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Intravenous calcium and magnesium prevents oxaliplatin-induced sensory
neurotoxicity in adjuvant colon cancer: Results of a phase III placebo-controlled,
double-blind trial (N04C7)
Intravenous calcium and magnesium prevents oxaliplatin-induced sensory
neurotoxicity in adjuvant colon cancer: Results of a phase III placebo-controlled,
double-blind trial (N04C7)
DA Nikcevich, A Grothey, JA Sloan, JW Kugler, PT Silberstein, T Dentchev, DB Wender, PJ Novotny,
HE Windschitl, CL Loprinzi
For the North Central Cancer Treatment Group
• I have no relevant relationships to discuss.
BackgroundBackground
• Cumulative peripheral sensory neurotoxicity (PSN) is the dose-limiting toxicity of oxaliplatin
• PSN commonly leads to early discontinuation of oxaliplatin-based therapy in the palliative and adjuvant setting
• In a retrospective, non-randomized study, intravenous administration of calcium and magnesium salts (CaMg) was associated with reduced oxaliplatin-induced PSN (Gamelin, Clin Cancer Res 2004).
• N04C7 prospectively evaluated the activity of IV CaMg as a neuroprotectant against cumulative oxaliplatin-related PSN in a placebo-controlled phase III trial
N04C7 Cancer Control Phase III Trial – Study Design
N04C7 Cancer Control Phase III Trial – Study Design
• 1g Ca-gluconate and 1g Mg-sulfate in 100 mL D5W over 30 min immediately before and after oxaliplatin (placebo = 100 mL D5W)
• Neurotoxicity recorded in 3 different ways:• NCI-CTC v3.0 (primary endpoint)• Oxaliplatin-specific scale• Patient questionnaires
Pts to receiveadj. FOLFOXPts to receiveadj. FOLFOX
IV CaMg
% of Grade 2+ sNT
% of Grade 2+ sNTR
IV placeboIV placebo
Key Inclusion CriteriaKey Inclusion Criteria
• Resected adenocarcinoma of the colon, stage II or III
• No evidence of residual disease
• Scheduled to receive 12 cycles of oxaliplatin-based adjuvant chemotherapy with 85 mg/m2 oxaliplatin every 2 weeks (e.g. mFOLFOX6 or FOLFOX4)
• Age >18 years
• No pre-existing peripheral neuropathy of any grade
• No hypercalcemia
• No digitalis medication, no history of AV block
StatisticsStatistics
• Primary endpoint
• Percentage of patients with Grade 2+ chronic PSN during or at end of therapy
• After discussions with NCI, CTC v3.0 “enhanced” by patient-reported outcomes (PRO) used
• With 150 patients per arm, 80% power to detect a 15% difference (25% vs 40%) in incidence of Grade 2+ PSN
• Stratification factors: Age (< vs >65), gender, regimen (FOLFOX4 vs mFOLFOX6)
StatisticsStatistics
• Selected secondary endpoints
• Time-to-onset and duration of G2+ (and G3+) PSN
• Percentage of patients with acute neuropathic events
• Percentage of patients discontinuing adjuvant therapy
• Average cumulative oxaliplatin dose
• Duration of therapy
• Various QOL parameters (questionnaires)
• Pharmacogenomic analysis (e.g. GSTP1 polymorphism)
Neurotoxicity EvaluationNeurotoxicity Evaluation
Grade NCI-CTC 3.0Oxaliplatin-specific
scale
Iloss of deep tendon reflexes or paresthesia, including tingling, but not interfering with function
sensory symptoms of short duration
II
objective sensory alteration or paresthesia, including tingling, interfering with function, but not interfering with activities of daily living
sensory symptoms persisting between cycles
IIIsensory alteration or paresthesia interfering with activities of daily living
sensory symptoms causing functional impairment
IVPermanent sensory losses that are disabling -
PRO-”Enhanced” NCI-CTC in N04C7PRO-”Enhanced” NCI-CTC in N04C7
Do you have problems writing?
Grade I “No, I might feel some tingling in my hands, but I have no problems writing”
Grade II “It is a bit harder than before, but I can still write”Grade III “I have severe difficulties writing” or
“I cannot write anymore”Grade IV “I haven’t been able to write for weeks”
Study CharacteristicsStudy Characteristics
• Study designed to randomize a total of 300 patients
• Accrual halted and study terminated prematurely in August 2007 when interim analysis of the palliative COncePT trial suggested that CaMg reduced activity of oxaliplatin-based therapy (Hochster et al. Letter to Editor, JCO 2007)
• At time of study closure, 104 patients randomized, 102 patients had started study medication (50 CaM, 52 PL)
• Presented analyses based on intention-to-treat analysis of these 102 patients
• Data cut-off after 127 days (4 months plus 1 week) due to premature study closure
Pertinent Patient characteristicsPertinent Patient characteristics
% PatientsCaMg(N=50)
Placebo(N=52)
Total(N=102)
Age >65 34 38.5 36.3
Male 54 52 53
Caucasian 96 96 96
mFOLFOX6 98 94 96
Adverse EventsAdverse Events
No difference between CaMg and Placebo in any recorded adverse events incl.
• Anemia
• Leuko-/neutropenia
• Thrombocytopenia
• Infection
• Diarrhea
• Dehydration
• Cardiac events
• Pain
• Myalgia
• Muscle weakness
• Hypersensitivity
• Taste abnormality
• Stomatitis
• Nausea/vomiting
• Hypercalcemia
• Incidence of any toxicity
Primary Endpoint Grade 2+ sNT (CTC Scale)
Primary Endpoint Grade 2+ sNT (CTC Scale)
Neurotoxicity Grade
CaMg(N=50)
Placebo(N=52)
P-value(Chi-Square)
Missing 0 1
0.038Grade 0/1 78% 59%
Grade 2+ 22% 41%
Time to Grade 2+ sNT (CTC scale)Time to Grade 2+ sNT (CTC scale)
Primary Endpoint Grade 2+ sNT (Oxaliplatin Scale)
Primary Endpoint Grade 2+ sNT (Oxaliplatin Scale)
Neurotoxicity Grade
CaMg(N=50)
Placebo(N=52)
P-value(Chi-Square)
Missing 0 1
0.018Grade 0/1 72% 49%
Grade 2+ 28% 51%
Time to Grade 2+ sNT (Oxaliplatin scale)Time to Grade 2+ sNT (Oxaliplatin scale)
QOL AssessmentQOL Assessment
• At each visit, patients completed 3 questionnaires• General QOL questionnaire• Brief Fatigue Inventory• Specific neurotoxicity evaluation form which tried to
distinguish between• Acute vs chronic neuropathy
• “Symptoms immediately after last treatment”• “Symptoms within last 2 weeks”
• QOL analysis ongoing, presented results preliminary
QOL Assessment (Acute PSN)QOL Assessment (Acute PSN)
Swallowing discomfort Muscle cramps
p=0.065 p=0.012
p-value for comparison of areas under the curves
QOL Assessment (Chronic PSN)QOL Assessment (Chronic PSN)
Numbness fingers/toes Tingling fingers/toes
p=0.021 p=0.062
p-value for comparison of areas under the curves
ConclusionsConclusions
• Results and conclusions are affected by early, premature discontinuation of study due to external reasons
• Despite early termination, our study demonstrates neuroprotective activity of CaMg against oxaliplatin-induced chronic PSN in adjuvant colon cancer in
• NCI-CTC assessment
• Oxaliplatin-specific scale
• Select QOL parameters
• Effect on acute neuropathy still indeterminate
ConclusionsConclusions
• In view of its negligible toxicity, its low cost, and its demonstrated lack of interference with chemotherapy, CaMg could be considered as a standard component of oxaliplatin-based therapy
• Additional studies of CaMg as neuroprotectant with other neuropathic chemotherapy are contemplated