Discontinuation Of Oxaliplatin Research Articles

Oxaliplatin-induced peripheral neuropathy with hepatic arterial versus intravenous infusion in metastatic colorectal cancer.

Oxaliplatin, a major drug in metastatic colorectal cancer (mCRC), is responsible for cumulative, dose-limiting peripheral neuropathy (PN). Whether the hepatic arterial infusion (HAI) route can limit oxaliplatin-induced PN in comparison with the intravenous (IV) route has not been specifically explored so far. We compared the frequency and severity of PN in oxaliplatin-naive patients with mCRC included in trials that evaluated treatment with oxaliplatin administered either by HAI (ACCORD 04, CHOICE, OSCAR, and PACHA-01 trials) or by IV route (FFCD 2000-05 trial). We retrieved anonymized, prospectively collected data from trial databases for the ACCORD 04, CHOICE, and FFCD 2000-05 trials and through a review of Gustave Roussy patients' electronic medical records for PACHA-01 and OSCAR trials. The primary endpoint was the incidence of clinically significant PN (grades 2 to 4) according to the cumulative dose of oxaliplatin received. Secondary endpoints were time to onset of neuropathy as a function of the cumulative dose of oxaliplatin, discontinuation of oxaliplatin for neurotoxicity, and safety. A total of 363 patients were included (IV, 300; HAI, 63). In total, 180 patients in the IV group (60%) and 30 patients in the HAI group (48%) developed clinically significant PN, with no significant difference between the two groups (p = 0.23). No difference was shown in the time to onset of PN either (p = 0.23). The administration of oxaliplatin HAI rather than IV in the treatment of mCRC does not reduce the incidence, precocity, and severity of PN.

Case report: Oxaliplatin-induced idiopathic non-cirrhotic portal hypertension: a case report and literature review

Oxaliplatin has become a widely used agent in neoadjuvant chemotherapy for gastrointestinal tract tumors and is an integral part of the therapeutic approach for managing colorectal cancer recurrences and metastases, resulting in a more favorable prognosis for patients. Nevertheless, oxaliplatin can give rise to idiopathic non-cirrhotic portal hypertension (INCPH). The emergence of INCPH can disrupt tumor chemotherapy and incite persistent adverse reactions in later stages, significantly complicating clinical management. Consequently, we have presented a case report of INCPH induced by oxaliplatin chemotherapy with the aim of advancing the diagnosis and treatment of this condition, with a particular focus on the clinical manifestations. This study has ascertained that the condition is primarily attributed to complications related to portal hypertension, such as gastrointestinal bleeding, splenomegaly, and hypersplenism. The pathological features primarily involve hepatic sinus dilation and congestion, portal obstruction, absence, stenosis, shunting, localized venous and perisinusoidal fibrosis, as well as hepatocellular atrophy. Treatment primarily concentrates on strategies typically employed for cirrhosis. Endoscopic ligation, sclerotherapy, and non-selective beta-blockers (NSBBs) can be selected to prevent and treat variceal hemorrhage. Transjugular intrahepatic portosystemic shunt (TIPS) and liver transplantation can also be chosen for severe cases. Notably, despite the timely discontinuation of oxaliplatin, most patients continue to experience disease progression, ultimately resulting in a poor prognosis due to either tumor advancement or the ongoing progression of portal hypertension. This emphasizes the importance for physicians to be aware of and consider the risk of INCPH when prescribing oxaliplatin.

Safety outcomes of rapid- versus standard-infusion rate oxaliplatin.

The National Comprehensive Cancer Network guidelines state that the oxaliplatin dose of 85 mg/m2 used in various gastrointestinal cancer regimens may be infused over a rapid rate of 85 min instead of the standard time of 120 min. We evaluated the safety outcomes of rapid administration of oxaliplatin compared to standard infusion. We performed a retrospective, cohort study by chart review. Adult patients who received oxaliplatin as part of a FOLFOX, FOLFOXIRI, or FOLRINOX chemotherapy regimen from January 1, 2018, through June 30, 2021, were included. Primary outcomes were the incidence of hypersensitivity reaction (HSR) and treatment modification of oxaliplatin due to adverse drug events. Secondary outcomes included peripheral neuropathy (PN), myelosuppressive signs, and oxaliplatin-related emergency department visit and/or hospital admission. A total of 178 patients were included (90 and 88 in the rapid-rate and standard-rate groups, respectively). Rapid-rate oxaliplatin was not associated with increased HSR or difference in toxicity requiring dose reduction, delayed dose, or slowed infusion rate, but was associated with increased rate of permanent discontinuation of oxaliplatin, 7.8% and 1.1% in the rapid-rate group and standard-rate groups, respectively (p = 0.032). Peripheral neuropathy occurred in 72.2% and 42% of patients in the rapid-rate group and standard-rate groups, respectively (relative risk for PN, 2.09; 95%, CI: 1.43-3.04; p < .001). There were no differences in any other adverse drug event measured. Rapid-rate oxaliplatin was associated with minimal treatment modifications; however, there was an increase in PN incidence. A faster rate of oxaliplatin administration may not be worth the increased risk of PN.

Comparison of the Efficacy and Safety of 3 Months of CAPOX Followed by 3 Months of Capecitabine and 6 Months of CAPOX/FOLFOX in the Adjuvant Treatment of Low-Risk Stage III Colon Cancer Treated Surgically

Introduction: In the adjuvant treatment of low-risk stage III colon cancer treated surgically, 3 months of CAPOX followed by 3 months of capecitabine is not a common clinical practice. Since there are no data on this practice in the literature, we have no idea how often it is used. However, it should be noted that this application is used in some centers due to the cumulative neurotoxicity of oxaliplatin but there are insufficient data in the literature on its efficacy. Methods: The data of patients with colon cancer treated surgically who were followed up in 12 different oncology centers in Turkey between November 2004 and June 2022 were analyzed retrospectively. Results: The study included 194 patients. The treatment arms were as follows: 3 months of CAPOX followed by 3 months of capecitabine = arm A and CAPOX/FOLFOX (6 months) = arm B. There were 78 patients (40.2%) in arm A and 116 patients (59.8%) in arm B. The median age and sex distribution were similar between the treatment arms. The median follow-up period of all patients was 34.4 months (95% confidence interval, 29.1–39.7). When arm A was compared with arm B, 3-year disease-free survival (DFS) was 75.3% versus 88.4% and 5-year DFS was 75.3% versus 82.8%, respectively. There were similar DFS outcomes between the treatment arms (p = 0.09). Rates of any grade of neuropathy were numerically lower in arm A, but the difference between the treatment arms was not statistically significant (51.3% vs. 56.9%; p = 0.44). The frequency of neutropenia was similar between the treatment arms. Conclusion: In this study, the efficacy and safety of the 3 months of CAPOX followed by 3 months of capecitabine chemotherapy regimen in the adjuvant treatment of low-risk stage III colon cancer treated surgically were proven. This result may also support the discontinuation of oxaliplatin at 3 months while continuing fluoropyrimidines, which is a common clinical practice but lacks sufficient data.

Unusual stroke-like symptoms with oxaliplatin use.

Oxaliplatin has become the mainstay of treatment for many cancers, but its use can be accompanied by unusual side effects. We describe herein a 74-year-old patient with pancreatic cancer who developed severe motor weakness affecting lower extremities after starting treatment with oxaliplatin on three separate occasions. Our patient also experienced slurred speech, with decreased ability to phonate and word-finding difficulty. Brain imaging studies did not suggest recent brain ischemia, and the symptoms resolved within 15-20 h. Oxaliplatin had to be discontinued due to suboptimal tolerance and a short-lived clinical response. After discontinuation of oxaliplatin, she did not experience any more similar symptoms. A score of 9 on the Naranjo nomogram supported a definite causality relationship between oxaliplatin and the observed neurologic toxicity. Rare reports of stroke-like events have previously been described with oxaliplatin. While the exact mechanism of these phenomena is not known, alterations in neuronal sodium channels might be involved. Clinicians, pharmacists, and patients need to be aware of these rare but important side effects of oxaliplatin. Nonetheless, work-up for a cerebrovascular accident is still warranted as hypercoagulability related to malignancy can also predispose the patients to strokes.

Prognostic Impact of Early Treatment and Oxaliplatin Discontinuation in Patients With Stage III Colon Cancer: An ACCENT/IDEA Pooled Analysis of 11 Adjuvant Trials.

Oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (CC) for 6 months remains a standard in high-risk stage III patients. Data are lacking as to whether early discontinuation of all treatment (ETD) or early discontinuation of oxaliplatin (EOD) could worsen the prognosis. We studied the prognostic impact of ETD and EOD in patients with stage III CC from the ACCENT/IDEA databases, where patients were planned to receive 6 months of infusional fluorouracil, leucovorin, and oxaliplatin or capecitabine plus oxaliplatin. ETD was defined as discontinuation of treatment and EOD as discontinuation of oxaliplatin only before patients had received a maximum of 75% of planned cycles. Association between ETD/EOD and overall survival and disease-free survival (DFS) were assessed by Cox models adjusted for established prognostic factors. Analysis of ETD and EOD included 10,447 (20.9% with ETD) and 7,243 (18.8% with EOD) patients, respectively. Compared with patients without ETD or EOD, patients with ETD or EOD were statistically more likely to be women, with Eastern Cooperative Oncology Group performance status ≥ 1, and for ETD, older with a lower body mass index. In multivariable analyses, ETD was associated with a decrease in disease-free survival and overall survival (hazard ratio [HR], 1.61, P < .001 and HR, 1.73, P < .001), which was not the case for EOD (HR, 1.07, P = .3 and HR, 1.13, P = .1). However, patients who received < 50% of the planned cycles of oxaliplatin had poorer outcomes. In patients treated with 6 months of oxaliplatin-based chemotherapy for stage III CC, ETD was associated with poorer oncologic outcomes. However, this was not the case for EOD. These data favor discontinuing oxaliplatin while continuing fluoropyrimidine in individuals with significant neurotoxicity having received > 50% of the planned 6-month chemotherapy.

Prognostic impact of early treatment discontinuation and early oxaliplatin discontinuation in patients treated with 6 months of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer: an ACCENT/IDEA pooled analysis of 11 trials.

11 Background: Six months of oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (CC) remains a standard in high-risk stage III patients. Early treatment discontinuation (ETD) could worsen the prognosis. In addition, there is current lack of data on the prognostic impact of early oxaliplatin only discontinuation (EOD). Methods: We studied the prognostic impact of ETD and EOD in patients with stage III CC who participated in 11 relevant clinical trials of the ACCENT and IDEA databases, where patients were planned to receive 6 months of adjuvant fluoropyrimidine plus oxaliplatin (FOLFOX or CAPOX). ETD was defined as discontinuation of treatment before 75% of cycles of chemotherapy. EOD was defined as discontinuation of oxaliplatin only, while continuing the fluoropyrimidine, before 75% of cycles of oxaliplatin. Association between ETD/EOD and overall survival (OS) and disease-free survival (DFS) was assessed by Cox model adjusted for prognostic factors. Results: ETD analysis included 10,444 patients (FOLFOX n = 7,033; CAPOX n = 3,411), with 20.9% of patients with ETD (17.8% with FOLFOX and 27.2% with CAPOX, p &lt; 0.001). Out of 7,243 patients, 18.8% experienced EOD (17.4% FOLFOX versus 21.4% with CAPOX, p &lt; 0.001). Compared to patients without ETD or EOD, patients with ETD or EOD were statistically more likely to be women, older, with higher ECOG-PS ≥ 1, and in addition for ETD, a Body Mass Index (BMI) &lt; 18.5 kg/m2. In multivariate analyses, ETD was associated with a decrease in DFS and OS in the overall population (HR: 1.40 95%CI 1.23-1.58, p &lt; 0.001 and HR: 1.51 95%CI 1.31-1.74, p &lt; 0.001, respectively). The same pattern was present with FOLFOX and CAPOX regimen, and also in low-risk and high-risk groups for each regimen with the exception of the CAPOX regimen in the low-risk group for DFS and OS. By contrast, EOD was not associated with reduced DFS or OS in the overall population (HR: 1.10 95%CI 0.77-1.58, p = 0.6 and HR: 0.97 95%CI 0.62-1.52, p = 0.9, respectively), in the low-risk group (HR: 0.97 95%CI 0.56-1.66, p = 0.9 and HR: 0.97 95%CI 0.51-1.82, p = 0.9, respectively) and high-risk group (HR: 1.22 95%CI 0.74-2.02, p = 0.4 and HR: 1.05 95%CI 0.53-2.08, p = 0.9, respectively) and for all subgroups of regimen. Conclusions: In patients treated with 6 months of oxaliplatin-based adjuvant chemotherapy for stage III CC, ETD was associated with a decrease in DFS and OS. By contrast, EOD was not significantly associated with poorer outcomes. In case of relevant neurotoxicity during a 6 months schedule, these data are not in favor of continuing oxaliplatin beyond 75% of planned cycles of adjuvant chemotherapy, and demonstrate that fluoropyrimidines remain the cornerstone of adjuvant chemotherapy in localized CC.

Monosialotetrahexosylganglioside in the treatment of chronic oxaliplatin-induced peripheral neurotoxicity: TJMUCH-GI-001, a randomised controlled trial.

BackgroundChronic oxaliplatin-induced peripheral neurotoxicity (OIPN) is the most troublesome and dose-limiting side effect of oxaliplatin. There is no effective treatment for chronic OIPN. We conducted a randomised controlled trial to investigate the efficacy of monosialotetrahexosylganglioside (GM1) in treating chronic OIPN.MethodsIn this single-centre, double-blind, phase Ⅲ trial, gastrointestinal cancer patients with persistent chronic OIPN were randomised in 1:1 ratio to receive either GM1 or placebo at Tianjin Medical University Cancer Institute and Hospital, China. GM1 was dosed at 60 mg daily for every 3 weeks or 40 mg daily for every 2 weeks. Seven- and fourteen- day infusions were administered to concurrent oxaliplatin users and oxaliplatin discontinuation patients, respectively. The primary endpoint was the relief of neurotoxicity (≥30% improvement), measured by a newly developed patient reported outcome measure (MCIPN) based on prior questionnaires including the European Organization for Research and Treatment of Cancer Quality of Life Chemotherapy Induced Peripheral Neuropathy Questionnaire twenty-item scale. Visual analogue score (VAS) was used as another instrument for patients to evaluate the total Chronic OIPN treatment effect. VAS responders (≥30% improvement), double responders (≥30% improvement in both MCIPN and VAS), and high responders (≥50% improvement in the MCIPN total score) were also calculated. The secondary endpoints were safety and quality of life. The additional endpoints are progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), and tumour response. (Trial registration number: NCT02486198 at ClinicalTrials.gov).FindingsBetween May 2015 to December 2017, 145 patients were randomly assigned to receive either GM1 (n=73) and placebo (n=72). Majority of the patients in both arms (90% in GM1 and 83% in placebo) continued receiving oxaliplatin on the trial. More patients responded in the GM1 group than in the placebo group (MCIPN responders: 53% vs 14%, VAS responders: 49% vs 22%, double responders: 41% vs 7%, and high responders: 32% vs 13%, all P < ·01). Analyses were also performed in concurrent oxaliplatin users. The results were consistent with those of the whole group. No deleterious effects of GM1 on survival or tumour response were found. There were no ≥G3 GM1-related adverse events.InterpretationIn patients with chronic OIPN, the use of GM1 reduces the severity of chronic OIPN compared with placebo.FundingThis work was supported by clinical trial development fund of Tianjin Medical University Cancer Institute and Hospital (No.C1706).

Survival outcomes associated with completion of adjuvant oxaliplatin-based chemotherapy for stage III colon cancer: A national population-based study.

The impact of cycle completion rates of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer in real-world practice is unknown. We assessed its impact, and that of treatment modification, on 3-year cancer-specific mortality. Four thousand one hundred and forty-seven patients with pathological stage III colon cancer undergoing major resection from 2014 to 2017 in the English National Health Service were included. Chemotherapy data came from linked national administrative datasets. Competing risk regression analysis for 3-year cancer-specific mortality was performed according to completion of <6, 6-11, or 12 5-fluoropyrimidine and oxaliplatin (FOLFOX) cycles, or <4, 4-7, or 8 capecitabine and oxaliplatin (CAPOX) cycles, adjusted for patient, tumour and hospital-level characteristics. Median age was 64 years. Thirty-two per cent of patients had at least one comorbidity. Forty-two per cent of patients had T4 disease, and 40% had N2 disease. Compared to completion of 12 FOLFOX cycles, cancer-specific mortality was higher in patients completing <6cycles [subdistribution hazard ratios (sHR) 2.17; 95% CI 1.56-3.03] or 6-11 cycles (sHR 1.40; 95% CI 1.09-1.78) (P < .001). Compared to completion of 8 CAPOX cycles, cancer-specific mortality was higher in patients completing <4cycles (sHR 2.02; 95% CI 1.53-2.67) or 4-7cycles (sHR 1.63; 95% CI 1.27-2.10) (P < .001). Dose reduction and early oxaliplatin discontinuation did not impact mortality in patients completing all cycles. Completion of all cycles of chemotherapy was associated with improved cancer-specific survival in real-world practice. Poor prognostic factors may have affected findings, however, patients completing <50% of cycles had poor outcomes. Clinicians may wish to facilitate completion with treatment modification in those able to tolerate it.

P-10 Prevalence and risk factors of chronic neuropathy in 225 colorectal cancer patients treated with oxaliplatin-based regimens in Tunisia

Oxaliplatin is largely used in colorectal cancers (CRC). A major side effect is acute and chronic peripheral neuropathy. The aim of our study was to evaluate the prevalence and risk factors of oxaliplatin-induced chronic neuropathy and to study the consequences on treatment observation. We conducted a retrospective study including patients with CRC treated in the oncology department of the military hospital of Tunis between January 2013 and December 2020. Patients were treated with oxaliplatin-based regimens: FOLFOX, FOLOFORINOX, and XELOX. Evaluation of neuropathy was done according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE V4). 225 patients were included. Median age was 58 years. Sex ratio was 1.32. 54% were aged above 60 years. 33% had diabetes. 64% presented neuropathy: 57% grade 1, 29% grade 2 and 14% grade 3. The average cumulative dose leading to the occurrence of neurotoxicity (all grades) was 510.32 mg/m2. We noted a correlation between diabetes, cumulative dose of oxaliplatin, and the incidence of chronic neuropathy. No correlation was found between sex, age, high BMI, chronic renal dysfunction, and neuropathy incidence. Neuropathy required a dose adjustment (a 25% decrease in the initial dose of oxaliplatin) in 32% of cases. Patients had to delay their treatment in 14.5% of cases. The discontinuation of oxaliplatin was decided in 16% of cases. The most prescribed treatment for neuropathy was pregabalin (74%), followed by carbamazepine (11.8%). Medication was not sufficient to stop neuropathy in 77.7% of cases. The incidence of chronic oxaliplatin-induced neuropathy was high and contributed to treatment delay and modification in many cases. Diabetes and cumulative dose of oxaliplatin were associated with chronic neuropathy.

XELOX or mFOLFOX6 chemotherapy combined with resection of primary lesion versus chemotherapy alone for colon cancer with unresectable metastases: A randomized clinical trial.

3590 Background: It is still controversial for colon cancer patients with unresectable metastases whether to resect the primary tumor when there are no symptoms of primary lesion. Methods: This is an open-label, single-center, prospective, randomized, controlled phase II trial. Colon cancer patients aged 18-80 years with unresectable metastases at enrollment will be randomly allocated to either resection group (group A) or chemotherapy group (group B), and stratified by tumor response and number of organ metastases, after receiving induction chemotherapy with 4 cycles of XELOX or 6 cycles of mFOLFOX6, excluding those with disease progression, lesions radically resectable, or primary lesion unresectable. Patients in group A received resection of primary lesion and then continued chemotherapy, and patients in group B just continued chemotherapy, both up to 4 cycles of XELOX or 6 cycles of mFOLFOX6, and capecitabine maintenance afterwards. If progression occurs 3 months after discontinuation of oxaliplatin and toxicity has recovered to grade I, the original regimen can be applied again. The primary endpoint was TFS (time to failure of strategy, defined as the time from randomization to secondary progression in patients received re-introduce of the induction chemotherapy regimen, or to first progression in patients without re-introduce of the original regimen). The secondary endpoints included progression-free survival (PFS, the time from randomization to first progression), overall survival (OS, the time from enrollment to death), and adverse events (AEs). Efficacy data were analyzed on an intention-to-treat (ITT) basis. This study is registered with ClinicalTrials.gov, number NCT02291744. Results: Between April, 2015, and July, 2020, 140 patients were enrolled, and 54 patients withdrew due to colon obstruction (16), perforation (1), disease progression (22), death (1), radical resection (3), or other reasons (11). Finally, 86 patients were randomized into group A (n = 42) or group B (n = 44). The median TFS was 143 days (95%CI: 104.9-181.1) in group A, and 196 days (95%CI: 96.5-295.5) in group B (HR:0.930 95%CI:0.589-1.468, p = 0.755). The median PFS was 147 days (95%CI: 105.7-188.3) in group A, and 206 days(95%CI:180.9-231.1) in group B (HR:0.831, 95%CI:0.522-1.323, p = 0.436). The median OS was 530 days (95%CI: 308.9-751.1) in group A, and 779 days (95%CI:626.3-931.7) in group B (HR:0.948 95%CI:0.554-1.622, p = 0.845). The incidence of treatment-related AEs was similar between two groups. Conclusions: Resection of primary tumor after induction chemotherapy could not bring survival benefits. It’s not recommended for patients without symptoms of primary lesion to receive primary tumor resection, but it also requires individualized treatment as colon obstruction or perforation occurred in some patients. Clinical trial information: NCT02291744.

Real-world survival outcomes associated with completion of adjuvant chemotherapy for stage III colon cancer.

3596 Background: The optimal duration of adjuvant combination chemotherapy administered to patients with stage III colon cancer is debated. Our study assessed the effect of completed chemotherapy cycles on 3-year colon cancer-specific mortality, as well as the effect of dose reduction and early discontinuation of oxaliplatin in patients with 100% completion, within a real-world population. Methods: 4,147 patients undergoing major resection between 01 June 2014 and 30 April 2017 with pathological stage III colon cancer in the English National Health Service were identified. Chemotherapy data were obtained from linked administrative hospital records and a national chemotherapy dataset. Patients were stratified according to completion of &lt; 50% ( &lt; 6 FOLFOX cycles or &lt; 4 CAPOX cycles), 50-92% (6-11 FOLFOX cycles or 4-7 CAPOX cycles) or 100% of cycles (12 FOLFOX cycles or 8 CAPOX cycles). Competing-risk regression analysis for 3-year colon cancer-specific death was performed with adjustment for patient, tumour and hospital-level characteristics to estimate subdistribution hazard ratios (sHR) as a measure of relative risk. Results: Patients included within our study were less fit and had increased rates of high-risk disease (T4 and/or N2 pathological staging) compared to the IDEA study. For FOLFOX, the 3-year cumulative incidence of colon cancer-specific death in patients completing 100% of cycles was 15.1% (95% CI, 12.8% to 17.6%), 18.2% (95% CI, 15.3% to 21.3%) for 50-92% of cycles and 26.4% (95% CI, 20.6% to 32.5%) for &lt; 50% of cycles. For CAPOX, this was 12.0% (95% CI, 10.2% to 14.0%) for 100% completion of cycles, 18.2% (95% CI, 15.6% to 21.0%) for 50-92% of cycles, and 19.8% (95% CI, 15.8% to 24.1%) for &lt; 50% cycles. Compared to 100% completion of FOLFOX cycles, colon cancer-specific death was higher in patients recorded as completing &lt; 50% (sHR 2.17; 95% CI, 1.56 to 3.03; P = &lt; 0.001) and 50-92% of FOLFOX cycles (sHR 1.40; 95% CI, 1.09 to 1.78; P = 0.007). Compared to 100% completion of CAPOX cycles, colon cancer-specific death was higher in patients recorded as completing &lt; 50% (sHR 2.02; 95% CI 1.53 to 2.67; P&lt; 0.001) and 50-92% of CAPOX cycles (sHR 1.63; 95% CI 1.27 to 2.10; P&lt; 0.001). Dose reduction and early discontinuation of oxaliplatin did not have a statistically significant effect on mortality. Conclusions: Patients within the real world setting were more likely to have poor prognostic factors. Those who completed adjuvant chemotherapy for stage III colon cancer had improved survival rates regardless of dose reduction or early discontinuation of oxaliplatin.

SAPPHIRE: a randomised phase II study of planned discontinuation or continuous treatment of oxaliplatin after six cycles of modified FOLFOX6 plus panitumumab in patients with colorectal cancer

BackgroundFluorouracil (5-FU), leucovorin (LV) and oxaliplatin (FOLFOX) plus panitumumab therapy is a commonly used first-line chemotherapy for metastatic colorectal cancer (mCRC). However, the long-term administration of oxaliplatin is associated with peripheral neuropathy (PN). We investigated whether the planned discontinuation of oxaliplatin after FOLFOX plus panitumumab therapy can maintain efficacy and reduce PN incidence. Patients and methodsChemotherapy-naive patients with RAS wild-type mCRC, aged ≥20 years, were enrolled and received six cycles of modified FOLFOX6 (mFOLFOX6) plus panitumumab as induction therapy. Patients who completed induction therapy without progression were randomised to mFOLFOX6 plus panitumumab (group A) or to 5-FU/LV plus panitumumab (group B). The primary end-point was the progression-free survival (PFS) rate at 9 months after randomisation. The secondary end-points were PFS, overall survival (OS), time to treatment failure (TTF), response rate (RR) and safety. ResultsIn total, 164 patients were enrolled; of whom, 113 patients were then randomised (group A, n = 56; group B, n = 57). The median follow-up after randomisation was 19.6 months. The PFS rates at 9 months and median PFS were 46.4% (80% confidence interval [CI], 38.1–54.9) and 9.1 months (95% CI, 8.6–11.1) in group A, compared with 47.4% (80% CI, 39.1–55.8) and 9.3 months (95% CI, 6.0–13.0) in group B, respectively. RR, OS and TTF were also similar in both groups. Grade ≥2 PN incidence was lower in group B (9.3%) than in group A (35.7%). ConclusionPlanned discontinuation of oxaliplatin after six cycles of mFOLFOX6 plus panitumumab is a potential treatment option in patients with mCRC, achieving similar efficacy while reducing oxaliplatin-associated PN compared with mFOLFOX6 plus panitumumab. Trial registration numberNCT02337946

Characteristics of colorectal patients who discontinued oxaliplatin therapy.

e15155 Background: The 3rd generation platinum-based drug, Oxaliplatin, is indicated for treatment of stage II-IV colorectal cancer (CRC). Oxaliplatin combination with Fluorouracil and Leucovorin (FOLFOX) yields a 5-year disease free survival rate of 78%. Oxaliplatin use is limited by dose-limiting side effects such as neurotoxicity, peripheral neuropathy, and hepatotoxicity. Between 60 and 95% of Oxaliplatin treated patients experience neurotoxicity. The incidence of neuropathy varies between 4 and 98%, and of hepatotoxicity between 10 and 50%. There are few effective treatments to prevent or modulate neurotoxicity although infusions of calcium and magnesium may be beneficial. We sought to understand the factors that influence the discontinuation of Oxaliplatin. Objectives: 1) Determine the characteristics of CRC patients who discontinued chemotherapy involving Oxaliplatin; and 2) Examine metabolic panel monitoring among CRC patients. Methods: A retrospective chart review of newly-diagnosed adult patients with CRC stages II, III, and IV at Sanford Health. We used SAS v.9.4 to analyze demographic and clinical data. All P were two-sided, and P &lt; .05 were considered significant. IRB approval was obtained from Sanford Health and the University of North Dakota. Results: Data for 197 patients who received chemotherapy involving Oxaliplatin were studied. The mean [SD] age at diagnosis was 58.4 [± 12.9]. The majority 117 (59%) were male and 188 (96%) were White. 48% of patients had stage III and 35% had stage IV disease. 167 (85%) of patients received FOLFOX therapy. 56 (30%) discontinued Oxaliplatin. The median [range] number of cycles of chemotherapy completed before discontinuing Oxaliplatin was 8 [1-16]. Relative to patients who did not discontinue, patients who discontinued were significantly more likely to have of the descending colon (46% vs. 38%; P=0.023). Discontinuers were significantly more likely to experience moderate to severe symptoms (42% vs. 25%; P=0.032). Only 25 (13%) of patients had serum magnesium measured prior to starting chemotherapy. However, the median [range] serum potassium was significantly lower among discontinuers prior to starting chemotherapy (3.9 [3.2-5.3] vs. 4.1 [2.8-8.1]; P=0.023). Among patients (92%) who developed some form of peripheral neuropathy, the mean [SD] serum calcium was significantly lower among discontinuers (9.22 ± 0.52 vs. 9.40 ± 0.49; P=0.044). Conclusions: This study showed that serum potassium and calcium were significantly lower among patients who discontinued Oxaliplatin. Magnesium was measured rarely.

Panitumumab-based maintenance after oxaliplatin discontinuation in metastatic colorectal cancer: A retrospective analysis of two randomised trials.

Panitumumab is approved for RAS wild‐type metastatic colorectal cancer and was evaluated in Phase III (PRIME, NCT00364013) and Phase II (PEAK, NCT00819780) first‐line randomised studies. This retrospective analysis of these trials investigated efficacy and toxicity of panitumumab‐based maintenance after oxaliplatin discontinuation in RAS wild‐type patients. First‐line regimens were FOLFOX4 ± panitumumab in PRIME and mFOLFOX6 plus panitumumab or mFOLFOX6 plus bevacizumab in PEAK. Outcomes included median progression‐free survival (PFS) and overall survival (OS), from randomisation and oxaliplatin discontinuation, and toxicity. Overall, median duration of panitumumab plus 5‐fluorouracil/leucovorin (5‐FU/LV) maintenance was 21 (interquartile range: 11–41) weeks; that of 5‐FU/LV ± bevacizumab maintenance was 16 (6–31) weeks. Median OS from randomisation was 40.2 (95% confidence interval: 30.3–50.4) and 39.1 (34.2–63.0) months for panitumumab plus 5‐FU/LV maintenance and 24.1 (17.7–33.0) and 28.9 (21.0–32.0) months for 5‐FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively. Median PFS from randomisation was 16.6 (11.3–23.6) and 15.4 (11.6–18.4) months for panitumumab plus 5‐FU/LV maintenance and 12.6 (9.4–16.2) and 13.1 (9.5–16.6) months for 5‐FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively. From oxaliplatin discontinuation, median OS was 33.9 (24.7–42.8) and 33.5 (24.5–54.9) months for panitumumab plus 5‐FU/LV maintenance and 16.4 (12.4–24.1) and 23.3 (15.7–26.3) months for 5‐FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively; PFS was 11.7 (7.8–19.2) and 9.7 (5.8–14.8) months and 7.1 (5.6–10.2) and 7.0 (3.9–10.6) months, respectively. The most frequently reported adverse events were rash, fatigue and diarrhoea. Maintenance of panitumumab plus 5‐FU/LV after oxaliplatin discontinuation was well tolerated and may be an acceptable treatment paradigm for patients demonstrating a good response to first‐line treatment. Prospective studies are warranted.

PD-011 - SAPPHIRE: A randomized phase II study of oxaliplatin discontinuation after 6 cycles of mFOLFOX6 + panitumumab therapy in patients with colorectal cancer: Final analysis of efficacy and safety results

PD-011 - SAPPHIRE: A randomized phase II study of oxaliplatin discontinuation after 6 cycles of mFOLFOX6 + panitumumab therapy in patients with colorectal cancer: Final analysis of efficacy and safety results

A Prospective Study of Chronic Oxaliplatin-Induced Neuropathy in Patients with Colon Cancer: Long-Term Outcomes and Predictors of Severe Oxaliplatin-Induced Neuropathy.

Background and PurposeThe objective of this study was to determine the incidence and long-term outcomes of oxaliplatin-induced peripheral neuropathy (OIPN), as well as predictors of its severe form.MethodsSixty-nine patients who were taking oxaliplatin for colon cancer were prospectively followed prior to starting chemotherapy and after 4, 8, and 12 cycles of chemotherapy. Thirty-six patients completed the follow-up at 1 year after the end of chemotherapy. The patients were assessed using clinical assessment scales and nerve conduction studies (NCS) at each follow-up visit.ResultsBy applying the National Cancer Institute Common Toxicity criteria, OIPN was classified as grade 1 in 30 (44%) patients, grade 2 in 25 (36%), and grade 3 in 10 (14%) at the completion of therapy. At 1 year after the treatment, OIPN of grades 1, 2, and 3 was found in 50, 3, and 11% of the patients, respectively. Multivariate analysis showed that reductions of the amplitude of the sensory action potential of >11.5% in the median nerve between baseline and four cycles of chemotherapy (odds ratio=5.603, p=0.031) and of >22.5% in the sural nerve between four and eight cycles of chemotherapy (odds ratio=5.603, p=0.031) were independently associated with the risk of developing grade-3 OIPN.ConclusionsWhile the severity of OIPN can improve after oxaliplatin discontinuation, more than half of the patients in this study still had OIPN at 1 year after discontinuation. Early changes in the NCS results for sensory nerves can predict the development of severe OIPN during treatment.

MFOLFOX6 Plus Panitumumab Versus 5-FU/LV Plus Panitumumab After Six Cycles of Frontline mFOLFOX6 Plus Panitumumab: A Randomized Phase II Study of Patients With Unresectable or Advanced/Recurrent, RAS Wild-type Colorectal Carcinoma (SAPPHIRE)—Study Design and Rationale

BackgroundIn Japan, oxaliplatin (OXA)/5-fluorouracil (5-FU)/leucovorin (LV)—the mFOLFOX6 regimen—is the most frequently used first-line chemotherapy backbone for metastatic colorectal cancer. However, peripheral nerve disorders caused by OXA during mFOLFOX6 therapy can decrease patients' quality of life. OXA can be safely discontinued from a FOLFOX regimen after 6 cycles during first-line therapy. Also, for patients who discontinue OXA without having experienced peripheral nerve disorders, reintroducing OXA in the later stages of treatment could remain an option. Patients and MethodsThe study is a phase II, multicenter, open-label, parallel-group, randomized, controlled exploratory study comparing the efficacy and safety of mFOLFOX6 plus panitumumab and 5-FU/LV plus panitumumab in patients with chemotherapy-naïve, unresectable, advanced or recurrent colorectal carcinoma of RAS wild-type (SAPPHIRE; ClinicalTrials.gov identifier, NCT02337946). Eligible patients will receive 6 cycles of mFOLFOX6 plus panitumumab combination therapy, followed by 1:1 randomization to either further treatment with mFOLFOX6 plus panitumumab or discontinuation of OXA and treatment with 5-FU/LV plus panitumumab. Up to 100 randomized patients will receive treatment for approximately 12 months or until any of the criteria for treatment discontinuation have been met. The primary endpoint is progression-free survival rate at 9 months after the day of randomization. The secondary endpoints are progression-free survival, overall survival, response rate, and interval to treatment failure. Safety will be evaluated according to the incidence and severity of adverse events, including the incidence of peripheral nerve and skin disorders. Additional endpoints will include maintenance of performance status, continuation of OXA in the mFOLFOX6 plus panitumumab group, and continuation of panitumumab in both groups.

Hyperacute peripheral neuropathy is a predictor of oxaliplatin-induced persistent peripheral neuropathy.

Chronic peripheral neuropathy is a major adverse response to oxaliplatin-containing chemotherapy regimens, but there are no established risk factors pertaining to it. We investigated the efficacy of hyperacute peripheral neuropathy (HAPN) as a predictor of oxaliplatin-induced persistent peripheral neuropathy (PPN). Forty-seven cases of stage III colorectal cancer who received adjuvant chemotherapy with oxaliplatin after curative surgery between January 2010 and August 2014 were retrospectively reviewed. HAPN was defined as acute peripheral neuropathy (APN) occurring on day 1 (≤24h after oxaliplatin infusion) of the first cycle. PPN was defined as neuropathy lasting >1year after oxaliplatin discontinuation. The average total dose of oxaliplatin was 625.8mg/m2, and the average relative dose intensity was 66.7%. Twenty-two of the 47 patients (46.8%) had PPN and 13 (27.7%) had HAPN. Male sex, treatment for neuropathy, HAPN, and APN were significantly more frequent in patients with PPN (p=0.013, 0.02, <0.001, and 0.023, respectively). There was no significant difference in the total oxaliplatin dose between patients with and without PPN (p=0.061). Multivariate analyses revealed total dose of oxaliplatin and HAPN as independent predictors of PPN [p=0.015; odds ratio (OR)=1.005, 95% confidence interval (CI), 1.001-1.009 and p=0.001; OR=75.307, 5.3-1070.123, respectively]. The total dose of oxaliplatin was relatively lower in patients with HAPN than that in those without HAPN in the PPN-positive group (not significant, p=0.068). HAPN was found to be a predictor of oxaliplatin-induced PPN.

502P - Pharmacological bioquivalence of branded and generic oxaliplatin: from preclinical assessment to clinical incidence of hypersensitivity reactions in patients with colorectal cancer

Generic drugs represent a relevant, potential opportunity in terms of cost savings. However, several physicians are uncomfortable with the replacement of the branded drugs with generic equivalents, indicating among several reasons their hypothetical lower tolerability. In the preclinical phase we in vitro tested the concentrations, stability and efficacy in CACO-2 cell line of branded versus two generic oxaliplatin formulations. In a second step we retrospectively collected safety and toxicity data from 427 colorectal cancer patients submitted to an oxaliplatin-based regimen between January 1994 and June 2014 at our institution. Patients were stratified according whether they received branded (BRAND group) or generic oxaliplatin (GENERIC group). Primary aim of this second step was the assessment of the hypersensitivity reaction (HSR) incidence. Secondary aims were the evaluation of hematological and non-hematological toxicities and, in metastatic patients, clinical outcomes. Preclinical tests did not demonstrated differences in concentration and stability in different storing conditions between branded and generic formulations. Furthermore, dose- and time-dependent anti-proliferative activities were similar.The incidence of HSRs was 12.1% in BRAND (33/273 patients) and 9.8% (15/154) in GENERIC group (p = 0.46). Occurrence of grade III-IV HSRs and severe HSRs leading to oxaliplatin discontinuation were comparable. In metastatic patients no significant difference in response rate was reported. A longer PFS was recorded in the BRAND group (14.4 vs 12.4 months, log rank p < 0.03), whereas OSs were comparable (24.9 vs 26.9 months; log-rank p = 0.14). Tested generic and branded oxaliplatin formulations had equivalent concentrations of the active drug, and presented similar stability and in vitro efficacy. Likewise, the incidence of oxaliplatin-induced HSRs as well as toxicity profiles and clinical outcomes were similar. According to our data, generic oxaliplatin can be considered a safe and active alternative to the branded formulation.