Randomized phase 2 study of gemcitabine and cisplatin with or without vitamin supplementation in patients with advanced esophagogastric cancer

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Purpose

Preclinical research and prior clinical observations demonstrated reduced toxicity and suggested enhanced efficacy of cisplatin due to folic acid and vitamin B12 suppletion. In this randomized phase 2 trial, we evaluated the addition of folic acid and vitamin B12 to first-line palliative cisplatin and gemcitabine in patients with advanced esophagogastric cancer (AEGC).

Methods

Patients with AEGC were randomized to gemcitabine 1250 mg/m ² (i.v. days 1, 8) and cisplatin 80 mg/m ² (i.v. day 1) q 3 weeks with or without folic acid (450 µg/day p.o.) and vitamin B12 (1000 µg i.m. q 9 weeks). The primary endpoint was response rate (RR). Secondary endpoints included overall survival (OS), time to progression (TTP), toxicity, and exploratory biomarker analyses. Cisplatin sensitivity and intracellular platinum levels were determined in adenocarcinoma cell lines cultured under high and low folate conditions in vitro.

Results

Adenocarcinoma cells cultured in medium with high folate levels were more sensitive to cisplatin and this was associated with increased intracellular platinum levels. In the randomized phase 2 clinical trial, which ran from October 2004 to September 2013, treatment was initiated in 78 of 82 randomized pts, 39 in each study arm. The RR was similar; 42.1% for supplemented patients vs. 32.4% for unsupplemented patients; p = 0.4. Median OS and TTP were 10.0 and 5.9 months for supplemented vs. 7.7 and 5.4 months for unsupplemented patients (OS, p = 0.9; TTP, p = 0.9). Plasma homocysteine was lower in the supplemented group [ n = 20, 6.9 ± 1.6 (mean ± standard error of mean, SEM) µM; vs. 12.5 ± 4.0 µM; p < 0.001]. There was no significant difference in the C _max of gemcitabine and cisplatin in the two treatment groups.

Conclusion

Folic acid and vitamin B12 supplementation do not improve the RR, PFS, or OS of cisplatin and gemcitabine in patients with AEGC.

Related collections

Most cited references 31

Record: found
Abstract: found
Article: not found

Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.

Nicholas Vogelzang, James J Rusthoven, James T Symanowski … (2003)

Patients with malignant pleural mesothelioma, a rapidly progressing malignancy with a median survival time of 6 to 9 months, have previously responded poorly to chemotherapy. We conducted a phase III trial to determine whether treatment with pemetrexed and cisplatin results in survival time superior to that achieved with cisplatin alone. Chemotherapy-naive patients who were not eligible for curative surgery were randomly assigned to receive pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1, or cisplatin 75 mg/m2 on day 1. Both regimens were given intravenously every 21 days. A total of 456 patients were assigned: 226 received pemetrexed and cisplatin, 222 received cisplatin alone, and eight never received therapy. Median survival time in the pemetrexed/cisplatin arm was 12.1 months versus 9.3 months in the control arm (P =.020, two-sided log-rank test). The hazard ratio for death of patients in the pemetrexed/cisplatin arm versus those in the control arm was 0.77. Median time to progression was significantly longer in the pemetrexed/cisplatin arm: 5.7 months versus 3.9 months (P =.001). Response rates were 41.3% in the pemetrexed/cisplatin arm versus 16.7% in the control arm (P <.0001). After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxicity, resulting in a significant reduction in toxicities in the pemetrexed/cisplatin arm. Treatment with pemetrexed plus cisplatin and vitamin supplementation resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone in patients with malignant pleural mesothelioma. Addition of folic acid and vitamin B12 significantly reduced toxicity without adversely affecting survival time.

0 comments Cited 701 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Capecitabine and oxaliplatin for advanced esophagogastric cancer.

David Cunningham, Naureen Starling, Sheela Rao … (2008)

We evaluated capecitabine (an oral fluoropyrimidine) and oxaliplatin (a platinum compound) as alternatives to infused fluorouracil and cisplatin, respectively, for untreated advanced esophagogastric cancer. In a two-by-two design, we randomly assigned 1002 patients to receive triplet therapy with epirubicin and cisplatin plus either fluorouracil (ECF) or capecitabine (ECX) or triplet therapy with epirubicin and oxaliplatin plus either fluorouracil (EOF) or capecitabine (EOX). The primary end point was noninferiority in overall survival for the triplet therapies containing capecitabine as compared with fluorouracil and for those containing oxaliplatin as compared with cisplatin. For the capecitabine-fluorouracil comparison, the hazard ratio for death in the capecitabine group was 0.86 (95% confidence interval [CI], 0.80 to 0.99); for the oxaliplatin-cisplatin comparison, the hazard ratio for the oxaliplatin group was 0.92 (95% CI, 0.80 to 1.10). The upper limit of the confidence intervals for both hazard ratios excluded the predefined noninferiority margin of 1.23. Median survival times in the ECF, ECX, EOF, and EOX groups were 9.9 months, 9.9 months, 9.3 months, and 11.2 months, respectively; survival rates at 1 year were 37.7%, 40.8%, 40.4%, and 46.8%, respectively. In the secondary analysis, overall survival was longer with EOX than with ECF, with a hazard ratio for death of 0.80 in the EOX group (95% CI, 0.66 to 0.97; P=0.02). Progression-free survival and response rates did not differ significantly among the regimens. Toxic effects of capecitabine and fluorouracil were similar. As compared with cisplatin, oxaliplatin was associated with lower incidences of grade 3 or 4 neutropenia, alopecia, renal toxicity, and thromboembolism but with slightly higher incidences of grade 3 or 4 diarrhea and neuropathy. Capecitabine and oxaliplatin are as effective as fluorouracil and cisplatin, respectively, in patients with previously untreated esophagogastric cancer. (Current Controlled Trials number, ISRCTN51678883 [controlled-trials.com].). Copyright 2008 Massachusetts Medical Society.

0 comments Cited 605 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Vitamin status and intake as primary determinants of homocysteinemia in an elderly population.

D Rush, J Selhub, Miriam I. Rosenberg … (1993)

To describe the distribution of plasma homocysteine concentrations in an elderly population and to analyze the relationship between homocysteine level and intake of vitamins and serum levels of vitamins that serve as coenzymes in homocysteine metabolism. Cross-sectional analysis of homocysteine levels and vitamin blood levels and intake in elderly participants in the Framingham Study. Population-based cohort in Framingham, Mass. A total of 1160 adult survivors, aged 67 to 96 years, from the original Framingham Heart Study cohort. Plasma homocysteine concentration correlated with plasma folate, vitamin B12, pyridoxal-5'-phosphate (PLP), and oral intakes of these vitamins, and the contribution of these vitamins to the prevalence of elevated homocysteine in the population. Homocysteine levels were positively correlated with age after controlling for vitamin concentrations. After controlling for age, sex, and levels of other vitamins, homocysteine exhibited a strong inverse association with plasma folate. When subjects were grouped by deciles of plasma folate, mean homocysteine was significantly higher in the lowest two folate deciles (15.6 and 13.7 mumol/L, respectively) than in the highest decile (11.0 mumol/L). Homocysteine demonstrated weaker, inverse associations with plasma vitamin B12 and PLP. Similar inverse associations were demonstrated between homocysteine and intakes of folate and vitamin B6, but not vitamin B12. Prevalence of high homocysteine (> 14 mumol/L) was 29.3% in this cohort, and was greatest among subjects with low folate status. Inadequate plasma concentrations of one or more B vitamins appear to contribute to 67% of the cases of high homocysteine. These results indicate a strong association between homocysteine concentration and folate, vitamin B12, and vitamin B6 status, as well as age. It is possible that a substantial majority of the cases of high homocysteine in this older population can be attributed to vitamin status.

0 comments Cited 123 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Hans J. van der Vliet: 31-20-4445152 , jj.vandervliet@vumc.nl

Journal

Journal ID (nlm-ta): Cancer Chemother Pharmacol

Journal ID (iso-abbrev): Cancer Chemother. Pharmacol

Title: Cancer Chemotherapy and Pharmacology

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0344-5704

ISSN (Electronic): 1432-0843

Publication date (Electronic): 25 April 2018

Publication date PMC-release: 25 April 2018

Publication date (Print): 2018

Volume: 82

Issue: 1

Pages: 39-48

Affiliations

[1 ]ISNI 0000 0004 0435 165X, GRID grid.16872.3a, Department of Medical Oncology, , VU University Medical Center, ; Amsterdam, The Netherlands

[2 ]Department of Internal Medicine, Amstelland Hospital, Amstelveen, The Netherlands

[3 ]Department of Internal Medicine, Noordwest Ziekenhuisgroep Alkmaar, Alkmaar, The Netherlands

[4 ]ISNI 0000 0001 2186 0438, GRID grid.411667.3, Department of Medical Oncology, , Georgetown University Medical Center, ; Washington, DC USA

[5 ]ISNI 0000 0004 0435 165X, GRID grid.16872.3a, Department of Medical Oncology, , VU University Medical Center, ; Room 3A38, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands

Article

Publisher ID: 3588

DOI: 10.1007/s00280-018-3588-6

PMC ID: 6010482

PubMed ID: 29696360

SO-VID: 34d1ecf6-8373-46ba-9d76-6e2e2e1dafae

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 5 January 2018

Date accepted : 20 April 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100010806, Amgen Nederland;

Funded by: FundRef http://dx.doi.org/10.13039/100004312, Eli Lilly and Company;

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: esophagogastric cancer,cisplatin,gemcitabine,vitamin b12,folic acid

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: esophagogastric cancer, cisplatin, gemcitabine, vitamin b12, folic acid

Randomized phase 2 study of gemcitabine and cisplatin with or without vitamin supplementation in patients with advanced esophagogastric cancer

Read this article at

Abstract

Purpose

Methods

Results

Conclusion

Related collections

Karger: Oncology

Most cited references 31

Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.

Capecitabine and oxaliplatin for advanced esophagogastric cancer.

Vitamin status and intake as primary determinants of homocysteinemia in an elderly population.

Author and article information

Contributors

Journal

Affiliations

Article

History

Funding

Categories

Custom metadata

Comments

Comment on this article

Similar content 214

Cited by 5

Most referenced authors 566