI DLBCL patients were enrolled in the study. One hundred and five patients received cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP) only, whereas 60 patients underwent surgery plus R-CHOP. Metabolic tumor volume (MTV) was defined initial tumor burden as target GI lesion above SUV, 2.5 by PET as a contouring border. Over a median follow-up period of 36.6 months, receiver operating characteristic (ROC) analysis indicated that the best cut-off values for MTV and SUV(max) were 160.1 cm(3) and 12.0, respectively. The estimated area under the ROC curve was higher for MTV than SUV(max). Thus, MTV was a better predictor for survival than SUV(max). In patients with a low MTV (<160.1 cm(3)), there were no significant differences in survival between patients undergoing R-CHOP alone and surgery plus R-CHOP (P = 0.347 for progression-free survival [PFS]; P = 0.148 for overall survival [OS]). Conversely, in patients with a high MTV (>160.1 cm(3)), survival was longer in those who underwent surgery plus R-CHOP than in those treated with R-CHOP alone (P < 0.001 for PFS; P < 0.001 for OS). Multivariate analysis revealed that high MTV is an independent factor for predicting survival. Even in the era of rituximab, treatment of PGI DLBCL is not easy in patients with a high MTV.

Metabolic Tumor Volume Has Potential Clinical Impact Compared with SUVmax in Primary Gastrointestinal Diffuse Large B Cell lymphoma

Abstract 4983 Background:Primary gastrointestinal (GI) lymphoma is the most commonly involved extranodal site and represents 10–15% of all Non-Hodgkin’s Lymphoma cases. Recent studies showed that the prognostic value of early 18F-FDG PET using maximum standardized uptake volume (SUVmax) on pretreatment was important prognostic factor in primary GI diffuse large B cell lymphoma (DLBCL). However, initial tumor burden is still an important subject associated with prognosis even extranodal DLBCL. The purpose of this study was to assess the prognostic impact of metabolic tumor volume (MTV) as tumor burden using by PET scan technique compared with initial SUVmax in primary GI DLBCL. Patients and methods:From April, 2006 to July, 2009, 125 stage IE (58 patients) or IIE (67 patients) primary GI DLBCL patients with localized lymph node involvement were enrolled and assigned to 6 or 8 cycles of R-CHOP therapy. Median follow-up was 36 months. Median age was 62 years (range, 20–79 years). Seventy-four patients were male and remainders were female. Numbers of patients above 60 years were 71. Twenty-five patients had an Eastern Cooperative Oncology Group performance status of more than two. Calculatory system by computer automatically delineated a extranodal target lesions above SUV, 2.5 and MTV of GI lesion was 3-dimensional reconstructed by fusion software. The SUVmax was collected from predominant GI lesion and calculated based on the attenuation-corrected images, the amount of injected 18F-FDG and body weight. Results:The extranodal sites of GI tract were included stomach and duodenum (64 patients, 51.2%), jejunum (10 patients, 8%), terminal ileum (30 patients, 24%), cecum (7 patients, 5.6%), ascending colon (8 patients, 6.4%), transverse colon (3 patients, 2.4%) and decending colon (3 patients, 2.4%). We used ROC curve analysis. 158.3cm3 was decided as best ideal cut-off value of MTV and 15.5 was decided as the cut-off value of SUVmax. Several factors (age, sex, disease status and IPI score) between high MTV (≥158.3cm3) and low MTV group (<158.3cm3) were not significantly different. However, SUVmax higher in high MTV group than low MTV group (p<0.001). In response by revised International Workshop Criteria, low MTV group had excellent response rates than high MTV group (CR, p<0.001; PR, p=0.014; SD & PD, p<0.001). Moreover, 3-year PFS was higher in low MTV group than high MTV group (low MTV group, 96.7%; high MTV group, 37.1%; p<0.001) and 3-year OS was also higher in low MTV group than high MTV group (low MTV group, 97.8%; high MTV group, 42.9%; p<0.001). The PFS and OS were higher in low SUVmax group (<15.5) than high SUVmax group (≥15.5) (p<0.001, p<0.001, respectively). In univariate analysis, high IPI score is still important prognostic factor for PFS and OS (PFS: HR, 4.181 [1.844-9.478] p=0.001 & OS: HR, 4.300 [1.801-10.263] p=0.001). High MTV and high SUVmax were also poor prognostic factors for PFS and OS (high MTV; PFS: HR, 26.543 [7.923-88.231] p<0.001 & OS: HR, 32.458 [7.579-139.018] p<0.001) (high SUVmax; PFS: HR, 6.998 [2.399-20.418] p<0.001 & OS: HR, 13.976 [3.257-59.979] p<0.001). In multivariate analysis, high MTV group (PFS: HR, 19.850 [5.193-75.870] p<0.001 & OS: HR, 17.918 [3.694-86.904] p<0.001) and high IPI score (PFS: HR, 2.659 [1.136-6.223] p=0.024 & OS: HR, 2.866 [1.175-6.989] p=0.021) were independent prognostic factors for PFS and OS. However, SUVmax had not significant value for survival. Conclusion:In primary GI DLBCL, high MTV is very important and potential prognostic factor compared with SUVmax for predicting the survival. Therefore, more aggressive treatment strategy would be performed in primary GI DLBCL patients having initial high tumor burden. Disclosures:No relevant conflicts of interest to declare.

Chemoresistance As a Function of the Pretherapy Tumor Burden and the Chemotherapy Regimen Administered: Differences Observed With 2 Current Chemotherapy Regimens for Advanced Hodgkin Lymphoma

The mature results from trials comparing ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, dacarbazine) and BEACOPP (bleomycin, etoposide, Adriamycin [doxorubicin], cyclophosphamide, Oncovin [vincristine], procarbazine, prednisone) chemotherapies in advanced Hodgkin lymphoma will be available in some years. An early comparison of their curative potential can however be obtained from an assessment of initial tumor burden and chemoresistance. Less than a complete remission after treatment and relapse occurring within 12 months thereafter were assumed to be clinical expressions of chemoresistance. The tumor burden was calculated from the measurements of all the lesions documented by staging computed tomography (CT) and was normalized to body surface area to give the relative tumor burden (rTB). Using logistic regression analysis, the relationship between initial rTB, chemoresistance, and chemotherapy regimen administered was retrospectively studied in 222 patients selected from those enrolled in 2 similar randomized trials. The median rTB volumes were 157.9 cm(3)/m(2) in the 115 patients treated with ABVD vs. 154.6 cm(3)/m(2) in the 107 patients treated with BEACOPP, and the distribution of the volumes was identical in the 2 groups. The rTB was confirmed as the best predictor of early treatment failures (22 less than complete responses plus 21 early relapses). For the same rTB, the risk of chemoresistance to BEACOPP was about half that of the chemoresistance to ABVD or, for a given risk of chemoresistance, BEACOPP cured patients with an rTB 89.1 cm(3)/m(2) greater than that cured by ABVD (ie, more than 50% of the median tumor load of patients with advanced-stage disease). This account of rTB allows an early comparative evaluation of the curative ability of different chemotherapy regimens.

Treatment of Elderly Patients with Acute Myeloid Leukemia Adjusted to Age, Performance Status, Organ Function and the Presence of Co-Morbidities. Final Results of the Polish Adult Leukemia Group (PALG) 1/2005 Study.

AbstractAbstract 1067Elderly patients with acute myeloid leukemia are heterogenous group with poor outcome. All age, biological status and co-morbidities limit applicability of intensive chemotherapy. The PALG elaborated original system allowing stratification of patients aged >60 years to three groups with different therapeutic approach. Altogether 537 patients with newly diagnosed AML and median age 70 years (range 60–93) were classified as 1) ‘fit’ (n=163): age 60–79y, ECOG 0–2, proper liver and kidney function, without comorbidities, 2) ‘unfit’ (n=210): age >60 years, ECOG 0–2, normal liver and kidney function, comorbidities allowed, 3) ‘frail’ (n=164): ECOG 3–4. According to PALG 1/2005 protocol ‘fit’ patients were treated similarly as younger adults with daunorubicin (DNR, 3 days) + cytarabine (AraC, 7 days) +/− cladribine, followed by DNR + AraC consolidation and maintenance. ‘Unfit’ patients received either two courses of AraC+DNR (2+5) or AraC (5 days) + thioguanine + methotrexate, followed by manitenance. ‘Frail’ patients were considered for palliative cytoreduction and supportive care. Results:Complete remission (CR) rate was 35% for ‘fit’, 22% for ‘unfit’ and 0% for ‘frail’ patients. Median survival in the respective groups equaled 39 weeks, 26 w., and 14 w., while the probability of survival at 1 year was 39%, 27% and 10%. The rate of early (up to 8 weeks) mortality was 31%, 24% and 31%, respectively. In the Cox model the only factor independently affecting the risk of overall mortality in both ‘fit’ and x'unfit' group was serum LDH above upper quartile (HR=2, p=0.005 for ‘fit’, HR=1.65, p=0.006 for 'unfit'). Among 'frail' patients the risk of mortality was increased in patients with performance status ECOG>2 (HR=1.85, p=0.0008), initial WBC >8.5×10e9/L (HR=1.65, p=0.006), and bone marrow blasts >58% (HR=1.8, p=0.001).We conclude that the proposed stratification system is feasible for elderly AML patients and represets a model for further developments of individualized therapeutic approaches. Survival of patients in whom remission induction therapy may be applied depends on initial tumor burden as reflected by high serum LDH level. The outcome of patients referred for palliative treatment depends additionally on initial performance status. In contrast, neither age nor karyotype were found to independently affect outcome in this study. Disclosures:No relevant conflicts of interest to declare.

Patterns of Referral and Resection Among Patients with Liver-Only Metastatic Colorectal Cancer (MCRC)

Rates of metastatectomy vary among patients with liver-only metastatic colorectal cancer (MCRC). This study describe predictors of referral to a hepatobiliary surgeon (HBS) and hepatic resection in a population-based setting. Patients referred to the British Columbia Cancer Agency (BCCA) with synchronous or relapsed MCRC isolated to the liver in 2002-2004 were identified. Classification of tumor burden as "high" or "low" was based on prognostic features defined by LiverMetSurvery registry. Metastases larger than 5 cm, bilobar, or more than 3 metastases were classified as high tumor burden. Multivariate logistic regression models were used to identify predictors of HBS referral and subsequent metastatectomy. Overall survival was calculated by the Kaplan-Meier method. Of 618 patients with isolated hepatic metastasis, 148 (24%) were referred to a HBS and 99 (16%) underwent resection. Advanced age was the most common reason for not referring 64 patients (10%) with ECOG performance status 0/1 and low tumor burden. In multivariate analysis, variables associated with referral were younger age (P < .001), ECOG performance status 0/1 (P < .002), chemotherapy for metastatic disease (P = .007), 1-3 metastasis (P < .001), and unilobar disease (P < .001). Median patient survival was 0.99 years (95% confidence interval [95% CI], 0.89-1.10 years) among nonreferred, 1.83 years (95% CI, 1.37-2.31 years) if referred but not resected, and 3.85 years (95% CI, 2.90-4.80 years) if resected. A significant proportion of patients are not referred to a HBS because of advanced chronological age. Resection of hepatic metastases was associated with improved overall survival irrespective of initial tumor burden.