Chemotherapeutic Agent Toxicity, Colorectal Cancer, Neuropathy, Neurotoxicity
Conditions
Keywords
neurotoxicity, neuropathy, chemotherapeutic agent toxicity, stage II colon cancer, stage III colon cancer, stage IV colon cancer, stage II rectal cancer, stage III rectal cancer, stage IV rectal cancer, adenocarcinoma of the colon, adenocarcinoma of the rectum
Brief summary
RATIONALE: Chemoprotective drugs, such as calcium gluconate and magnesium sulfate, may prevent neurotoxicity caused by oxaliplatin. It is not yet known which administration schedule of calcium gluconate and magnesium sulfate is more effective in preventing neurotoxicity. PURPOSE: This randomized phase III trial is studying different administration schedules of calcium gluconate and magnesium sulfate and comparing how well they work in neurotoxicity in patients with colon cancer or rectal cancer receiving oxaliplatin-based combination chemotherapy.
Detailed description
OBJECTIVES: Primary * To determine whether 2 schedules of calcium gluconate and magnesium sulfate infusions (given before and after chemotherapy or just before chemotherapy) can prevent or ameliorate chronic, cumulative oxaliplatin-induced sensory neurotoxicity in patients with colon or rectal cancer receiving adjuvant FOLFOX chemotherapy comprising leucovorin calcium, fluorouracil, and oxaliplatin. Secondary * To determine whether these 2 infusion schedules can increase the cumulative oxaliplatin doses that can be delivered without dose-limiting chronic neurotoxicity. * To determine whether these 2 infusion schedules can ameliorate acute neuropathy associated with oxaliplatin. * To determine whether these 2 infusion schedules cause adverse events. * To investigate whether these 2 infusions schedules influence patient quality of life. * To describe baseline and post-treatment neurological quantitative sensory testing abnormalities in the study participants. Tertiary * To explore if polymorphisms in the GSTP1, GSTM1, ERCC2, and XRCC1 genes are associated with early onset of oxaliplatin-induced neurotoxicity. OUTLINE: This is a multicenter study. Patients are stratified according to age (\< 65 years vs ≥ 65 years), gender, regimen (FOLFOX4 vs modified FOLFOX6 vs other), and stage of disease (II vs III vs IV). Patients are randomized to 1 of 3 treatment arms. * Arm I: Patients receive calcium gluconate IV and magnesium sulfate IV over 30 minutes immediately before and after oxaliplatin administration (part of FOLFOX chemotherapy comprising leucovorin calcium, fluorouracil, and oxaliplatin). * Arm II: Patients receive placebo IV over 30 minutes immediately before and after oxaliplatin administration (part of FOLFOX chemotherapy). * Arm III: Patients receive calcium gluconate and magnesium sulfate IV over 30 minutes immediately before and placebo IV over 30 minutes immediately after oxaliplatin administration (part of FOLFOX chemotherapy). In all arms, courses repeat every 14 days for 6 months in the absence of disease progression or unacceptable toxicity. Blood samples are collected before the second course of treatment for translational research. Patients complete questionnaires on side effects, quality of life, and chemotherapy-induced peripheral neuropathy periodically. After completion of study treatment, patients are followed up at 3, 6, 12, and 18 months.
Interventions
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed adenocarcinoma of the colon or rectum * Has undergone curative resection and is considered to have stage II or III disease or completely resected stage IV disease with no evidence of residual tumor * Scheduled to receive 6 months of oxaliplatin-based adjuvant chemotherapy with 85 mg/m\^2 oxaliplatin every 2 weeks (this includes, for instance, FOLFOX4 or modified FOLFOX6) * Patients receiving bevacizumab or cetuximab in combination with FOLFOX as part of a clinical trial or clinical practice are eligible PATIENT CHARACTERISTICS: * ECOG performance status 0-2 * WBC ≥ 3,000/mm\^3 * ANC ≥ 1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Hemoglobin ≥ 10.0 g/dL * Total bilirubin ≤ 1.5 times upper limit of normal (ULN) * Serum creatinine ≤ 1.5 times ULN * Serum calcium ≤ 1.2 times ULN * Serum magnesium ≤ 1.2 times ULN * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * Able to complete questionnaires (alone or with assistance) * Able to comply with study treatment * Willing to return to enrolling institution for follow-up * Willing to provide blood sample for research purposes * No pre-existing peripheral neuropathy of any grade * No family history of a genetic/familial neuropathy * No second or third degree AV heart block or a history of second or third degree heart block * Bundle branch blocks are allowed. * No other medical conditions that, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient PRIOR CONCURRENT THERAPY: * See Disease Characteristics * Central venous access line present, or scheduled to have a central line placed before starting chemotherapy and study treatment * No prior treatment with neurotoxic chemotherapy (e.g., oxaliplatin, cisplatin, taxanes, or vinca alkaloids) * No concurrent digitalis medication * No concurrent treatment with the anticonvulsants carbamazepine (e.g., Tegretol®), phenytoin (e.g., Dilantin®), valproic acid (e.g., Depakene®), gabapentin (Neurontin®), or pregabalin (Lyrica®) * No concurrent neurotropic agents, including venlafaxine (Effexor), desvenlafaxine (Pristiq®), milnacipran (Savella®), or duloxetine (Cymbalta) * No concurrent tricyclic antidepressants (such as amitryptilline), or any other agent specifically being given to prevent or treat neuropathy * No concurrent drugs given as a neuroprotectant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sensory Area Under the Curve(AUC) Score. Oxaliplatin-induced Sensory Neuropathy as Repeatedly Measured by the EORTC QLQ-CIPN20 Sensory Subscale During Chemotherapy | Up to 18 months | The oxaliplatin-induced sensory neuropathy as repeatedly measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced peripheral neuropathy (EORTC QLQ-CIPN20) sensory subscale during the chemotherapy. This is a multivariate repeated measurement of CIPN with possibly variable cycles for every patient. The CIPN sensory subscale will be calculated by standard scoring algorithm and converted to 0-100 scale, where higher scores represent a higher quality of life. Rather than choosing the CIPN20 sensory subscale at a fixed cycle of chemotherapy, we will adopt a summary measure, area under the curve (AUC) of CIPN20 sensory subscale as the primary endpoint. This AUC will be prorated by the number of chemotherapy cycles patients received. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC) of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced Peripheral Neuropathy (EORTC QLQ-CIPN20) Motor Neuropathy Subscale Scores | Up to 18 Months | The oxaliplatin-induced motor neuropathy as repeatedly measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced peripheral neuropathy (EORTC QLQ-CIPN20) motor neuropathy subscale during the chemotherapy. This is a multivariate repeated measurement of CIPN with possibly variable cycles for every patient. The CIPN motor neuropathy subscale will be calculated by standard scoring algorithm and converted to 0-100 scale, where higher scores represent a higher quality of life. Rather than choosing the CIPN20 motor neuropathy subscale at a fixed cycle of chemotherapy, we will adopt a summary measure, area under the curve (AUC) of CIPN20 motor neuropathy subscale as the endpoint. This AUC will be prorated by the number of chemotherapy cycles patients received. |
| Percentage of Patients Experiencing Grade 2+ and Grade 3+ Chronic Cumulative Neurotoxicity. | Up to 18 months | Grades are determined by the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.0) and oxaliplatin-specific neurotoxicity scale, during and after chemotherapy. Higher grades symbolize greater severity of the adverse event. |
| Time to Onset of Grade 2+ and Grade 3+ Chronic Cumulative Neurotoxicity and the Duration of the Chronic Cumulative Neurotoxicity During and After Chemotherapy | Up to 18 months | Time to onset of grade 2+ and grade 3+ chronic cumulative neurotoxicity, the duration of the chronic cumulative neurotoxicity during and after the adjuvant oxaliplatin-based chemotherapy. Grades are determined by the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.0) and oxaliplatin-specific neurotoxicity scale, during and after chemotherapy. Higher grades symbolize greater severity of the adverse event. |
| Cumulative Oxaliplatin Doses That Can be Administered Without Dose-limiting Chronic Neurotoxicity | Up to 18 months | A patient has a dose-limiting chronic neurotoxicity when they discontinue oxaliplatin-based chemotherapy because of neurotoxicity. |
| Area Under the Curve (AUC) of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced Peripheral Neuropathy (EORTC QLQ-CIPN20) Autonomic Neuropathy Subscale Scores | Up to 18 months | The oxaliplatin-induced autonomic neuropathy as repeatedly measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced peripheral neuropathy (EORTC QLQ-CIPN20) autonomic subscale during the chemotherapy. This is a multivariate repeated measurement of CIPN with possibly variable cycles for every patient. The CIPN autonomic subscale will be calculated by standard scoring algorithm and converted to 0-100 scale, where higher scores represent a higher quality of life. Rather than choosing the CIPN20 autonomic subscale at a fixed cycle of chemotherapy, we will adopt a summary measure, area under the curve (AUC) of CIPN20 autonomic subscale as the endpoint. This AUC will be prorated by the number of chemotherapy cycles patients received. |
| Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Up to 18 months | This is the percent of patients who scored \>=50 in all sequences of all cycles by arm for side effect Q1: Sensitivity to touching cold. This is a\> repeated measurement of CIPN with possibly variable cycles for every patient. The CIPN subscale will be calculated by standard scoring algorithm and converted to 0-100 scale. Where 0 is no sensitivity and 100 is as bad as it can be. |
| Incidence of Calcium Gluconate and Magnesium Sulfate-induced Adverse Events as Measured by CTCAE Version 4.0 | Up to 18 months | — |
| Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Up to 18 months | This is a multivariate repeated measurement of CIPN with possibly variable cycles for every patient. The supplemental quality of life (QOL) subscale will be calculated by standard scoring algorithm and converted to 0-100 scale, where higher scores represent a higher quality of life. Rather than choosing the subscale at a fixed cycle of chemotherapy, we will adopt a summary measure, area under the curve (AUC) . This AUC will be prorated by the number of chemotherapy cycles patients received. |
| Percentage of Patients Discontinuing Oxaliplatin-based Chemotherapy Because of Neurotoxicity | Up to 18 months | — |
Countries
Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) Patients receive calcium gluconate and magnesium sulfate IV over 30 minutes immediately before and after oxaliplatin administration (part of FOLFOX chemotherapy comprising leucovorin calcium, fluorouracil, and oxaliplatin).\>\>
\>\> calcium gluconate: Given IV\>\>
\>\> magnesium sulfate: Given IV\>\>
\>\> oxaliplatin | 118 |
| Placebo (Pre and Post) Patients receive placebo IV over 30 minutes immediately before and after oxaliplatin administration (part of FOLFOX chemotherapy).\>\> \>\> placebo: Given IV\>\>
\>\> oxaliplatin | 119 |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) Patients receive calcium gluconate and magnesium sulfate IV over 30 minutes immediately before and placebo IV over 30 minutes immediately after oxaliplatin administration (part of FOLFOX chemotherapy).\>\> \>\> calcium gluconate: Given IV\>\>
\>\> magnesium sulfate: Given IV\>\>
\>\> placebo: Given IV\>\>
\>\>
\>\>
\>\>\> oxaliplatin | 116 |
| Total | 353 |
Baseline characteristics
| Characteristic | Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Placebo (Pre and Post) | Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Total |
|---|---|---|---|---|
| Age, Continuous | 57 years | 56 years | 57 years | 56 years |
| Region of Enrollment Ecuador | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 118 Participants | 118 Participants | 116 Participants | 352 Participants |
| Sex: Female, Male Female | 62 Participants | 62 Participants | 60 Participants | 184 Participants |
| Sex: Female, Male Male | 56 Participants | 57 Participants | 56 Participants | 169 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 107 / 117 | 108 / 119 | 105 / 116 |
| serious Total, serious adverse events | 13 / 117 | 9 / 119 | 8 / 116 |
Outcome results
Primary
Sensory Area Under the Curve(AUC) Score. Oxaliplatin-induced Sensory Neuropathy as Repeatedly Measured by the EORTC QLQ-CIPN20 Sensory Subscale During Chemotherapy
The oxaliplatin-induced sensory neuropathy as repeatedly measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced peripheral neuropathy (EORTC QLQ-CIPN20) sensory subscale during the chemotherapy. This is a multivariate repeated measurement of CIPN with possibly variable cycles for every patient. The CIPN sensory subscale will be calculated by standard scoring algorithm and converted to 0-100 scale, where higher scores represent a higher quality of life. Rather than choosing the CIPN20 sensory subscale at a fixed cycle of chemotherapy, we will adopt a summary measure, area under the curve (AUC) of CIPN20 sensory subscale as the primary endpoint. This AUC will be prorated by the number of chemotherapy cycles patients received.
Time frame: Up to 18 months
Population: All enrolled patients with Baseline and more than 1 cycle of Sensory data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Sensory Area Under the Curve(AUC) Score. Oxaliplatin-induced Sensory Neuropathy as Repeatedly Measured by the EORTC QLQ-CIPN20 Sensory Subscale During Chemotherapy | 89.2 score on a scale | Standard Deviation 8.5 |
| Placebo (Pre and Post) | Sensory Area Under the Curve(AUC) Score. Oxaliplatin-induced Sensory Neuropathy as Repeatedly Measured by the EORTC QLQ-CIPN20 Sensory Subscale During Chemotherapy | 88.3 score on a scale | Standard Deviation 9.7 |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Sensory Area Under the Curve(AUC) Score. Oxaliplatin-induced Sensory Neuropathy as Repeatedly Measured by the EORTC QLQ-CIPN20 Sensory Subscale During Chemotherapy | 87.1 score on a scale | Standard Deviation 9.9 |
Comparison: Two-sample t-tests or Wilcoxon rank-sum tests will be used\>\> to compare the AUC of CIPN sensory subscale between each of the two schedules of\>\> Ca/Mg infusions vs placebo arms at the 2.5% significance level. If the CIPN sensory\>\> subscales are observed to be unbalanced, we will adjust for the baseline CIPN sensory\>\> subscale scores from the AUC or incorporate them as a covariate in generalized linear\>\> regression model.p-value: 0.73Wilcoxon (Mann-Whitney)
Comparison: Two-sample t-tests or Wilcoxon rank-sum tests will be used\>\> to compare the AUC of CIPN sensory subscale between each of the two schedules of\>\> Ca/Mg infusions vs placebo arms at the 2.5% significance level. If the CIPN sensory\>\> subscales are observed to be unbalanced, we will adjust for the baseline CIPN sensory\>\> subscale scores from the AUC or incorporate them as a covariate in generalized linear\>\> regression model.p-value: 0.29Wilcoxon (Mann-Whitney)
Secondary
Area Under the Curve (AUC) of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced Peripheral Neuropathy (EORTC QLQ-CIPN20) Motor Neuropathy Subscale Scores
The oxaliplatin-induced motor neuropathy as repeatedly measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced peripheral neuropathy (EORTC QLQ-CIPN20) motor neuropathy subscale during the chemotherapy. This is a multivariate repeated measurement of CIPN with possibly variable cycles for every patient. The CIPN motor neuropathy subscale will be calculated by standard scoring algorithm and converted to 0-100 scale, where higher scores represent a higher quality of life. Rather than choosing the CIPN20 motor neuropathy subscale at a fixed cycle of chemotherapy, we will adopt a summary measure, area under the curve (AUC) of CIPN20 motor neuropathy subscale as the endpoint. This AUC will be prorated by the number of chemotherapy cycles patients received.
Time frame: Up to 18 Months
Population: All patients with at least baseline and more than 1 cycle of Motor Neuropathy data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Area Under the Curve (AUC) of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced Peripheral Neuropathy (EORTC QLQ-CIPN20) Motor Neuropathy Subscale Scores | 94.1 AUC QLQ-CIPN20 Motor Neuropathy Score | Standard Deviation 7.9 |
| Placebo (Pre and Post) | Area Under the Curve (AUC) of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced Peripheral Neuropathy (EORTC QLQ-CIPN20) Motor Neuropathy Subscale Scores | 93.3 AUC QLQ-CIPN20 Motor Neuropathy Score | Standard Deviation 8 |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Area Under the Curve (AUC) of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced Peripheral Neuropathy (EORTC QLQ-CIPN20) Motor Neuropathy Subscale Scores | 91.6 AUC QLQ-CIPN20 Motor Neuropathy Score | Standard Deviation 10.5 |
Comparison: We will not adjust p-values (or significance level) for multiple\>\> comparisons among the numerous hypothesis testings of secondary endpoints due to the\>\> exploratory nature of these secondary analyses. The significance results from secondary\>\> analyses will be interpreted cautiously in a hypothesis-generating fashion.p-value: 0.29Wilcoxon (Mann-Whitney)
Comparison: We will not adjust p-values (or significance level) for multiple\>\> comparisons among the numerous hypothesis testings of secondary endpoints due to the\>\> exploratory nature of these secondary analyses. The significance results from secondary\>\> analyses will be interpreted cautiously in a hypothesis-generating fashion.p-value: 0.25Wilcoxon (Mann-Whitney)
Secondary
Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire
This is a multivariate repeated measurement of CIPN with possibly variable cycles for every patient. The supplemental quality of life (QOL) subscale will be calculated by standard scoring algorithm and converted to 0-100 scale, where higher scores represent a higher quality of life. Rather than choosing the subscale at a fixed cycle of chemotherapy, we will adopt a summary measure, area under the curve (AUC) . This AUC will be prorated by the number of chemotherapy cycles patients received.
Time frame: Up to 18 months
Population: All patients that had at least one cycle of treatment and submitted a patient-reported quality of life (QOL) as measured by the supplemental QOL questionnaire
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Constipation | 90.1 score on a scale | Standard Deviation 13 |
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Numbness in finger and toes | 83.4 score on a scale | Standard Deviation 14.8 |
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Bowel Problems | 89.1 score on a scale | Standard Deviation 13.4 |
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Diarrhea | 86.7 score on a scale | Standard Deviation 15.5 |
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Swallowing | 91.2 score on a scale | Standard Deviation 10 |
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Tingling in finger and toes | 78.9 score on a scale | Standard Deviation 16.5 |
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Stomach Cramping | 92.8 score on a scale | Standard Deviation 11.4 |
| Placebo (Pre and Post) | Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Numbness in finger and toes | 81.8 score on a scale | Standard Deviation 15.7 |
| Placebo (Pre and Post) | Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Diarrhea | 86.2 score on a scale | Standard Deviation 15.7 |
| Placebo (Pre and Post) | Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Constipation | 88.8 score on a scale | Standard Deviation 13.4 |
| Placebo (Pre and Post) | Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Stomach Cramping | 90.6 score on a scale | Standard Deviation 12.6 |
| Placebo (Pre and Post) | Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Bowel Problems | 88.5 score on a scale | Standard Deviation 14.4 |
| Placebo (Pre and Post) | Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Swallowing | 87.6 score on a scale | Standard Deviation 13.8 |
| Placebo (Pre and Post) | Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Tingling in finger and toes | 76.5 score on a scale | Standard Deviation 17.3 |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Stomach Cramping | 89.4 score on a scale | Standard Deviation 15.6 |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Numbness in finger and toes | 80.0 score on a scale | Standard Deviation 17.3 |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Constipation | 88.0 score on a scale | Standard Deviation 18.8 |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Diarrhea | 84.5 score on a scale | Standard Deviation 16 |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Tingling in finger and toes | 76.3 score on a scale | Standard Deviation 17.6 |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Bowel Problems | 84.6 score on a scale | Standard Deviation 19 |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Area Under the Curve (AUC) of Patient-reported Quality of Life (QOL) as Measured by the Supplemental QOL Questionnaire | Swallowing | 86.7 score on a scale | Standard Deviation 14.1 |
Secondary
Area Under the Curve (AUC) of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced Peripheral Neuropathy (EORTC QLQ-CIPN20) Autonomic Neuropathy Subscale Scores
The oxaliplatin-induced autonomic neuropathy as repeatedly measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced peripheral neuropathy (EORTC QLQ-CIPN20) autonomic subscale during the chemotherapy. This is a multivariate repeated measurement of CIPN with possibly variable cycles for every patient. The CIPN autonomic subscale will be calculated by standard scoring algorithm and converted to 0-100 scale, where higher scores represent a higher quality of life. Rather than choosing the CIPN20 autonomic subscale at a fixed cycle of chemotherapy, we will adopt a summary measure, area under the curve (AUC) of CIPN20 autonomic subscale as the endpoint. This AUC will be prorated by the number of chemotherapy cycles patients received.
Time frame: Up to 18 months
Population: All patients with Baseline and more than one cycle of EORTC CIPN-20 Autonomic data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Area Under the Curve (AUC) of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced Peripheral Neuropathy (EORTC QLQ-CIPN20) Autonomic Neuropathy Subscale Scores | 89.8 score on a scale | Standard Deviation 12.5 |
| Placebo (Pre and Post) | Area Under the Curve (AUC) of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced Peripheral Neuropathy (EORTC QLQ-CIPN20) Autonomic Neuropathy Subscale Scores | 86.7 score on a scale | Standard Deviation 14.3 |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Area Under the Curve (AUC) of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Chemotherapy-induced Peripheral Neuropathy (EORTC QLQ-CIPN20) Autonomic Neuropathy Subscale Scores | 84.5 score on a scale | Standard Deviation 15.1 |
Comparison: We will not adjust p-values (or significance level) for multiple\>\> comparisons among the numerous hypothesis testings of secondary endpoints due to the\>\> exploratory nature of these secondary analyses. The significance results from secondary\>\> analyses will be interpreted cautiously in a hypothesis-generating fashion.p-value: 0.054Wilcoxon (Mann-Whitney)
Comparison: We will not adjust p-values (or significance level) for multiple\>\> comparisons among the numerous hypothesis testings of secondary endpoints due to the\>\> exploratory nature of these secondary analyses. The significance results from secondary\>\> analyses will be interpreted cautiously in a hypothesis-generating fashion.p-value: 0.27Wilcoxon (Mann-Whitney)
Secondary
Cumulative Oxaliplatin Doses That Can be Administered Without Dose-limiting Chronic Neurotoxicity
A patient has a dose-limiting chronic neurotoxicity when they discontinue oxaliplatin-based chemotherapy because of neurotoxicity.
Time frame: Up to 18 months
Population: All patients that discontinued treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Cumulative Oxaliplatin Doses That Can be Administered Without Dose-limiting Chronic Neurotoxicity | 8.1 Doses | Standard Deviation 3 |
| Placebo (Pre and Post) | Cumulative Oxaliplatin Doses That Can be Administered Without Dose-limiting Chronic Neurotoxicity | 8.4 Doses | Standard Deviation 2.5 |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Cumulative Oxaliplatin Doses That Can be Administered Without Dose-limiting Chronic Neurotoxicity | 8.0 Doses | Standard Deviation 2.6 |
p-value: 0.89Kruskal-Wallis
p-value: 0.496Kruskal-Wallis
Secondary
Incidence of Calcium Gluconate and Magnesium Sulfate-induced Adverse Events as Measured by CTCAE Version 4.0
Time frame: Up to 18 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Incidence of Calcium Gluconate and Magnesium Sulfate-induced Adverse Events as Measured by CTCAE Version 4.0 | 290 Number of reported Adverse Events |
| Placebo (Pre and Post) | Incidence of Calcium Gluconate and Magnesium Sulfate-induced Adverse Events as Measured by CTCAE Version 4.0 | 259 Number of reported Adverse Events |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Incidence of Calcium Gluconate and Magnesium Sulfate-induced Adverse Events as Measured by CTCAE Version 4.0 | 296 Number of reported Adverse Events |
Secondary
Percentage of Patients Discontinuing Oxaliplatin-based Chemotherapy Because of Neurotoxicity
Time frame: Up to 18 months
Population: All patients that received treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Percentage of Patients Discontinuing Oxaliplatin-based Chemotherapy Because of Neurotoxicity | 34.7 percentage of patients |
| Placebo (Pre and Post) | Percentage of Patients Discontinuing Oxaliplatin-based Chemotherapy Because of Neurotoxicity | 27.7 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Percentage of Patients Discontinuing Oxaliplatin-based Chemotherapy Because of Neurotoxicity | 30.5 percentage of patients |
p-value: 0.52Chi-squared
p-value: 0.66Chi-squared
Secondary
Percentage of Patients Experiencing Grade 2+ and Grade 3+ Chronic Cumulative Neurotoxicity.
Grades are determined by the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.0) and oxaliplatin-specific neurotoxicity scale, during and after chemotherapy. Higher grades symbolize greater severity of the adverse event.
Time frame: Up to 18 months
Population: All patients that under went at least one cycle of treatment and were analyzed for chronic cumulative neurotoxicity (NCI CTCAE version 4.0 and oxaliplatin-specific neurotoxicity scale) during and after chemotherapy
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Percentage of Patients Experiencing Grade 2+ and Grade 3+ Chronic Cumulative Neurotoxicity. | grade 2+ | 42.7 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Percentage of Patients Experiencing Grade 2+ and Grade 3+ Chronic Cumulative Neurotoxicity. | grade 3+ | 7.7 percentage of patients |
| Placebo (Pre and Post) | Percentage of Patients Experiencing Grade 2+ and Grade 3+ Chronic Cumulative Neurotoxicity. | grade 2+ | 44.8 percentage of patients |
| Placebo (Pre and Post) | Percentage of Patients Experiencing Grade 2+ and Grade 3+ Chronic Cumulative Neurotoxicity. | grade 3+ | 7.8 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Percentage of Patients Experiencing Grade 2+ and Grade 3+ Chronic Cumulative Neurotoxicity. | grade 2+ | 46.1 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Percentage of Patients Experiencing Grade 2+ and Grade 3+ Chronic Cumulative Neurotoxicity. | grade 3+ | 7.8 percentage of patients |
Secondary
Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin
This is the percent of patients who scored \>=50 in all sequences of all cycles by arm for side effect Q1: Sensitivity to touching cold. This is a\> repeated measurement of CIPN with possibly variable cycles for every patient. The CIPN subscale will be calculated by standard scoring algorithm and converted to 0-100 scale. Where 0 is no sensitivity and 100 is as bad as it can be.
Time frame: Up to 18 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 10 | 29 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 6 | 31 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 1 | 10 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 2 | 24 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 3 | 32 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 4 | 34 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 5 | 34 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 7 | 35 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 8 | 32 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 9 | 34 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 11 | 28 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 12 | 27 percentage of patients |
| Placebo (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 4 | 37 percentage of patients |
| Placebo (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 5 | 33 percentage of patients |
| Placebo (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 6 | 37 percentage of patients |
| Placebo (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 12 | 45 percentage of patients |
| Placebo (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 7 | 34 percentage of patients |
| Placebo (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 2 | 27 percentage of patients |
| Placebo (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 8 | 34 percentage of patients |
| Placebo (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 10 | 39 percentage of patients |
| Placebo (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 9 | 37 percentage of patients |
| Placebo (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 1 | 13 percentage of patients |
| Placebo (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 11 | 39 percentage of patients |
| Placebo (Pre and Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 3 | 33 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 11 | 33 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 12 | 32 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 4 | 36 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 5 | 39 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 9 | 32 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 6 | 33 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 3 | 32 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 1 | 14 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 7 | 34 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 10 | 30 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 2 | 28 percentage of patients |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Percentage of Patients With Acute Neuropathy Associated With Oxaliplatin | Cycle 8 | 33 percentage of patients |
Secondary
Time to Onset of Grade 2+ and Grade 3+ Chronic Cumulative Neurotoxicity and the Duration of the Chronic Cumulative Neurotoxicity During and After Chemotherapy
Time to onset of grade 2+ and grade 3+ chronic cumulative neurotoxicity, the duration of the chronic cumulative neurotoxicity during and after the adjuvant oxaliplatin-based chemotherapy. Grades are determined by the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.0) and oxaliplatin-specific neurotoxicity scale, during and after chemotherapy. Higher grades symbolize greater severity of the adverse event.
Time frame: Up to 18 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Time to Onset of Grade 2+ and Grade 3+ Chronic Cumulative Neurotoxicity and the Duration of the Chronic Cumulative Neurotoxicity During and After Chemotherapy | Time to Grade 2 Neuropathy | 171 Days |
| Calcium Gluconate + Magnesium Sulfate (Pre and Post) | Time to Onset of Grade 2+ and Grade 3+ Chronic Cumulative Neurotoxicity and the Duration of the Chronic Cumulative Neurotoxicity During and After Chemotherapy | Time to Grade 3 Neuropathy | NA Days |
| Placebo (Pre and Post) | Time to Onset of Grade 2+ and Grade 3+ Chronic Cumulative Neurotoxicity and the Duration of the Chronic Cumulative Neurotoxicity During and After Chemotherapy | Time to Grade 2 Neuropathy | 173 Days |
| Placebo (Pre and Post) | Time to Onset of Grade 2+ and Grade 3+ Chronic Cumulative Neurotoxicity and the Duration of the Chronic Cumulative Neurotoxicity During and After Chemotherapy | Time to Grade 3 Neuropathy | 208 Days |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Time to Onset of Grade 2+ and Grade 3+ Chronic Cumulative Neurotoxicity and the Duration of the Chronic Cumulative Neurotoxicity During and After Chemotherapy | Time to Grade 2 Neuropathy | 171 Days |
| Calcium Gluconate + Magnesium Sulfate (Pre), Placebo (Post) | Time to Onset of Grade 2+ and Grade 3+ Chronic Cumulative Neurotoxicity and the Duration of the Chronic Cumulative Neurotoxicity During and After Chemotherapy | Time to Grade 3 Neuropathy | NA Days |