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Background: Some studies have demonstrated that higher baseline plasma levels of 25-hydroxivitamin D [25(OH)D] are associated with a significant reduction in colorectal cancer (CRC) incidence. Patients with metastatic CRC (mCRC) tend to be vitamin D insufficient, but the effect of vitamin D on the survival of mCRC patients still remains uncertain. In this study, we evaluated the association between cholecalciferol 2,000 IU daily supplementation and survival of mCRC patients. Methods: Seventy-two patients with mCRC were included. Seventy-one patients with 25(OH)D levels <75 nmol/l were randomized to receive standard chemotherapy or standard chemotherapy with cholecalciferol 2,000 IU daily. The primary endpoint was overall survival (OS) and the secondary endpoint was progression-free survival (PFS). The follow-up period was 46 mo. Results: All but one patient (98.6%) was vitamin D insufficient. There was no statistically significant difference in OS or PFS between those who received vitamin D supplements and controls. Conclusions: The majority of patients with mCRC are vitamin D insufficient at the time of diagnosis. In our study, adding 2,000 IU of cholecalciferol daily for 2 yr to standard chemotherapy did not show any benefit in OS or PFS. +
Publication: Vitamin D Supplementation and Survival of Patients with Non–small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial +
Purpose: Higher serum 25-hydroxyvitamin D (25(OH) D) levels are reportedly associated with better survival in early-stage non–small cell lung cancer (NSCLC). There- fore, whether vitamin D supplementation can improve the prognosis of patients with NSCLC was examined (UMIN000001869).
Patients and Methods: A randomized, double-blind trial comparing vitamin D supplements (1,200 IU/day) with placebo for 1 year after operation was conducted. The primary and secondary outcomes were relapse-free survival (RFS) and overall survival (OS), respectively. Prespecified subgroup analyses were performed with stratification by stage (early vs. advanced), pathology (adenocarcinoma vs. others), and 25(OH)D levels (low, <20 ng/mL vs. high, ≥20 ng/mL). Polymorphisms of vitamin D receptor (VDR) and vitamin D–binding protein (DBP) and survival were also examined.
Results: Patients with NSCLC (n = 155) were randomly assigned to receive vitamin D (n = 77) or placebo (n = 78) and followed for a median of 3.3 years. Relapse and death occurred in 40 (28%) and 24 (17%) patients, respectively. In the total study population, no significant difference in either RFS or OS was seen with vitamin D compared with the placebo group. However, by restricting the analysis to the subgroup with early- stage adenocarcinoma with low 25(OH)D, the vitamin D group showed significantly better 5-year RFS (86% vs. 50%, P = 0.04) and OS (91% vs. 48%, P = 0.02) than the placebo group. Among the examined polymorphisms, DBP1 (rs7041) TT and CDX2 (rs11568820) AA/AG genotypes were markers of better prognosis, even with multivariate adjustment.
Conclusions: In patients with NSCLC, vitamin D supplementation may improve survival of patients with early-stage lung adenocarcinoma with lower 25(OH)D levels. +
Publication: Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial +
Abstract A double-blind placebo-controlled randomized phase II trial was performed to determine whether High Dose Vitamin D2 supplementation (HDD) in women receiving adjuvant anastrozole improves aromatase inhib- itor-induced musculoskeletal symptoms (AIMSS) and bone loss. Patients with early breast cancer and AIMSS were stratified according to their baseline 25-hydroxy vitamin D (25OHD) level. Stratum A (20–29 ng/ml) received either HDD 50,000 IU capsules weekly for 8 weeks then monthly for 4 months or placebo. Stratum B (10–19 ng/ml) received either HDD for 16 weeks and then monthly for 2 months, or placebo. AIMSS was assessed by the Brief Pain Inventory-Short Form (BPI-SF), the Fibromyalgia Impact Questionnaire (FIQ), and the Health Assessment Questionnaire-Disability Index (HAQ-DI) at baseline, 2, 4, and 6 months. Bone Mineral Density (BMD) was measured at baseline and at 6 months. The primary endpoint of the study was the change-from-baseline musculoskeletal pain. The secondary endpoint was the percent change in BMD at 6 months. Sixty women were enrolled. Baseline charac- teristics were comparable between the groups. At 2 months, FIQ pain (P = 0.0045), BPI worst-pain (P = 0.04), BPI average-pain (P = 0.0067), BPI pain- severity (P = 0.04), and BPI interference (P = 0.034) scores were better in the HDD than placebo group. The positive effect of HDD on AIMSS was stronger across all time points in Stratum B than Stratum A (FIQ pain, P = 0.04; BPI average, P = 0.03; BPI severity, P = 0.03; BPI interference, P = 0.04). BMD at the femoral neck decreased in the placebo and did not change in the HDD group (P = 0.06). Weekly HDD improves AIMSS and may have a positive effect on bone health. Vitamin D supplementation strategies for breast cancer patients on AI should be further investigated. +
Radiation dermatitis occurs frequently during adjuvant radiation therapy for breast cancer. Prevention of radiation dermatitis by applying various creams and ointments has a limited success, and Aqua cream which has urea as one of its active ingredients is used in many institutions as a preventive treatment. The primary goal of this study is to assess the effect of vitamin D (calcipotriol) ointment in prevention of radiodermatitis in breast cancer patients compared to Aqua cream. Twenty-three women with localized breast cancer who underwent breast-conserving surgery and opted to receive adjuvant radiotherapy to breast only were enrolled in this study. A cream containing an active vitamin D analog, calcipotriol (Daivonex), was randomly applied either to the medial or to the lateral half of the irradiated breast, while Aqua cream was applied to the complimentary half of the same breast along the whole treatment days, each day, after the delivery of radiation. Skin reaction was recorded and compared between the two halves of the breast. Vitamin D was well tolerated by patients with no local or systemic allergic reactions. Radiation dermatitis was not significantly different between both treatment arms. Topical vitamin D ointment is not superior to Aqua cream for prevention of radiation-induced dermatitis in women treated with adjuvant radiation for breast cancer. +
Publication: Vitamin E for prevention of oxaliplatin-induced peripheral neuropathy: A pilot randomized clinical trial +
CONTEXT AND OBJECTIVE
Oxaliplatin is one of the chemotherapy regimens most used for treating colorectal cancer. One of the main limitations to its use is induction of peripheral neuropathy. Previous studies have shown that vitamin E can reduce the incidence of peripheral neuropathy by 50%. This study aimed to assess the effectiveness of vitamin E for prevention of oxaliplatin-induced peripheral neuropathy.
DESIGN AND SETTING
Prospective, phase II, randomized pilot study developed at a university hospital in the Greater ABC region.
METHODS
Patients were randomized five days before starting oxaliplatin treatment, to receive either vitamin E or placebo until the end of the chemotherapy regimen. The outcome was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE), version 3, and specific gradation scales for oxaliplatin-induced peripheral neuropathy. Patients with colorectal and gastric cancer who had been scheduled to receive oxaliplatin-based chemotherapy were included. Both groups received calcium and magnesium supplementation before and after oxaliplatin infusions.
RESULTS
Eighteen patients were randomized to the vitamin E group and 16 to the placebo group. Cumulative incidence of 83% with peripheral neuropathy grades 1/2 was observed in the vitamin E group, versus 68% in the placebo group (P = 0.45). A trend towards more diarrhea was observed among patients who received vitamin E (55.6% vs. 18.8%; P = 0.06). There were no other significant differences in toxicity between the groups.
CONCLUSIONS
No significant decrease in the incidence of acute oxaliplatin-induced peripheral neuropathy was demonstrated through vitamin E use. +
Publication: Vitamin E neuroprotection against cisplatin ototoxicity: Preliminary results from a randomized, placebo-controlled trial +
Background.
Few studies have investigated the effect of vitamin E in reducing the cisplatin (CDDP)-induced ototoxicity. This study evaluated vitamin E supplementation as a protecting agent against CDDP-induced ototoxicity.
Methods.
Patients who started CDDP were randomly assigned to receive vitamin E supplementation at 400 mg per day (group 1) or placebo (group 2). Audiograms and evoked brainstem responses were obtained at baseline, and after 1, 2, and 3 months.
Results.
Twenty-three patients affected by solid malignancies were enrolled (13 in group 1 and 10 in group 2). At 1 month, a significant hearing loss in group 2 at both 2000 HZ (right ear: p=0.05; left ear: p=0.04) and 8000 HZ (right ear: p=0.04; left ear: p=0.03) was detected when compared to baseline values. Audiograms did not show significant changes. At 1 month, evoked brainstem responses remained unchanged in both arms without significant differences between groups.
Conclusion.
These preliminary findings confirm the neuroprotective properties of vitamin E against the CDDP-induced ototoxicity. +
The clinical use of platinum-based antineoplastic agents is limited by severe peripheral neurotoxicity reported in up to 90% of patients receiving a cumulative dose higher than 300 mg/m². Recent studies support that cisplatin-induced neuropathy is related to degeneration of large dorsal root ganglion cell bodies with the loss of large myelinated fibers. Evidence suggests that side effects induced by cisplatin treatment are, at least in part, the result of the formation of free radicals. Several studies have reported interesting results of vitamin E supplementation against cisplatin peripheral neurotoxicity. In animals, supplementation with antioxidants (vitamin E and C, selenium) protects against renal toxicity and ototoxicity induced by cisplatin; moreover, human studies indicate that cisplatin treatment induces a decrease in plasma antioxidant levels due to oxidative stress. It has been noticed that clinical and neuropathologic features observed in cisplatin-induced neuropathy are similar to those observed in vitamin E deficiency neuropathy. In a previous study, we reported a significant neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy. A recent Cochrane review analyzed neuroprotective strategies in cisplatin neuropathy including vitamin E supplementation, reporting the encouraging but inconclusive results of several studies. The review concluded that there is a lack of randomized controlled trials using objective measures of neuropathy and including adequate numbers of patients. The aim of the present phase III, randomized, placebo-controlled study is to confirm the neuroprotective effect of vitamin E supplementation in patients treated with cisplatin. +
Publication: Vitamin E reduces superficial bladder cancer recurrence: A randomized controlled Trial +
Background
Most patients with superficial bladder cancer who undergo transurethral resection of bladder tumor show recurrence of the disease. Numerous studies have explored ways to decrease bladder cancer recurrence, including the intake of vitamins and antioxidants. This study aimed to investigate the effect of vitamin E on the recurrence of non-invasive bladder cancer.
Methods
In this randomized controlled trial, 46 patients with a single, low-grade, superficial bladder cancer, less than 3 cm in diameter, were randomly divided into two groups: vitamin E intake (400 IU daily) and no intake of vitamin E. Ultrasound and urinalysis were performed every three months to detect bladder cancer recurrence.
Results
There was no significant difference between the groups in age, tumor size, mean time to recurrence, and follow-up time. The recurrence rate was 28.3% throughout the follow-up period (19% in the study group and 36% in the controls) (CI=0.19 – 0.92, RR=0.53, CI=0.11 – 0.94, OR=0.42, P=0.04). In both groups, most (69.2%) recurrences occurred during the first year. The rate of recurrence decreased in smokers from 50% in the study group to 25% in the control group (P=0.06) and from 26.7% to 15.4% in the non-smokers in the control and study groups, respectively (P=0.15).
Conclusion
Intake of vitamin E significantly decreased bladder cancer recurrence, especially among smokers, possibly due to higher levels of oxidants, which vitamin E may target in smokers. +
Publication: ZeOxaNMulti Trial: A Randomized, Double-Blinded, Placebo-Controlled Trial of Oral PMA-Zeolite to Prevent Chemotherapy-Induced Side Effects, in Particular, Peripheral Neuropathy +
Chemotherapy-induced peripheral neuropathy (CIPN) is the most frequently reported adverse effect of oxaliplatin. In this study, we set out to evaluate the role of the panaceo-micro-activation (PMA) zeolite in the reduction of the incidence of CIPN and hematological and liver toxicity. The possible impact of the PMA-zeolite as an adjuvant therapeutic agent is based on its detoxification properties toward agents promoting the development of neuropathy (e.g., ammonium - recognized as a neurotoxic agent produced by tumors), as well as its positive impact on immunity and oxidative stress through its effects in the gastrointestinal tract. From April 2015 to October 2018, a total of 120 patients (pts) diagnosed with predominantly colorectal cancer requiring oxaliplatin-based chemotherapy were randomized to receive either the PMA-zeolite (Multizeo Med) or placebo while undergoing oxaliplatin-based chemotherapy. A nerve-conduction study (NCS) was planned at the baseline, after three and six months of chemotherapy, to evaluate CIPN. Furthermore, the evaluation of hematological and liver toxicity was performed during every cycle of chemotherapy. 70.6% and 64.3% of patients developed CIPN in the placebo and the PMA-zeolite group, respectively. Patients treated with the PMA-zeolite were able to undergo more cycles of chemotherapy (p = 0.03), which also indicates a significant improvement in tolerance to the therapy. The group treated with the PMA-zeolite showed a lower CIPN (although not statistically significant within the whole group of subjects) compared to patients receiving placebo. This advantage was, however, statistically significant in men (p = 0.047). In addition, supplementation with the PMA-zeolite resulted in a lower incidence of severe-grade hematological toxicity (trend toward statistical significance of p = 0.09 was observed). Cancer patients may benefit from the therapy with the appropriate certified zeolite-products (e.g., the PMA-zeolite) for human use in CIPN. The lower CIPN (statistically significant results in the male subgroup) was accompanied by a trend of lower incidence of severe-grade hematological toxicity. Furthermore, these benefits led to a better tolerance toward chemotherapy (increase in cycles) and allow an improved compliance with the oncological treatment protocol.
Publication: Zinc sulfate in the prevention of radiation-induced oropharyngeal mucositis: a prospective, placebo-controlled, randomized study +
PURPOSE: To determine the effect of oral zinc sulphate supplementation on radiation-induced oropharyngeal mucositis in patients with head-and-neck cancer. MATERIALS AND METHODS: Thirty patients with head-and-neck cancer were randomly assigned to receive either zinc sulfate or placebo. Primary tumors were localized in the larynx in 14 patients, in the nasopharynx in 4, in the oral cavity in 4, in a salivary gland in 1, in the maxillary sinus in 1, in neck nodes (lymphoma presenting primarily) in 3 and in neck metastases from an unknown primary in 3. In the placebo group, 3 patients were excluded; 1 patient died during treatment, 1 left the study, and 1 did not come to the 6 week control visit. The patients were treated with telecobalt radiotherapy at conventional fractionation (2 Gy/fraction, five fractions weekly, for 20-35 fractions within 4-7 weeks). The median radiation dose was 6400 cGy (4000-7000 cGy). Oral mucositis was assessed by two independent physicians, experts in radiation oncology, using the Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring criteria. RESULTS: In the zinc sulfate group, Grade 3-4 mucositis was not detected in any patient; Grade 0 mucositis was detected in 2, and Grade 1 in 8, and Grade 2 in 5 patients. In the placebo group, Grade 2 mucositis was detected in 4 and Grade 3 in 8 patients. We observed that the degree of mucositis in the patients in the zinc sulfate group was significantly lower than that in the placebo group (p < 0.05). Confluent mucositis developed earlier in the placebo group than in the zinc sulfate group after the onset of treatment (p < 0.05) and started to improve sooner in the zinc sulfate group than in the placebo group (p < 0.05). CONCLUSIONS: Zinc sulfate is beneficial in decreasing the severity of radiation-induced mucositis and oral discomfort. These results should be confirmed by additional evaluation in randomized studies with a larger number of patients. +
Publication: Zinc supplementation to improve mucositis and dermatitis in patients after radiotherapy for head-and-neck cancers: a double-blind, randomized study +
Purpose: To determine whether zinc supplementation can accelerate the healing of mucositis and dermatitis after
radiotherapy.
Methods and Materials: In this double-blind study, patients were placed into two randomized groups (experi- mental and control) of 50 patients each. The groups were homogeneous with respect to medical history, tumor characteristics, and therapeutic details. The experimental group received a standard dose of a zinc supplement, and the control group was given a placebo.
Results: Patients in the control group developed Grade 2 mucositis and dermatitis earlier and sooner than patients in the experimental group. There was also a significant difference in the development of Grade 3 mucositis and dermatitis between the two groups. Patients in the experimental group were found to have milder mucositis and dermatitis. Zinc supplementation did not show much benefit in those patients receiving concurrent chemotherapy or make a substantial impact on weight changes.
Conclusions: Zinc supplementation used in conjunction with radiotherapy could postpone the development of severe mucositis and dermatitis for patients with cancers of the head and neck. Zinc supplementation can also alleviate the degree of mucositis and dermatitis. The impact of zinc on tumor growth and patient survival is under further investigation. +
Publication: β-carotene supplementation in patients radically treated for stage I-II head and neck cancer: Results of a randomized trial +
This study was aimed at evaluating the efficacy of beta-carotene in improving survival (S) and in disease-free survival (DFS) and reducing the incidence of second primary tumors (SPT) in patients with a radically treated stage I-II squamous head and neck tumors. Eligible patients were randomly allocated to receive beta-carotene (n=104) or no treatment (n=110). beta-carotene was administered at the dose of 75 mg/day for 3-month cycles within one month intercycle intervals for a 3-year period. The 3-year compliance to the beta-carotene was 68.7%. Only eight patients reported drug-related toxicity (7.8%). The median follow-up of all patients was 59 months. The median follow-up was 61 months (range 1-116 months) in the beta-carotene and 58 months (1-123 months) in the control group. The 10-year DFS was 75.7% for the patients in the beta-carotene and 74.3% for those in the control group (P=0.56). The 10-year S was 85.9% in the beta-carotene group and 80.9% in the control group (P=0.20). beta-carotene supplementation had no significant effect on the incidence of second primary tumors (RR=0.99; 95% C.I. 0.28-3.44). A statistically non-significant 40% reduction in the risk of death among subjects assigned to the beta-carotene compared to the controls was observed (RR=0.60; 95% C.I. 0.26-1.38). No increase in the death from cardiovascular diseases was observed among patients treated with beta-carotene. Our results might support the hypothesis that an adequate beta-carotene treatment could be potentially associated with a decreased risk of death in these patients. +
Publication: ‘Palliative-D’ - Vitamin D Supplementation to Palliative Cancer Patients: A Double Blind, Randomized Placebo-Controlled Multicenter Trial +
The aim of the ‘Palliative-D’ study was to test the hypothesis that correction of vitamin D de- ficiency reduces opioid use in cancer patients admitted to palliative care. A multicenter randomized, placebo-controlled, double-blind trial in three home-based palliative care facilities in Sweden was performed. Patients with advanced cancer and 25-hydroxyvitamin D < 50 nmol/L were randomized to vitamin D3 4000 IU/day or placebo for 12 weeks. The primary endpoint was the difference of long-acting opioid use (fentanyl ug/h) between the groups during 12 weeks, based on four time points. Secondary outcomes included changes in antibiotic use, fatigue and Quality of Life (QoL). A total of 244 patients were randomized, and 150 patients completed the 12 weeks. The major reason for drop-out was death due to cancer. The vitamin D-group had a significantly smaller increase of opioid doses compared to the placebo-group; beta coefficient −0.56 (p = 0.03), i.e., 0.56 μg less fentanyl/h per week with vitamin D treatment. Vitamin D-reduced fatigue assessed with ESAS was −1.1 points after 12 weeks (p < 0.01). Antibiotic use or QoL did not differ significantly between the groups. The treatment was safe and well-tolerated. In conclusion, correction of vitamin D deficiency may have positive effects on opioid use and fatigue in palliative cancer patients, but only in those with a survival time more than 12 weeks. +