Low-grade Toxicity Research Articles

The impact of low-grade toxicity in older people with cancer undergoing chemotherapy.

Background:Significant toxicity in chemotherapy trials is usually defined as grade ⩾3. In clinical practice, however, multiple lower grade toxicities are often considered meaningful. The purpose of this observational cohort study was to identify which level of toxicity triggers treatment modification and early discontinuation of chemotherapy in older people.Methods:Patients aged 65+ were recruited in a central London hospital. A total of 108 patients were recruited at the start of new chemotherapy treatment between October 2010 and July 2012.Results:Mean age was 72.1±5 years, median 72 and range 65–86 years. Of the patients, 50.9% (55) were male with gastrointestinal (49), gynaecological (18), lung (15) and other cancers (26). Chemotherapy was palliative in 59.3% (64/108), curative/ neoadjuvant/adjuvant in the others. Mean number of cycles completed was 4.2±3. Treatment modifications due to toxicity occurred in 60 (55.6%) patients, 35% (21/60) of whom had no greater than grade 2 toxicity. Early treatment discontinuation because of toxicity occurred in 23 patients (21.3%), 39.1% (9/23) of whom had no greater than grade 2 toxicity.Conclusions:Many older patients did not complete treatment as planned. Treatment was modified/discontinued even for one or two low-grade toxicities. Further work is required to clarify whether low-grade toxicity has a greater clinical impact in older people, or whether clinicians have a lower threshold for modifying/discontinuing treatment in older people.

Abstract 3747: Predicting Maximum Tolerated Dose during Phase I using anticipatory toxicity models

Abstract A critical component of the early development of anticancer agents is the assessment of the Maximum Tolerated Dose during Phase I. In practice, clinical toxicities are graded on a scale of severity, ranging from Grade 1 (least severe) to Grade 4. This categorical scale is also used for continuous readouts, such as neutropenia. As the underlying pathophysiology can be expected to remain the same, and vary by degree or intensity alone, the dose-response (or concentration- response) of lower-grade toxicities should foreshadow the incidence of higher-grade toxicities, which represent different thresholds on the same concentration-response curve. If the concentration- response of Grade 4 toxicity can be predicted from that of Grade 1 toxicity, then the accurate estimation of the MTD should be feasible from a careful estimation of the Grade 1 toxicity. In this work, we demonstrate the development of anticipatory toxicity models that are capable of predicting higher-grade toxicities during dose-escalation. First, we used a simple empirical approach that relies on a minimum of assumptions. We have previously shown that the nadir of neutropenia is strongly correlated with the maximum moving average concentration over the dosing window. Using this pharmacokinetic parameter as an independent variable, we developed a set of analytical expressions to connect the concentration- response of each lower grade of toxicity to the corresponding higher grades of toxicity. Next, we tested this family of anticipatory toxicity models on a simulated dataset of neutropenia generated from a previously published model of clinical neutropenia for a range of chemotherapeutics (Friberg et al., 2002). Finally, we validated our anticipatory toxicity models with in-house preclinical data. Next, we extended the development of anticipatory toxicity models to a model-based approach. We fitted the lower grades of toxicity from the simulated dataset described above to fit a semi-mechanistic model of neutropenia, showing that the model can predict higher grades of toxicity. Next, we again validated the anticipatory toxicity models built on a semi-mechanistic basis using in-house preclinical data. Each of the two approaches presented here may be better suited for different situations. The empirical approach is better suited for toxicities with a poorly understood mechanistic basis, while the semi-mechanistic approach is well suited for neutropenia and other hematological toxicities. In either case, the anticipatory toxicity models were able to accurately predict the incidence of higher-grade toxicities in the given datasets. Thus, a careful analysis of these lower-grade toxicities may provide the opportunity to accelerate clinical development through the design of alternative clinical dose-escalation schemes. Such alternative escalation schemes may also be safer, as they focus on the forward prediction of the MTD before it is reached. Citation Format: Ekta Kadakia, Snehal Samant, Christopher J. Zopf, Dean Bottino, Greg Hather, Santhosh Palani, Wen Chyi Shyu, Arijit Chakravarty. Predicting Maximum Tolerated Dose during Phase I using anticipatory toxicity models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3747. doi:10.1158/1538-7445.AM2014-3747

Final Efficacy and Safety Results of Pemetrexed Continuation Maintenance Therapy in the Elderly from the PARAMOUNT Phase III Study

The PARAMOUNT Phase III trial showed that maintenance pemetrexed after pemetrexed plus cisplatin induction was well tolerated and effective for patients with advanced nonsquamous non-small-cell lung cancer. Approximately 17% of patients receiving maintenance therapy in this study were 70 years of age or older. Here we report efficacy and safety results from the PARAMOUNT study for elderly (≥70 years) and non-elderly (<70 years) patients. Final efficacy and safety data from the PARAMOUNT study were analyzed post hoc using subgroup analyses for elderly and non-elderly patients. The median age was 73 years in the elderly subgroup (n = 92) and 60 years in the non-elderly subgroup (n = 447). Subgroups had similar baseline characteristics, except for a higher percentage of males and patients with a performance status of one in the elderly subgroup. For elderly patients, the median PFS was 6.4 months for pemetrexed and 3.0 months for placebo; the median OS was 13.7 months for pemetrexed and 12.1 months for placebo. For non-elderly patients, the median PFS was 4.0 months for pemetrexed and 2.8 months for placebo; the median OS was 13.9 months for pemetrexed and 10.8 months for placebo. Elderly patients experienced similar levels of low-grade toxicities, but had a higher percentage of grade 3/4 anemia and neutropenia than non-elderly patients, although importantly, this did not translate into increased febrile neutropenia. Continuation maintenance pemetrexed had comparable survival and toxicity profiles in the elderly and non-elderly subgroups. However, grade 3/4 anemia and neutropenia were numerically higher for elderly patients.

Long-Term and Low-Grade Safety Results of a Phase III Study (PARAMOUNT): Maintenance Pemetrexed Plus Best Supportive Care Versus Placebo Plus Best Supportive Care Immediately After Induction Treatment With Pemetrexed Plus Cisplatin for Advanced Nonsquamous Non–Small-Cell Lung Cancer

IntroductionIn the PARAMOUNT (“A Phase 3, Double-Blind, Placebo-Controlled Study of Maintenance Pemetrexed plus Best Supportive Care vs. Best Supportive Care Immediately Following Induction Treatment with Pemetrexed Plus Cisplatin for Advanced Non-Squamous Non–Small-Cell Lung Cancer”) trial, patients with advanced nonsquamous non–small-cell lung cancer (NS-NSCLC) benefited from pemetrexed maintenance therapy after induction therapy with pemetrexed and cisplatin by extending survival, delaying disease progression, and maintaining quality of life (QoL). However, low-grade 1 or 2 toxicities during long-term maintenance treatment may become burdensome and impact QoL. Materials and MethodsPatients in this double-blind study (n = 539), who had completed 4 induction cycles (pemetrexed with cisplatin) without progressive disease (PD) and had an ECOG performance status of 0/1, were randomized 2:1 to pemetrexed maintenance (500 mg/m2, day 1) plus best supportive care (BSC) or placebo plus BSC until PD. Adverse events (by maximum Common Terminology Criteria for Adverse Events [CTCAE] grade) and QoL (EuroQol 5-dimensional [EQ-5D] scale) were assessed. ResultsA median of 4 maintenance cycles was administered (range, pemetrexed 1-44; mean ± SD 7.9 ± 8.3; placebo 1-38; mean ± SD 5.0 ± 5.2), with 28% of pemetrexed and 12% of placebo patients receiving ≥ 10 maintenance cycles. The pemetrexed dose intensity was 94%. More patients receiving pemetrexed (12%) than placebo discontinued because of possible drug-related CTCAEs (4%; P = .005). Overall, pemetrexed was associated with significantly more (P < .05) low-grade events (grade 1/2 nausea, grade 2 anemia, edema, and neutropenia) than placebo. Overall, the incidence of low-grade fatigue, anemia, and neutropenia decreased with long-term pemetrexed exposure; however, renal events increased across treatment arms. EQ-5D analyses demonstrated no treatment-by-time interaction or overall treatment differences between the 2 arms. ConclusionPARAMOUNT demonstrated a low incidence of low-grade toxicities with long-term pemetrexed exposure without compromising QoL in patients with NS-NSCLC.

Abstract A166: A Phase I pharmacokinetic/pharmacodynamic (PK/PD) study of the sachet formulation of the oral dual PI3K-mTOR inhibitor BEZ235 given twice daily (BID) in patients (pts) with advanced solid tumors.

Abstract Background: The PI3 kinase pathway is the most dysregulated pathway in cancers and is an attractive target for antitumor therapy. BEZ235 is a potent, highly specific and selective PI3K inhibitor that also binds to the catalytic site of mTOR, inhibiting mTORC1/2. Methods: Pts were enrolled in a 3+3 dose escalation design to determine the maximum tolerated dose, toxicities, PK, and PD of BEZ235 when administered BID as an oral sachet formulation. For intrapatient PK comparison, pts received the total dose in a QD schedule for the first 8 days of the initial 28 day cycle. The QD lead-in was later eliminated. PK and PD assessments (PET scans, skin biopsies, and blood-based biomarkers) were collected and disease assessments were conducted every 2 cycles. Results: 33 pts (median age 62, range 20-86 yrs; 17 male/16 female) received BEZ235 at the doses described below in the table. Two DLTs of gr 3 mucositis occurred early in the treatment cycle at 600 mg BID, so the lead-in QD dosing was eliminated. However, DLTs of fatigue and mucositis limited dosing at 600 mg BID in subsequent pts. The 400 mg BID dose level was re-explored, but dosing was again limited by DLTs and chronic low grade toxicities. Twelve pts were enrolled at an intermediate dose of 300 mg BID with no QD lead-in, and DLT (gr 3 mucositis) was reported in a single patient. Preliminary PK data demonstrate a consistent increase in PK parameters (Cmax and AUC) with dose level compared to QD dosing. PET scan evaluations demonstrate anti-PI3K activity via decreased SUV uptake at various doses, including the lowest dose. 15 pts experienced stable disease as their best response. Conclusions: The recommended dose of BEZ235 administered twice daily as an oral sachet formulation is 300 mg BID. The toxicity profile for BID dosing is similar to that reported for other PI3K and mTOR inhibitors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A166. Citation Format: Johanna C. Bendell, Carla Kurkjian, Jeffrey R. Infante, Todd Bauer, Howard A. Burris, David R. Spigel, Denise A. Yardley, F Anthony Greco, Kent C. Shih, Dana S. Thompson, Suzanne F. Jones. A Phase I pharmacokinetic/pharmacodynamic (PK/PD) study of the sachet formulation of the oral dual PI3K-mTOR inhibitor BEZ235 given twice daily (BID) in patients (pts) with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A166.

Feasibility and Results of Radical Surgery and Adjuvant Therapy in Patients Older than 70 Years with Pancreatic Adenocarcinoma

Context High morbidity rates following pancreatic surgery and adverse effects of chemo-radiation treatments still make surgeons and oncologist reluctant to candidate elderly patients to these surgical or medical therapies. Objective Evaluation of postoperative outcomes and adjuvant chemo-radiation protocols adherence among over 70-year-old patients with pancreatic adenocarcinoma (PDAC) treated in a referral center for pancreatic disease. Methods Between January 2010 and May 2013 we performed 161 pancreatic resection for PDAC (including invasive IPMN): 106 pancreatico­duodenectomies (PD), 44 left spleno-pancreatectomies (LP), and 11 total pancreatectomies (TP). In the present study we focused on over 70-year-old patients treated with surgery and, successively, candidate or not to adjuvant therapy. We prospectively recorded data about perioperative outcomes as well as patient’s adherence to planned chemo-radiation schedules. Results In our series over 70-year-old patients were 75 (47.2%). Median age at surgery was 76 years (range: 70-85 years). Thirty-one patients (41.3%) had ASA ≥3. Mean BMI was 23.6 kg/m 2 . Forty-seven patients received PD, 21 had LP, 7 underwent TP. Overall morbidity was 48% (Clavien Dindo ≥3: 12%); POPF was 13.3% (ISGPF B-C: 4.4%); biliary fistula rate was 5.5%; DGE rate was nihil; PPH was 5.3% (4 cases, 2 of them requiring reintervention); medical complications were 14.5%; reintervention were 5.3% (4 cases); mortality was 1.3% (1 case). Median LOS was 10 days (range: 5-31 days). Patients candidate for adjuvant treatment were 39 (52.0%): 25 chemotherapy (64.1%), 6 radiotherapy (15.4%), 8 combined chemo-radiation (20.5%). Of the other patients, 27 (36.0%) were not enrolled in any adjuvant schedule after surgery, 8 (10.7%) resulted stage 0-I at histology and 1 (1.3%) died during surgical hospitalization. Among patient undergoing chemotherapy, 70% received gemcitabine, 9% PEX-G, and 6% GemOx. Thirty-three percent of the patients experienced low grade toxicity (G1-2), while 18% had high grade (G3-4). Twelve percent of the patients could not complete the schedule because of toxicity or disease progression during the treatment. Median survival after surgery was 25 months. Conclusions The morbidity and mortality rate we observed in elderly patients is acceptable and aligned with data reported in larger series. In a similar way, adjuvant treatments toxicity appeared limited, and patients adherence to scheduled therapy adequate. An accurate preoperative and postoperative asses­sment, referring to biological more than chronological age, is mandatory in evaluation of cases eligible to surgery and adjuvant treatments.

First-in-human phase I study of the liposomal RNAi therapeutic Atu027 in patients with advanced cancer.

2508 Background: Atu027 is a novel vascular stabilising, anti-metastatic, RNAi therapeutic, targeting systemic endothelial cell function and the tumor vasculature. Atu027 comprises a liposomal particle, containing an siRNA, which silences expression of the PKC pathway signalling molecule PKN3. Atu027 was previously shown to restrict tumor growth, local invasion and both, lymph node as well as pulmonary metastasis in mouse xenograft models. Methods: 34 patients with advanced cancer received 10 escalating doses of Atu027 without pre-medication as single and repeated i.v. infusions (qw2x4 per 28-d cycle) with a 3-wks dose intermission. Primary end points were safety, pharmacokinetics and -dynamics (biomarker identification). Response was monitored by CT/MR imaging at baseline, after treatment and at final follow-up (EoS) and was assessed according to RECIST. Results: Atu027 was well tolerated up to 0.336 mg/kg (around twice the predicted effective siRNA plasma levels). An MTD was not achieved. Around 50% of patients experienced disease stabilization according to RECIST. 8 patients had stable disease at EoS and 2 with neuroendocrine cancer had disease stabilization for 9 or 22 months. Partial regression of pulmonary metastasis and a regression of liver metastases were observed in subjects with neuroendocrine and breast cancer, respectively. An improved ECOG performance status was observed in patients of higher dose levels. Most AEs were low grade toxicities (1 or 2), including fatigue and increased lipase. Transient complement system activation was observed for certain factors. Area exposure levels of siRNA strands were dose-proportional and peaks were reached during 4 h-infusion. Of 102 plasma proteins assessed, sFLT1 (sVEGF-R1) was the most promising as a potential biomarker, with decreases from baseline in most pts from dose level 4-10 after treatment. Conclusions: Atu027 was well tolerated and there was suggestion of a clinically meaningful antitumor activity. In view of this further clinical trials can be initiated at a dose of up to 0.336 mg/kg and sFLT1 will be investigated as a potential biomarker. Clinical trial information: NCT00938574.

Phase I clinical trial of external hyperthermia and intravesical mitomycin C to treat BCG-refractory bladder cancer.

e15560 Background: Patients with non-muscle-invasive bladder cancer (NMIBC) that fail intravesical bacillus Calmette-Guérin (BCG) are at high risk for progression. Radical cystectomy is an effective but morbid treatment option. We tested the safety and efficacy of combined intravesical mitomycin C (MMC) and external deep regional hyperthermia (HT) as a bladder-sparing approach for BCG-refractory NMIBC. Methods: Patients with BCG-refractory NMIBC were eligible for this phase I clinical trial. Treatment consisted of intravesical MMC (40 mg in 40 mL) with concurrent HT with target temperature of 42°C. MMC dwell time was 60-120 min and heating time was 40-60 min. HT was delivered using a BSD2000 device and temperatures monitored with skin, bladder and rectal probes. Treatment was given weekly for 6 weeks (induction) then monthly for 4 months (maintenance). The primary endpoint was toxicity which was assessed using CTCAE 3.0. Secondary endpoints included recurrence-free survival (RFS), progression-free survival (PFS), cystectomy, and overall survival (OS) which were assessed at 3 month intervals with cystoscopy and cytology for 2 years. Results: Fifteen patients were eligible and consented to the clinical trial. Median age was 66 years and 87% were male. Median follow-up was 2.85 years. One patient did not tolerate supine position, two completed induction but recurred prior to maintenance, one recurred after 3 maintenance treatments, and 11 patients received all 10 treatments. The 2 year RFS was 33% (median RFS = 15.4 mos). Six patients (40%) required cystectomy (median time = 20.1 mos). No patient had bladder progression but two patients developed ureteral tumors (not present on baseline imaging). Two patients died, one from ureteral cancer and one of cardiovascular disease, for a 3-year OS of 83% (median OS not reached). No grade III toxicities were observed. Common toxicities were abdominal pain (36%), cystitis (22%), pruritis and urinary tract infection (14%). Conclusions: The combination of MMC and HT for BCG refractory NMIBC was safe and associated with low grade toxicity. While recurrence was common, progression did not occur, and recurrent patients were safely salvaged with cystectomy. Clinical trial information: NCT00734994.

Concurrent chemoradiation therapy in cervical cancer: Prognostic factors, toxicity, and long-term survival in a center of reference for gynecologic cancer.

e16539 Background: Concurrent chemoradiation therapy has been the standard treatment in locally advanced cervical cancer since 1999, and our institution is a centre of reference for treatment of this pathology. Methods: In a homogeneous series of 288 patients treated between 1996 and December 2011, survival data, prognostic factors and toxicity of the treatment have been analyzed. The treatment includes external beam radiotherapy, concurrent weekly chemotherapy and brachytherapy. Results: Median age of the patients is 54 years old, and the FIGO classification for disease stages shows 14.6% IB2, 47.1% IIB, 24.4% III, and 7.8% IVA. Squamous cell carcinoma (77.4%) and adenocarcinoma (16.8%) are the most common histologies. After a median follow-up of 4.4 years, the 5-year overall survival rate is 80.2%. Classified by diagnostic stage, they are 85% in IB2, 76% in IIB, 70% in III, and 68% in IVA. The main location for recurrence is cervix (11.8%), and the most common site for distant disease is lung (4.8%). For patients with disease progression, 24.4% have local and distant recurrence. After local recurrence, radical surgery with pelvic exenteration was practised in 6 cases, 5 of them are still alive. In the multivariate analysis, the prognostic factors for overall survival that have been identified with a statistical significance, are HPV and HIV infection, high stages of disease and older patients. Performance status ≥1 and brachytherapy have only a significant value in the univariate analysis. The acute toxicity grade ≥3 was observed in 19.4% of patients (14.1% haematological). The most frequent low grade toxicity was 46.3% haematological, 40% of bowel-related toxicity, 38.9% of nausea and vomiting, and 8.1% of renal dysfunction. Chronic toxicity grade ≥3 has been only seen in 1.2% of patients (renal dysfunction), and in the low grades, it is a 6% of bowel-related toxicity and 1.4% of mild renal dysfunction. Conclusions: This long follow-up series shows a good overall survival rate with chemoradiation therapy in locally advanced stages of cervical cancer, with a low rate of acute and, especially, chronic toxicity, indicating a good quality of life for these patients.

Glufosinate Herbicide Intoxication Causing Unconsciousness, Convulsion, and 6th Cranial Nerve Palsy

Although glufosinate ammonium herbicides are considered safe when used properly, ingestion of the undiluted form can cause grave outcomes. Recently, we treated a 34-yr-old man who ingested glufosinate ammonium herbicide. In the course of treatment, the patient developed apnea, mental deterioration, and sixth cranial nerve palsy; he has since been discharged with full recovery after intensive care. This case report describes the clinical features of glufosinate intoxication with a focus on sixth cranial nerve palsy. Our observation suggests that neurologic manifestations after ingestion of a "low-grade toxicity herbicide" are variable and more complex than that was previously considered.

Abstract FO02-02: What are the hurdles for moving approved drugs into the prevention setting?

Abstract Most anticancer agents are initially tested in patients with metastatic disease. Early dose finding studies evaluate the tolerability and safety of such agents, and the recommended Phase II dose is most commonly derived from toxicity assessments in the first 3-6 weeks of treatment. An acceptable maximally tolerated dose allows dose-limiting toxicities in at least one of 6 patients or &amp;lt;33% of the treated patients. Dose limiting toxicities are typically defined as grade 3 non-hematological toxicities and grade 4 hematological toxicities occurring in the first 3-4 weeks of treatment. Hence, most agents that receive approval from trials in metastatic patients are derived from studies with a relatively short exposure time and allow a considerable negative impact on quality of life. Similarly, novel anti-cancer agents that are tested and approved in the adjuvant setting are usually administered for a limited time span. Cytotoxic agents have therefore rarely been considered as chemopreventive agents. The emergence of more effective targeted agents or biologics are of great interest as potential chemoprevention agents. However, the motivation of treatment adherence and the acceptance of severe side effects of agents is higher when treating metastatic disease or when preventing a recurrence after a diagnosis of limited stage disease. Many of the targeted agents and biologics are developed similar to cytotoxic agents based on the maximally tolerated dose rather than optimal biological dose. In contrast, cancer prevention agents may have to be given over prolonged periods to patients who have an elevated risk of developing cancer solely based on genomic testing or population studies. The uncertainty of the individual risk and potential benefit has to be weight against toxicities and impact on quality of life. The acceptance of grade 3 and 4 toxicities in this population is very limited. The use of a targeted or biologic agent originally approved for metastatic disease in the prevention setting, will require a reassessment of what are acceptable doses for long-term use based on lower grade toxicities. Furthermore, a more in depth understanding of the effective biological and molecular concentrations and the development of predictive biomarker will be paramount. Citation Format: Pamela N. Munster. What are the hurdles for moving approved drugs into the prevention setting? [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr FO02-02.

Population Pharmacokinetic Analysis of 5-FU and 5-FDHU in Colorectal Cancer Patients: Search for Biomarkers Associated with Gastro-Intestinal Toxicity

The anticancer drug 5-fluorouracile (5-FU) which is indicated for the treatment of a variety of solid malignancies such as colorectal, breast, head and neck neoplasms is extensively biotransformed to 5 fluoro-5,6- dihydrouracil (5-FDHU) by the dihydropyrimidine deshydrogenase enzyme (DPD). DPD deficiency is recognized as an important risk factor, predisposing patient to undergo severe/lethal toxicities. To date, relationships between 5-FU, 5- FDHU and toxicity following i.v. bolus administration has not been studied using the population pharmacokinetics approach. Retrospective pharmacokinetic data of 5-FU and 5-FDHU from 127 colorectal cancer patients were used for the population pharmacokinetic analysis. Treatment schedule consisted of an adjuvant therapy with 5-FU plus leucovorin. 5- FU and 5-FDHU complete plasma profiles recorded on day-1 of the first chemotherapy cycle were modeled simultaneously using NONMEM software. Gastro-intestinal adverse events graded according to the WHO criteria were recorded after the first cycle. A population logistic regression model was developed to identify predictive factors of these adverse events. A three-compartment pharmacokinetic mixture model best described 5-FU and 5-FDHU kinetics profiles. Linear and saturated elimination from the central compartment of 5-FU and a linear elimination from the 5-FDHU compartment were used. A bimodal distribution of the inter-compartmental clearance was observed allowing two subpopulation with high (17 L/h) and low values (3.35 L/h). DPD-phenotype is suspected to explain this mixture. No covariates were introduced in the final model. Also, no relationship was found between maximal metabolism rate and DPD-phenotype. Predictive factors associated with occurrence of high grade gastro-intestinal adverse events were gender, dose and lean body mass suggesting serious cautions with the BSA-weighted dose for women. For the low-grade toxicities, 5-FU area under curve was predictive for woman and 5-FDHU area under curve for men. A population pharmacokinetic mixture model was developed to describe kinetic profiles of 5-FU and its major metabolite. This model has significant implications, to identify patients with potentially low DPD phenotype requiring earlier adjustment of the 5-FU dose. Also this analysis highlights the need for developing alternative dosing-scheme for women.

1275P - Updated Safety and Quality of Life (QOL) Results of Paramount Study: Maintenance Pemetrexed (PEM) Plus Best Supportive Care (BSC) vs Placebo (PBO) Plus Bsc Immediately Following Induction Treatment with Pem Plus Cisplatin (CP) for Advanced Nonsquamous Non-Small Cell Lung Cancer (NS-NSCLC)

ABSTRACT Objectives The PARAMOUNT trial showed that continuation maintenance therapy with pem after induction therapy with pem plus CP significantly reduced the risk of disease progression (HR = 0.62) and death (HR = 0.78) in patients (pts) with advanced NS-NSCLC. The purpose of this abstract is to present the updated safety and patients' QoL results from the continuation maintenance treatment of the PARAMOUNT trial. Methods In this phase III, randomized, double-blind, PBO-controlled study, 939 pts were treated with pem (500 mg/m2) plus CP (75 mg/m2) on day 1 of four 21-day cycles. Patients (n = 539) who had not progressed and had an Eastern Cooperative Oncology Group performance status (PS) of 0/1, were randomized (2:1; stratified for PS, induction response, and disease stage) to maintenance pem (500 mg/m2, day 1) plus BSC (n = 359) or PBO plus BSC (n = 180) until disease progression. All pts received vitamin B12, folic acid, and dexamethasone. All randomized pts were qualified for the maintenance phase safety analyses, which included summaries of the incidence of adverse events by maximum Common Terminology Criteria Adverse Events, version 3, grade. All enrolled patients that had provided baseline and at least 1 subsequent measurement for EuroQol 5-dimensional (EQ-5D) scale were included in the analysis of patient-reported outcomes. Results Safety and the QoL analyses in the continuation maintenance therapy will be presented. Conclusions The long-term and low-grade toxicities of continuation maintenance therapy with pem will be discussed. Disclosure C.M. Visseren-Grul: Employed by and own stock in Eli Lilly and Company. L. Paz-Ares: I have advisory board relationship and honararia to disclose with Eli Lilly and Company, Bayer, Roche, Pfizer. I. M. Dediu: Advisory Board - Eli Lilly and Company. M. Thomas: Advisory Board - Eli Lilly and Company Corporate Sponsored Trial - Eli Lilly and Company. N. Chouaki: Employed by and own stock in Eli Lilly and Company. A. Zimmermann: Employed by and own stock in Eli Lilly and Company. J. Pujol: Advisory Board - Eli Lilly and Company. C. Gridelli: Advisory Board, corporate-sponsored research, and honoraria/speaker bureau with Eli Lilly and Company. All other authors have declared no conflicts of interest.

The Management of Skin Toxicity during Cetuximab Treatment in Advanced Colorectal Cancer: How much does it Cost? A Retrospecive Economic Assessment from a Single-Center Experience

Skin rash is a predictable and manageable side effect of anti-EGFR therapy such as cetuximab. The aim of this study is to estimate the costs for the foreseeable management of skin toxicity in patients treated with cetuximab in our institute in order to assess the direct medical economic impact. We retrospectively analyzed all consecutive patients with advanced colorectal cancer treated with cetuximab at our institute from June 2006 to May 2011. We evaluated the severity and mean duration of skin rash for each grade and we identified the costs for the different therapeutic interventions. Patients were treated according to the general consensus management of skin toxicity associated with cetuximab treatment. We evaluated 31 patients. The median follow-up was 28.95 months (range, 1.84-75.49). At last follow-up 10 patients (32.3%) were alive with metastases, 18 patients (58.1%) had died, 1 patient (3.2%) was alive without evidence of disease, and 2 patients (6.5%) were lost to follow-up. The median progression-free survival was 8.26 months and the median overall survival 32.89 months. Nineteen patients (61.3%) developed skin toxicities: 7 patients (22.6%) grade 1, 9 patients (29.0%) grade 2, 3 patients (9.7%) grade 3; no grade 4 skin toxicity was observed. The median duration of grade 1 toxicity was 79 days (no specific treatments were started), of grade 2 toxicity 95 days (cost range, € 199.50-294.50) and of grade 3 toxicity 64 days (cost range, € 159.42-233.90). Our experience, through the analysis of nonselected cases, showed that the management of skin toxicities related to cetuximab is not so expensive. We recommend proper care of low-grade toxicities in order to reduce progression to high-grade toxicities and the resulting risk of hospitalization, which really impacts on costs.

Safety and Efficacy of Everolimus in Adult Patients with Neuroendocrine Tumors

Neuroendocrine tumors (NETs) consist of a diverse family of tumors which are derived from the neuroendocrine system. Most NETs are well or moderately differentiated tumors with a relatively indolent growth pattern. However, these tumors can cause significant clinical disease due to release of functional products that mediate the carcinoid syndrome and other diverse sequela. They also can grow progressively and cause symptoms from local invasion or distant metastasis. NETs are optimally treated with surgery and somatosatin analogs (SSA’s) to control symptoms but are relatively insensitive to systemic chemotherapy. As a result, patients with advanced unresectable NETs have a poor prognosis. In 2011, two targeted therapies, sunitinib and everolimus were approved in the subset of progressive pancreatic NETs (pNETs). Everolimus is an oral inhibitor of the growth stimulatory mTOR pathway. In Phase 2 trials in NETs and pNETs, everolimus was well tolerated and associated with some response and widespread disease stabilization. In follow-up, randomized Phase 3 trials, everolimus was compared to placebo. In the RADIANT-2 trial, everolimus and a somatostatin analog were used in patients with functional NETs and treatment was associated with an an improvement in progression-free survival (PFS). In the RADIANT-3 trial, patients with pNET were randomized to receive everolimus or placebo along with best supportive care. Everolimus was again associated with improvement in PFS compared to placebo and it has been approved by the FDA for patients with progressive pNET. Everolimus is associated with frequent low grade toxicity but is also notable for increased rates of infection as well as non-infectious pneumonitis. mTOR inhibition with everolimus represents a significant advance in the treatment of advanced neuroendocrine tumors.

Long-Term Outcomes From a Prospective Trial of Stereotactic Body Radiotherapy for Low-Risk Prostate Cancer

Hypofractionated radiotherapy has an intrinsically different normal tissue and tumor radiobiology. The results of a prospective trial of stereotactic body radiotherapy (SBRT) for prostate cancer with long-term patient-reported toxicity and tumor control rates are presented. From 2003 through 2009, 67 patients with clinically localized low-risk prostate cancer were enrolled. Treatment consisted of 36.25 Gy in 5 fractions using SBRT with the CyberKnife as the delivery technology. No patient received hormone therapy. Patient self-reported bladder and rectal toxicities were graded on the Radiation Therapy Oncology Group scale (RTOG). Median follow-up was 2.7 years. There were no grade 4 toxicities. Radiation Therapy Oncology Group Grade 3, 2, and 1 bladder toxicities were seen in 3% (2 patients), 5% (3 patients), and 23% (13 patients) respectively. Dysuria exacerbated by urologic instrumentation accounted for both patients with Grade 3 toxicity. Urinary incontinence, complete obstruction, or persistent hematuria was not observed. Rectal Grade 3, 2, and 1 toxicities were seen in 0, 2% (1 patient), and 12.5% (7 patients), respectively. Persistent rectal bleeding was not observed. Low-grade toxicities were substantially less frequent with QOD vs. QD dose regimen (p = 0.001 for gastrointestinal and p = 0.007 for genitourinary). There were two prostate-specific antigen (PSA), biopsy-proven failures with negative metastatic workup. Median PSA at follow-up was 0.5 ± 0.72 ng/mL. The 4-year Kaplan-Meier PSA relapse-free survival was 94% (95% confidence interval, 85%-102%). Significant late bladder and rectal toxicities from SBRT for prostate cancer are infrequent. PSA relapse-free survival compares favorably with other definitive treatments. The current evidence supports consideration of stereotactic body radiotherapy among the therapeutic options for localized prostate cancer.

Research Highlights

Research Highlights

A Phase 1/2 Study of RAD001, a mTOR Inhibitor, In Patients with Myelofibrosis: Final Results

AbstractAbstract 314 Background:Akt/mTOR activation has been found in association with dysregulated JAK2/STAT5 signaling due to JAK2V617F mutation. Increased phosphorylation of STAT5 and Akt was detected in patients (pts) with myeloproliferative neoplasms (MPN) (Grimwade LF, BJH 2009). We reported (Bogani C, ASH 2009) that RAD001, an oral inhibitor of mTOR, inhibited the proliferation of human and murine JAK2V617F-mutated cells and impaired colony formation by MPN progenitor cells, suggesting potential clinical activity. Methods:We will report final data from an investigator-initiated, multicenter phase I/II trial with RAD001 in myelofibrosis, primary (PMF) and post-polycythemia vera/essential thrombocythemia (PPV/PET MF). Inclusion criteria were intermediate/high risk score (Lille criteria) or need of treatment because of progressing splenomegaly. Phase I involved a 3+3 pts scheme in 3 sequential cohorts at 5.0, 7.5, and 10 mg daily for 3 mo to establish maximum tolerated dose (MTD). Phase II was a two-stage Simon design involving 16+14 pts at MTD for 4 mo. The protocol was approved by IRBs and pts provided informed consent. The study was supported by Agenzia Italiana per il Farmaco (AIFA) and AIRC-Gruppo Italiano Malattie Mieloproliferative (AGIMM). Results:Phase I: there was no DLT at 10 mg daily, considered as MTD; there were 2 major (MR), 3 moderate (MO) and 1 minor (MI) and 3 no (NR) responses. In part 1 of Phase II, >1/16 pts achieved MR; according to study design, 14 additional pts were enrolled in part 2 (n=30). 20 patients had low and 10 intermediate Lille score; according to IWG-MRT criteria, 5, 10, 8 and 7 were low, int-I, int-II and high risk score, respectively. There were 16 PMF, 8 PPV- and 6 PET-MF. 20 pts were JAK2V617Fpos, 3 were MPLW515pos.Patients evaluable for intention-to-treat (ITT) analysis as of aug 1st were 26; the remaining 4 pts will be updated at meeting. Therapy was discontinued in 5 pts: 1 pt's decision at d60 without evidence of any >grade-2 toxicity, 2 at d60 and d90 for physician's decision due to grade-2 toxicity, 1 death due to respiratory failure at d60, 1 at d30 for grade-3 acute renal failure. 21/26 pts (81%) were available for per-protocol analysis. Therapy was generally well tolerated; commonest toxicities were grade-2 mouth ulcers and grade-1/2 hypertrigliceridemia. Hematological toxicities: 3 grade-2 and 4 grade-3 reversible anemia, one grade-2 neuthropenia, one grade-2 and 1 grade-3 reversible thrombocytopenia.A reduction of spleen size consistent with CR, PR or NR was obtained in 8%, 46%, and 46% of the pts, respectively. 11 of 21 pts (52%) had complete resolution of systemic symptoms, and 14 of 19 pts (74%) reported disappearance of pruritus. Two pts achieved PR in anemia with decrease in transfusion requirement >50%, while in 3 pts Hb increased of 2g/dL. A CR in platelets was obtained in 3 of 19 pts and CR in leucocytes in 2 of 18 pts with abnormal blood count. Overall, according to ITT analysis: 6 major (23%), 6 moderate (23%), 2 minor (8%) and 12 NR (46%) (EUMNET criteria). According to IWG-MRT criteria, there were 6 (23%) clinical improvement. Per-protocol analysis: 33% major, 19% moderate, 5% minor, 43% NR; 24% clinical improvement. No disease progression.Changes induced by RAD001 in some biological parameters were preliminary evaluated and will be finally updated at meeting. Blood levels of CCDN1 mRNA, a target of mTOR, significantly decreased in responders (MR+MO) versus non-responders (P=0.02). In the 13 JAK2-mutated pts who completed the treatment, the V617F allele burden was 61.6+/−15.8 versus 66.6+/−19.6% at baseline. There was a trend (P=0.07) towards a reduction of granulocyte WT1mRNA copy number in responders versus non-responders. We found no correlation of circulating CD34+ cells or CXCR4 expression with clinical response. A set of 46 inflammatory protein markers and cytokines were quantified before and at d30 of treatment. Some, including IL-10 and MIP-1beta, showed significant decrease while others increased, including Factor VII, IL-8 and MMP-2. Levels of MIP-1 beta were significantly lower in responders (P=0.006). Conclusions:These data indicate that mTOR pathway targeting with RAD001 in MF pts induces an appreciable rate of response in splenomegaly, constitutional symptoms, and pruritus, with low-grade toxicity. However, effects on JAK2V617F mutational load were minimal, and should be better evaluated after longer trial duration. Disclosures:Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: This is an investigator-initiated, non-sponsored, clinical trial with RAD001 in myelofibrosis. Paratore:Novartis: Employment.

Recent Advances

The U.S. population is now healthier and more long-lived than ever, and the average life expectancy for a woman born today is about 80 years. An elderly woman's life expectancy, which is related to comorbidity and functional status, is particularly important when determining the appropriate choice of adjuvant chemotherapy and endocrine therapy. In addition, the disease stage and the tumor's biologic characteristics (grade and hormone/human epidermal growth factor [HER]-2 receptor status) must be considered when formulating a treatment plan for 3 clinically distinctive breast cancer subgroups: (1) hormone receptor negative (HR-) and HER-2 negative ("triple-negative" tumors, about 15% of older patients); (2) hormone receptor positive (HR+) and HER-2 negative (the largest group comprising about 70% of older patients); and (3) HER-2 positive irrespective of HR status (about 15% of older patients). The functional status of an older woman can be estimated by a Comprehensive Geriatric Assessment (CGA). A traditional CGA is time consuming, but testing of shorter, validated CGA instruments is ongoing. Monitoring toxicity in the elderly is especially important because even low-grade toxicity can have a significant effect on function. Eligible older women should be considered for state-of-the-art treatment, including clinical trials to determine the optimal adjuvant regimens for this patient population and how the therapies affect the woman's functioning and quality of life.

Clinical compliance with an oral uracil/tegafur (UFT) plus leucovorin (LV) regimen as adjuvant chemotherapy in Japanese colorectal cancer patients

The combination of oral uracil/tegafur (UFT) plus leucovorin (LV) is widely accepted as adjuvant chemotherapy for stages II and III of colorectal cancer. However, the clinical compliance of Japanese patients with this regimen has not been clearly elucidated to date. A total of 40 Japanese outpatients were treated with oral UFT plus LV as adjuvant chemotherapy following colorectal cancer surgery between January 2005 and June 2007. UFT capsules (300-500 mg/body per day) and LV tablets (75 mg/body per day, administered with each dose of UFT) were to be taken for 28 days, followed by 7 days of rest, with this cycle repeated every 35 days for 6 months or until recurrence. The patients were classified into the following three groups based on compliance: the completed group (n = 21), the modified group (n = 12), and the discontinued group (n = 7). The UFT doses (mean +/- SD) were 267 +/- 35 mg/m(2) in the completed group, 276 +/- 50 mg/m(2) in the modified group, and 288 +/- 22 mg/m(2) in the discontinued group. The UFT dose in the discontinued group tended to be higher than that in the completed group (P = 0.12). The most frequent symptoms of nonhematologic toxicity were appetite loss (45%) and fatigue (45%). There were no hematologic or nonhematologic toxicities of grade 3 or 4. The regimen of oral UFT plus LV produced only low-grade toxicity and was convenient for outpatients. It appears that the initial UFT dose might be associated with the development of toxicity in the oral UFT plus LV regimen.