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Publication: Placebo-Controlled, Double-Blind, Randomized Study of a Dry Guarana Extract in Patients with Head and Neck Tumours Undergoing Chemoradiotherapy: Effects on Fatigue and Quality of Life +
Fatigue is a common symptom in patients with head and neck carci- noma who undergo chemoradiotherapy. Guarana (Paullinia cupana) is a plant that grows in the Brazilian Amazon region that was used previously to treat fatigue induced by chemotherapy.
Methods: In this phase II prospective study, we evaluated 60 patients with stage I–IV head and neck squamous cell carcinoma before, during, and after chemoradiotherapy. The patients were randomized into two arms: placebo versus guarana at a dose of 50 mg twice a day during the chemoradiotherapy treatment. We used the FACT-HN, EORTC-HN35, and EORTC-Q30 questionnaires to assess fa- tigue and quality of life (QOL).
Results: A significant worsening of QOL in the overall (p = 0.0054), functional (p = 0.018), and symptom (p = 0.0042) domains after the second cycle of chemotherapy was observed in patients using guarana compared to the placebo group. No significant differences in any QOL domain for either the guarana or placebo group were observed when the first and the fourth evaluations of each domain in each group were compared. Regarding the FACT-HN35 questionnaire, the guarana group showed improvement after the first cycle of chemoradiotherapy with respect to pain (p = 0.0133), social eating (p = 0.0227), swallowing (p = 0.0254), coughing (p = 0.0107), and weight loss (p = 0.012); however, after treatment completion (after the third cycle) weight loss worsened (p = 0.0074) and greater use of a nasogastric tube (p = 0.051), in addition to increased use of analgesics (p = 0.0253), was observed in the guarana group. Regarding the EORTC-QOL C30 questionnaire, improvement of symptoms in the three domains (functional, overall, and symptoms) was observed in patients using guarana. No significant difference was observed between the groups regarding toxicity as graded by the Common Terminology Criteria for Adverse Events (CTCAE) scale. Conclusion: We propose that guarana is not beneficial for this patient population. +
Publication: Polaprezinc prevents oral mucositis associated with radiochemotherapy in patients with head and neck cancer +
Oral mucositis is frequent but serious adverse event associated with radiotherapy or radiochemotherapy in head and neck cancer severely impairs health-related quality of life, leading to poor prognosis due to discontinuation of the therapy. Although a number of compounds have been tested for prophylaxis of oral mucositis, few of them are satisfactory. We investigated the effect of polaprezinc (zinc L-carnosine), a gastric mucosal protective drug, on radiochemotherapy-induced oral mucositis, pain, xerostomia and taste disturbance in patients with head and neck cancer. Patients were randomly assigned to receive polaprezinc (n = 16) or azulene oral rinse as the control (n = 15). The incidence rates of mucositis, pain, xerostomia and taste disturbance were all markedly lower in polaprezinc group than in control. Moreover, the use of analgesics was significantly (p = 0.003) less frequent and the amount of food intake was significantly (p = 0.002) higher in polaprezinc group than in control. On the other hand, tumor response rate in patients with neoadjuvant radiochemotherapy was not significantly affected by polaprezinc, in which the response rate (complete plus partial response) was 88% for polaprezinc and 92% for control (p = 1.000). Therefore, it is highly assumable that polaprezinc is potentially useful for prevention of oral mucositis and improvement of quality of life without reducing the tumor response. +
Publication: Predictors of hand-foot syndrome and pyridoxine for prevention of capecitabine-induced hand-foot syndrome: a randomized clinical trial +
Importance: Hand-foot syndrome (HFS) is a common adverse effect of capecitabine treatment.
Objective: To compare the incidence and time to onset of grade 2 or greater HFS in patients receiving pyridoxine vs placebo and to identify biomarkers predictive of HFS. Design, Setting, and Participants: This single-center, randomized double-blind, placebo-controlled phase 3 trial conducted at National Cancer Centre Singapore assessed whether oral pyridoxine could prevent the onset of grade 2 or higher HFS in 210 patients scheduled to receive single-agent capecitabine chemotherapy for breast, colorectal, and other cancers.
Interventions: Patients were randomized to receive concurrent pyridoxine (200 mg) or placebo daily for a maximum of 8 cycles of capecitabine, with stratification by sex and use in adjuvant or neoadjuvant vs palliative setting. Patients were withdrawn from the study on development of grade 2 or higher HFS or cessation of capecitabine. Main Outcomes and Measures Primary end point was the incidence of grade 2 or higher HFS in patients receiving pyridoxine. Secondary end points included the time to onset (days) of grade 2 or higher HFS and identification of biomarkers predictive of HFS, including baseline folate and vitamin B12 levels, as well as genetic polymorphisms with genome-wide arrays.
Results: In this cohort of 210 patients (median (range) age, 58 (26-82) years; 162 women) grade 2 or higher HFS occurred in 33 patients (31.4%) in the pyridoxine arm vs 39 patients (37.1%) in the placebo arm (P = .38). The median time to onset of grade 2 or higher HFS was not reached in both arms. In univariate analysis, the starting dose of capecitabine (odds ratio (OR), 1.99; 95% CI, 1.32-3.00; P = .001), serum folate levels (OR, 1.27; 95% CI, 1.10-1.47; P = .001), and red blood cell folate levels (OR, 1.25; 95% CI, 1.08-1.44; P = .003) were associated with increased risk of grade 2 or higher HFS. In multivariate analyses, serum folate (OR, 1.30; 95% CI, 1.12-1.52; P < .001) and red blood cell folate (OR, 1.28; 95% CI, 1.10-1.49; P = .001) were the only significant predictors of grade 2 or higher HFS. Grade 2 or higher HFS was associated with 300 DNA variants at genome-wide significance (P < 5 × 10−8), including a novel DPYD variant (rs75267292; P = 1.57 × 10−10), and variants in the MACF1 (rs183324967, P = 4.80 × 10−11; rs148221738, P = 5.73 × 10−10) and SPRY2 (rs117876855, P < 1.01 × 10−8; rs139544515, P = 1.30 × 10−8) genes involved in wound healing.
Conclusions and Relevance: Pyridoxine did not significantly prevent or delay the onset of grade 2 or higher HFS. Serum and red blood cell folate levels are independent predictors of HFS.
Publication: Preventing Paclitaxel-Induced Peripheral neuropathy: A Phase 2 Trial of Vitamin E Supplementation +
A randomized, controlled trial was performed to assess the efficacy and safety of vitamin E supplementation for prophylaxis against paclitaxel-induced peripheral neuropathy (PIPN). Thirty-two patients undergoing six courses of paclitaxel-based chemotherapy were randomly assigned to receive either chemotherapy with vitamin E (300 mg twice a day, Group I) or chemotherapy without vitamin E supplementation (Group II). A detailed neurological examination and electrophysiological study was performed during and 3 months after chemotherapy. The severity of PIPN was summarized by means of a modified Peripheral Neuropathy (PNP) score. The incidence of neurotoxicity differed significantly between groups, occurring in 3/16 (18.7%) patients assigned to the vitamin E supplementation group and in 10/16 (62.5%) controls (P=0.03). The relative risk (RR) of developing PIPN was significantly higher in controls than in vitamin E group patients (RR=0.3, 95% confidence interval (CI)=0.1–0.9). Mean PNP scores were 2.25 ± 5.1 (range 0–15) for patients in Group I and 11 ± 11.63 (range 0–32) for those in Group II (P=0.01). Vitamin E supplementation was well tolerated and showed an excellent safety profile. This study shows that vitamin E effectively and safely protects patients with cancer from the occurrence of paclitaxel-induced peripheral nerve damage. A double-blind, placebo-controlled trial is needed to confirm these results. +
Publication: Preventive effects of zinc sulfate on taste alterations in patients under irradiation for head and neck cancers: A randomized placebo-controlled trial +
BACKGROUND: Taste abnormalities are common among cancer patients after starting radiotherapy or chemotherapy. Considering the role of zinc and reports on its beneficial effects in taste perception, we evaluated the preventive effects of zinc sulfate on radiation-induced taste alterations. MATERIALS AND METHODS: In a randomized, placebo-controlled trial, adult patients with head and neck cancers who were on schedule for radiotherapy, with or without chemotherapy, were allocated to receive zinc sulfate (50 mg, three times a day) or placebo; started with beginning of radiotherapy and continued for one month later. Taste acuity was determined by measuring detection and recognition thresholds for four taste qualities at baseline, at the end of radiotherapy, and a month later using the Henkin method. RESULTS: Thirty-five patients (mean age = 59.2 +/- 16.5, 60% male) completed the trial. The two groups were similar at baseline. After radiotherapy, and one month later, there was a significant increase in taste perception threshold for bitter, salty, sweet, and sour tastes in the placebo group (p = 0.001). In those who received zinc, there was only slight increase in threshold for perception of the salty taste (p = 0.046). No relevant side effects due to zinc sulfate were reported. CONCLUSION: Zinc supplementation in head/neck cancer patients under radiotherapy can prevent radiation-induced taste alterations. Further studies with longer follow-ups and with different doses of zinc supplementation are warranted in this regard. +
Purpose
Hot flashes are a significant issue for many breast cancer survivors, with concerns over the use of hormonal treatments. This trial aimed to evaluate vitamin E as a potential nonhormonal treatment for hot flashes in this population.
Methods
We conducted a placebo-controlled, randomized, crossover trial. After a 1-week baseline period, patients received either vitamin E 800 IU daily for 4 weeks followed by an identical-appearing placebo for another 4 weeks, or vice versa. Diaries measured toxicities and hot flashes during these periods.
Results
Among the 120 patients assessed for toxicity, none were reported. Of the 105 patients who completed the first treatment period, both study arms showed a similar reduction in hot flash frequencies (25% vs. 22%; P = .90). However, crossover analysis indicated a slight decrease in hot flashes with vitamin E compared to placebo (one less hot flash per day, P ≤ .05). At the study's conclusion, patients did not prefer vitamin E over placebo (32% vs. 29%, respectively).
Conclusion
While statistically significant, the reduction in hot flashes with vitamin E was clinically modest. +
Publication: Protective effect of alpha-tocopherol in head and neck cancer radiation-induced mucositis: A double-blind randomized trial +
Background. The study was designed to test whether vitamin E (VE) provides oral mucosal protection in patients with irradiated cancers of the head and neck. Methods. Fifty-four patients with cancer of the oral cavity and oropharynx were randomly assigned to rinse the oral cavity in an oil solution containing either VE or placebo before every conventional fraction of 2 Gy and again 8 to 12 hours later during the 5 to 7 weeks of radiotherapy (RT). Results. Thirty-six events/167 patient-weeks (21.6%) and 54 events/161 patient-weeks (33.5%) of symptomatic mucositis were observed in VE and placebo groups, respectively (p = .038). VE reduced the risk by 36%. Subjective data at the end of the treatment revealed that VE decreased pain grades 2 to 3 during RT (3 of 28 patients vs 14 of 26 patients, p = .0001). No significant influence was detected in survival. Conclusion. VE decreased the incidence of symptomatic oral radiation-induced mucositis in patients with cancer of the oropharynx and oral cavity. +
Publication: Purified Dry Extract of Paullinia cupana (Guarana) (PC-18) for Chemotherapy-Related Fatigue in Patients with Solid Tumors: An Early Discontinuation Study +
Purpose: Paulliniacupana(guarana)is anA mazonian plant that has been previously shown to be effective in treating chemotherapy-related fatigue (CRF) in patients with breast cancer. We aimed to evaluate the efficacy of a purified dry extract of P. cupana (PC-18) in patients with various solid tumors treated with chemotherapy.
Methods: We included 40 patients with solid tumors who showed increases in their Brief Fatigue Inventory (BFI) questionnaire scores after 1 week of systemic chemotherapy. PC-18 was administered at 37.5 mg by mouth two times per day (PO bid), starting after 1 week of chemotherapy, for 3 weeks (induction phase). Patients who had an improvement in or stabilization of their BFI scores were randomized to receive either PC-18 at the same dose or placebo for the following 3 weeks (maintenance phase).
Results: After PC-18 treatment, the BFI fatigue scores improved or stabilized in 36 out of the 40 patients (mean BFI score difference = 2.503; 95% confidence interval: 1.716–3.375, p = .0002). Three weeks after randomization (16 patients on PC-18 and 17 on placebo), we observed no significant differences in the BFI, Functional Assessment of Chronic Illness Therapy, Hospital Anxiety and Depression Scale, and Pittsburgh Sleep Quality Index scores between patients randomized to PC-18 versus placebo.
Conclusions: We conclude that the PC-18 extract may be effective for the treatment of CRF in patients with a variety of solid tumors. A conditioning effect, which was observed in patients who had a beneficial effect of PC-18 on CRF, may explain the better than expected fatigue scores of the placebo-treated patients. +
Publication: Radioprotective effect of vitamin E on salivary glands after radioiodine therapy for differential thyroid cancer: A randomized-controlled trial +
Objectives
This study aimed to examine the radioprotective effect of vitamin E on salivary glands after radioactive iodine (<sup>131</sup>I) therapy in patients with differentiated thyroid cancer.
Patients and methods
Eighty-two patients with differentiated thyroid cancer were enrolled in this study. They were divided randomly into four groups (control group: 22 cases, group A: 23 cases, group B: 22 cases, and group C: 15 cases) before postsurgical ablation therapy with 100 mCi <sup>131</sup>I. The patients in groups A, B, and C received vitamin E 100, 200, and 300 mg/day orally, respectively, for a duration of 1 week before to 4 weeks after <sup>131</sup>I therapy. Salivary gland function was assessed using salivary gland scintigraphy immediately before and 6 months after <sup>131</sup>I therapy. Uptake fraction (UF), uptake index (UI), excretion fraction (EF), and excretion ratio (ER) of each salivary gland were measured and compared.
Results
On comparison between before and after <sup>131</sup>I therapy in the control group, there was a significant decrease in UF of both right and left parotid glands (all P<0.01). In group A, a significant increase in EF of the right parotid gland (P<0.01) and UI of the right submandibular gland (P<0.05) was found. In group B, there was a significant increase in UI of the right parotid gland and both submandibular glands (all P<0.01). In group C, there was a significant increase in UF of the left parotid gland (P<0.05) and the right submandibular gland (P<0.01). Also, there was a statistical increase in UI in both submandibular glands (all P<0.01). However, on comparing the changes in the post-<sup>131</sup>I therapy salivary scintigraphy parameters among the four groups, there was a significant difference in ΔUI of the right parotid gland (P<0.05) and both submandibular glands (all P<0.01), as well as ΔER of the left parotid gland (P<0.05) and ΔUF of the left submandibular gland (P<0.05).
Conclusion
Vitamin E exerts significant protective effects on the parotid and submandibular glands after <sup>131</sup>I therapy.
Publication: Randomized Clinical Trial of Brewed Green and Black Tea in Men With Prostate Cancer Prior to Prostatectomy +
Background. Preclinical and epidemiologic studies suggest chemopreventive effects of green tea (GT) and black tea (BT) in prostate cancer. In the current study we determined the effect of GT and BT consumption on biomarkers related to prostate cancer development and progression. Methods. In this exploratory, open label, phase II trial 113 men diagnosed with prostate cancer were randomized to consume six cups daily of brewed GT, BT or water (control) prior to radical prostatectomy (RP). The primary endpoint was prostate tumor markers of cancer development and progression determined by tissue immunostaining of proliferation (Ki67), apoptosis (Bcl-2, Bax, Tunel), inflammation (nuclear and cytoplasmic nuclear factor kappa B (NFkB)) and oxidation (8-hydroxydeoxy-guanosine (8OHdG)). Secondary endpoints of urinary oxidation, tea polyphenol uptake in prostate tissue, and serum prostate specific antigen (PSA) were evaluated by high performance liquid chromatography and ELISA analysis. Results. Ninety three patients completed the intervention. There was no significant difference in markers of proliferation, apoptosis and oxidation in RP tissue comparing GT and BT to water control. Nuclear staining of NFkB was significantly decreased in RP tissue of men consuming GT (P¼0.013) but not BT (P¼0.931) compared to water control. Tea polyphenols were detected in prostate tissue from 32 of 34 men consuming GT but not in the other groups. Evidence of a systemic antioxidant effect was observed (reduced urinary 8OHdG) only with GT consumption (P¼0.03). GT, but not BT or water, also led to a small but statistically significant decrease in serum prostate-specific antigen (PSA) levels (P¼0.04).Conclusion. Given the GT-induced changes in NFkB and systemic oxidation, and uptake of GT polyphenols in prostate tissue, future longer-term studies are warranted to further examine the role of GT for prostate cancer prevention and treatment, and possibly for other prostate conditions such as prostatitis.
Publication: Randomized Double-Blind Placebo-Controlled Trial of Acetyl-L-Carnitine for the Prevention of Taxane-Induced Neuropathy in Women Undergoing Adjuvant Breast Cancer Therapy +
Purpose
Chemotherapy-induced peripheral neuropathy (CIPN) is common and leads to suboptimal treatment. Acetyl-L-carnitine (ALC) is a natural compound involved in neuronal protection. Studies have suggested ALC may be effective for the prevention and treatment of CIPN.
Patients and Methods
A 24-week randomized double-blind trial comparing ALC (3,000 mg per day) with placebo in women undergoing adjuvant taxane-based chemotherapy was conducted. The primary objective was to determine if ALC prevents CIPN as measured by the 11-item neurotoxicity (NTX) component of the Functional Assessment of Cancer Therapy (FACT) –Taxane scale at 12 weeks. Secondary objectives included changes in 24-week end points, functional status (FACT–Trial Outcome Index(TOI)), fatigue (Functional Assessment of Chronic Illness Therapy (FACIT) –Fatigue), and NTX grade.
Results
A total of 409 patients were evaluable (208 received ALC; 201, placebo). In a multivariate linear regression, week-12 scores were 0.9 points lower (more CIPN) with ALC than placebo (95% CI, −2.2 to 0.4; P = .17), whereas week-24 scores were 1.8 points lower with ALC (95% CI, −3.2 to −0.4; P = .01). Patients receiving ALC were more likely to have a > 5-point decrease in FACT-NTX scores (38% v 28%; P = .05), and FACT-TOI scores were 3.5 points lower with ALC (P = .03). Grade 3 to 4 neurotoxicity was more frequent in the ALC arm (eight v one). No differences between arms were observed for FACIT-Fatigue or other toxicities. Serum carnitine level increased with ALC but remained stable with placebo.
Conclusion
There was no evidence that ALC affected CIPN at 12 weeks; however, ALC significantly increased CIPN by 24 weeks. This is the first study to our knowledge showing that a nutritional supplement increased CIPN. Patients should be discouraged from using supplements without proven efficacy. +
Publication: Randomized Phase III Clinical Trial of Five Different Arms of Treatment in 332 Patients with Cancer Cachexia +
Purpose.
A phase III, randomized study was carried out to establish the most effective and safest treatment to improve the primary endpoints of cancer cachexia—lean body mass (LBM), resting energy expenditure (REE), and fatigue—and relevant secondary endpoints: appetite, quality of life, grip strength, Glasgow Prognostic Score (GPS) and proinflammatory cytokines.
Patients and Methods.
Three hundred thirty-two assessable patients with cancer-related anorexia/cachexia syndrome were randomly assigned to one of five treatment arms: arm 1, medroxyprogesterone (500 mg/day) or megestrol acetate (320 mg/day); arm 2, oral supplementation with eicosapentaenoic acid; arm 3, L-carnitine (4 g/day); arm 4, thalidomide (200 mg/day); and arm 5, a combination of the above. Treatment duration was 4 months.
Results.
Analysis of variance showed a significant difference between treatment arms. A post hoc analysis showed the superiority of arm 5 over the others for all primary endpoints. An analysis of changes from baseline showed that LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) significantly increased in arm 5. REE decreased significantly and fatigue improved significantly in arm 5. Appetite increased significantly in arm 5; interleukin (IL)-6 decreased significantly in arm 5 and arm 4; GPS and Eastern Cooperative Oncology Group performance status (ECOG PS) score decreased significantly in arm 5, arm 4, and arm 3. Toxicity was quite negligible and was comparable between arms.
Conclusion.
The most effective treatment in terms of all three primary efficacy endpoints and the secondary endpoints appetite, IL-6, GPS, and ECOG PS score was the combination regimen that included all selected agents. +
Publication: Randomized Trial of Antioxidant Vitamins to Prevent Acute Adverse Effects of Radiation Therapy in Head and Neck Cancer Patients +
Purpose
Many cancer patients take antioxidant vitamin supplements with the hope of improving the outcome of conventional therapies and of reducing the adverse effects of these treatments. A randomized trial was conducted to determine whether supplementation with antioxidant vitamins could reduce the occurrence and severity of acute adverse effects of radiation therapy and improve quality of life without compromising treatment efficacy.
Patients and Methods
We conducted a randomized, double-blind, placebo-controlled trial among 540 head and neck cancer patients treated with radiation therapy. Patients were randomly assigned into two arms. The supplementation with α-tocopherol (400 IU/d) and α-carotene (30 mg/d) or placebos was administered during radiation therapy and for 3 years thereafter.During the course of the trial, supplementation with α-carotene was discontinued because of ethical concerns.
Results
Patients randomly assigned in the supplement arm tended to have less severe acute adverse effects during radiation therapy (odds ratio OR, 0.72; 95% CI, 0.52 to 1.02). The reduction was statistically significant when the supplementation combined α-tocopherol and α-carotene for
adverse effects to the larynx (OR, 0.38; 95% CI, 0.21 to 0.71) and overall at any site (OR, 0.38; 95% CI, 0.20 to 0.74). Quality of life was not improved by the supplementation. The rate of local recurrence of the head and neck tumor tended to be higher in the supplement arm of the trial (hazard ratio, 1.37; 95% CI, 0.93 to 2.02).
Conclusion
Supplementation with high doses of α-tocopherol and α-carotene during radiation therapy could reduce the severity of treatment adverse effects. However, this trial suggests that use of high doses of antioxidants as adjuvant therapy might compromise radiation treatment efficacy. +
Publication: Randomized Trial of Supplemental beta-Carotene to Prevent Second Head and Neck Cancer +
β-carotene has established efficacy in animal models of oral carcinogenesis and has been shown to regress oral precancerous lesions in humans. The purpose of this study was to see whether these effects extended to the prevention of oral/pharyngeal/laryngeal (head and neck) cancer in humans. The subject population for this randomized, placebo-controlled, double-blinded clinical trial included 264 patients who had been curatively treated for a recent early-stage squamous cell carcinoma of the oral cavity, pharynx, or larynx. Patients were assigned randomly to receive 50 mg of β-carotene per day or placebo and were followed for up to 90 months for the development of second primary tumors and local recurrences. After a median follow-up of 51 months, there was no difference between the two groups in the time to failure (second primary tumors plus local recurrences: relative risk (RR), 0.90; 95% confidence interval (CI), 0.56–1.45). In site-specific analyses, supplemental β-carotene had no significant effect on second head and neck cancer (RR, 0.69; 95% CI, 0.39–1.25) or lung cancer (RR, 1.44; 95% CI, 0.62–3.39). Total mortality was not significantly affected by this intervention (RR, 0.86; 95% CI, 0.52–1.42). Whereas none of the effects were statistically significant, the point estimates suggested a possible decrease in second head and neck cancer risk but a possible increase in lung cancer risk. These effects are consistent with the effects observed in trials using intermediate end point biological markers in humans, in which β-carotene has established efficacy in oral precancerous lesions but has no effect or slightly worsens sputum cytology, and in animal carcinogenicity studies, in which β-carotene has established efficacy in buccal pouch carcinogenesis in hamsters but not in animal models of respiratory tract/lung carcinogenesis, with some suggestions of tumor-promoting effects in respiratory tract/lung. If our results are replicated by other ongoing/completed trials, this suggests a critical need for mechanistic studies addressing differential responses in one epithelial site (head and neck) versus another (lung).
Publication: Randomized Trial of Vitamin C/E Complex for Prevention of Radiation- Induced Xerostomia in Patients with Head and Neck Cancer +
Objective. The present study was conducted to determine the preventive efficacy of vitamin C/E complex supplementation for radiotherapy (RT)–induced xerostomia in patients with head and neck cancer.
Study Design. Prospective, double-blinded, randomized, placebo-controlled study.
Setting. A single tertiary referral institution.
Subjects and Methods. The trial group (n = 25) received antioxidant supplements (100 IU of vitamin E 1 500 mg of vitamin C) twice per day during RT, while the control group (n = 20) received an identical placebo. Pre-RT and 1 and 6 months post-RT, patient-reported xerostomia questionnaires, observer-rated xerostomia score, and salivary scintigraphy were serially obtained to compare xerostomia severity between the 2 groups.
Results. The trial group showed greater improvements in xerostomia questionnaire and score at 6 months post-RT when compared with those at 1 month post-RT (P = .007 and .008, respectively). In contrast, the control group showed no changes between 1 and 6 months post-RT. By salivary scintigraphy, there was no difference in maximal accumulation or ejection fraction between the 2 groups. However, the trial group maintained significantly better oral indices at the prestimulatory (P = .01) and poststimulatory (P = .009) stages at 1 month post-RT, compared with the control group. At the final follow-up, there was no difference in overall survival and disease-free survival between the 2 groups.
Conclusions. Our data suggest that short-term supplementation with an antioxidant vitamin E/C complex exerts a protective
effect against RT-induced xerostomia. +
Publication: Randomized controlled trial of high‐dose versus standard‐dose vitamin D3 for prevention of aromatase inhibitor‐induced arthralgia +
Purpose: Half of hormone receptor-positive(HR+) breast cancer patients will develop joint pain,termed aromatase inhibitor- induced arthralgia (AIA), while taking aromatase inhibitor therapy. Though there is no universally accepted effective treat- ment for AIA, there has been some evidence to support high-dose vitamin D as a treatment.
Methods: We randomized post-menopausal women who were beginning adjuvant AI therapy to receive standard-dose vita- min D3 (800 IU daily for 52 weeks), or high-dose vitamin D3 (50,000 IU weekly for 12 weeks, followed by 2000 IU daily for 40 weeks). The primary end point was development of AIA. The trial was designed to enroll 184 patients. This futility analysis was performed after 93 patients were enrolled.
Results: The high-dose vitamin D regimen was effective in raising serum vitamin D levels, but there was no significant dif- ference in development of AIA between the two arms. In the high-dose arm, 25 patients (54%) developed AIA, compared to 27 patients (57%) in the standard-dose arm. The planned futility analysis was positive; thus, the study was terminated. Neither baseline vitamin D nor 12-week vitamin D level was predictive of AIA development.
Conclusion: Although vitamin D levels were increased in the high-dose arm, there was no significant signal for benefit of high-dose vitamin D supplementation for AIA prevention in this unblinded trial. This study, along with several others, implies that vitamin D likely does not play a significant role in AIA for the majority of patients. +
Publication: Randomized phase II trial of selenomethionine as a modulator of efficacy and toxicity of chemoradiation in squamous cell carcinoma of the head and neck +
AIM: To investigate whether selenomethionine (SLM) reduces mucositis incidence in patients with head and neck squamous cell cancer (HNSCC) undergoing concurrent chemoradiation (CRT).
METHODS: In this multi-institutional, randomized, double-blind phase II trial, patients with Stage III or IV HNSCC received SLM 3600 μg/m² or placebo twice daily for 7 days prior to CRT, once daily during CRT, and daily for 3 weeks following CRT. CRT consisted of 70 Gy at 2 Gy per fraction with cisplatin 100 mg/m² IV on days 1, 22, and 43.
RESULTS: Eighteen patients were randomized, 10 received SLM, and there were no differences in baseline factors. There was no difference in mucositis or patient-reported side effects between groups. There was no difference in overall or relapse-free survival at 12 months.
CONCLUSION: Addition of SLM to CRT for HNSCC was well-tolerated but did not lower the incidence of severe mucositis or improve quality of life or survival outcomes. +
Publication: Randomized trial of vitamin B6 for preventing hand-foot syndrome from capecitabine chemotherapy +
Background: Capecitabine is an oral fuoropyrimidine that is used to treat various malignancies. Hand-foot syndrome (HFS) is a dose-limiting toxicity of capecitabine that can limit the use of this agent in some patients. Some investigators have observed that pyridoxine (vitamin B6) can ameliorate HFS that is caused by capecitabine. We designed a prospective trial to determine if pyridoxine can prevent HFS in patients who receive capecitabine.
Methods: In our double-blind, placebo-controlled trial, we randomly assigned eligible patients who were treated with capecitabine to receive either daily pyridoxine 100 mg or placebo along with their capecitabine-containing chemotherapy regimen. Patients were observed during the frst 4 cycles of capecitabine treatment. The primary endpoint was the incidence and grade of HFS that occurred in both study arms.
Results: Between 2008 and 2011, 77 patients were randomly assigned to receive either pyridoxine (n = 38) or placebo (n = 39). Dosages of capecitabine were equally matched between both arms of the study. HFS occurred after a median of 2 chemotherapy cycles in both groups. HFS developed in 10 of 38 (26%) patients in the pyridoxine group and in 8 of 39 (21%) patients in the placebo group (P = .547). Therefore, the risk of HFS was 5 percentage points higher in pyridoxine group (95% confdence interval (CI) for difference, –13 percentage points to +25 percentage points). Given our study results, a true beneft from pyridoxine can be excluded. No difference in HFS grades was observed.
Limitations: Single-institution study.
Conclusion: Prophylactic pyridoxine (vitamin B6), given concomitantly with capecitabine-containing chemotherapy, was not effective for the prevention of HFS. +
Publication: Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms in women with breast cancer receiving adjuvant letrozole. The VITAL trial +
Purpose: Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) frequently occur in women being treated for breast cancer. Prior studies suggest high prevalence of vitamin D deficiency in breast cancer patients with musculoskeletal (MS) pain. We conducted a randomized, placebo-controlled trial to determine if 30,000 IU vitamin D3 per week (VitD3) would prevent worsening of AIMSS in women starting adjuvant letrozole for breast cancer.
Methods: Women with stage I-III breast cancer starting adjuvant letrozole and 25(OH)D level ≤40 ng/ml were eligible. All subjects received standard daily supplement of 1200 mg calcium and 600 IU vitamin D3 and were randomized to 30,000 IU oral VitD3/week or placebo. Pain, disability, fatigue, quality of life, 25(OH)D levels, and hand grip strength were assessed at baseline, 12, and 24 weeks. The primary endpoint was incidence of an AIMSS event.
Results: Median age of the 160 subjects (80/arm) was 61. Median 25OHD (ng/ml) was 25 at baseline, 32 at 12 weeks, and 31 at 24 weeks in the placebo arm and 22, 53, and 57 in the VitD3 arm. There were no serious adverse events. At week 24, 51% of women assigned to placebo had a protocol defined AIMSS event (worsening of joint pain using a categorical pain intensity scale (CPIS), disability from joint pain using HAQ-II, or discontinuation of letrozole due to MS symptoms) vs. 37% of women assigned to VitD3 (p = 0.069). When the brief pain inventory (BPI) was used instead of CPIS, the difference was statistically significant: 56 vs. 39% (p = 0.024).
Conclusions: Although 30,000 IU/week of oral vitamin D3 is safe and effective in achieving adequate vitamin D levels, it was not associated with a decrease in AIMSS events based on the primary endpoint. Post-hoc analysis using a different tool suggests potential benefit of vitamin D3 in reducing AIMSS. +
Publication: Randomized, Double-Blind, Placebo-Controlled Trial of Polyphenon E in Prostate Cancer Patients before Prostatectomy: Evaluation of Potential Chemopreventive Activities +
Compelling preclinical and pilot clinical data support the role of green tea polyphenols in prostate cancer prevention. We conducted a randomized, double-blind, placebo-controlled trial of polyphenon E (enriched green tea polyphenol extract) in men with prostate cancer scheduled to undergo radical prostatectomy. The study aimed to determine the bioavailability of green tea polyphenols in prostate tissue and to measure its effects on systemic and tissue biomarkers of prostate cancer carcinogenesis. Participants received either polyphenon E (containing 800 mg epigallocatechin gallate) or placebo daily for 3 to 6 weeks before surgery. Following the intervention, green tea polyphenol levels in the prostatectomy tissue were low to undetectable. Polyphenon E intervention resulted in favorable but not statistically significant changes in serum prostate-specific antigen, serum insulin-like growth factor axis, and oxidative DNA damage in blood leukocytes. Tissue biomarkers of cell proliferation, apoptosis, and angiogenesis in the prostatectomy tissue did not differ between the treatment arms. The proportion of subjects who had a decrease in Gleason score between biopsy and surgical specimens was greater in those on polyphenon E but was not statistically significant. The study's findings of low bioavailability and/or bioaccumulation of green tea polyphenols in prostate tissue and statistically insignificant changes in systemic and tissue biomarkers from 3 to 6 weeks of administration suggests that prostate cancer preventive activity of green tea polyphenols, if occurring, may be through indirect means and/or that the activity may need to be evaluated with longer intervention durations, repeated dosing, or in patients at earlier stages of the disease. +