Norton-Simon Hypothesis Research Articles

A mathematical justification for metronomic chemotherapy in oncology

We mathematically justify metronomic chemotherapy as the best strategy to apply many cytotoxic drugs in oncology for both curative and palliative approaches, assuming the classical pharmacokinetic model together with the Emax pharmacodynamic and the Norton-Simon hypothesis. From the mathematical point of view, we will consider two mixed-integer nonlinear optimization problems, where the unknowns are the number of the doses and the quantity of each one, adjusting the administration times a posteriori.

ES21.02 Biological Disease Characterization of OMD

Tabled 1Variation in the characterization of OMDTrialOMD characteristicsOMD timingIyengar et al (2017)· ≤6 sites of extracranial disease (including primary) · ≤3 sites in liver or lung ·Up to 2 contiguous vertebral metastases considered a single siteAfter first-line therapy and without progressionGomez et al (2016)· ≤3 metastatic sites · Any N1-3 thoracic nodes considered a single site · Satellite lesions counted as separate sitesAfter first-line therapy and without progressionParikh et al (2014)· ≤5 metastatic sitesAfter first-line therapy and without progressionCheruvu et al (2011)· ≤8 metastatic sitesAt time of initial stagingKhan et al (2006)· 1-2 metastatic sites · Definitive (surgery and/or chemoradiation) treatment of thoracic diseaseAfter treatment of thoracic disease Open table in a new tab Recent years have seen a marked increase in interest in the concept of oligometastatic disease (OMD) in non-small cell lung cancer (NSCLC). Lacking a precise and consistent definition, OMD is generally considered to represent a relatively favorable clinical state, with more indolent biology, a limited number of disease sites, and potential for prolonged periods of disease control. Discussions of oligometastatic NSCLC area inexorably linked with management considerations, specifically the use of local therapies such as surgery and radiation therapy. There are numerous clinical and biological rationales to support such approaches: (1) disease progression most commonly occurs in original sites of gross disease1; (2) metastatic sites may propagate secondary metastases (parallel progression model)2; (3) solid tumors are composed of faster growing (sensitive) and slower growing (resistant) cell populations (Norton-Simon hypothesis)3; (4) resistance depends on spontaneous mutations and therefore increases with time (Goldie-Coldman hypothesis).4 Nevertheless, several questions regarding the characterization and optimal management of OMD remain (Table 1). Up to how many sites of disease constitute an oligometastatic state? Does a “site” of disease comprise a single lesion or neighboring tumors? Does the anatomic site matter? For instance, brain metastases have historically been considered a more favorable location for definitive treatment of OMD, and their emergence may reflect pharmacokinetic failure rather than molecular evolution.5,6 Additionally, there are likely meaningful clinical differences between OMD states depending on whether they are defined at diagnosis (de novo), after initial exposure to systemic therapy (induced), recurrence, or progression. OMD may also have a distinct biologic phenotype. The metastatic cascade includes loss of cellular adhesion, increased motility, primary tumor invasiveness, entry into and survival in the circulation, and entry into and colonization of distant organs.7 Tumor dormancy, regulated in part by interferon signaling, may impact the number, location, and timing of metastases.8 Expression of genes that positively regulate the cell cycle may determine whether cancer growth occurs as polymetastasis versus oligometastasis. Ideally, ongoing and future clinical trials will collect biospecimens for discovery and validation of OMD biomarkers, thereby enabling the identification of cases most likely to benefit from OMD treatment paradigms. 1. Rusthoven KE, Hammerman SF, Kavanagh BD, Birtwhistle MJ, Stares M, Camidge DR. Is there a role for consolidative stereotactic body radiation therapy following first-line systemic therapy for metastatic lung cancer? A patterns-of-failure analysis. Acta Oncol 2009;48:578-83. 2. Klein CA. Parallel progression of primary tumours and metastases. Nat Rev Cancer 2009;9:302-12. 3. Norton L, Simon R. Tumor size, sensitivity to therapy, and design of treatment schedules. Cancer Treat Rep 1977;61:1307-17. 4. Goldie JH, Coldman AJ. A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 1979;63:1727-33. 5. Hu C, Chang EL, Hassenbusch SJ, 3rd, et al. Nonsmall cell lung cancer presenting with synchronous solitary brain metastasis. Cancer 2006;106:1998-2004. 6. Grommes C, Oxnard GR, Kris MG, et al. "Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol 2011;13:1364-9. 7. Gupta GP, Massague J. Cancer metastasis: building a framework. Cell 2006;127:679-95. 8. Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nature reviews Immunology 2006;6:836-48. stereotactic radiation therapy, Oligometastatic, Non-Small Cell Lung Cancer

First person profile: Larry Norton, MD: A world-renowned breast cancer researcher, Dr. Norton has used his passion for music and math to revolutionize oncology.

First person profile: Larry Norton, MD: A world-renowned breast cancer researcher, Dr. Norton has used his passion for music and math to revolutionize oncology.

Nonlinear composite adaptive control of cancer chemotherapy with online identification of uncertain parameters

Abstract A new composite adaptive control strategy is developed for both of the reduction of cancer tumor volume and the online identification of tumor parameters during the drug delivery process in chemotherapy. This control strategy is developed for three different nonlinear mathematical cell-kill models of the cancer tumor including the log-kill hypothesis, Norton-Simon hypothesis and Emax hypothesis. All of these models are considered to have fully parametric uncertainties. The stability, tracking convergence and parameters identification convergence during the chemotherapy process are proved using the Lyapunov method. For the first time, the parameters identification of the uncertain chemotherapy process is investigated for three nonlinear models in addition to the control of tumor volume. The effects of uncertainty amount are studied on the performance of the proposed adaptive controller. Comprehensive results are presented and compared for three cell-kill models. Based on the obtained results, the composite adaptive controller has a robust performance in both of the tumor volume manipulation and the parameters identification in the presence of high uncertainties. It is shown that the identification convergence is achieved even with the existence of 70% uncertainty. Moreover, as the parametric uncertainty increases, very slight variation in the initial tumor volume error (with respect to the desired volume) is occurred.

Nonlinear cancer chemotherapy: Modelling the Norton-Simon hypothesis

A fundamental model of tumor growth in the presence of cytotoxic chemotherapeutic agents is formulated. The model allows to study the role of the Norton-Simon hypothesis in the context of dose-dense chemotherapy. Dose-dense protocols aim at reducing the period between courses of chemotherapy from three weeks to two weeks, in order to avoid tumor regrowth between cycles. We address the conditions under which these protocols might be more or less beneficial in comparison to less dense settings, depending on the sensitivity of the tumor cells to the cytotoxic drugs. The effects of varying other parameters of the protocol, as for example the duration of each continuous drug infusion, are also inspected. We believe that the present model might serve as a foundation for the development of more sophisticated models for cancer chemotherapy.

Optimal control problems for the Gompertz model under the Norton-Simon hypothesis in chemotherapy

We study a collection of problems associated with the optimization of cancer chemotherapy treatments, under the assumptions of Gomperztian-type tumor growth and that the drug killing effect is proportional to the rate of growth for the untreated tumor (Norton-Simon hypothesis). Classical pharmacokinetics and different pharmacodynamics (Skipper and Emax) are considered, together with a toxicity limit or the penalization of the accumulated drug effect. Existence and uniqueness of the optimal control is proved in some cases, while in others the total amount of drug is the unique relevant aspect to take into account and the existence of an infinite number of optimal controls is shown. In all cases, explicit expressions for the solutions are derived in terms of the problem data. Finally, numerical results of illustrative examples and some conclusions are presented.

Chemotherapeutic Dose Scheduling Based on Tumor Growth Rates Provides a Case for Low-Dose Metronomic High-Entropy Therapies.

We extended the classical tumor regression models such as Skipper's laws and the Norton-Simon hypothesis from instantaneous regression rates to the cumulative effect over repeated cycles of chemotherapy. To achieve this end, we used a stochastic Moran process model of tumor cell kinetics coupled with a prisoner's dilemma game-theoretic cell-cell interaction model to design chemotherapeutic strategies tailored to different tumor growth characteristics. Using the Shannon entropy as a novel tool to quantify the success of dosing strategies, we contrasted MTD strategies as compared with low-dose, high-density metronomic strategies (LDM) for tumors with different growth rates. Our results show that LDM strategies outperformed MTD strategies in total tumor cell reduction. This advantage was magnified for fast-growing tumors that thrive on long periods of unhindered growth without chemotherapy drugs present and was not evident after a single cycle of chemotherapy but grew after each subsequent cycle of repeated chemotherapy. The evolutionary growth/regression model introduced in this article agrees well with murine models. Overall, this model supports the concept of designing different chemotherapeutic schedules for tumors with different growth rates and develops quantitative tools to optimize these schedules for maintaining low-volume tumors. Cancer Res; 77(23); 6717-28. ©2017 AACR.

Carfilzomib Induction with Lenalidomide and Clarithromycin Consolidation and Lenalidomide Maintenance (CarBiRD) for Multiple Myeloma (MM)

Carfilzomib Induction with Lenalidomide and Clarithromycin Consolidation and Lenalidomide Maintenance (CarBiRD) for Multiple Myeloma (MM)

The prisoner's dilemma as a cancer model.

Tumor development is an evolutionary process in which a heterogeneous population of cells with different growth capabilities compete for resources in order to gain a proliferative advantage. What are the minimal ingredients needed to recreate some of the emergent features of such a developing complex ecosystem? What is a tumor doing before we can detect it? We outline a mathematical model, driven by a stochastic Moran process, in which cancer cells and healthy cells compete for dominance in the population. Each are assigned payoffs according to a Prisoner's Dilemma evolutionary game where the healthy cells are the cooperators and the cancer cells are the defectors. With point mutational dynamics, heredity, and a fitness landscape controlling birth and death rates, natural selection acts on the cell population and simulated 'cancer-like' features emerge, such as Gompertzian tumor growth driven by heterogeneity, the log-kill law which (linearly) relates therapeutic dose density to the (log) probability of cancer cell survival, and the Norton-Simon hypothesis which (linearly) relates tumor regression rates to tumor growth rates. We highlight the utility, clarity, and power that such models provide, despite (and because of) their simplicity and built-in assumptions.

Constructal approach to cell membranes transport: Amending the 'Norton-Simon' hypothesis for cancer treatment.

To investigate biosystems, we propose a new thermodynamic concept that analyses ion, mass and energy flows across the cell membrane. This paradigm-shifting approach has a wide applicability to medically relevant topics including advancing cancer treatment. To support this claim, we revisit ‘Norton-Simon’ and evolving it from an already important anti-cancer hypothesis to a thermodynamic theorem in medicine. We confirm that an increase in proliferation and a reduction in apoptosis trigger a maximum of ATP consumption by the tumor cell. Moreover, we find that positive, membrane-crossing ions lead to a decrease in the energy used by the tumor, supporting the notion of their growth inhibitory effect while negative ions apparently increase the cancer’s consumption of energy hence reflecting a growth promoting impact. Our results not only represent a thermodynamic proof of the original Norton-Simon hypothesis but, more concretely, they also advance the clinically intriguing and experimentally testable, diagnostic hypothesis that observing an increase in negative ions inside a cell in vitro, and inside a diseased tissue in vivo, may indicate growth or recurrence of a tumor. We conclude with providing theoretical evidence that applying electromagnetic field therapy early on in the treatment cycle may maximize its anti-cancer efficacy.

Dose-Dense Approaches to Ovarian Cancer Treatment

Currently, paclitaxel and carboplatin are administered every 3 weeks as the standard agents for the first-line treatment of advanced ovarian cancer. The concept of "dose-dense therapy" is based on the Norton-Simon hypothesis that a shorter interval between the doses of cytotoxic agents is more effective in reducing tumor burden than dose escalation. The results of phase III clinical trials demonstrating the superiority of weekly paclitaxel administration, compared with a 3-week schedule in breast cancer in both the metastatic and adjuvant settings support the hypothesis. The Japanese Gynecologic Oncology Group reported the results from a phase III study comparing the conventional paclitaxel and carboplatin every 3-week administration vs dose-dense weekly administration of paclitaxel combined with the every 3-week administration of carboplatin in advanced epithelial ovarian cancer, Fallopian tube, or primary peritoneal cancer. The median progression-free survival (PFS), the primary endpoint of this study, was substantially improved in the dose-dense treatment group (28 vs 17.2 months, hazard ratio [HR]: 0.71, 95% CI: 0.58-0.88, P = 0.0015), and the overall survival (OS) at 3 years was also higher in the dose-dense treatment group (72 · 1%) than in the conventional treatment group (65.1%; HR 0.75, 0.57-0.98; P = 0 · 03). The long-term outcomes at a median follow-up period of 76.8 months were reported. The median PFS was significantly longer in the dose-dense regimen than in the conventional regimen (28.2 vs 17.5 months; hazard ratio [HR], 0.76; 95% CI, 0.62-0.91; P = 0.0037), and the median OS was 100.5 months (95% CI 65.2-∞) in the dose-dense regimen and 62.2 months (52.1-82.6) in the conventional regimen (HR, 0.79; 95% CI, 0.63-0.99; P = 0.039; log-rank test). Dose-dense treatment offers a potential new standard of care for first-line chemotherapy for patients with advanced epithelial ovarian cancer. Ongoing studies will clarify the best dose, schedule, and route of administration.

Adaptive robust control of cancer chemotherapy in the presence of parametric uncertainties: A comparison between three hypotheses

In this paper, an adaptive robust control strategy is developed for the manipulation of drug usage and consequently the tumor volume in cancer chemotherapy. Three nonlinear mathematical cell-kill models including log-kill hypothesis, Norton–Simon hypothesis and Emax hypothesis are considered in the presence of uncertainties. The Lyapunov stability theorem is used to investigate the global stability and tracking convergence of the process response. For the first time, performance of the uncertain process is investigated and compared for three nonlinear models. In addition, the effects of treatment period, initial value of tumor volume (carrying capacity) and the uncertainty amount on dynamic system behaviour are studied. Through a comprehensive evaluation, results are presented and compared for three cell-kill models. According to the results, for a wide range of model uncertainties, the adaptive controller guarantees the robust performance. However, for a given treatment period, more variation in drug usage is required as the amount of model uncertainty increases. Moreover, for both the nominal and uncertain models, less drug usage is required as the treatment period increases.

Optimal robust control of drug delivery in cancer chemotherapy: A comparison between three control approaches

During the drug delivery process in chemotherapy, both of the cancer cells and normal healthy cells may be killed. In this paper, three mathematical cell-kill models including log-kill hypothesis, Norton–Simon hypothesis and Emax hypothesis are considered. Three control approaches including optimal linear regulation, nonlinear optimal control based on variation of extremals and H∞-robust control based on μ-synthesis are developed. An appropriate cost function is defined such that the amount of required drug is minimized while the tumor volume is reduced. For the first time, performance of the system is investigated and compared for three control strategies; applied on three nonlinear models of the process. In additions, their efficiency is compared in the presence of model parametric uncertainties. It is observed that in the presence of model uncertainties, controller designed based on variation of extremals is more efficient than the linear regulation controller. However, H∞-robust control is more efficient in improving robust performance of the uncertain models with faster tumor reduction and minimum drug usage.

Efficacy and safety of dose-dense modified TCF regimen (TCF-dd) in metastatic or locally advanced gastroesophageal cancer (GEC).

4112 Background: TCF is a standard first line option for GEC. The Norton-Simon hypothesis suggests that chemotherapy efficacy can be enhanced by decreasing intervals between cycles. We previously reported on the high activity of TCF-dd in GEC (Tomasello 2010). The aim of this study is to investigate the efficacy and safety of this intensified dose-dense regimen in a single-center large cohort of patients (pts). Methods: 150 pts with measurable or evaluable GEC, PS 0-2, with adequate organ function, treated in our center from 2004 to 2012 received TCF-dd: Docetaxel (60-85 mg/m2 d 1), Cisplatin (50-75 mg/m2 d 1), l-Folinic Acid (100 mg/m2 d 1-2), 5-FU (400 mg/m2 bolus d 1-2, and 600 mg/m2 as a 22 h continuous infusion d 1-2), plus Pegfilgrastim 6 mg d 3, every 14 days. Pts aged ≥ 65 years received the same schedule with a dose reduction by 30%. Analysis was based on the intention to treat population. Results: At a median follow-up of 44 months, 128 pts were evaluable for response, all for survival. Median age 65 (range 31-81), M:F 112:38. 17 pts (11%) with locally advanced inoperable GEC, 133 pts (89%) with metastatic GEC. Metastatic sites: liver 40%, peritoneum 31%, bone 14%, lung 12%. A median of 4 cycles (range 1-7) per patient was administered. 33% required a dose reduction. 33% were treated without any delay. 10 CR, 74 PR, 24 SD and 20 PD were observed, for an ORR of 66% (95% CI 57-74). Median OS was 13 months (95% CI 9.7-14.2). Most frequent grade 3/4 toxicities: neutropenia (34%), asthenia (28%), thrombocytopenia (17%), hypokalemia (16%), diarrhea (11%), febrile neutropenia (10%), anemia (9%), and stomatitis (4%). 11 pts (7%) [7 metastatic, 4 locally advanced] became operable after TCF-dd and underwent surgery. We identified 12 metastatic pts (8%) with overall survival > 3 years and 7 (5%) still maintaining a long lasting CR at the time of the current analysis. Conclusions: TCF-dd in GEC is very active and may be an option for conversion therapy. Toxicity can be relevant and requires a careful monitoring.

Extracranial Oligometastases: A Subset of Metastases Curable With Stereotactic Radiotherapy

The term oligometastases, introduced in 1995 and detailed more recently, describes an intermediate state of cancer spread between localized disease and widespread metastases. Metastases from solid tumors are regarded as representative of disseminated cancer and are not considered curable, with the rare exception, such as germ cell tumors. By contrast, evidence has emerged that patients with limited metastatic disease, such as liver metastasis from colon or rectal cancer, can be cured by removal of the metastasis, drawing increased focus on the potential for intermediate states of metastatic cancer involvement. The implication of the concept of an oligometastatic state is that metastatic disease may be cured with metastasis-directed therapy. As a further conceptual refinement, Niibe et al have suggested the concept of oligorecurrence to consider patients with a limited number of metastases and controlled primary tumors as a group with an improved prognosis as compared with patients with limited metastasis and uncontrolled primary tumors. The oligometastatic hypothesis is distinct from other potentially important uses of radiotherapy and surgery in metastatic disease, such as consolidation of chemotherapy responses or as an application of the Norton-Simon hypothesis, which predicts that effectiveness of chemotherapy is proportional to the growth rate of the tumor and that the fastest growth rates occur in nonbulky tumors. Aggressive local therapy to metastatic lesions can downsize tumors, and the remaining cells might therefore be more sensitive to chemotherapy. Our review will focus on extracranial oligometastases because intracranial oligometastasis is an established clinical entity where surgery, radiotherapy, and radiosurgery have defined roles supported by phase III randomized trials and detailed outcome analyses.

The Norton–Simon hypothesis and the onset of non-genetic resistance to chemotherapy induced by stochastic fluctuations

By studying a simple but realistic biophysical model of tumor growth in the presence of a constant continuous chemotherapy, we show that if an extended Norton–Simon hypothesis holds, the system may have multiple equilibria. Thus, the stochastic bounded fluctuations that affect both the tumor carrying capacity and/or the drug pharmacodynamics (and/or the drug pharmacokinetics) may cause the transition from a small equilibrium to a far larger one, not compatible with the life of the host. In particular, we mainly investigated the effects of fluctuations that involve parameters nonlinearly affecting the deterministic model. We propose to frame the above phenomena as a new and non-genetic kind of resistance to chemotherapy.

Sequential chemotherapy with dose-dense docetaxel, cisplatin, folinic acid and 5-fluorouracil (TCF-dd) followed by oxaliplatin, folinic acid, 5-fluorouracil, and irinotecan (COFFI) in locally advanced or metastatic gastric cancer (MGC).

4097 Background: MGC is a chemosensitive tumour. According to the Norton-Simon hypothesis, a reduction of tumor burden could best be achieved by shortening the interval between the cycles, and the resistance might be overcome by switching from initial chemotherapy to a new, non cross-resistant one. We previously reported on the high efficacy of a new strategy using 2 sequential, non cross-resistant chemotherapy regimens in MGC (Cancer Chemother Pharmacol 11 Jan; 67 (1): 41-8). Aim of this study is to evaluate this therapeutic approach in a larger case series. Methods: 43 patients (pts) treated at our centre from November 04 to April 11 were included. All pts were chemo-naïve and received 4 cycles of TCF-dd (see reference above for doses) every 2 weeks. Subsequently and irrespective of their response, they received 4 cycles of COFFI (see reference above ) every 2 weeks. In both regimens pegfilgrastim 6 mg sc on day 3 was included. Results: Median age: 63; 74% male. PS 0-1. After the first regimen (TCF-dd) 43 pts were evaluable for response.We registered 3 CR, 27 PR, 7 SD, 5 PD and 1 not evaluable for an ORR at ITT of 70% (95% CI, 58-85). All pts proceeded to the second regimen (COFFI) and 40 pts were evaluable for response. The 3 CR observed after TCF-dd were maintained. Among the 27 pts with PR after TCF-dd, 2 achieved CR, 14 improved the response, 6 maintained PR, 3 progressed. Among the 7 pts with SD after TCF-dd, 1 achieved CR, 3 achieved PR, 2 progressed and 1 is not valuable. Among the 5 pts with PD after TCF-dd, 1 achieved CR, 4 achieved RP. After COFFI we observed 5 CR, 21 PR, 9 SD and 5 PD. The ORR in the 40 pts was 60% (95% CI, 50-80). Considering both regimen ORR was 93%. mTTP was 12.1 months (95% CI, 8,1-16,2). mOS was 16.1 months (95% CI, 12.7-21.6). At Dec '11, 4 out of 8 pts who achieved CR are alive and disease free. Most frequent G3-4 toxicities were: astenia (32%), neutropenia (35%), anemia (14%), neurotoxicity (21%). Conclusions: The study confirms that a sequential dose-dense strategy using TCF-dd followed by COFFI is feasible and highly effective and deserves to be tested in a randomized study which is on going.

P1-03-02: The Norton-Simon Hypothesis and Cancer Stem Cells: How Cancer Stem Cells May Explain the Effectiveness of Dose-Dense Chemotherapy.

Abstract Background: Systemic therapies are effective initially in controlling and reversing tumor growth; however, residual cancers will invariably re-grow despite this initial response. We have published data from paired human breast cancer samples that standard therapy every three weeks kills dividing daughter cells but not tumor-initiating cells (TICs), so that samples obtained after therapy are enriched for CD44+/CD24−/low putative “tumor-initiating” or “cancer stem” cells, indicating that standard treatment regimens are missing the critical targets, TICs. Interestingly, we have recent data in human breast tumors that indicate that TICs may in fact be chemosensitive initially, with a decrease in TICs observed within two days of chemotherapy, but shortly thereafter, TICS are actually induced by chemotherapy. Materials and Methods: To evaluate TICs response to chemotherapy, mice with human breast tumor xenograft lines BCM-2665a and BCM-2147 were treated with vehicle, 10-, or 33-mg/kg docetaxel, and then tumors were collected for TIC assays and molecular analysis at both 48 and 72h after treatment. Using Affymetrix gene expression microarrays and reverse phase protein array (RPPA) analysis with 119 different validated antibodies, we identified pathways involved in regulation of TICs. Results: According to flow cytometric analysis for TIC markers and mammosphere (MS) formation efficiency, BCM-2665 TICs were reduced by docetaxel treatment compared to vehicle-treated at 48h post 10 mg/kg docetaxel (4-fold decrease) and 48 and 72h post 33 mg/kg docetaxel compared to control (14- and 2-fold decrease, respectively). Although the BCM-2147 TICs did not significantly decrease at any time points or doses tested, they were clearly induced at 72h post-treatment compared to control. Additionally, BCM-2665 TICs were increased within 72h post 10 mg/kg docetaxel, indicating that these time points are ideal for defining the mechanisms responsible for induction of TICs. Ingenuity Pathway Analysis of Affymetrix microarray data for both BCM-2665 and BCM-2147 revealed induction of inflammatory pathways, suggesting leukocyte infiltration associated with induction of TICs. Furthermore, RPPA analysis confirmed gene expression changes from the microarray data, and implicated apoptosis and inflammatory pathways. Sixteen of 28 proteins significantly changed with activation of CSC are involved in development of leukocytes. Discussion: These findings are consistent with the Norton-Simon Hypothesis in that chemotherapy regimens given more frequently may in fact eliminate TICs, thereby explaining the proven increased effectiveness of dose-dense chemotherapy. Based on when TICs became chemoresistant, we are comparing dose-dense treatment (4 mg/kg docetaxel every 3 days) to a traditional single dose of 32 mg/kg, in an effort to eliminate the tumor cells that cause tumor recurrence. Furthermore, our analysis of gene expression at both the RNA and protein level implicated the immune cells as TICs inducers. Since our immunocompromised mice lack T- and B- cells but have active macrophages, macrophages are indicated as inducers of TICs. We are focusing our current efforts at identifying how immune cells activate TICs and thus enhance tumorigenesis. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-03-02.

Abstract LB-100: The Norton-Simon hypothesis and cancer stem cells: how cancer stem cells may explain the effectiveness of dose-dense chemotherapy

Abstract Systemic therapies are effective initially in controlling and reversing tumor growth; however, residual cancers will invariably re-grow despite this initial response. We have published data from paired human breast cancer samples that standard therapy every three weeks kills dividing daughter cells but not tumor-initiating cells (TICs), so that samples obtained after therapy are enriched for CD44+/CD24−/low putative “tumor-initiating” or “cancer stem” cells. These data indicate that standard treatment regimens are missing the critical targets, TICS; thus, we are trying to identify novel therapeutic combinations and regimens that will eliminate these TICS that ultimately cause breast tumor recurrence and metastasis. Interestingly, we have recent data in human breast tumors that indicate that TICs may in fact be initially chemosensitive, with a decrease in TICs observed within three days of chemotherapy, but shortly thereafter, TICS are actually induced by chemotherapy. To evaluate TIC response to chemotherapy, mice with xenografted human breast tumors were treated with docetaxel (20 mg/kg) or vehicle, and then tumors were collected and dissociated for TICs assays either 3d or 14d after treatment. According to multiple assays for TICs, TICs were reduced compared to vehicle-treated at 3d post-docetaxel, and increased at 14d. This was evident in both primary and secondary mammosphere (MS) formation. Flow cytometric analyses for TICs markers (CD44+/CD24−/low and ALDH+) further corroborated these data. These results indicate TICs were initially responsive but became chemoresistant, or even activated by chemotherapy. To further define TICs response to chemotherapy, mice with xenografted human breast tumors were treated with vehicle, 10 mg/kg docetaxel, or 33 mg/kg docetaxel, and then tumors were collected and dissociated for TICs assays either 48h or 72h after treatment. Although BCM-2147 TICs did not significantly decrease at any time points or doses tested, they were induced by 72h post-treatment compared to control (ALDH+ 2- to 4-fold increased). In contrast, according to TIC markers and MS formation efficiency, BCM-2665 TICS were reduced by docetaxel compared to vehicle at 48h post 10 mg/kg docetaxel (4-fold decrease), and 48h and 72h post 33 mg/kg docetaxel compared to control (14- and 2-fold decrease, respectively). Furthermore, BCM-2665 ALDH+ cells showed 6-fold increased proliferation 72h post cisplatin compared to control, indicating that chemotherapy may inducing proliferation of TICs. When TICs are induced to proliferate, they may be more susceptible to traditional proliferative targets such as chemotherapy. These findings are consistent with the Norton-Simon Hypothesis in that chemotherapy regimens given more frequently may in fact eliminate TICs, thereby explaining the proven increased effectiveness of dose-dense chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-100. doi:10.1158/1538-7445.AM2011-LB-100

The role of cytoreduction for metastatic and recurrent colorectal cancer in the era of multidisciplinary treatments.

e14091 Background: Advance in chemotherapy for colorectal cancer (CRC) has been increasing the opportunity to resect metastatic disease which was initially unresectable with possible curative intent. Cytoreduction is a standard modality in advanced ovarian cancer with significant better survival. According to Norton-Simon hypothesis, the rationale of cytoreduction is that the less the amount of tumor cells is, the better tumor cells respond to chemotherapy. This study aimed to evaluate the role of cytoreduction for metastatic and recurrent colorectal cancer in the era of multidisciplinary treatments. Methods: We performed a retrospective review of 201 patients with unresectable primary, synchronous metastatic (stage IV), and metachronous metastatic (recurrent) CRC at our institution from 2000 to 2009. All patients received 5-fluorouracil (5-FU)-based, oxaliplatin- or irinotecan-based triple-drug chemotherapy (infusional 5-FU, leucovorin, and oxaliplatin; infusional 5-FU, leucovorin, and irinotecan) with or without bevacizumab. Cytoreductive procedures included the resection of primary and/or metastatic disease or radiofrequency ablation (RFA) for metastatic disease in either debulking or possible curative setting. Results: Seventy out of 201 patients (34.8%) had cytoreduced primary or metastatic tumor in combination with systemic chemotherapy (cytoreduction group). Resection and RFA were performed for 51 and 34 lesions, respectively. Patients' performance status and chemotherapy response were significantly better in cytoreduction group (p < 0.01). A possible curative cytoreduction was achieved in 23 (32.9%) of 70 patients. The remaining 47 patients underwent debulking cytoreduction. Cytoreduction group had significantly better survival than non-cytoreduction (chemotherapy alone) group (p < 0.0001). The duration from initial chemotherapy to cytoreduction was significantly shorter in chemotherapy with bezacizumab (p < 0.01). Conclusions: Cytoreduction may become the standard care for metastatic and recurrent colorectal cancer as one of multidisciprinary treatment modalities with either debulking or possible curative intent. No significant financial relationships to disclose.