NCI Common Toxicity Criteria Research Articles

Oral alpha-lipoic acid to prevent chemotherapy-induced peripheral neuropathy: a randomized, double-blind, placebo-controlled trial

Chemotherapy-induced peripheral neuropathy is frequently a dose-limiting factor in cancer treatment and may cause pain and irreversible function loss in cancer survivors. We tested whether alpha-lipoic acid (ALA) could decrease the severity of peripheral neuropathy symptoms in patients undergoing platinum-based chemotherapy. Cancer patients 18 years or older were randomly selected to receive either 600 mg ALA or a placebo three times a day orally for 24 weeks while receiving chemotherapy regimens including cisplatin or oxaliplatin. Neuropathy was measured by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) scale and the NCI Common Toxicity Criteria for Adverse Events neurotoxicity grades. Results from timed functional tests and the Brief Pain Inventory (BPI) were secondary endpoints. Seventy of 243 (29 %) patients completed the study (24 weeks). Both the ALA and the placebo arms had a comparable drop-out rate. No statistically significant differences were found between the ALA and the placebo groups for FACT/GOG-Ntx scores, BPI scores, and patients' functional outcomes. This strategy of oral ALA administration was ineffective at preventing neurotoxicity caused by oxaliplatin or cisplatin. High attrition rates due to poor patient compliance and manner of dosage administration in this trial demonstrated a lack of feasibility for this intervention. Future studies to explore ALA as a neuroprotective agent should take heed of the barriers confronted in this study.

Abstract P4-16-08: Neoadjuvant depot hydroxy-progesterone and vitamin D3 in large operable and locally advanced breast cancer: Planned safety and response analysis of a phase III randomized controlled trial

Abstract Background- The active metabolite of Vitamin D, 1,25-dihydroxycholecalciferol (Arachitol), and D3 analogs are known to be cytotoxic, anti-proliferative, pro-apoptotic[2] and potentiate responsiveness to cytotoxic agents such as doxorubicin.[3] Depot hydroxy-progesterone caproate (DHPC) has shown benefit in disease-free and overall survival when given as a single dose prior to definitive surgery in women with node positive operable breast cancer. [1] We undertook a factorial randomized controlled phase III study to evaluate the safety and efficacy of these interventions in the neoadjuvant setting in patients with operable and locally advanced breast cancer (NCT01608451). Methods- The study was planned as a phase III, 2×2 factorial, randomized controlled trial with a sample size of 800. Women with high-risk (clinically T2N2, T3N1-3, all M0) operable or locally advanced breast cancer who were planned for neoadjuvant chemotherapy prior to surgery, were recruited in the study. Patients were randomized (2×2) to one of the following 4 arms: patients in Arm A received standard 4 cycles of anthracycline-based neoadjuvant chemotherapy followed by surgery, those in Arm B received 500 mg of DHPC 5-14 days prior to each cycle of chemotherapy and prior to surgery, those in Arm C received intramuscular injection of 300,000 IU Arachitol, and those in Arm D received a combination of both the experimental interventions at similar time points. The primary endpoint was disease-free survival and the secondary endpoints were overall survival, pathological complete response (pCR, defined as absence of invasive cancer in breast and axillary lymph nodes in the surgical specimen), and toxicity (defined by NCI Common Toxicity Criteria). We are reporting here a planned analysis of the secondary endpoints, after recruitment of 1/6th of total sample size, on toxicity and responses in the study arms. Results- From September 2007 to December 2010, 120 patients were recruited in the study, 27 in Arm A, 33 in Arm B, 29 in Arm C and 31 in Arm D. The arms were balanced with respect to known prognostic variables including age, clinical tumor size, clinical nodal status and ER/PR and HER2 status. Of the 120 patients, 44(36.6%) were ER &/or PR positive with HER2 negative tumors, 27(22.3%) triple negative, 41(33.9%) ER &/or PR any with HER2 positive, and receptor status was unknown in 6.6%. The rates of all grades and grade III-IV febrile neutropenia, hepatic dysfunction, renal dysfunction and dyselectrolytemia were not different between the 4 arms. Surgery was performed in 114 of 120 patients(95.0%). The pCR rates in DHPC arm vs no DHPC was 5/51(9.8%) and 5/59(8.5%) respectively. The pCR rates in Arachitol versus no Arachitol arms were 5/55(9.0%) in both arms. Conclusions- The addition of depot hydroxy-progesterone and vitamin D3 in neoadjuvant setting were found to be safe and well tolerated. Further details of toxicity, response and the ongoing study will be presented at the Symposium.

Pilot study assessing a seven-day continuous intrathecal topotecan infusion for recurrent or progressive leptomeningeal metastatic cancer

To determine the feasibility and toxicity profile of topotecan administered as a seven-day continuous intrathecal infusion for patients with leptomeningeal metastasis secondary to recurrent or progressive central nervous system cancer. Two patients with central nervous system leptomeningeal metastasis were treated with a seven-day continuous infusion of topotecan (0.2 mg/day) administered via continuous intrathecal/intraventricular infusion at a rate of 0.6 mL/h, totaling 1.4 mg/course. CSF and plasma concentrations of topotecan closed lactone (the active metabolite) were quantified at various points during topotecan infusion. Patients were monitored for neurologic and systemic toxicities according to NCI common toxicity criteria. Both patients tolerated the seven-day continuous topotecan without any significant adverse events. One patient received a second course 21 days after treatment initiation. CSF concentration of topotecan closed lactone ranged from 3.73 to 312 ng/mL (median = 131 ng/mL) and plasma topotecan closed lactone ranged from 0.44 to 1.78 ng/mL (median = 0.92 ng/mL). The median CSF topotecan concentration was greater than the median serum topotecan concentration by a 44-fold magnitude when samples were obtained at the same time point. None of the patients experienced any grade 3 or higher hematological toxicities or signs of arachnoiditis. A seven-day continuous intrathecal infusion of topotecan is well tolerated and has the potential of maximizing central nervous system drug exposure.

Measures of polypharmacy and chemotherapy toxicity in older adults with cancer.

9545 Background: Polypharmacy is common and associated with adverse clinical outcomes in older adults. Potentially inappropriate medication (PIM) use serves as an adjunctive assessment of polypharmacy. The goals of this study in an outpatient population of older adults with cancer (CA) were: 1) to estimate the prevalence of polypharmacy using multiple measures; and 2) to determine the relationship between polypharmacy and chemotherapy (chemo) toxicity. Methods: Medication use was evaluated in 500 patients (pts) age ≥65 years with invasive CA who were starting a new chemo regimen. Polypharmacy was defined by number of daily medications (meds), including non-prescription meds. PIM use was defined by 4 indices: Beers (2003 and 2012 update), Zhan, and HEDIS Drugs to Avoid in the Elderly (DAE) criteria. Prevalence of polypharmacy, PIM, and their association with grade 3-5 chemo toxicity [NCI Common Toxicity Criteria (v. 3.0)] were analyzed using chi square test and unconditional logistic regression. Results: All 500 pts were evaluable [mean age, 73 years (range 65-91); 56% female; 61% stage IV]. The mean number of daily meds was 5 (range 0-23); 38% used ≤3 daily meds, 51% used 4-9 meds, and 11% using ≥10 meds. Using 0-3 daily meds as the referent group, no association was found between daily meds and chemo tox: 4-9 meds, OR 1.34 (95% CI: 0.92-1.97); ≥10, OR 0.82 (95% CI: 0.45-1.49). PIM use was identified in 87 (17%), 147 (29%), 54 (11%), and 69 (13%) patients utilizing the 2003 Beers, 2012 Beers, Zhan, and HEDIS DAE criteria, respectively. There was no association between each PIM use index and chemo toxicity (p>0.10 for all). Conclusions: Polypharmacy and PIM use were common in the geriatric oncology population. Although polypharmacy did not increase the risk of chemotherapy toxicity in this sample, further studies of polypharmacy’s impact on additional outcomes, including non-chemotherapy adverse drug events, in older persons with cancer are warranted.

Phase II study of trabectedin in pretreated patients with recurrent epithelial ovarian cancer (REOC).

5559 Background: The prognosis of patients with REOC is extremely poor after several lines of chemotherapy. The choice and timing of therapies must be individualized to optimize survival and quality of life. This open-label, nonrandomized, phase II study was aimed at evaluating efficacy and toxicity of Trabectedin as a single-agent therapy in patients with preteated Recurrent Epithelial Ovarian Cancer (REOC). Methods: Sixteen patients (median age 51 yrs, range 44 – 71) with REOC who progressed after 2 (18.7%), 3 (56.3%) or 4 (25.0%) previous lines of chemotherapy were treated with Trabectedin at the dose of 1.1 mg/m2 via a 3-hour i.v. infusion with dexamethasone pretreatment every 3 weeks until disease progression, unacceptable toxicity or when a stability of disease was reached. Clinical objective response was the primary efficacy endpoint; the secondary one was safety. Response to treatment was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST, version 1.1), and toxicities were graded according to NCI Common Toxicity Criteria, version 2.0. Results: The median number of treatment cycles per patients was 5 (range, 2-9 cycles). A total of 81 cycles were administered. A dose reduction was never required. Main toxicities included anemia (20.9%), leucopenia (15.0%), thrombocytopenia (4.5%) and asthenia (22.2%). No deaths were attributable to therapy. No one showed complete response, while 9/16 partial response (56.2%) and 4/16 stable disease (25.0%) were observed. 3/19 pts (18.8%) progressed on therapy. The median progression-free interval was 18 weeks in patients with partial response; stable disease was maintained for a median time of 12 weeks. Conclusions: Trabectedin 1.1mg/m2 given as a 3-hour i.v. infusion every 3 weeks was well tolerated and has confirmed a very interesting antitumor activity in this heavily pretreated population and it seems also to be a very tolerable regimen. The co-treatment with dexamethasone improves the safety of Trabectedin by reducing drug-induced myelosuppression and hepatotoxicity. Trabectedin has a manageable toxicity profile, and can be safely administered thanks to its secure action profile also in patients with no other viable therapeutic options.

Abstract P3-08-05: Title: Copy number variation and risk of chemotherapy-related infection.

Abstract Background: Copy-number variations (CNVs) are DNA changes that result in regions of the genome being either duplicated (copy number gains) or deleted (copy number losses). CNVs have been identified in 12% of the human genome. Although CNVs do not appear to have a major role in disease susceptibility, it is known that they are involved in drug metabolism, toxicity and response. Infection is a common dose and/or treatment limiting chemotherapy-related toxicity. Infections can be a major cause of morbidity and mortality. Although a limited number of studies have investigated the association of single nucleotide polymorphisms (SNPs) with severity of infection, no studies so far have identified CNV associations with chemotherapy-related infection. In a non-oncological setting, CNVs have been noted to be associated with altered risk of certain types of infections and severe sepsis. This study aims to evaluate whether CNV are associated with the risk of chemotherapy-related infection in a genome wide association study (GWAS) of breast cancer patients recruited to clinical trials and treated with chemotherapy regimens including paclitaxel, epirubicin, cyclophosphamide, gemcitabine, 5fluorouracil and methotrexate. Method: DNA from blood and saliva samples were collected as part of the pharmacogenetics GWAS, PGSNPS. Chemotherapy-related infection was assessed using the NCI Common Toxicity Criteria (CTC). Patients (n = 1921 samples) were classified as cases (NCI CTC grades 2–4) or as controls (NCI CTC grades 0–1). The Affymetrix SNP6.0 array, which contains more than 946,000 probes for the detection of CNVs and more than 906,600 SNPs, was used as the copy number estimation platform. DNA was segmented using DNAcopy (circular binary segmentation). CNVs were called based on their median and standard deviation. Log-ratios larger than the median plus 2 times the standard deviation were considered gains and log-ratios with values smaller than 2.5 times the standard deviation were considered as losses. Only regions with a copy number alteration present in at least a 10% of the samples were considered for the analysis. Fisher's exact test was performed on each of these regions and the variable ‘infection’. 2-side p-values were obtained and adjusted using Benjamin-Hochberg correction. Results: One CNV region (frequency of gain 0.16) showed an association with increased risk of infection (Odds Ratio=1.79, 95% Confidence Interval [1.34–2.40], P = 6.37 × 10−5). Five other CNV regions demonstrated copy number gains and three CNV regions showed copy number losses that were associated with an increased risk of infection (P = 10−4). All regions had a frequency of gain or loss > 0.10 and were therefore not rare variants. Conclusion: These data suggest that CNVs may play a role in increased risk of chemotherapy-related toxicity. The most significant CNVs associated with infection are currently undergoing validation using an independent cohort of adjuvant breast cancer patients with similar exposure to chemotherapy and comparable documentation of chemotherapy-related infection. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-08-05.

NCI Common Toxicity Criteria and Mortality After Chemotherapy for Acute Myeloid Leukemia (AML)

Abstract 1479Abnormal values for creatinine, bilirubin, AST, and ALT following chemotherapy, in particular in phase 1 trials, are interpreted using NCI common toxicity criteria. By convention, grade 3 or 4 toxicity leads to dose reduction while grade 1 or 2 toxicity does not. However, grade 3 – 4 toxicity is typically asymptomatic, calling into question the relevance of these criteria. In an attempt to provide a more empirical basis for decisions we analyzed the relation between (a) grades of NCI toxicity for bilirubin, creatinine, ALT, and AST following chemotherapy for AML and (b) death. Specifically we examined 752 courses of chemotherapy in 533 patients delivered at the University of Washington or Fred Hutchinson Cancer Research Center for newly- diagnosed or relapsed/refractory AML between 2002 and 2012. Patients had at least 2 sets of renal and liver function test values but were excluded if either pretreatment bilirubin or creatinine was greater than 2.0 to better approximate a population in an early phase trial. We compared initial and maximal lab values in the first 28 days in the 40 courses that resulted in death before 28 days, and in the 712 courses that did not (6% death rate; the death rate per patient was 7%). Maximum lab values for creatinine were strongly related to mortality, with grade O having a 1.0% mortality rate and with each increasing grade having a statistically significant increase in mortality over the immediately preceding level: grade I: 5%, grade II: 22%, grade III or IV: 50%. Bilirubin had a significant increase in mortality at grade II (10.0%, p=.009 relative to grade O) and grade III-IV (15.4%, p=.0007 relative to grade O). AST was also associated with increased mortality at grade II (9.5%, p=.04 relative to grade O) and grade III-IV (15.6%, p =.0006 relative to grade O). ALT was not correlated to mortality, even at grade III-IV (9.5% versus 5.3% at grade 0, p=0.23). Although these correlations obviously do not imply causation, it might be argued that grade II toxicity for creatinine, associated with a 4-fold increase in mortality, should result in dose reduction. In contrast, it might be argued that dose reduction should not occur for grade III/IV ALT toxicity, which correlated poorly with mortality. In any event our data suggest that if the principal purpose of toxicity grading is to guide subsequent dose reduction to prevent death, the NCI toxicity criteria should be revisited. Disclosures:No relevant conflicts of interest to declare.

Efficacy and Safety of Deferasirox in Patients with Transfusional Iron Overload After Allogeneic Hematopoietic Cell Transplantation: The CICL670ADE02 Trial

AbstractAbstract ▪485▪This icon denotes a clinically relevant abstractTransfusional iron overload (TIO) contributes considerably to treatment-related morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Data on post-HCT treatment of secondary hemochromatosis are limited. The results of an open-label, single arm, multi-center trial evaluating the efficacy and safety of the iron chelator deferasirox (DEX) in recipients of HCT with TIO are presented. Patients and methods:The study was conducted in 6 German centers. The primary objective was to evaluate if DEX could provide clinically acceptable chelation in a target pool of 76 adult patients (pts) with TIO 3–12 months after related/unrelated HCT irrespective of conditioning regimens. TIO was defined as a serum ferritin (SF) ≥1000ng/ml without active inflammation (CRP <10mg/l), and a history of >20 units of red blood cell transfusions (RBC) or 100mL/kg of prepacked red blood cells. Main exclusion criteria were ANC <1000/mm3, transaminases (TA) >5xULN, and serum creatinine (Cr) >1.5xULN. DEX 30 minutes prior to lunch was started with 10 mg/kg/d over 52 weeks or until SF <500ng/ml was reached. Subsequent dose adjustments were performed in steps of 5–10 mg/kg/d based on SF and safety assessments. DEX was reduced by 10mg/kg if Cr increased by >33% of baseline (BL) or was >1.5xULN. DEX had to be interrupted if any toxicity > grade 2 according to the NCI common toxicity criteria (CTC) occurred. An independent Data Safety Monitoring Board reviewed safety data on an ongoing basis. Surrogate markers monitored were SF, serum transferrin and transferrin saturation (TS). Results:After a median of 168 days after HCT, 47 (62%) males and 29 (38%) females [median age 56 y] were included. Cyclosporine was taken by 54 (71%) pts. Median number of RBC prior to study entry was 37 units. Post-HCT, 14 (18.4%) pts received transfusions. Post-HCT HFE genotype was mutated in 27/67(40%) pts (heterozygote-H63D,n=13; heterozygote-C282Y,n=7; heterozygote for other mutations, n=6; homozygote-H63D,n=1). At BL, median SF and TS were 2045ng/ml and 56% respectively at a median CRP of 2.7 mg/l. SF correlated with TS (r=0.5, p<.0001), and the number of RBC (p=0.01). DEX was started with a median daily dose of 625mg. From BL to the end of study (EOS), mean daily dose was 629 (9 mg/kg/day) with a median of 503.7mg. SF declined steadily with a median of 957ng/ml at EOS representing a 53% reduction from BL (p<.0001). An initial rise in TS with a median of 92% at a median of 7 weeks was followed by a steady decrease reaching a median of 44.4% at EOS. Over time, stable trough serum cyclosporine levels per patient were measured irrespective of DEX dose. Hb improved under treatment with a median Hb of 12.7g/dl at EOS representing a 12.4% increase from BL. Chronic GvHD was documented in 34 (44.7%) pts (limited 79%; extensive 21%). DEX was discontinued in 8 (9.3%) pts due to relapse/progression of hematologic disease and in one patient (1.3%) due to anemia. Overall, in 1008 safety assessments performed, leucopenia, neutropenia, thrombocytopenia, and TA elevations >grade 2 were 1.6%, 2.3%, 5.5%, and 2.8% respectively. Main non-hematologic adverse events (AEs) were gastrointestinal (GIT) (nausea, vomiting, diarrhea) (16.9%); infections (15.1%); skin (rash, erythema) (4.4%). Cr values above BL were observed in 41 (54%) pts. At EOS, median Cr was above BL by a median of 10 μmol/l. AEs were mostly mild to moderate, transient, and dose-related. On study, a median of 2 drug dosage adjustments/interruptions were made mainly for Cr elevation (27%), GIT-AEs (15%), TA elevation (10.4%), and skin AEs (3.8%). Study drug was permanently discontinued because of GIT-AEs in 3 (4%), skin AEs in 3 (4%), TA in 2 (2.6%), and Cr in 2 (2.6%) pts. Conclusions:A highly significant reduction in serum ferritin could be induced with deferasirox after allogeneic HCT with an acceptable safety profile. Stable trough serum cyclosporine levels could be maintained over time irrespective of the daily dose of deferasirox. Our results indicate that a daily dose of 7.5–10mg/kg is effective, and well tolerated in a complex cohort with TIO after allogeneic HCT. Disclosures:Al-Ali:Novartis: Honoraria. Lieder:Novartis Germany: Employment. Albrecht:Novartis Germany: Employment. Leismann:Novartis Germany: Employment. Bug:Novartis Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grant Other. Kroeger:Novartis Germany: Honoraria, Research Funding. Platzbecker:Novartis Germany: Advisory Board Other, Honoraria.

The Effect of Diabetes on Oxaliplatin-Induced Peripheral Neuropathy

Chemotherapy-induced neurotoxicity is a significant source of morbidity for cancer patients. This study aimed to assess the relationship between preexisting diabetes and clinically significant (National Cancer Institute Common Toxicity Criteria grades 2 and 3) OXIPN; between diabetes, and the cumulative dose at onset of OXIPN; and between other preexisting medical conditions and the development of OXIPN. We reviewed medical records of all patients with stage II-IV colon cancer treated in the Albert Einstein Cancer Center, Philadelphia, with oxaliplatin from 2005 to 2009. Exclusion criteria included preexisting neuropathy, previous neurotoxic chemotherapy exposure, and incomplete medical records. The NCI Common Toxicity Criteria was used to grade sensory neuropathy. Univariate analysis was used to estimate odds ratios and confidence limits for prevalence of OXIPN in patients with and without diabetes. The mean level and cumulative doses were compared using the t test. Sixty-two patients met the study criteria; 23 oxaliplatin-treated patients were excluded. The crude incidence of any OXIPN was 65%. There was no relationship found between development of OXIPN and the presence of diabetes, smoking, hypertension, or statin use. However, the mean cumulative dose of oxaliplatin was significantly lower for patients with diabetes who developed neuropathy, compared with those without diabetes (388 vs. 610 mg/m(2); P = .021). Although the presence of diabetes did not appear to affect the severity of OXIPN, patients with diabetes developed OXIPN at a lower cumulative dose of oxaliplatin (P < .05). The results may have implications for treatment of patients with diabetes and colon cancer.

Mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) chemotherapy for treatment of metastatic or recurrent uterine leiomyosarcoma.

e15523 Background: Metastatic or recurrent uterine leiomyosarcoma is often treated with chemotherapy. There are a limited number of viable regimens that are effective and well tolerated. Our objective was to evaluate the efficacy and toxicity of the MAID chemotherapy regimen in women with advanced uterine leiomyosarcoma. Methods: We conducted a retrospective analysis of 18 patients who received MAID chemotherapy for metastatic or recurrent uterine leiomyosarcoma between 1998 and 2010. Ten patients had received prior radiation therapy (3) and/or gemcitabine-docetaxel chemotherapy (8). The MAID regimen was administered intravenously in the hospital every three weeks as follows: mesna 120 mg/m2 prior to ifosfamide day 1 and 1.2 mg/m2 infusion over 8 hours starting immediately after the ifosfamide d 1-3, doxorubicin 15 mg/m2 d 1-3, ifosfamide 1.2 gm/m2 d 1-3, and dacarbazine 200 mg/m2 d 1-3. Disease response was evaluated by physical exam and imaging studies. Toxicity was assessed using NCI Common Toxicity Criteria. Results: Response to MAID chemotherapy was observed in 7 (39%) of 18 patients: 2 (11%) complete responses and 5 (28%) partial responses. Stable disease was noted in 8 patients (44%) and disease progression occurred in 3 patients (17%). There was no difference in response rates between patients who had received prior chemotherapy (3/8, 38%) and patients who had not received prior chemotherapy (4/10, 40%). A total of 90 cycles of chemotherapy were administered with a median of 5.5 (range 1-9) cycles per patient. Grades 3 and 4 toxicity requiring dose reduction of treatment delay complicated only 4 cycles (4.4%), including only one admission for neutropenic fever. There were no reported cases of cardiac dysfunction, hemorrhagic cystitis, or encephalopathy. The median progression-free survival was 10 (range 6-152) months for responders, 7.5 (range 3-120) months for those with stable disease, and 0 months for those with progressive disease. Conclusions: This is the largest series of uterine leiomyosarcoma patients treated with MAID chemotherapy. MAID chemotherapy in the dosage schedule utilized is a well-tolerated and effective regimen.

Concomitant chemoradiotherapy phase II study comparing pemetrexed/carboplatin with paclitaxel/carboplatin in patients with unresectable stage III non-small cell lung cancer.

e17527 Background: Concomitant chemoradiotherapy is the standard treatment of unresectable stage III non-small cell lung cancer (NSCLC). However, the optimal chemotherapy regimen is still controversial. We have conducted a phase II study to evaluate concomitant treatment using pemetrexed/carboplatin or paclitaxel/carboplatin in these patients. The purpose of this study is to compare the feasibility and activity, and also assess its impact on progression-free survival (PFS). Methods: A total of 37 patients were enrolled between January 2008 and May 2011. Patients received concomitant chemoradiotherapy [thoracic radiotherapy and pemetrexed 500mg/m2, carboplatin AUC 5 every 3 weeks for 2 cycles; or paclitaxel 50mg/m2, carboplatin AUC 2 weekly for 6 weeks. ] Objective response rate according to the RECIST criteria was recorded and toxicity was evaluated using the NCI Common Toxicity Criteria. The Kaplan–Meier method was used to evaluate patient survival. Univariate analysis of patient characteristics and tumor responses was conducted using the Chi-square and Fisher's exact test. Results: The overall response rate for pemetrexed/carboplatin was statistically superior to paclitaxel/carboplatin (P &lt;0.05). In patients with adenocarcinoma, there was a significant improvement in PFS with pemetrexed/carboplatin versus paclitaxel/carboplatin (11.6 vs. 9.3 months, respectively). For pemetrexed/carboplatin, rates of grade 3 or 4 neutropenia, anemia, thrombocytopenia, and febrile neutropenia were significantly lower (P &lt;0.05), whereas grade 3 or 4 fatigue (P = 0.08) was more common. Conclusions: This data suggests that concomitant chemoradiotherapy with pemetrexed/carboplatin was better tolerability and more efficacy than paclitaxel/carboplatin in a Chinese population with unresectable stage III NSCLC. Better outcomes were observed in patients with adenocarcinoma in pemetrexed/carboplatin. Although the data presented herewith appears more promising in pemetrexed/carboplatin, this study is relatively small, and more data from randomized trials are needed to further validate this regimen.

Phase I trial of yttrium 90 resin microspheres in the treatment of colon cancer liver metastases progressing despite hepatic arterial as well as systemic chemotherapy: Preliminary results.

625 Background: Prospective evaluation of the safety of Selective Interval Radiation Therapy (SIRT) using yttrium 90 microspheres (Y90) in patients with colon cancer liver metastases (CLM) who failed hepatic arterial (pump) and systemic chemotherapy. Methods: This prospective single center study, assessed the safety, dose limiting toxicities (DLT) and the maximum tolerated dose (MTD) of Y90 in a selected, heavily pretreated population. Upon IRB and FDA approval individualized Y90 doses were calculated according to a volumetric method and the body surface area (BSA) method as instructed by the company. SIRT treatment was administered in three escalating dose levels (cohorts): the first cohort received 70%, the second 85%, and the third 100% of the calculated dose. All patients received chemotherapy as deemed by the patients' medical oncologist post SIRT treatment. DLT was defined as new, post treatment, grade 3 toxicities, and evaluated according to the NCI Common Toxicity Criteria (NCI-CTC) 3.0. Response to treatment was evaluated by imaging (using a combination of WHO, RECIST, modified RECIST and SUV changes) and CEA levels. Kaplan Meier methodology was employed to calculate Progression Free (PFS) and Overall (OS) Survival. Results: From September 2009-2011, 19 patients received Y90. Common complaints post treatments were: grade 1-2 fatigue and grade 1 fever, which are known side effects of SIRT. No DLTs were observed. Grade 3 hyperbilirubinemia was recorded for two patients and was attributed to progressive disease; one patient in the third cohort suffered grade 3 nausea and pain. Twelve patients (70.6%) responded (defined as stable disease or better) while five (29.4%) progressed-this was based on evaluations from initial post treatment imaging. Two patients’ imaging is pending. Median PFS and OS were 6 [95%CI: 3.2-9.7] and 16 [95%CI: 5.8-17.6] months respectively. Conclusions: It is safe to administer the entire dose of Y90 in patients with CLM who progressed despite prior pump and systemic chemotherapy. Oncologic outcomes are promising.

P5-19-05: Age-Related Changes in the Pharmacokinetics (pK), Response, and Toxicity of Weekly nab-Paclitaxel in Patients with Metastatic Breast Cancer (MBC).

Abstract Background: Although cancer is a disease of aging, few studies have evaluated the association between patient age and the pK or pharmacodynamics (pD) of cancer therapeutics. The goals of this study were 1) to evaluate the age-related changes in the pK and pD of weekly nab-paclitaxel in patients with MBC; 2) to determine response rate; and 3) to explore the relationship of age with pK and pD parameters (i.e., dose reductions, dose delays and grade ≥ 3 toxicities). Patients and Methods: Forty patients with MBC, receiving 1st or 2nd line chemotherapy, entered an IRB approved protocol to evaluate the age-related changes in the pK of weekly nab-paclitaxel administered at 100 mg/m2 IV for 3 weeks followed by a 1-week break. Patients were accrued from 4 age strata &amp;lt;50, 50–60, 60–70, and &amp;gt;70 years of age. Blood samples were collected for pK analysis with the first dose of nab-paclitaxel. Response was assessed every 2 cycles. Toxicity was graded using the NCI Common Toxicity Criteria for Adverse Events (v 3.0) and was adjudicated as attributable to nab-paclitaxel if it was possibly, probably, or definitely related. Linear regression analysis was used to examine the strength of the relationship between patient age and natural logarithm of 24 hour area under the curve (AUC). Two-sided two-sample t-tests were used to assess if there was a difference in mean age based on the presence of pD variables (i.e., dose reductions, dose delays and grade ≥ 3 toxicities). The significance level was set to 0.05. Results: Of the 40 patients who entered the study, 39 (98%) were evaluable with a mean age of 60 (SD=13.4; min=30; max=81). Patients were accrued in the following age cohorts: &amp;lt;50 (n= 10; 26%), 50–60 (n= 5; 13%), 60–70 (n= 15; 38%), and &amp;gt;70 (n= 9; 23%) years of age. The median number of courses completed was 4 (min=1, max=21). The response rate was: 0% (n=0) CR, 31% (n=12) PR, 38% (n=15) SD. Grade 3 toxicity was experienced by 26% (n=10). We observed 8% (n=3) grade 3 hematological toxicities [neutrophils (n=1; 3%), leukocytes (n=2; 5%)] and 18% (n=7) grade 3 non-hematological toxicities [nausea and hypophosphatemia (n=1; 3%), diarrhea and infection without neutropenia (n=1; 3%), fatigue (n=2; 5%), hyponatremia (n=1; 3%), and infections without neutropenia (n=2; 5%)]. There were no cases of grade 4 or 5 toxicity. Grade 2 sensory neuropathy was experienced by 8% (n=3; no cases in the 70+ age cohort). Dose reductions or course delays were experienced by 62% (n=24) and 21% (n=8), respectively. There was a borderline significant positive association between age and natural logarithm of total nab-paclitaxel 24 hour AUC (coef=.01; se=.006; p=0.055; n=36). There were no differences in the mean ages based on the presence of grade 3 or higher toxicity (p =0.75), need for dose reductions (p=0.48), or need for dose delays (p=0.61). Discussion: There is a borderline statistically significant relationship between age and 24 hour AUC but no differences in mean age based on pD variables (i.e., dose reductions, dose delays and grade ≥ 3 toxicities) were identified. The treatment is well-tolerated across all age groups. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-19-05.

Impact of National Cancer Institute's Common Toxicity Criteria and Common Terminology Criteria for Adverse Events on Quality of Treatment Related Harms Reporting: An Analysis of National Cancer Institute's Co-Operative Group Phase III Randomized Controlled Trials

Abstract 673 Background:Informed decision making in health care requires balancing of information related to benefit and harms of treatments. However, it is shown that the amount of space dedicated for presenting information on harms in randomized trials is less than that used to list authors' names and affiliations. Poor or absent reporting of treatment-related harms can mislead decision makers at all levels (public, researchers, funding agencies). Several efforts have been made to improve the quality of data collection and reporting of treatment-related harms. In oncology, after recognizing that many cancer treatments are toxic, and not infrequently result in severe morbidity and even death, the National Cancer Institute's (NCI) lead the way to standardize terminology and data collection on treatment-related harms. The first standards for collection of harms data in cancer known as Common Toxicity Criteria (CTC) were developed in 1982 followed by three revisions. Here we investigate the impact of NCI CTC and NCI common terminology criteria for adverse events (CTCAE) on quality of reporting of treatment-related harms in a cohort of NCI cooperative group (NCI-COG) trials. Methods:We extracted data on elements addressing assessment of treatment-related harms from protocols and matching publications from all consecutive phase III NCI-COG randomized controlled trials (RCTs) for the years 1955 to 2006. RCTs reporting treatment-related mortality data as deaths per arm and treatment-related morbidity data as per patient per arm were categorized to have good quality. RCTs reporting treatment-related morbidity data in the aggregate method such as % of events per arm were categorized as intermediate quality while RCTs which did not report any treatment-related harms data were classified as poor quality. Results:We reviewed 429 RCTs enrolling 157,337 patients. Twenty seven percent (115/429) of RCTs had good quality of reporting of treatment-related harms while 63% (271/429) of RCTs were of intermediate quality. Only 10% (43/429) of RCTs had poor quality of reporting of treatment-related harms. Quality of treatment-related harms reporting did not improved with time. Nine percent (37/429) of RCTs were published before introduction of NCI CTC v1.0 while 66% (284/392) were published after NCI CTC v1.0 but before introduction of NCI v2.0 and 85% (92/108) of RCTs were published after NCI CTC v2.0 but before NCI CTCAE (figure). The quality of treatment-related harms reporting improved after introduction of NCI CTC v1.0 (p-value=0.002) while NCI CTC v2.0 (p-value= 0.78) and NCI CTACE (p-value=0.001) did not have positive impact on treatment-related harms reporting (figure). The NCI CTC/NCI CTCAE or similar standardized treatment-related harms assessment instrument was explicitly referred to in 55% (235/429) of protocols vs. 47% (203/429) of publications. Forty five percent (193/429) of protocols mentioned seriousness of treatment-related harms compared to 33% (142/429) of publications. Severity of treatment-related harms was mentioned in 63% (272/429) of protocols versus 71% (303/429) of publications. Conclusion:Quality of treatment-related harms reporting in NCI-COG RCTs did not improved with time. The introduction of NCI CTC initially did improve quality of treatment-related harms reporting. However, NCI CTC V2.0 and NCI CTCAE did not subsequently appear to impact reporting of quality of treatment-related harms in NCI-COG RCTs. Disclosures:No relevant conflicts of interest to declare.

Cyclophosphamide, Adriamycin, Vincristine and Prednisone Plus Rituximab (CHOP-R) in Fludarabine (F) Refractory Chronic Lymphocytic Leukemia (CLL) or CLL with Autoimmune Cytopenia (AIC) or Richter's Transformation (RT): Final Analysis of a Phase II Study of the German CLL Study Group

Cyclophosphamide, Adriamycin, Vincristine and Prednisone Plus Rituximab (CHOP-R) in Fludarabine (F) Refractory Chronic Lymphocytic Leukemia (CLL) or CLL with Autoimmune Cytopenia (AIC) or Richter's Transformation (RT): Final Analysis of a Phase II Study of the German CLL Study Group

Taxane-induced nail changes: Predictors and efficacy of the use of frozen gloves and socks in the prevention of nail toxicity

PurposeThe primary endpoint of this study was to determine predictors of taxane-related nail toxicity. The secondary endpoint was to evaluate the efficacy of the use of frozen gloves and socks in the prevention of taxane-related nail toxicity. MethodsThis descriptive, interventional, cross-sectional study was conducted with 200 patients. The patients were assigned to the frozen gloves/socks intervention group or control group. Frozen gloves/socks were applied only in hourly taxane-based treatments. The Patients Record Forms of the clinic were used in data collection. Nail changes were graded using the NCI Common Toxicity Criteria for each patient and treatment. Logistic regression analysis was performed to predict the factors that affect nail changes. ResultsThe majority of the patients enrolled in the study were women diagnosed with breast cancer. The two groups were statistically similar for the cancer diagnosis, type and number of taxane cycles administered. Grade 1 nail toxicity was found in 34%, grade 2 in 11%, and grade 3 in 5.5% patients. Taxane-related nail toxicity was higher in patients who were female, had a history of diabetes, received capecitabine in conjunction with docetaxel and had breast or gynecological cancer diagnosis. Nail changes increased with an increase in the number of taxane cycles administered, BMI and severity of treatment-related neuropathy. ConclusionsThe multivariate analysis demonstrated that BMI, breast or ovarian cancer diagnosis and the number of taxane cycles administered were the independent factors for this toxicity. No statistically significant difference in nail toxicity incidence and time to occurrence of nail changes was found between the intervention and the control groups.

Prospective analysis of chemotherapy-induced neuropathy in patients with gynecologic malignancies.

e19737 Background: Chemotherapy induced peripheral neuropathy (PN) is a serious dose- limiting toxicity affecting chemotherapy administration. It is unclear how many patients are assessed for PN. The incidence and severity of PN depend on the chemotherapeutic agents, cumulative dose, schedule and patient characteristics. Taxanes and platinum analogs are associated with the highest incidence of PN. Few tools have been validated to assess the incidence and severity of PN. The NCI Common Toxicity criteria (NCI-CTCAE), Patient Neurotoxicity Questionnaire (PNQ), and Functional Assessment of Cancer Therapy Neurotoxicity Subscale (FACT-Ntx) are the most studied. The primary objective of our study was the prospective evaluation of the incidence of severe PN (NCI-CTCAE≥2) in patients with gynecologic malignancy receiving taxane/platinum regimen. The secondary endpoint was to determine the questionnaire that was the most sensitive in predicting PN; NCI-CTCAE and PNQ. Methods: Fifty-one patients with ovarian or endometrial cancer receiving carboplatin-paclitaxel based chemotherapy were enrolled and 451 assessments were completed. Assessments were performed at baseline, chemotherapy visists and monthly follow ups. Results: Seventeen patients had baseline PN and 29 (85.3%) patients developed PN during treatment. The table depicts the mean cumulative doses for both agents and both tools. Conclusions: The incidence of carboplatin-induced PN has been reported to range from 13% to 42% and the reported incidence of paclitaxel induced PN varied from 18% to 29% (every 3 weeks dosing, mean cumulative dose to onset of grade ≥ 2 PN-715 mg/m2). We report the incidence of severe PN in 85.3% of patients receiving combination of carboplatin/paclitaxel. These preliminary results show trend for PNQ tool to detect both sensory and motor PN at lower mean cumulative doses when compared to NCI-CTCAE. Our higher incidence of PN than previously reported for carboplatin/paclitaxel demonstrated a need for standarization of detection and treatment of PN. Tool No. of Patients (%) Paclitaxel (mg) Carboplatin (mg) NCI-CTCAE sensory 20 (58.8) 1,138 1,907 NCI-CTCAE motor 16 (47.1) 1,142 1,810 PNQ sensory 18 (52.9) 818 1,383 PNQ motor 18 (52.9) 1,003 1,588

Predictors of chemotherapy-induced peripheral numbness or tingling in patients with cancer.

e19674 Background: Chemotherapy-induced peripheral numbness or tingling (CIPNT) continues to be a substantial problem for many cancer patients. The purpose of this study was to identify the predictors of CIPNT. Methods: This prospective descriptive study was conducted at Adnan Aydiner Oncology Center with 490 cancer patients between December 2005 and January 2011. Personal characteristics, illness related characteristics and symptom severity of the patients were assessed by using Patients Clinical Record Forms. The severity of CIPNT and other chemotherapy related side effects was graded by the NCI Common Toxicity Criteria at each treatment of the patient. Frozen gloves were applied only in hourly taxane based treatment. Descriptive statistics and nonparametric tests were used during the data analysis. Logistic regression analysis was performed to predict the factors affecting the CIPNT. For all statistical analyses, a two-sided p value of less than 0.05 was considered to be statistically significant. Results: Most of the patients were women and their mean age was 55.72±11.63. Most of them had breast (36.9%) and lung (36.1%) cancer diagnosis and 51.8% had received taxan based therapy. Grade 1 CIPNT was found in 288 out of 490 patients (58,8%), grade 2 in 67 (13,7%), and grade 3 in 43 (8,8%) patients. In univariate analysis the factors affecting CIPNT were gender, age, body mass index, occupation, hypertension, primary tumor, stage of disease, type of chemotherapy agent, interval or number of the chemotherapy cycles, and baseline level of leukocyte or hemoglobin. Frozen glove did not prevent CIPNT. A multivariate analysis of 12 out of 22 clinical and biological factors selected after univariate analysis showed a higher risk of CIPNT in patients who had colorectal or ovarian cancer (OR 3,35 [1.82-6.14]), metastatic disease (OR 3,39 [1.87-6.17]), hypertension (OR 4,94 [1.96-12.29]), women (OR 4,34 [2.16-8.71]), weekly-biweekly therapy (OR 2,37 [1.16-4.83]) and old age (OR 1,03 [1.01-1.06]), respectively. Conclusions: Our data showed that many clinical and biological factors of the patients could predict a higher risk of CIPNT. In contrast to our thoughts frozen gloves did not reduced CIPNT associated with taxane.

Endostar in combination with radiotherapy and paclitaxel/carboplatin in patients with unresectable non-small cell lung cancer of stage III: Preliminary results of a phase II study.

7043 Background: A feasibility study was performed to examine the safety and activity profile of Endostar in combination with radiotherapy and Paclitaxel/Carboplatin in patients with unresectable non-small cell lung cancer(NSCLC) of stage III. Methods: Patients with unresectable stage III NSCLC will receive thoracic radiation therapy in 2Gy fractions five times weekly to a total dose of 60-66 Gy and concurrent with Endostar 7.5 mg/m2 over 3 hours d1-14, paclitaxel 50 mg/m2 weekly over 1 hour, carboplatin AUC=2 mg/mL/min over 30 min weekly. Followed by Endostar 7.5 mg/m2 d1-14, paclitaxel 175 mg/m2 d1 and carboplatin AUC=5 mg/mL/min d1 every 3 weeks for 2 cycles as consolidation treatment. Objective response rate according to the RECIST criteria was recorded and toxicity was evaluated using the NCI Common Toxicity Criteria. Results: 12 eligible patients enrolled in the study received concurrent Endostar, paclitaxel/carboplatin and definitive thoracic radiation therapy (TRT). Three patients were unable to complete the followed consolidation treatment (two because of pulmonary toxicity and one because of progressive disease). 9 patients (75.0%) had a partial response, while 2 patient’s disease remained stable and 1 patient had progression of the disease. The overall response rate (75.0%,95% confidence interval (CI): 51%-97%) didn’t exceed the goal per study design (85.0%), and the study was therefore closed according to the protocol definition. Main toxicity (grade 3 or greater, %): neutropenia 5 (41.7%); thrombocytopenia 2 (16.7%); anaemia 2 (16.7%); nausea/vomiting 1 (8.3%); anorexia 2 (16.7%), dysphagia 2 (16.7%), radiation pneumonitis 4 (33.3%) and fatigue 1 (8.3%). Conclusions: Our results do not support further trials of Endostar in combination with radiochemotherapy in patients with Stage III NSCLC. Endostar likely enhances radiation pneumonitis. The impact of Endostar on survival as a first-line treatment in combination with radiochemotherapy remains to be determined.

Abstract LB-154: Anti-tumor effect of dendritic cell-based immunotherapy in the patients with advanced breast cancer.

Abstract Background and objective: Tumor-specific cytotoxic T lymphocytes (CTLs) can be activated in vivo by dendritic cell (DC)-based vaccination. However, clinical responses to the immunotherapy with DC vaccination have only been observed in a minority of patients with solid cancer. In the current study, the clinical efficacy of the DC vaccine pulsed with the peptide derived from breast cancer-associated antigens has been evaluated in the patients with advanced, inoperable breast cancer. Patients and Methods: 21patients with advanced, inoperable breast cancer refractory to standard treatment were entered the study. DCs which were generated from CD14+ monocytes from leukapheresis by 6-day cultivation with granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-4, were matured by OK-432, a streptococcal agent, and were pulsed with the pancreatic cancer-associated antigens, such as WT1, MUC1. These DCs (1 × 107) were intradermally administered more than 5 times at 14-day intervals. Results: Of the 21 patients, complete response (CR) was observed in 0 (0%), partial response (PR) in 2 (9.6%), stable disease (SD) in 7 (33.3%), progressive disease (PD) in 12 (57.1%). Response rate was 9.6%. Tumor control rate was 42.9%. Mean survival time after DC therapy was 514days. Severe side effects of more than grade 3 which were assessed in accordance with NCI-Common Toxicity Criteria v.2.0, were not observed. Conclusions: It was strongly suggested that the DC vaccination pulsed with cancer associated-peptides was safety and effective in the patients with the inoperable breast cancer refractory to standard treatment. 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-154. doi:10.1158/1538-7445.AM2011-LB-154