Tumor Volume Doubling Time Research Articles

Doubling Time of Residual Tumor Volume for Metastatic Neuroendocrine Tumors Determines Survival Outcomes after Hepatic Resection

Introduction: Estimates of the percentage of resectable tumor to guide debulking surgery for metastatic gastro-entero-pancreatic neuroendocrine tumors (GEP-NET) does not account for tumor biology and absolute hepatic tumor burden. Thus, we studied the growth kinetics of residual metastatic disease after debulking surgery for GEP-NET to determine whether these tumor-specific factors correlated with survival. Methods: Patients with measurable residual metastatic disease by imaging after debulking surgery for GEP-NET with or without resection of primary tumors between 2000-2017 were studied. Residual tumor volumes were measured over time to determine tumor growth kinetics. The primary outcome of interest was time from debulking surgery to adjuvant therapy or death. Results: Twenty-eight patients had residual metastatic GEP-NET and half had an estimated ≥90% debulking resection. Median residual tumor volume (Y0) after debulking surgery was 3.0 (IQR 0.45-20.8) ml. Median tumor volume doubling time was 53.9 (IQR 29-159.2) weeks. Grade of tumor differentiation, Ki-67 index, and estimated percentage of debulking were not associated with outcomes. Multi-variate analysis showed that, after adjusting for Y0 and the use of somatostatin-analogues post-operatively, only tumor volume doubling time ≥52 weeks was associated with the time to adjuvant therapy or death (HR 0.17 95%CI 0.04-0.82). Patients with a tumor doubling time ≥52 weeks had improved overall survival at 1, 3, and 5 years when compared to a doubling time < 52 weeks (100.0%, 90.9%, 90.9% vs 92.3%, 68.4%, 68.4%; p=0.034). Conclusions: Tumor volume doubling time, not the proportion of debulking performed, determines outcomes after debulking surgery for residual metastatic GEP-NET.

Mammographic sensitivity as a function of tumor size: A novel estimation based on population-based screening data

BackgroundInstead of a single value for mammographic sensitivity, a sensitivity function based on tumor size more realistically reflects mammography’s detection capability. Because previous models may have overestimated size-specific sensitivity, we aimed to provide a novel approach to improve sensitivity estimation as a function of tumor size. MethodsUsing aggregated data on interval and screen-detected cancers, observed tumor sizes were back-calculated to the time of screening using an exponential tumor growth model and a follow-up time of 4 years. From the observed number of detected cancers and an estimation of the number of false-negative cancers, a model for the sensitivity as a function of tumor size was determined. A univariate sensitivity analysis was conducted by varying follow-up time and tumor volume doubling time (TVDT). A systematic review was conducted for external validation of the sensitivity model. ResultsAggregated data of 22,915 screen-detected and 10,670 interval breast cancers from the Dutch screening program were used. The model showed that sensitivity increased from 0 to 85% for tumor sizes from 2 to 20 mm. When TVDT was set at the upper and lower limits of the confidence interval, sensitivity for a 20-mm tumor was 74% and 93%, respectively. The estimated sensitivity gave comparable estimates to those from two of three studies identified by our systematic review. ConclusionDerived from aggregated breast screening outcomes data, our model’s estimation of sensitivity as a function of tumor size may provide a better representation of data observed in screening programs than other models.

PET standardized uptake values of primary lung cancer for comparison with tumor volume doubling times

ObjectiveTo determine the relationship between two documented indicators of tumor aggressiveness, SUV and volume doubling time (VDT) for stage I non-small cell lung cancer (NSCLC). Methods116 pathology proven solid NSCLC patients with 2 pretreatment CT and 1 PET/CT scan were retrospectively identified. The 2 CT scans were at least 85 days apart. SUV values were collected from PET/CT reports and CT derived VDT's were calculated assuming an exponential growth rate. Corrected SUV values were also obtained for all cases. Median VDT, SUV and corrected SUV values were reported according to cancer histology. Relationships between VDT, SUV and corrected SUV were examined. Results91 Adenocarcinomas and 25 squamous-cell carcinomas had median VDT values of 150.6 and 110.0 days respectively. Median SUV values were 5.1 and 12.3 for adenocarcinoma and squamous-cell carcinoma, respectively (p = 0.0003); median corrected SUV values were 16.8 and 31.7 respectively (p = 0.003). A statistically significant monotonic relationship was observed between increased SUV uptake and faster VDT (p = 0.05) and corrected SUV and VDT (P = 0.0002). When stratified by cancer histology, the relationship between VDT and either SUV or corrected SUV was statistically significant for adenocarcinomas (p = 0.02 and p = 0.0001, respectively), but not for squamous-cell carcinoma (p = 0.85 and p = 0.37, respectively). ConclusionWe demonstrated an overall significant relationship between VDT, SUV and corrected SUV. The relationship, however, was stronger for adenocarcinomas than for squamous-cell carcinomas. This implies that the primary determinant for these relationships is histology and within each cell type, there are other factors that have strong influences.

Extraordinarily long-inactive solitary fibrous tumor transformed to produce big insulin-like growth factor-2, leading to hypoglycemia and rapid liposarcoma growth: a case report

BackgroundA high-molecular-weight form of insulin-like growth factor-2 (IGF-2), known as “big” IGF-2, is occasionally produced by various tumor types, leading to hypoglycemia. Although solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm, it has been estimated that 4–6% of SFT patients develop hypoglycemia due to circulating big IGF-2. The mean time elapsed from tumor detection until the onset of hypoglycemia is reportedly less than one year (8.5 ± 1.9 months).Case presentationA 68-year-old man was hospitalized for exacerbation of recurring hypoglycemic episodes. He had been diagnosed with an SFT 17 years before the onset of hypoglycemia, and the SFT had already been very large at that time. The tumor, which was non-resectable and refractory to chemotherapies, had slowly increased in size since the initial diagnosis. Half a year before the hypoglycemic episodes manifested, another tumor, adjacent to the left kidney, was newly identified. Fluorodeoxyglucose positron emission tomography-computed tomography scanning, revealed the left peri-renal tumor to show much higher fluorodeoxyglucose uptake than the preexisting SFT, suggesting that it was unlikely to be a metastasis from the SFT. Abundant serum big IGF-2 was detected by western immunoblot analysis, indicating it to be the cause of the hypoglycemia. Since the 17 years between SFT detection and the onset of IGF-2-induced hypoglycemia was an extremely long period as compared with those in previous reports, we initially suspected that the new, peri-renal tumor had produced big IGF-2, but transcatheter arterial embolization of its feeding arteries did not suppress hypoglycemia. Notably, by measuring the tumor volume doubling time, the peri-renal tumor growth was shown to be markedly accelerated in parallel with exacerbation of the hypoglycemia. The patient died of heart failure 21 months after the onset of hypoglycemia. Unexpectedly, autopsy revealed that big IGF-2 had been produced only by the preexisting SFT, not the peri-renal tumor, and that the peri-renal tumor was a dedifferentiated liposarcoma.ConclusionsWe should keep in mind that even a long-inactive SFT can undergo transformation to produce big IGF-2, which then acts on both insulin and IGF-1 receptors, possibly leading to both hypoglycemia and the development/growth of another tumor, respectively.

Impact of delays in radiotherapy of head and neck cancer on outcome

BackgroundIn head and neck cancer (HNC), the relationship between a delay in starting radiotherapy (RT) and the outcome is unclear. The aim of the present study was to determine the impact of the amount of time before treatment intervention (TTI) and the growth kinetics of individual tumors on treatment outcomes and survival.MethodsTwo hundred sixty-two HNC patients with 273 primary tumors, treated with definitive (chemo) RT, were retrospectively analyzed. The TTI was defined as the time interval between the date of histopathologic diagnosis and the first day of the RT course. Volumetric data on 57 tumors were obtained from diagnostic and RT planning computer tomography (CT) scans in order to calculate the tumor growth kinetic parameters.ResultsNo significant association between locoregional control or cause-specific hazards and TTI was found. The log hazard for locoregional recurrence linearly increased during the first 40 days of waiting for RT, although this was not significant. The median tumor volume relative increase rate and tumor volume doubling time was 3.2%/day and 19 days, respectively, and neither had any impact on locoregional control or cause-specific hazards.ConclusionThe association between a delay in starting RT and the outcome is complex and does not harm all patients waiting for RT. Further research into imaging-derived kinetic data on individual tumors is warranted in order to identify patients at an increased risk of adverse outcomes due to a delay in starting RT.

A Mathematical Model to Predict Diagnostic Periods for Secondary Distant Metastases in Patients with ER/PR/HER2/Ki-67 Subtypes of Breast Cancer

Previously, a consolidated mathematical model of primary tumor (PT) growth and secondary distant metastasis (sdMTS) growth in breast cancer (BC) (CoMPaS) was presented. The aim was to detect the diagnostic periods for visible sdMTS via CoMPaS in patients with different subtypes ER/PR/HER2/Ki-67 (Estrogen Receptor/Progesterone Receptor/Human Epidermal growth factor Receptor 2/Ki-67 marker) of breast cancer. CoMPaS is based on an exponential growth model and complementing formulas, and the model corresponds to the tumor-node-metastasis (TNM) staging system and BC subtypes (ER/PR/HER2/Ki-67). The CoMPaS model reflects (1) the subtypes of BC, such as ER/PR/HER2/Ki-67, and (2) the growth processes of the PT and sdMTSs in BC patients without or with lymph node metastases (MTSs) in accordance with the eighth edition American Joint Committee on Cancer prognostic staging system for breast cancer. CoMPaS correctly describes the growth of the PT in the ER/PR/HER2/Ki-67 subtypes of BC patients and helps to calculate the different diagnostic periods, depending on the tumor volume doubling time of sdMTS, when sdMTSs might appear. CoMPaS and the corresponding software tool can help (1) to start the early treatment of small sdMTSs in BC patients with different tumor subtypes (ER/PR/HER2/Ki-67), and (2) to consider the patient almost healthy if sdMTSs do not appear during the different diagnostic periods.

Abstract 19: Examination of HJC0152, a putative modulator of glucose and energy metabolism, for mammary cancer prevention

Abstract Breast cancer (BC) is the most common cancer in women in the US. Approximately 30-40% of BC cases are estrogen-receptor (ER)-negative (ENBC); the majority of these are triple-negative (TNBC). No drugs have been shown to effectively prevent ENBC including TNBC. TNBC incidence is higher in young African American and Hispanic/Latina women, thus the need for preventive agents for TNBC is critical. Developing agents targeting non-ER-based oncogenic pathways will therefore offer alternative and potentially more effective approaches for preventing ENBC/TNBC. Glucose metabolism is an essential energy-producing process for normal cells and is aberrant and reprogrammed in cancer cells including BC cells. We recently developed HJC0152, a novel small-molecule glucose metabolism modulator as a potential cancer preventive agent. HJC0152 has been shown to inhibit glycolysis by differentially regulating glycolytic enzyme expression and the function of mitochondrial respiratory complexes in both EPBC and TNBC cells, leading to reduced production of energy molecule adenosine-triphosphate (ATP), induced apoptosis, and decreased proliferation and tumor progression. In this study, we determined the preventive anti-cancer efficacies of long-term and short-term (inhibition of premalignant lesions) HJC0152 administration in mouse models of ENBC and TNBC. HJC0152 was given orally 6 days/wk for 2-10 months in well-established ENBC model, MMTV-erbB2; and TNBC model, C3(1)/TAgSV40. HJC0152 at 50 and 75 mg/Kg doses delayed and partially prevented mammary tumor development in ENBC (MMTV-erbB2) mice (p=0.0034 for all groups). A maximum 6-week delay was achieved for median time to tumor formation (TTF). In the TNBC (C3(1)/TAgSV40) model, HJC0152 significantly delayed mammary tumor development (p=0.0114 for all groups) and achieved 3.3-week delay for median TTF. Up to 21% less mice developed mammary tumors in both models. In addition, TNBC mice developed less number of tumors per mouse than in ENBC mice, and the tumor volume doubling time increased from 6.9 to 9.2 days. In the short-term premalignant lesion study, the number of mammary intraepithelial neoplasia (MIN) lesion (representing human DCIS) was significantly decreased (p=0.034) in the HJC0152-treated MMTV-erbB2 mice. In the HJC0152-treated C3(1)/TAgSV40 mice, the number of hyperplasia and MIN lesions were significantly decreased (p=0.0014 and 0.0203, respectively). These results demonstrate that HJC0152 suppresses mammary tumor development in ENBC and TNBC models via reducing premalignant lesions, even in the most aggressive TNBC model, C3(1)/TAgSV40. There were no significant side effects or toxicity signs observed in both long- and short-term prevention experiments. We conclude that HJC0152 has promising cancer preventive efficacy by targeting non-ER-based signaling pathways such as STAT3 signaling and glucose metabolism. This study was supported by a NIH/NCI PREVENT Program fund. *Current Affiliation: LSUHSC. Citation Format: Hyejin Kim, Xi Liu, Yefei Wen, Jia Zhou, Romaine Fernando, Shizuko Sei, Powel H. Brown, Qiang Shen. Examination of HJC0152, a putative modulator of glucose and energy metabolism, for mammary cancer prevention [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 19.

Hepatocellular carcinoma tumour volume doubling time: a systematic review and meta-analysis

BackgroundTumour growth patterns have important implications for surveillance intervals, prognostication and treatment decisions but have not been well described for hepatocellular carcinoma (HCC). The aim of our study was to...

The natural history of untreated estrogen receptor-positive, Her2-negative invasive breast cancer.

Using prior mammograms from patients with delays in their breast cancer diagnoses, we sought to describe in-vivo growth kinetics of untreated breast cancer to determine if the time they became clinically apparent can be predicted. Patient and tumor characteristics were collected from those who presented with "missed," untreated breast cancer to a breast center in a single institution. Only patients whose biopsied masses revealed estrogen receptor-positive, Her2-negative (ER+/Her2-) invasive cancers were included. Two attending radiologists reviewed images from prior mammograms. Rates of change in volume were calculated in mm3/day, and a logarithmic equation was used to calculate tumor volume doubling time (TVDT). A Spearman's Rho correlation was performed for the continuous variables, and the Mann-Whitney U and Kruskal-Wallis tests were used to compare categorical data. A p value < 0.05 was considered statistically significant. Logistic regression was performed to determine if patient or tumor characteristics were correlated to tumor growth velocity. Of the 36 ER+/Her2- invasive breast cancers included in the analysis, 13 (36%) were at least cT2 (of TNM), 7 (19%) were grade 3, and 7 (19%) were node positive at diagnosis. Grade (p = 0.043) and pathologic invasive tumor size (p = 0.001) were positively correlated to tumor growth velocity. Median TVDT was 385days (23-1897). Age, nodal positivity, Oncotype Dx® Recurrence Score, time of diagnostic delay, and spheroid-ellipsoid discrepancy (SED) were not related to tumor growth velocity in this sample. In this cohort of patients with untreated ER+/Her2- invasive breast cancers, grade and pathologic tumor size were found to be positively correlated to growth velocity. The growth rates in a homogeneous group of tumors varied widely and could not be predicted. One possible explanation for this finding is that other difficult-to-measure biologic factors such as tumor microenvironment may play a greater role in tumor progression than traditional clinicopathologic characteristics.

Structural Doubling Time Predicts Overall Survival in Patients with Medullary Thyroid Cancer in Patients with Rapidly Progressive Metastatic Medullary Thyroid Cancer Treated with Molecular Targeted Therapies.

Purpose: To evaluate the impact of structural disease progression of metastatic lesions after initial surgery on overall survival (OS) of patients presenting with metastatic medullary thyroid cancer (MTC). We used tumor volume doubling time (TVDT) as a marker of structural disease progression and aimed to correlate the average structural tumor volume doubling time (midDT) with OS in MTC patients after initial surgery. Methods: In this retrospective study, we examined the clinical characteristics; average tumor volume doubling times of neck, lung, and liver metastasis; and disease-specific survival of patients with metastatic MTC. Results: Tumor growth is constant in MTC metastasis, irrespective of location of the metastasis. The median correlation coefficient (r) and the coefficient of determination (r2) were similar in lung metastasis (r = 0.91, r2 = 0.95) and liver metastasis (r = 0.88, r2 = 0.94), and comparable in neck metastasis (r = 0.73, r2 = 0.85). Patients with metastatic MTC with a midDT ≤1 year have a worse prognosis than those with higher midDT (p = 0.002). Those with midDT ≤1 year had a median OS of 11.1 years [confidence interval (CI) 7.4-14.8 years]. In contrast, patients with midDT 1-3 years had a median OS of 16.5 years [CI 10.3-22.6 years]. All patients with midDT ≥3 survived by the end of the follow-up period. Preliminary results suggest that measurement of midDT can predict response to molecular targeted therapies. Conclusions: In conclusion, TVDT is a strong predictor of OS in patients with recurrent or metastatic MTC, can be used as a marker of progression, and potentially can help select patients who may benefit from molecular targeted therapy.

Radiological audit of interval breast cancers: Estimation of tumour growth rates

IntroductionThis multicentre, retrospective study aimed to establish correlation between estimated tumour volume doubling times (TVDT) from a series of interval breast cancers with their clinicopathological features. The potential impact of delayed diagnosis on prognosis was also explored. Materials and methodsInterval cancers, where screening mammograms demonstrated changes that were retrospectively classified as either uncertain or suspicious, were reviewed from five screening units within the UK NHS Breast Screening Programme (NHSBSP). Data collected included the time interval between screening mammogram and cancer diagnosis, the size of the initial mammographic abnormality and of the subsequent cancer, demographics, mammographic density and tumour biology. We estimated volume doubling times and the estimated change in size and node status, which would have followed if these cancers had been detected at the previous screen. Results306 interval cancers meeting the inclusion criteria were identified. Average time from screening to diagnosis was 644 days (SD 276 days). 19% were diagnosed in the first twelve months, 42% in the subsequent twelve months and 39% thereafter. Overall average estimated TVDT was 167 days (95% CI 151–186). Significant differences were noted with age (p = 0.01), grade (p < 0.001) and ER status (p < 0.001) with women under 60, grade 3 cancers and ER negative cancers having shorter TVDTs. HER2 positive tumours had shorter doubling times than HER2 negative, but this difference was not statistically significant. It was estimated that diagnosing these cancers at the previous screen would have increased ten-year survival from 82% to 86%. ConclusionHigh grade, ER negativity and younger age were associated with shorter durations of TVDT. The role of HER2 status on interval cancer growth rate requires further assessment. It is likely that the delayed diagnosis of interval cancers confers a 4% reduction in ten-year survival.

Hopf bifurcation analysis of a tumor virotherapy model with two time delays

Oncolytic virotherapy is gradually applied in clinical trial, which provides a new potential approach to cancer treatment. Tumor volume doubling time (TVDT) is so short that the infection delay caused by oncolytic virus should be considered in the modeling of virotherapy. A DDE model is constructed by adding two infection delays based on an ODE model that describes the dynamics of cancer cells, tumor cells, immune cells and oncolytic viruses. According to the different values of two delays, three cases of the model are discussed to investigate the stability and bifurcation of both the virus-free equilibrium and the positive equilibrium. Finally, some numerical simulations are performed to verify the obtained theoretical conclusions based on clinical trial data.

Estimating the Growth Rate of Lung Metastases in Differentiated Thyroid Carcinoma: Response Evaluation Criteria in Solid Tumors or Doubling Time?

Background: Estimating the growth rate of lung metastases for the treatment of patients with metastases of differentiated thyroid carcinoma (DTC) is important. This study aimed to evaluate survival outcomes according to different criteria for estimating the growth rate of lung metastases. Methods: Patients with macronodular (≥1 cm) lung metastases of DTC who underwent total thyroidectomy and high-dose radioactive iodine therapy between 1995 and 2013 were enrolled. The time to progressive disease (PD) by the Response Evaluation Criteria in Solid Tumors (RECIST), average tumor volume doubling time of the two dominant target lung lesions (midDT), and thyroglobulin doubling time (TgDT) were measured in each patient, and their association with disease-specific survival (DSS) was evaluated. Results: Forty-four patients with target lung metastatic nodules with an initial maximal diameter of 1.3 cm (median) were followed-up for a median of 6.8 years after the diagnosis of lung metastases. Based on RECIST, 12 patients (27.3%) showed fast tumor progression, with time to PD <1 year. When assessed by midDT, nine patients (20.5%) had midDT ≤1 year, showing rapid tumor progression. Seven of 33 patients (21.2%) who were negative for thyroglobulin antibody had midDT <1 year. Growth rates assessed by all three criteria were significantly associated with DSS. However, midDT had the highest predictive value for DSS, with a proportion of variation explained of 33.6%. Five-year DSS was 29.6% in patients with midDT ≤1 year, 50.0% in patients with time to PD <1 year, and 42.9% in patients with TgDT <1 year. Conclusions: Among the different criteria for estimating the growth rate of metastases in patients with lung metastases of DTC, midDT was the most powerful for predicting DSS, in comparison with RECIST and TgDT. Performing at least three serial chest computed tomography scans during the first year from the diagnosis of lung metastases can facilitate early detection of patients with rapid tumor progression and provide objective guidance for initiation of systemic therapy.

225Ac-labeled Girentuximab for Targeted Alpha Therapy of CAIX-expressing Renal Cell Cancer Xenografts

Despite progress in the treatment of clear cell renal cell carcinoma (ccRCC), the prognosis of patients with metastasized disease remains poor. Therefore, novel treatment options need to be developed. A rapidly advancing field of interest is targeted radionuclide therapy using α-emitting radionuclides, such as actinium-225 (225Ac). Carbonic anhydrase IX (CAIX) is over expressed in ccRCC and can be targeted effectively using the monoclonal antibody girentuximab. The aim of this preclinical study was to investigate the in vivo tumor targeting properties of 255Ac-labeled girentuximab, and assess the therapeutic efficacy and toxicity in mice. Girentuximab was conjugated with DOTA and labeled with 225Ac and its binding to CAIX-expressing SK-RC-52 cells was determined in vitro. Immunodeficient mice bearing subcutaneous SK-RC-52 xenografts were injected intravenously with 30 ug [225Ac]AcDOTA-girentuximab (50 kBq). The biodistribution of [225Ac]Ac-DOTA-girentuximab was determined at 24, 72 and 168 hours post injection (p.i.). Subsequently, therapeutic efficacy was evaluated for different doses (3.7, 9.3 and 18.5 kBq) by measuring tumor growth using caliper measurements up to 4 weeks p.i. Toxicity was monitored by measuring body weight. Furthermore, non-tumor bearing mice were used to analyze nephrotoxicity by immunohistochemistry and [99mTc]Tc-DMSA renal imaging, and blood samples were collected to assess hematotoxicity. Labeling efficiency exceeded 96% and [225Ac]Ac-DOTA-girentuximab demonstrated specific binding to CAIX-expressing SK-RC-52 cells in vitro. In vivo, maximum tumor uptake was reached at 168 hours; 124.2 ± 28.8 %ID/g, while the corresponding blood level was 4.0 ± 2.2 %ID/g. The tumor to blood ratio was 35.5 ± 9.3 at 168 hours p.i. compared to 11.2 ± 3.1 at 72 hours p.i. Mean tumor volume doubling times were 22 ± 11, 33 ± 24 and 31 ± 20 days for 3.7, 9.3 and 18.5 kBq for treated groups respectively, compared to 17 ± 5 days for the control group. Tumor-bearing mice showed no weight loss after treatment. Assessment of nephro- and hematotoxicity is still ongoing. Girentuximab can be efficiently labeled with actinium-225 and shows excellent tumor targeting. First data indicate that [225Ac]Ac-girentuximab may lead to tumor growth delay without short-term toxicity. However, future experiments in larger groups of animals should be performed to confirm these results and to monitor long term nephro- and hematotoxicity.

Prognostic impact of solid-part tumour volume doubling time in patients with radiological part-solid or solid lung cancer.

The measurement of part-solid and whole tumour sizes in patients with non-small-cell lung cancer (NSCLC) using computed tomography (CT) has been widely accepted for assessing clinical outcomes. Although the volume doubling time (VDT) of a tumour is useful for distinguishing high-risk nodules from low-risk ones, it remains to be clarified whether separate calculation of whole-tumour VDT and solid-part tumour VDT (SVDT) greatly affects the survival rate of patients with radiologically node-negative part-solid or solid NSCLC. The study included 258 patients with NSCLC who had radiologically node-negative, part-solid or solid tumours and who had at least 2 preoperative CT scans taken more than 30 days apart followed by radical lobectomy and systemic lymph node dissection between January 2012 and December 2015. Univariable and multivariable analyses of recurrence-free survival were performed using the Cox proportional hazards regression model. The mean whole-tumour VDT and SVDT were 375 and 458 days, respectively. Multivariable analyses demonstrated that whole-tumour VDT (P = 0.003), SVDT (P < 0.001), solid-part tumour size, whole-tumour size and comorbidities significantly affected the recurrence-free survival. Using the receiver operating characteristic curve, the cut-off value of the SVDT for recurrence was 215 days, and the 5-year recurrence-free survival rates for patients with SVDT >215 days and those with SVDT <215 days were 85.7% and 43.0%, respectively (P < 0.001). The calculation of SVDT in patients with node-negative, part-solid or solid NSCLC is highly useful for predicting postoperative survival outcomes.

Dentification and correction of the lead-time bias and length bias in cancer screening studies

Lead-time bias and length bias were common systematic errors in observational screening studies, which might be a common cause of overstating or distorting the true screening effects. One of key concerns in observational screening studies was how to estimate the screening effects based on the consideration of these two biases. This paper illustrated how to identify and correct the lead-time bias using the tumor volume doubling time and the non-homogeneous Poisson process, and how to correct the length bias using a weighted method. The application conditions of each method were also discussed to present several useful toolboxes to correct the lead-time bias and length bias appropriately and evaluate the effectiveness of the cancer screening program accurately.

Natural Progression and Factors Predicting Growth of Retroperitoneal Schwannoma.

Although knowledge of the natural history of retroperitoneal schwannoma, including growth rate, would be useful when determining the indications and timing of surgical treatment for such nonpalpable tumors, the existing evidence is unclear. We examined the natural history of retroperitoneal schwannoma and assessed whether magnetic resonance imaging (MRI) and clinical findings predict future growth. Among patients with retroperitoneal schwannoma treated in our department during the period from January 1, 2015 through December 31, 2015, eight who underwent follow-up assessment by MRI and did not undergo tumor resection for longer than 1 year were enrolled. Changes in lesion size were examined in relation to selected clinical and MRI findings. In cases of pressure erosion in the vertebral body, change in the size of the intraosseous region was compared to change in the size of the whole lesion. Median absolute growth rate (AGR) was 1.9 cm3 per year, median relative growth rate (RGR) was 5.6% per year, and median tumor volume doubling time (VDT) was 3.1 years. AGR, RGR, and VDT were not associated with any clinical variable. RGR and VDT values in the intraosseous region were about twice those of the whole lesions. The growth rates of retroperitoneal schwannomas varied. Additionally, no MRI or clinical findings predicted growth of retroperitoneal schwannoma. Therefore, careful follow-up is necessary for this tumor type, especially for lesions with bone erosion.

Determining Whether Tumor Volume Doubling Time and Growth Rate Can Predict Malignancy After Delayed Diagnostic Surgery of Follicular Neoplasm.

Background: Tumor volume doubling time (TVDT) is considered as a dynamic indicator of tumor growth and progression. We aimed to clarify whether TVDT should be considered in the cytological diagnosis of follicular neoplasms (FNs). Methods: This retrospective cohort study included 100 consecutive FN patients with a TVDT >1 year for whom surgical resection was delayed for >1 year. Changes in tumor volume and the TVDT of each nodule were calculated by serial neck ultrasonography (US) over a median follow-up of 50 months. Results: Among 100 surgically resected FNs, 58 (58%) were benign and 42 (42%) were malignant tumors. At the 5-year follow-up, most FN nodules showed volume increases of >50%, accounting for 65% of benign and 62% of malignant nodules. No significant difference was observed in tumor growth rates and time to a >50% increase in tumor volume between benign and malignant nodules (p = 0.299 and p = 0.378, respectively). The calculated TVDT and a >50% volumetric increase showed a linear relationship with a high concordance (R2 = 0.883; p < 0.001). The risk of malignancy was not significantly associated with TVDT (relative risk = 1.00; [95% confidence interval 0.99-1.01]; p = 0.784). Even when US features were considered, no significant association was found between TVDT and the risk of malignancy. Conclusions: The size of most FNs increased exponentially with time; the tumor growth rates of benign and malignant nodules were similar. Despite the usefulness of TVDT as an indicator of growing velocity of FN nodules, TVDT could not predict malignancy in FNs. Clinical surveillance based on the growth of thyroid nodules categorized as FNs on serial neck US does not predict the risk of malignancy.

Tumor Volume Doubling Time Is Useful in the Active Surveillance of Papillary Thyroid Microcarcinomas

Tumor Volume Doubling Time Is Useful in the Active Surveillance of Papillary Thyroid Microcarcinomas

Abstract 1928: Radiation response in preclinical orthotopic models of brain cancer

Abstract Glioblastoma (GBM) is a fast-growing, aggressive type of central nervous system tumor that forms on the supportive tissue of the brain. Primary treatment options for patients with GBMs have not changed much in many years, and still include surgery, radiation and/or chemotherapy treatment with temozolomide (TMZ). GBM is an incurable disease where there is a desperate need for continued development of novel therapeutic options. A number of preclinical models exist to support the early work needed to develop these new drugs. Here we describe three different preclinical models of brain cancer, U87MG-Luc, GL261-Luc and BT142. Each model was evaluated following orthotopic implantation into the brain. As radiation therapy remains a steadfast approach to GBM, we evaluated each model for its response to radiation and tracked disease progression and response to treatment with either bioluminescence imaging (BLI) or magnetic resonance imaging (MRI) along with traditional survival (morbidity/mortality) analysis. U87MG-Luc is a human glioblastoma cell line that was developed from an astrocytoma. We found that orthotopic implant of U87MG-luc results in reliable growth with a tumor doubling time of 4 days and a median survival time of 45 days. We tested this model with radiation therapy (2.5Gy for 5 days on, 2 days off, for 2 cycles) and found a 70% partial response rate as measured by BLI. We also tested this model with TMZ therapy (33.3mg/kg; orally every day for 5 days) and found a significant delay in disease progression, resulting in a 93% increase in life span. GL261-Luc is a murine glioblastoma model that grows quite aggressively in the mouse brain. We find a tumor volume doubling time of 2 days and a median survival time of 14 days. As this model grows in a mouse strain with an intact immune system it allowed us to evaluate the tumor infiltrating immune cell populations. While we found a low number of CD45+ cells infiltrating into GL261-Luc tumors, immune population changes over time will be described. In this model we tested increasing doses of radiation and found that a single dose of 15Gy was curative whereas the tumors were more moderately responsive to a single dose of 7.5Gy (30% tumor regressions). We then combined 7.5Gy with the immune checkpoint inhibitor anti-PD-1 and saw an improved outcome with a 100% response rate. BT142 is a human anaplastic oligoastroytoma that is relatively unique due to its isocitrate dehydrogenase (IDH1/2) mutational status which results in an accumulation of the oncometabolite 2-hydroxygluarate (2-HG) in the tumor. This tumor line grows in the NOD SCID mouse strain and we found a tumor doubling time of 5 days, as measured by MRI. The BT142 model has proven to be sensitive to radiation following a single dose of 10Gy but less responsive when lower dosage levels were administered on a fractionated schedule. Thus, a variety of human and mouse GBM models exist to enable further drug discovery and development efforts for this intractable disease. Citation Format: Erin E. Trachet, Sumithra Urs, Alden Wong, Scott Wise, Maryland Rosenfeld Franklin. Radiation response in preclinical orthotopic models of brain cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1928.