Cumulative Dose Of Oxaliplatin Research Articles

O3-068 - Phase II Study Of S-1, Oral Leucovorin, Oxaliplatin and Bevacizumab Combination Therapy (SOL + BV; SOLA) in Patients with Unresectable Metastatic Colorectal Cancer (MCRC)

ABSTRACT Background The results from a randomized phase II trial in the first-line treatment of mCRC indicated that SOL regimen (S-1, oral leucovorin; LV, and oxaliplatin) had promising activity with well-tolerated toxic effects compared with mFOLFOX6 (Ojima et al., ESMO 2011). The median progression-free survival (PFS) for SOL and mFOLFOX6 was 9.6 and 6.9 months, respectively (HR = 0.83). We evaluated the efficacy and safety of adding BV to SOL regimen in this study. Methods The inclusion criteria were: (i) histologically proven adenocarcinoma of colon or rectum, 2) age ≥20 years, (iii) no prior treatment for metastatic disease, (iv) at least one target lesion by RECIST ver1.0 criteria, (v) ECOG Performance Status 0-1. Patients received S-1 (40-60 mg bid) and LV (25 mg bid) orally for 1 week and L-OHP (85 mg/m2), and BV (5 mg/kg) on day 1, every 2 weeks. The primary end point was the response rate (RR). This trial was supported by Taiho Pharmaceutical Co., Ltd. (JAPIC Clinical Trials information Identifier: JapicCTI-090881). Results From October 2009 to April 2010, 31 patients were enrolled, and 29 patients were regarded as the population of full analysis set. Present data included the results of efficacy and safety up to 24 cycles or for at least a year. RR assessed by the independent review committee (IRC) was 86.2% (CR: 0 patients, PR: 25 patients), and disease control rate (DCR) was 100%. The median PFS assessed by IRC was 15.3 months, while further follow up is ongoing. One-year survival rate was 100%. The incidence of grade 3/4 adverse drug reactions were; neutropenia 16.7%, diarrhea 10.0%, hypertension 16.7%, and sensory neuropathy 53.3%. The median cumulative oxaliplatin dose was 915.0 mg/m2 (range 330–1735 mg/m2). The high prevalence of grade 3 neuropathy seemed due to the prolonged treatment duration. Reasons for discontinuation were progressive disease in 10 patients, and metastatectomy by tumor regression in 6 patients. The resection rate was 17.2%. Conclusions SOL + BV showed promising activity with high RR, DCR, PFS and resection rate with well-tolerated toxic effects in patients with unresectable mCRC.

1590P - Prospective Validation of Patient Neurotoxicity Questionnaire (PNQ) for Assessment of Oxaliplatin Neurotoxicty: CSP-HOR 16

ABSTRACT Background Oxaliplatin-containing regimens are the standard of care for colorectal cancers. Quality of life is impaired in patients with oxaliplatin neurotoxicity. Patient-reported outcomes are important for evaluating adverse effects that are difficult for physicians to assess objectively. We prospectively investigated the feasibility and validity of a patient-based scale, the Patient Neurotoxicity Questionnaire-Oxaliplatin (PNQ), for cumulative neurotoxicity of oxaliplatin. Methods We enrolled 121 oxaliplatin-naive patients treated with FOLFOX4 or modified FOLFOX6 for colorectal cancer. Neurotoxicity was evaluated with PNQ, Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and Functional Assessment of Cancer Therapy / Gynecologic Oncology Group-Neurotoxicity questionnaire (FACT/GOG-Ntx). Assessments were conducted at baseline, after q 2 treatment cycles and q 8 weeks after completion of chemotherapy. We evaluated compliance, correlation and concordance between PNQ, CTCAE and FACT/GOG Ntx-subscale, and test-retest reproducibility. The probability of experiencing neurotoxicity with cumulative oxaliplatin exposure was estimated by the Kaplan-Meier method. Results One hundred thirteen patients were evaluable. The median cumulative dose of oxaliplatin was 688.4 mg/m2 (range 83.4-1655.0). Questionnaire completion rate was > 90% for all assessments during treatment. CTCAE consistently resulted in lower sensitivity and correlation compared to PNQ (weighted kappa coefficients of sensory and motor components were 0.50 and 0.38). Sensory and motor component grades of PNQ were significantly correlated with the FACT/GOG Ntx-subscale (r = 0.63 and 0.45). The test-retest reliability of PNQ sensory and motor components demonstrated Spearman correlation coefficients of 0.81 and 0.59. PNQ sensory grades increased similarly with CTCAE. PNQ motor grades were worse compared to CTCAE. Conclusions The PNQ has adequate feasibility and validity to prospectively assess oxaliplatin neurotoxicity. The PNQ is a convenient, accurate and reliable assessment tool for oxaliplatin neurotoxicity. Disclosure All authors have declared no conflicts of interest.

591P - Colon Cancer Adjuvant Mfolfox-6 – Survival Impact of Oxaliplatin Reduced Dose-Intensity

ABSTRACT Background Adjuvant colon cancer treatment may include the oxaliplatin/fluoropirimidine combination. This association has shown benefit on progression free survival (PFS) and overall survival (OS) compared to fluoropirimidine monotherapy in these patients. Adverse events are frequent and may cause delay on treatment delivery or drug dose reduction. The survival impact of oxaliplatin reduced dose intensity (RDI) is unknown. Objective Evaluation of survival impact of oxaliplatin RDI in colon cancer patients treated with adjuvant mFOLFOX-6. Material and methods: A consecutive series of colon cancer patients treated with adjuvant mFOLFOX-6 at our institution between 09/2004 and 11/2009. The impact of Oxaliplatin Results There were no differences in age, sex, ECOG, comorbidity, histologic grade and stage distribution between groups. Two hundred and seventy seven (277) patients were identified (53% in group A). Fifty nine percent (59%) of patients completed the 12 mFOLFOX-6 cycles and the median duration of adjuvant chemotherapy was 6,5 months. The mean oxaliplatin dose-intensity was 71% (median 74%). Adverse events led to dose reduction and drug suspension in 53% and 40% of patients, respectively. There were 3 deaths during treatment. The main causes to RDI were grade ≥ 3 hematologic toxicity (47%) and neuropathy (12%) – median cumulative oxaliplatin dose at first neurologic severe event was 1024 mg. There were no differences in PFS and OS between RDI groups, neither after stage stratification. Conclusion In our cohort patient's characteristics and toxicity profile were similar to published trials. FOLFOX conclusion rate was inferior than the described in MOSAIC trial (59% vs 74,7%). Despite the inferior accomplishment rate, there was no impact in PFS and OS in oxaliplatin RDI Disclosure All authors have declared no conflicts of interest.

Analysis of neurosensory adverse events induced by FOLFOX4 treatment in colorectal cancer patients: a comparison between two Asian studies and four Western studies

The grades of neurosensory adverse events (NSAEs) induced by FOLFOX4 treatment were compared between Asian and Western colorectal cancer patients and correlated with cumulative oxaliplatin doses. A total of 3359 patients treated with FOLFOX4 were analyzed: 1515 from two Asian studies (Japanese Post Marketing Surveillance [J-PMS] and MASCOT) and 1844 from four Western studies (EFC2962, N9741, EFC4584, and MOSAIC). The onset of NSAEs was analyzed in terms of treatment duration and cumulative dose of oxaliplatin. The incidence of grade ≥3 NSAEs ranged from 2.0% to 4.4% in Asian studies and 9.3% to 19% in Western studies. The cumulative doses of oxaliplatin that induced grade ≥3 NSAEs in 10% of patients were higher in Asian studies (1526 mg/m2 or not reached) than in Western studies (805–832 mg/m2). No significant correlations were noted between occurrence of grade ≥3 NSAEs and demographic/baseline characteristics. The frequency of escalation from grade 0 to 1 in J-PMS was statistically significantly lower than that in EFC4584, and that from grade 0 to 1 and from grade 1 to 2 in MASCOT lower than that in MOSAIC. The cumulative oxaliplatin doses administered during grade escalation in J-PMS were similar to those in EFC2962 or EFC4584. All grade-3 NSAEs in MASCOT and 96% of those in MOSAIC improved to grade 2 or less within 12 months of follow-up. The Asian populations accrued to these studies appear to be less susceptible to the neurotoxicity of oxaliplatin than the mainly Caucasian populations in the Western studies.

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.

Incidence, characteristics, and associations of oxaliplatin-induced peripheral neuropathy in colorectal cancer patients: Results of a prospective, multicenter, international study.

9090 Background: We sought to trace the incidence and severity of oxaliplatin-induced peripheral neuropathy (OXLIPN) and to determine its clinical pattern. Among other associations, we also specifically aimed at testing whether the degree of acute neuropathy is clinically related to the development and severity of chronic OXLIPN. Methods: 170 patients (mean age 64y), scheduled to be treated with either FOLFOX or XELOX for metastatic colorectal cancer were studied. Patients were prospectively monitored at baseline and followed-up during chemotherapy in four European sites. The motor/neurosensory NCI-CTCv3 criteria and the clinical version of the Total Neuropathy Score were applied to clinically grade the severity of OXLIPN. Nerve conduction studies were also longitudinally performed. Results: Evidence of acute OXLIPN was disclosed in 146/170 patients (85.9%). The vast majority of patients manifested cold-induced perioral (95.2%) or pharyngolaryngeal dysesthesias (91.8%). Other uncommon symptoms, such as jaw spasm were also present. Severe acute OXLIPN, requiring prolongation of OXL infusion from 2 to 4-6 hours was evident in 32/146 patients (21.9%). Overall, 123/170 patients (72.4%) experienced chronic OXLIPN. Severities were grade I: 39 (22.9%); grade II: 52 (30.6%); grade III: 33 patients (19.4%). Worst severities were related to cumulative oxaliplatin dose (r:0.269;p&lt;0.001). Follow-up assessments revealed significant decrease in all sensory action potentials examined. The severity of the acute OXLIPN was significantly correlated with both the development (r:0.450;p&lt;0.001) and degree of the chronic form (r:0.703;p&lt;0.001). Conclusions: Most patients treated with oxaliplatin-based chemotherapy would manifest OXLIPN, mainly of moderate degree. The severity of the acute syndrome appears to clinically correlate with the degree of the chronic form of OXLIPN. Our data suggest that acute phenomena, related to axonal hyperexcitability, could contribute to the development of peripheral neuropathy; thus it could be advisable to test agents against acute OXLIPN in order to verify their effects on the chronic form.

Electroclinical biomarkers of early peripheral neurotoxicity from oxaliplatin

Peripheral neuropathy is the principal dose-limiting side effect of chemotherapy with oxaliplatin. Early biomarkers of oxaliplatin-related neuropathy (ON) are important for guiding management and as outcomes for neuroprotective trials. We compared a number of clinical and neurophysiological techniques to identify early features of ON. Median nerve motor excitability testing, nerve conduction studies, vibration perception threshold (VPT) and clinical assessments were carried out on 17 patients and 105 controls. Neuropathy was graded using the total neuropathy score and National Cancer Institute Common Toxicity Criteria scales. Oxaliplatin causes a length-dependent sensory neuropathy. The most sensitive early marker of neuropathy was abnormal VPT in the foot followed by diminished sensory nerve action potential amplitudes. Median nerve excitability studies revealed no biologically significant effects of treatment on motor axons. VPT is an easily applicable and effective marker of neuropathy at low cumulative doses of oxaliplatin. Nerve excitability measures may be useful in predicting ON but motor studies do not reveal early cumulative changes following treatment with the drug.

Acute inflammatory demyelinating polyradiculoneuropathy in a patient receiving oxaliplatin‐based chemotherapy

We report a case of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) that developed in a patient with cholangiocarcinoma after receiving oxaliplatin-based chemotherapy. A 62-year-old man had multiple hypodense lesions with delayed enhancement in the both lobes of the liver on abdominal computed tomography. He was treated with 5-fluorouracil, leucovorin and oxaliplatin (100 mg/m(2)). After eight cycles of treatment and a cumulative oxaliplatin dose of 780 mg/m(2), he developed an unsteady gait, dysphagia, weakness of both the upper and lower limbs and impairment of all sensory modalities. Nerve conduction studies confirmed the diagnosis of AIDP. Immunoglobulin G i.v. was administered for 5 days but the neurological deficits of both his upper and lower limbs did not improve. This case highlights unusual peripheral nervous system manifestations in a patient who received chemotherapy with oxaliplatin.

Impact of oxaliplatin-induced neuropathy: a patient perspective

Dose-limiting neurotoxicity is a major side effect of oxaliplatin treatment, producing initial acute neurotoxicity and chronic neuropathy with increasing exposure. The improvement in survival for patients with early-stage colorectal cancer treated with oxaliplatin has highlighted the need for valid and reliable assessment of peripheral neuropathy. The objective of this paper was to explore neuropathic symptoms in oxaliplatin-treated patients as assessed using different methods. Consecutive symptomatic patients reporting peripheral neuropathy after oxaliplatin chemotherapy for colorectal cancer were interviewed using a semi-structured clinical interview. Neurotoxicity was also assessed using the National Cancer Institute Common Toxicity Criteria scale (clinician-rated), patient 'self-report' questionnaires (PNQ), nerve conduction and clinical assessment. Twenty patients were assessed, 12.6 ± 2.8 months after treatment cessation (mean cumulative oxaliplatin dose, 789 mg/m(2)). In 40% of patients, neurotoxicity necessitated early cessation of treatment. Only 10% of patients were designated by clinicians with severe neurotoxicity, whilst, in contrast, patient interviews and self-report questionnaires described significant physical limitations due to neuropathic symptoms in 60% of patients. The majority (85%) of patients had objective evidence of sensory neuropathy with nerve conduction studies. Reports from clinical interviews were strongly correlated with patient self-assessment (Pearson coefficient = 0.790, p < 0.0005). Given the discrepancies in symptom prevalence highlighted by these findings, the monitoring of oxaliplatin-induced neurotoxicity would benefit from more informative clinical assessment, with inclusion of patient-reported outcome measures. Such an approach would be beneficial in a clinical trial setting to monitor the efficacy of interventions and in prospective studies of survivorship to determine the true burden of peripheral neuropathy in oxaliplatin-treated patients.

Phase II study of S-1, oral leucovorin, oxaliplatin, and bevacizumab combination therapy (SOL+BV; SOLA) in patients with unresectable metastatic colorectal cancer (mCRC).

611 Background: The results from a randomized phase II trial in the first-line treatment of mCRC indicated that SOL regimen (S-1, Oral Leucovorin; LV, and Oxaliplatin) had promising activity with well-tolerated toxicities compared to mFOLFOX6 (Ojima et al, ESMO 2011). The median progression-free survival (PFS) for SOL and mFOLFOX6 was 9.6 and 6.9 months, respectively (HR=0.83). We evaluated the efficacy and safety of adding BV to SOL regimen in this study. Methods: The inclusion criteria were; 1) histologically proven adenocarcinoma of colon or rectum, 2) age ≥ 20 years, 3) no prior treatment for metastatic disease, 4) at least one target lesion by RECIST ver1.0 criteria, 5) ECOG Performance Status 0-1. Patients (pts) received S-1 (40-60 mg bid) and LV (25 mg bid) orally for one week and L-OHP (85 mg/m2), and BV (5 mg/kg) on day 1, every 2 weeks. The primary endpoint was the response rate (RR). Results: From October 2009 to April 2010, 31 pts were enrolled, and 29 pts were regarded as the population of full analysis set. Present data included the results of efficacy and safety up to 24 cycles. RR assessed by the independent review committee was 86.2 % (CR: 0 pts, PR: 25 pts), and disease control rate (DCR) was 100%. The median PFS assessed by investigators was 12.5 months, while further follow up is ongoing. One year survival rate was 100%. The incidence of grade 3/4 adverse drug reactions were; neutropenia 16.7%, diarrhea 10.0%, hypertension 16.7%, and sensory neuropathy 53.3%. The median cumulative oxaliplatin dose was 915.0 mg/m2 (range 330-1735 mg/m2). The high prevalence of grade 3 neuropathy seemed due to the prolonged treatment duration. Reasons for discontinuation were progressive disease in 13 pts, and metastatectomy by tumor regression in 6 pts. The resection rate was 17.2 %. Conclusions: SOL+BV showed promising activity with high RR, DCR, PFS and resection rate with well tolerated toxicities in pts with unresectable mCRC. This trial was supported by Taiho Pharmaceutical CO.,LTD. (JAPIC Clinical Trials information Identifier: JapicCTI-090881).

Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial

Oxaliplatin neurosensory toxicity is dose limiting and may present as acute symptoms and/or cumulative peripheral neuropathy. From October 2005 to May 2008, patients with oxaliplatin-induced acute neurotoxicity were randomized into a double-blind study, to receive either venlafaxine 50 mg 1 h prior oxaliplatin infusion and venlafaxine extended release 37.5 mg b.i.d. from day 2 to day 11 or placebo. Neurotoxicity was evaluated using numeric rating scale (NRS) for pain intensity and experienced relief under treatment, the Neuropathic Pain Symptom Inventory and the oxaliplatin-specific neurotoxicity scale. The primary end point was the percentage of patients with a 100% relief under treatment. Forty-eight patients were included (27 males, median age: 67.6 years). Most patients had colorectal cancer (72.9%). Median number of cycles administered at inclusion was 4.5 (mean cumulative oxaliplatin dose: 684.6 mg). Twenty out of 24 patients in arm A (venlafaxine) and 22 out of 24 patients in arm B (placebo) were assessable for neurotoxicity. Based on the NRS, full relief was more frequent in the venlafaxine arm: 31.3% versus 5.3% (P=0.03). Venlafaxine side-effects included grade 1-2 nausea (43.1%) and asthenia (39.2%) without grade 3-4 events. Venlafaxine has clinical activity against oxaliplatin-induced acute neurosensory toxicity.

Neurotoxicidad asociada a oxaliplatino en la práctica clínica asistencial

ObjectivesTo evaluate the presence and severity of oxaliplatin-associated neurotoxicity in clinical practice and the clinical management of this adverse side effect. MethodObservational retrospective study including patients diagnosed with colorectal cancer that started an oxaliplatin-based chemotherapy regimen during 2008 at a secondary hospital. Data were obtained from an onco-haematological prescription programme at the hospital and from digital clinical histories. We compiled variables related to the clinical characteristics of the patients, antineoplastic treatment, neurotoxicity associated with oxaliplatin, and clinical management of this issue. ResultsOur study included a total of 64 patients. Neurotoxicity was recorded in 65.6% of cases, usually in mild or moderate forms. In approximately one third of patients who developed this adverse effect, the oxaliplatin prescription had to be modified. We observed a statistically significant relationship between cumulative oxaliplatin doses and the presence of neurological toxicity (P=.0004). ConclusionsThe presence of oxaliplatin-associated neurotoxicity and its distribution based on its severity was similar to rates published in the literature. The number of patients requiring a change in the oxaliplatin prescription could justify the need for studies that assess the clinical consequences of these modifications. We believe that effective strategies for neurological protection need to be developed in order to guarantee the safety and quality of life in these patients.

Oxaliplatin in the adjuvant treatment of colon cancer

Oxaliplatin in the adjuvant treatment of colon cancer

Randomized phase 2 sequencing and pharmacokinetic study of gemcitabine and oxaliplatin in advanced non‐small cell lung cancer

This multicentre phase II trial examined the combination of gemcitabine and oxaliplatin in patients with advanced non-small cell lung cancer (NSCLC). The effect of sequence administration was randomized and pharmacokinetics (PK) assessed. Eligible patients had stage IIIB or IV or recurrent NSCLC, no prior chemotherapy, World Health Organization performance status ≤2 and measurable disease. Treatment comprised: gemcitabine (1250 mg/m(2)) and oxaliplatin (70 mg/m(2)), each given on days 1 and 8 of a 21-day cycle. Patients were randomized 1:1 to the sequencing of the two drugs for the duration of their treatment. The primary end-point was response rate (RR). Secondary end-points included progression-free survival (PFS), overall survival (OS), toxicity, PK and the effect of drug sequencing. A total of 46 patients were enrolled of whom 43 were evaluable for response. Overall 13 patients (30%) achieved a partial response, PFS was 4.2 months (95% CI 2.8-5.8 months), and OS was 6.8 months (95% CI 4.4-10.1 months). There was only one case of grade 3 neurosensory toxicity despite a median cumulative oxaliplatin dose in excess of 500 mg/m(2) . No differences in clinical or PK end-points were observed between the two different sequencing arms. This oxaliplatin and gemcitabine schedule has shown activity in advanced NSCLC with modest toxicity. Neither clinical nor PK outcomes were influenced by the sequencing of these agents, although definite conclusions are limited by small patient numbers. The favorable toxicity profile of this doublet, in light of an encouraging RR, warrants its further investigation in NSCLC.

Allergic reactions (ARs) induced by FOLFOX4 treatment in colorectal cancer: A comparative analysis between Asian and Western patients (pts).

3623 Background: FOLFOX4 is a standard regimen either in the palliative or adjuvant chemotherapy for colorectal cancer. We previously reported the safety results of 2 Asian and 4 Western studies of FOLFOX4 (ASCO 2010, No.3611). This report summarizes ARs in these studies. Methods: A total of 3,359 colorectal cancer pts, 1,515 Asian and 1,844 Western, treated with FOLFOX4 from 2 Asian [J-PMS (Jpn Post Marketing Surveillance) and MASCOT] and 4 Western [de Gramont 1st line phase III (EFC2962), Goldberg 1st line phase III (N9741), Rothenberg 2nd line phase III (EFC4584) and MOSAIC] studies were included in this report. ARs were defined as anaphylactic reaction, anaphylactic shock, anaphylactoid reaction, drug hypersensitivity or hypersensitivity, and graded by NCI-CTC. They were collected prospectively and re-coded by MedDRA ver 9.0. Results: Pts received FOLFOX4 for median 6-12 cycles over median 16-28 weeks. There were no marked differences in dose intensity of oxaliplatin between 2 Asian and 4 Western studies. Grade ≥1 ARs were observed in 3.2-25% of pts and grade ≥3 in 0.6-3.1%. The incidence of ARs tended to increase modestly from 5-7 cycles of treatment. Many of grade ≥3 ARs developed without the preceding episode of grade-1 or -2 ARs. The cumulative doses of oxaliplatin that induced grade ≥1 ARs in 10% pts (CD10) calculated by Kaplan-Meier method were 595-1,280 mg/m2 with moderate variations among the studies. Analysis of correlation between ARs and demographic/baseline characteristics by multivariate logistic regression showed no significant regional differences. Conclusions: Although there were slight differences in incidences and CD10 of grade ≥1 ARs, no marked differences were observed in incidences of grade ≥3 ARs between Asian and Western pts treated with FOLFOX4. J-PMS MASCOT EFC2962 N9741 EFC4584 MOSAIC Line 1st ≥2nd Adjuvant 1st 1st 2nd Adjuvant Pt No. 222 1,134 159 209 259 268 1,108 Median cycles 8 6 12* 12 10 7 12* L-OHP CD (mg/m2) 657 500 967 839 765 589 888 Grade ≥ 1 ARs (%) 8.1 3.2 25.2 7.2 12.4 6.3 10.3 Grade ≥ 3 ARs (%) 2.3 0.6 3.1 1.9 1.5 1.1 3.0 Grade 4 ARs (%) 0 0.2 0.6 0.5 0 0.4 0.6 L-OHP CD10 (mg/m2) 889** 595 1,122 683 1,280 759 * Max 12 cycles. ** n=1,356.

Outcome of intravenous calcium and magnesium (Ca/Mg) in oxaliplatin-containing regimens compared with no Ca/Mg.

e19681 Background: Peripheral neuropathy (PN) is a cumulative toxicity of oxaliplatin (OX). Retrospective studies have reported that Ca/Mg infusions may reduce the incidence of PN and may allow patients to be treated without dose reductions for a longer duration. The objectives of this study were to retrospectively evaluate the effect of Ca/Mg on the number of treatment cycles, duration of OX therapy, cumulative OX dose, and progression free survival (PFS) in a large university-based practice. Methods: 149 patients treated with OX-containing regimens were retrospectively reviewed for co-administration of Ca/Mg infusions. Ca/Mg was given as 1 gm CaCl2 and 1 gm MgSO4 in 100 ml of IV solution over 30 min pre and post OX. Treatment assignment was at physician discretion. Patients were divided into groups based on histology, stage, and whether Ca/Mg was given. Patients in the “no Ca/Mg” group never received this treatment. All data were retrieved from the YCC EMR and reviewed by the authors. Patients were treated between 5/12/03 and 9/25/09. Results: 149 records were reviewed including 106 with Ca/Mg and 43 without. In patients with stage IV CRC, the Ca/Mg group (n=22) was associated with a statistically significant increased PFS (8.5 vs 4.6 months p=0.0394) compared to those not given Ca/Mg (n=13). There was a trend towards improved treatment duration (5.8 vs 3.8 months p=0.1065), cycles given (10.9 vs 7.8 cycles p=0.173), and total OX dose (677.5 vs 306.2 mg/m2 p=0.1366). In the adjuvant CRC setting, the Ca/Mg group (n=27) also showed a statistically significant improvement in PFS (36.3 vs. 22.8 months p=0.0445) compared to those not given Ca/Mg (n=10). Comparison of these adjuvant groups showed no statistical differences in total OX dose, duration of tx, or total tx cycles. Conclusions: In this retrospective chart review of patients treated with oxaliplatin-based chemotherapy, use of IV Ca/Mg showed a statistically significant increase in PFS in patients with CRC in both the adjuvant and metastatic settings. Despite the limited sample size and statistical power, significance and trends support the use of Ca/Mg to reduce the impact of PN, without signs of interfering with oxaliplatin anti-tumor activity.

Calcium and magnesium infusions for prevention of oxaliplatin-induced peripheral neuropathy.

387 Background: Oxaliplatin plays an important role in chemotherapy regimens for colorectal and other GI malignancies. Debilitating peripheral neuropathy (PN) often develops with use of this drug. One study (Grothey A et al, ASCO 2009, abst #4025) has shown that pre- and post-oxaliplatin infusions with calcium (Ca) and magnesium (Mg) may reduce this toxicity. To confirm this in an unselected indigent minority population, a retrospective review was performed comparing development of PN in oxaliplatin exposed patients treated with or without Ca/Mg. Methods: Records of patients who received oxaliplatin from 1/2008 to 12/2009 at MetroHealth Medical Center, a large safety net hospital in Cleveland, OH, were reviewed. 47 patients received Ca/Mg + oxaliplatin and 46 oxaliplatin alone. Data collected included age, race, gender, insurance status, performance status, tumor type, stage, concomitant diseases (DM and EtOH), number of cycles and cumulative dose of oxaliplatin. PN was determined using the Common Terminology Criteria of Adverse Events (CTCAE) version 3.0. Patients were followed 6 months after completion of oxaliplatin. Results: Demographic data was similar between the two groups. Colorectal cancer compromised 77% of the treatment group and 85% of control group. Patients who received Ca/Mg had significantly less PN in all three grades (1-3) compared with the control group (grade 1 89.4% vs. 71.7%, grade II 10.6% vs. 19.6%, grade 3 0% vs. 8.7%, respectively). The cumulative dose of oxaliplatin did not differ between the two groups (Ca/Mg median 1,143 range 260-2,169; control median 1,425 range 137-2,635). The combined total grades 2 and 3 in both the treatment and control (10.6% vs. 28.3%, p = 0.038) favored use of Ca/Mg. Conclusions: This small, retrospective study confirms that Ca/Mg infusions reduce the incidence of clinically significant (grade 2/3) PN in pts receiving oxaliplatin. No significant financial relationships to disclose.

Association of hypersensitivity reactions to oxaliplatin with cumulative dose of oxaliplatin.

584 Background: The incidence of hypersensitivity reactions (HSRs) to oxaliplatin (L-OHP) in colorectal cancer patients (CRC) receiving the 5-fluorouracil/leucovorin plus L-OHP (FOLFOX) regimen is reported to be 10 to 17%. There are several reports of clinical features of HSRs to L-OHP, but the relationship between HSRs and the cumulative dose of L-OHP has not been clarified. Methods: From August 2005 to July 2009, a total of 54 CRC patients who developed HSRs during treatment with mFOLFOX6 or mFOLFOX6 plus bevacizumab regimen as first-line treatment, were reviewed retrospectively. Within this patient group, sixteen patients had an L-OHP-free interval of at least three months or more. We investigated the clinical features of HSRs associated with L-OHP in our institution, and evaluated the degree to which its occurrence is dependent upon the cumulative dose of L-OHP in patients who had an interruption of L-OHP. Results: Within the sample of 54 patients, HSRs occurred after a median treatment course number of 8 (range 2-19), and the median cumulative dose of L-OHP being 700 mg/m2 (range 170-1615). In these subjects, grade1/2/3 HSRs developed in 33/20/1 patients, respectively. Re-challenge of L-OHP combined with prophylactic agents was performed in 42 patients (78%). There were 16 patients who had an L-OHP- free interval, in whom the major reason for L-OHP withdrawal was neurotoxicity, with reintroduction because of tumor progression or recurrence. Of these 16 patients, 10 developed the first HSRs after reintroduction of L-OHP. Among these 10 patients, grade1/2/3 HSRs developed in 6/3/1 patients, respectively, and occurred at a median course number of 2.5 following re-infusion of L-OHP, or 12 treatments after the initial infusion. The median cumulative dose of L-OHP at HSRs in this patient group was 213 mg/m2 after the re-introduced infusion, and a total of 1088 mg/m2 since initial onset of treatment. Conclusions: Our results suggest that the development of HSRs during L-OHP treatment depends on the cumulative dose from the initial administration even in patients who experienced an L-OHP-free interval. No significant financial relationships to disclose.

A randomized phase II study of modified OPTIMOX1 or FOLFOX in advanced colorectal cancer.

519 Background: A combination of leucovorin (LV) and fluorouracil (FU) with oxaliplatin (FOLFOX) is a standard first-line regimen for advanced or unresectable colorectal cancer. Sensory neurotoxicity is its dose-limiting toxicity, but the OPTIMOX1 (stop and go) approach offers a reasonable strategy. This study evaluates a new strategy of intermittent oxaliplatin treatment that is based on FOLFOX4 or modified FOLFOX6 (+/− bevacizumab), a simplified leucovorin and fluorouracil regimen with normal-dose oxaliplatin. Methods: Previously untreated patients were randomly assigned to either FOLFOX administered every 2 weeks until progression (arm FOL) or FOLFOX for six cycles, maintenance without oxaliplatin for six cycles, and continued every six cycles until progression (arm OPT). Results: Sixty patients (arm FOL [n=35], arm OPT [n=33]) were enrolled. The median number of treatment cycles was 10 (range, 3-28) in arm FOL and 12.5 (range, 1-32) in arm OPT. Cumulative dose of oxaliplatin was 850 mg/m2 in arm FOL and 552.5 mg/m2 in arm OPT. Median progression-free survival was 8.5 months in patients allocated to arm FOL compared with 15 months in patients allocated to arm OPT. Response rates evaluated by RECIST criteria were 50% with arm FOL and 64% with arm OPT. National Cancer Institute Common Toxicity Criteria grade 3 toxicity was observed in 37.1% of the patients in arm FOL and 24.0% of patients in arm OPT. Grade 3 sensory neuropathy was observed in 22.8% of the patients in arm FOL and 6% of patients in arm OPT. Conclusions: Our modified OPTIMOX1 regimen may be effective and safe treatment to prevent oxaliplatin-induced neuropathy in advanced or unresectable colorectal cancer patients. No significant financial relationships to disclose.

The Kampo medicine, Goshajinkigan, prevents neuropathy in patients treated by FOLFOX regimen

Oxaliplatin is now considered a standard treatment for advanced or unresectable colorectal cancer, but its main dose-limiting toxicity is sensory neuropathy. The OPTIMOX (stop and go) approach offers a reasonable strategy, but the preventive agent is not established. It is reported that the Kampo medicine, Goshajinkigan (GJG), has recently been considered an effective agent for the neuropathy of taxanes and for vibration sensation in patients with diabetic neuropathy. The aim of this study was to clarify the efficacy of GJG for peripheral neuropathy associated with oxaliplatin therapy. From 2007, 45 patients treated with modified FOLFOX6 for non-resectable or recurrent colorectal cancer participated in the study. Twenty-two patients (GJG group) received oral administration of 7.5g/day of GJG every day during mFOLFOX6 therapy and 23 patients (control group) did not receive GJG. Neuropathy was evaluated during every course according to DEB-NTC (Neurotoxicity Criteria of Debiopharm). The median number of cycles per patient in the GJG group was 13 (range 4-32), and in the control group was 12 (range 4-28). The cumulative dose of oxaliplatin was 1105mg/m(2) (GJG group) and 1120mg/m(2) (control group). The incidence of grade 3 peripheral neuropathy in the GJG group was significantly lower than in the control group (p<0.01, log-rank test). The incidence of grade 3 peripheral neuropathy after 10 courses was 0% in the GJG group and 12% in the control group, and after 20 courses was 33% in the GJG group and 75% in the control group. The percentage of grade 2 and 3 peripheral neuropathy in the GJG group was lower than that in the control group. There were no differences in adverse effects between the two groups except for peripheral neuropathy and influence on tumor response. The Kampo medicine, Goshajinkigan, is useful in preventing neuropathy in non-resectable or recurrent colorectal cancer patients treated with a FOLFOX regimen.