Phase II trial of oxaliplatin, leucovorin and fluorouracil in patients with advanced carcinoma of the esophagus

A. M. Mauer1,*, E. H. Kraut2, S. A. Krauss1, R. H. Ansari1, K. Kasza1, L. Szeto1, E. E. Vokes1 for the University of Chicago Phase II Network

1 University of Chicago Section of Hematology/Oncology and University of Chicago Cancer Research Center, Chicago, IL; 2 The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

Correspondence to: Dr A. M. Mauer, University of Chicago Medical Center, 5841 South Maryland Avenue, Chicago, Illinois 60637, USA. Email: amauer{at}medicine.bsd.uchicago.edu


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: The aim of the study was to evaluate the efficacy and tolerability of the combination of oxaliplatin, fluorouracil and leucovorin in patients with advanced esophagus cancer.

Patients and methods: Thirty-five patients with recurrent or metastatic esophageal adenocarcinoma or squamous cell carcinoma were enrolled. Up to one prior chemotherapy regimen was allowed. All patients had bi-dimensionally measurable disease. Patients received oxaliplatin 85 mg/m2 as a 2-h infusion on day 1. Leucovorin (500 mg/m2) followed by fluorouracil bolus (400 mg/m2) and 22-h continuous infusion fluorouracil (600 mg/m2) was administered on days 1 and 2. Granulocyte colony stimulating factor was not routinely administered unless the patient developed febrile neutropenia or prolonged neutropenia. Treatment was repeated every 14 days.

Results: Of the thirty-five patients enrolled, all were evaluated for toxicity and 34 were evaluated for response. The overall response rate was 40% (95% confidence interval, 24% to 57%) with complete and partial response rates of 3% and 37%, respectively. The median response duration was 4.6 months, and the median overall survival was 7.1 months. One-year survival was 31%. The major toxicity noted was cumulative neutropenia, with 29% developing grade 4 toxicity. There was one treatment-related death secondary to neutropenic sepsis. The most common non-hematologic toxicity encountered with this regimen was cumulative peripheral neuropathy, with 26% experiencing grade 2 or 3 toxicity.

Conclusions: The combination of oxaliplatin, leucovorin, and fluorouracil shows significant anti-tumor activity and a favorable toxicity profile in patients with metastatic carcinoma of the esophagus.

Key words: oxaliplatin, fluorouracil, leucovorin, esophagus cancer


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Carcinoma of the esophagus is a leading cause of cancer worldwide. Within the Western world, the incidence of adenocarcinoma of the esophagus and proximal stomach is increasing. In 2005, 14 250 new cases and 13 300 deaths from cancer of the esophagus are expected in the United States [1Go]. The poor prognosis associated with esophagus cancer reflects the early systemic spread and the lack of effective therapies to manage the disease. Chemotherapy, a cornerstone in the management of this disease, is utilized as part of combined modality therapy for locoregionally advanced disease or as palliative treatment for metastatic disease [2Go]. Active single agents produce modest objective response rates between 15% and 35% in metastatic esophageal cancer (EC). Many combination regimens have been studied, with cisplatin-based combinations demonstrating the most favorable response activity, and producing response rates of 35% in metastatic and 45%–55% in locally advanced EC. Cisplatin and fluorouracil remains a standard regimen in esophagus cancer that is utilized in the metastatic setting, as well as in combination with radiotherapy [3Go, 4Go]. The toxicity associated with cisplatin and fluorouracil-based combination regimens, including nephrotoxicity, neurotoxicity, myelosuppression, ototoxicity and stomatitis, can be considerable and limit dose intensity [5Go, 6Go]. There is continued search for novel regimens that are more active and better tolerated.

Oxaliplatin is a novel antineoplastic platinum derivative that has a more favorable toxicity profile than cisplatin [7Go]. At therapeutic doses, it is less emetogenic, nephrotoxic, ototoxic and myelosuppressive than cisplatin. In phase I trials, the dose-limiting toxicity of oxaliplatin was a cumulative sensory peripheral neuropathy. Oxaliplatin also produced an acute neurotoxicity distinct from the neuropathy noted with other platinum compounds. This unique neurotoxicity was characterized by a rapid onset that is precipitated by exposure to cold with regression between treatment cycles [8Go].

In preclinical studies, oxaliplatin demonstrated antitumor activity against multiple tumor cell lines [9Go–13Go] including some that are resistant to cisplatin and fluorouracil [9Go–13Go]. Oxaliplatin has also shown clinical activity in several solid tumors, including colorectal [14Go–16Go], lung [17Go], ovarian [18Go], pancreatic, and head and neck cancer [19Go]. Based on preclinical studies indicating that the combination of oxaliplatin and 5-fluorouracil exhibits synergy, clinical trials were undertaken to investigate the combination in colorectal [13Go], gastric [20Go], and breast cancer [21Go]. In phase II trials exploring various doses and schedules of oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin [22Go–27Go], the regimen demonstrated significant activity and good tolerability, where the predominant toxicities were neutropenia and peripheral neuropathy. We report results of a multi-institutional phase II study to test the efficacy of oxaliplatin and fluorouracil/leucovorin in patients with metastatic carcinoma of the esophagus and gastric cardia. The regimen utilized was based on the FOLFOX4 regimen [27Go, 28Go].


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient selection
Eligibility criteria included a histologically or cytologically confirmed diagnosis of cancer of the esophagus or gastric cardia. Patients were required to have recurrent or metastatic disease. Measurable disease was required. Prior treatment with a single chemotherapy regimen and radiotherapy was allowed. An Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 was necessary. Laboratory measures required at study entry included: white blood cell count ≥3500/µl; absolute neutrophil count ≥1500/µl; hemoglobin ≥10 g/dl; platelet count ≥100 000/µl; creatinine ≤1.5 times the institutional upper limit of normal or creatinine clearance ≥50 ml/min; bilirubin ≤1.5 mg/dl; and glutamic–oxaloacetic transaminase less than two times the institutional limit of normal. All participating institutions were required to have the treatment protocol reviewed by their institutional review board. Written informed consent was obtained from all patients prior to commencing protocol treatment. Before study entry, all patients underwent evaluation consisting of a complete history and physical examination; a chest and upper abdomen CT scan; and a bone scan.

Treatment
Protocol treatment was delivered in the outpatient setting. Oxaliplatin 85 mg/m2 was administered as a 2-h intravenous (i.v.) infusion on day 1. Leucovorin 500 mg/m2 i.v. was administered as a 2-h infusion followed by fluorouracil (400 mg/m2) as an i.v. bolus immediately followed by fluorouracil (600 mg/m2) as a 22-h continuous infusion on days 1 and 2. Prophylactic antiemetic support with ondansetron 24 mg and dexamethasone 20 mg was administered prior to each oxaliplatin dose. Prophylactic granulocyte colony stimulating factor was not routinely administered unless the patient developed febrile or prolonged neutropenia. Treatment cycles were administered every 14 days. Patients were counseled to avoid exposure to cold liquids or air because the acute neurotoxicity encountered with oxaliplatin appears to be exacerbated by exposure to cold.

Dose modifications
Dose modification of the oxaliplatin, leucovorin and fluorouracil was specified for myelosuppression, nephrotoxicity, neurotoxicity and hepatic dysfunction. Dose modification for toxicity was based on the worst toxicity observed during the previous course. Therapy was delayed 1 week for inadequate hematologic recovery (absolute neutrophil count <1500/µl or platelet count <100 000/µl) by day 15. For grade 4 neutropenia or thrombocytopenia, the oxaliplatin and fluorouracil doses were reduced 25% in the subsequent cycle. For grade 3 or 4 stomatitis or diarrhea, the doses of oxaliplatin and fluorouracil were reduced by 25% in the subsequent cycle after recovery to baseline. Oxaliplatin doses were reduced by 25% for significant neurotoxicity defined as persistent grade 2 neuropathy or any grade 3 neuropathy.

Assessment of response and toxicity
Patients were monitored biweekly throughout treatment by physical examination and recording of toxic effects. Toxicities were graded according to the NCI Common Toxicity Criteria (CTC) 2.0. A modified CTC sensory neuropathy grading scale and neurologic toxicity grading scale was used for the evaluation of oxaliplatin-associated sensory neuropathies to account for the unique, cold sensitive neuropathy noted with the drug, and for the determination of dose modifications (Table 1). Complete blood counts were performed at least weekly. Serum chemistry and liver function tests were obtained before each cycle of chemotherapy.


View this table:
[in this window]
[in a new window]
 
Table 1. Toxicity scale for the sensory neuropathies associated with oxaliplatin

 
Assessment of response to protocol therapy was performed after every four cycles of therapy and assigned based on the following criteria. A complete response (CR) was defined as the complete clinical and radiographic disappearance of tumor without the appearance of new lesions. A partial response (PR) was characterized as a reduction by at least 50% of the products of the longest perpendicular diameters of all measurable lesions. A partial response also required that there was no growth of other lesions or the appearance of new lesions over at least 28 consecutive days. Stable disease (SD) was defined as a decrease in the sum of the products of two perpendicular diameters of all measured lesions by <50% or an increase by <25% after a minimum of two cycles of therapy. Progressive disease (PD) was characterized as an increase in the product of the longest diameters of measured lesion by ≥25%, or the appearance of new lesions.

Those patients who achieved stable disease or response after four cycles of therapy continued to receive protocol-specified therapy until disease progression, unacceptable toxicity, or the patient's desire to discontinue therapy. The relative dose intensity was defined as the total dose administered for all cycles divided by the product of the dose administered in cycle 1 and the total number of treatment cycles.

Statistical analysis
The overall response rate (combining CR and PR) was computed using all enrolled patients, and a 95% confidence interval (CI) was constructed based on the binomial distribution but ignoring the multistage nature of the design. Progression-free survival (defined as the time from registration until progression or death from any cause) and survival (also from date of registration) curves were estimated for all enrolled patients using the Kaplan–Meier method, and approximate 95% CI were computed using the method described by Kalbfleisch and Prentice [29Go]. Confidence intervals for the median survival times were obtained as described in Brookmeyer and Crowley [30Go].


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
The patients who enrolled in this trial received therapy at one of several institutions within the University of Chicago Phase II Network and the Ohio State University Phase II Research Consortium. Between February 2000 and October 2001, a total of 35 patients enrolled in the study. Thirty-five patients were evaluated for toxicity and 34 were evaluated for response. The patients’ characteristics are presented in Table 2. There were 30 men and five women with a median age of 65 years (range 34–86 years). The majority of patients had good performance status and adenocarcinoma histology. The site of the primary tumor was esophagus in 30 patients and gastric cardia in five patients. One patient had locally recurrent disease and 34 had distant metastases. Eight patients had received prior radiation therapy. Four patients had received prior chemotherapy with cisplatin or carboplatin.


View this table:
[in this window]
[in a new window]
 
Table 2. Patient characteristics

 
Survival
All 35 subjects have died. For all patients, the median survival was 7.1 months (95% CI 5.9–10.9). The 1-year survival probability was 0.31 (95% CI 0.17–0.47) and the 2-year survival probability was 0.11 (95% CI 0.036–0.24; Figure 1). There was a significant difference in survival between the patients who had received prior chemotherapy versus those who had not (P value=0.011, log-rank test). Median survival was 7.6 and 2.1 months for chemotherapy-naïve patients and previously treated patients, respectively.



View larger version (9K):
[in this window]
[in a new window]
 
Figure 1. Kaplan–Meier survival curve.

 
Among all 36 patients, the median progression-free survival 4.6 months (95% CI 2.2–6.8), with a 1-year progression-free survival rate of 0.15. There was also a significant difference in progression-free survival between the two groups (P value=0.0009, log-rank test). Median progression-free survival was 4.9 and 1.7 months for chemotherapy-naïve patients and previously treated patients, respectively.

Response
The responses for all patients treated are shown in Table 3. Thirty-two patients completed at least four cycles of therapy and were evaluated using the radiologic parameters described above. Two patients were deemed to have clinical disease progression after less than four cycles of therapy and died while on study. One patient had a treatment-related death before radiologic evaluation. The overall response rate for all 35 patients was 40% (95% CI 24% to 58%). The overall response rate for the patients who were chemotherapy-naïve was 45% (95% CI 27% to 64%). No responses were noted in patients who had received chemotherapy prior to enrollment. Thirteen of the responding patients had tumors with adenocarcinoma and one had adenosquamous histology. One patient with a gastric cardia tumor achieved a partial response. Twenty-six patients (40%) had stable disease as the best response after four or more cycles of chemotherapy.


View this table:
[in this window]
[in a new window]
 
Table 3. Treatment response

 
Toxicity
The total number of treatment cycles administered was 322. The median number of cycles was seven per patient (range 1–26 cycles). Eleven patients (31%) received at least 12 cycles, and one (3%) received only one cycle of therapy.

The maximum hematologic toxicity experienced by patient is listed by grade of severity for each parameter in Table 4. Overall the hematologic toxicity encountered in patients treated at the recommended phase II dose was tolerable with 29% experiencing grade 4 neutropenia of any duration. One patient developed fatal sepsis while neutropenic. Cumulative thrombocytopenia was noted with this regimen with typical onset after four cycles of therapy. Seven patients developed cumulative myelosuppression that required a dose modification of the oxaliplatin dose.


View this table:
[in this window]
[in a new window]
 
Table 4. Maximum hematologic toxicity all cycles

 
The maximum non-hematologic toxicities noted for all patients treated are listed in Table 5. The predominant non-hematologic toxicity observed with this combination therapy was peripheral neuropathy that was cumulative and largely reversible following discontinuation of treatment. This toxicity was generally mild to moderate, with only one patient (3%) developing grade 3 peripheral neuropathy. In all, three patients required a dose reduction of oxaliplatin for grade 2 or 3 neuropathy. Four patients had dose reductions of fluorouracil and leucovorin for grade 3 diarrhea. Two patients discontinued protocol therapy as a result of treatment-related adverse events. One patient developed grade 3 hemolytic anemia with acute renal failure and thrombocytopenia after 16 cycles of therapy. This reaction was presumed related to oxaliplatin [31Go] and the patient was removed from study. Another patient discontinued protocol therapy after she experienced grade 3 cardiac ischemia that was considered to be secondary to fluorouracil.


View this table:
[in this window]
[in a new window]
 
Table 5. Maximum non-hematologic toxicity all cycles

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This study was undertaken to evaluate the combination regimen of oxaliplatin, leucovorin and fluorouracil in patients with advanced esophageal cancer. A current standard combination therapy for metastatic esophagus cancer, cisplatin and fluorouracil, yields response rates of 25%–33%, but the rate of complete response is low, the duration of response is short, and the toxicity is considerable. In a large phase II study reported by Bleiberg et al. [6Go], patients with locally advanced or metastatic carcinoma of the esophagus were treated with cisplatin 100 mg/m2, combined with 5-fluorouracil (5-FU) at a dose of 1000 mg/m2 as a continuous infusion from days 1 to 5. The toxicity was unacceptable with treatment-related death occurring in 16%. This finding further underscores the need to identify new treatment approaches in this disease.

Our phase II experience with oxaliplatin, fluorouracil and leucovorin confirms the feasibility of delivering these drugs at doses that are active in esophageal cancer, with an acceptable level of toxicity. In our trial neutropenia was designated as grade 4 in 29%. In most patients the neutropenia was of no clinical significance; the rate of febrile neutropenia was low at 6%. Of note, the incidence of severe neutropenia was higher than the rates reported for other trials studying the FOLFOX regimens. This difference may be secondary to the higher dose of leucovorin that was utilized in our trial. In addition, the incidence of neutropenia is generally lower for FOLFOX regimens that include infusional fluorouracil without bolus fluorouracil. Remarkable in this trial was the lack of grade 3 or 4 toxicity other than myelosuppression. The predominant non-hematologic toxicity of the regimen, peripheral neuropathy, was moderate in 25% of patients. This low rate of peripheral neuropathy may be due to the limited duration of therapy and short survival times.

This combination regimen demonstrates significant antitumor activity in advanced esophageal cancer and produced an overall response rate of 40% and a median survival time of 7.1 months. The response rate for patients with adenocarcinoma or mixed histology was 44%. The proportion of patients with squamous cell carcinomas enrolled in this trial was low, and this experience is not sufficient to conclude the activity of the regimen in that disease histology. The efficacy of this oxaliplatin, fluorouracil and leucovorin regimen compares favorably with results reported for other cisplatin-based therapies in adenocarcinomas of the esophagus and gasto-esophageal junction [32Go–34Go]. Based on the activity and tolerability of this regimen, further investigation of the combination in esophageal cancer is warranted. The combination of oxaliplatin, fluorouracil and leucovorin with a targeted therapy would be of interest. The investigation of oxaliplatin, fluorouracil and leucovorin-based approaches in the preoperative setting should also be undertaken now that there is support for this approach [35Go]. Khushalani and colleagues [36Go] have demonstrated the feasibility of combining oxaliplatin and fluorouracil with thoracic radiotherapy for advanced esophagus cancer.


    Acknowledgements
 
This study was presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, 18–20 May 2002.The work was supported by NCI Grant U01CA63187–01 and the University of Chicago Cancer Center (CM107102–02).

Received for publication March 4, 2004. Revision received March 21, 2005. Accepted for publication March 22, 2005.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Jemal A, Murray T, Ward E et al. Cancer statistics. CA Cancer J Clin 2005; 55: 10–30.[Abstract/Free Full Text]

2. Mauer AM, Weichselbaum RR. Multimodality therapy for carcinoma of the esophagus. In Posner MC, Vokes EE, Weichselbaum RR (eds): American Cancer Society Atlas. Hamilton, Ontario: BC Dekker 2002; 157–184.

3. Kelsen DP, Ginsberg R, Pajak TF et al. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 1998; 339: 1979–1984.[Abstract/Free Full Text]

4. Herskovic A, Martz K, al-Sarraf M et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992; 326: 1593–1598.[Abstract]

5. Levard H, Pouliquen X, Hay J et al. M5-Fluorourracil and cisplatin as palliative treatment of advanced oesophageal squamous cell carcinoma. A multicentre randomised controlled trial. The French Associations for Surgical Research. Eur J Surg 1998; 164: 849–857.[CrossRef][ISI][Medline]

6. Bleiberg H, Conroy T, Paillot B et al. Randomised phase II study of cisplatin and 5-fluorouracil (5-FU) versus cisplatin alone in advanced squamous cell oesophageal cancer. Eur J Cancer 1997; 33: 1216–1220.[CrossRef][Medline]

7. Extra JM, Marty M, Brienza S, Misset JL. Pharmacokinetics and safety profile of oxaliplatin. Semin Oncol 1998; 25 (Suppl 5): 13–22.[ISI][Medline]

8. Misset JL, Bleiberg H, Sutherland W et al. Oxaliplatin clinical activity: a review. Crit Rev Oncol Hematol 2000; 35: 75–93.[CrossRef][ISI][Medline]

9. Kraker AJ, Moore CW. Accumulation of cis-diamminedichloroplatinum(II) and platinum analogues by platinum-resistant murine leukemia cells in vitro. Cancer Res 1988; 48: 9–13.[Abstract]

10. Pendyala L, Creaven PJ. In vitro cytotoxicity, protein binding, red blood cell partitioning, and biotransformation of oxaliplatin. Cancer Res 1993; 53: 5970–5976.[Abstract]

11. Rixe O, Ortuzar W, Alvarez M et al. Oxaliplatin, tetraplatin, cisplatin, and carboplatin: spectrum of activity in drug-resistant cell lines and in the cell lines of the National Cancer Institute's Anticancer Drug Screen panel. Biochem Pharmacol 1996; 52: 1855–1865.[CrossRef][ISI][Medline]

12. Dunn TA, Schmoll HJ, Grunwald V et al. Comparative cytotoxicity of oxaliplatin and cisplatin in non-seminomatous germ cell cancer cell lines. Invest New Drugs 1997; 15: 109–114.[CrossRef][ISI][Medline]

13. Raymond E, Chaney SG, Taamma A, Cvitkovic E. Oxaliplatin: a review of preclinical and clinical studies. Ann Oncol 1998; 9: 1053–1071.[Abstract]

14. Becouarn Y, Rougier P. Clinical efficacy of oxaliplatin monotherapy: phase II trials in advanced colorectal cancer. Semin Oncol 1998; 25 (Suppl 5): 23–31.

15. Diaz-Rubio E, Sastre J, Zaniboni A et al. Oxaliplatin as single agent in previously untreated colorectal carcinoma patients: a phase II multicentric study. Ann Oncol 1998; 9: 105–108.[Abstract]

16. Machover D, Diaz-Rubio E, de Gramont A et al. Two consecutive phase II studies of oxaliplatin (L-OHP) for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines. Ann Oncol 1996; 7: 95–98.[Abstract]

17. Monnet I, Brienza S, Hugret F et al. Phase II study of oxaliplatin in poor-prognosis non-small cell lung cancer (NSCLC). ATTIT (Association pour le Traitement des Tumeurs Intra Thoraciques). Eur J Cancer 1998; 34: 1124–1127.

18. Chollet P, Bensmaine MA, Brienza S et al. Single agent activity of oxaliplatin in heavily pretreated advanced epithelial ovarian cancer. Ann Oncol 1996; 7: 1065–1070.[Abstract]

19. Degardin M, Cappelaere P, Krakowski I et al. Phase II trial of oxaliplatin (L-OHP) in advanced, recurrent and/or metastatic squamous cell carcinoma of the head and neck. Eur J Cancer B Oral Oncol 1996; 32B: 278–279.[Medline]

20. Louvet C, Andre T, Tigaud JM et al. Phase II study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients. J Clin Oncol 2002; 20: 4543–4548.[Abstract/Free Full Text]

21. Zelek L, Cottu P, Tubiana-Hulin M et al. Phase II study of oxaliplatin and fluorouracil in taxane- and anthracycline-pretreated breast cancer patients. J Clin Oncol 2002; 20: 2551–2558.[Abstract/Free Full Text]

22. Levi F, Misset JL, Brienza S et al. A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid, and oxaliplatin using an ambulatory multichannel programmable pump. High antitumor effectiveness against metastatic colorectal cancer. Cancer 1992; 69: 893–900.

23. Levi F, Perpoint B, Garufi C et al. Oxaliplatin activity against metastatic colorectal cancer. A phase II study of 5-day continuous venous infusion at circadian rhythm modulated rate. Eur J Cancer 1993; 9: 1280–1284.

24. Levi FA, Zidani R, Vannetzel JM et al. Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: a randomized multi-institutional trial. J Natl Cancer Inst 1994; 86: 1608–1617.[Abstract]

25. de Gramont A, Vignoud J, Tournigand C et al. Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer. Eur J Cancer 1997; 33: 214–219.[CrossRef][Medline]

26. de Gramont A, Louvet C, Andre T et al. A review of GERCOD trials of bimonthly leucovorin plus 5-fluorouracil 48-h continuous infusion in advanced colorectal cancer: evolution of a regimen. Groupe d'Etude et de Recherche sur les Cancers de l'Ovaire et Digestifs (GERCOD). Eur J Cancer 1998; 34: 619–626.

27. de Gramont A, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18: 2938–2947.[Abstract/Free Full Text]

28. Andre T, Bensmaine MA, Louvet C et al. Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J Clin Oncol 1999; 17: 3560–3568.[Abstract/Free Full Text]

29. Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. New York: John Wiley and Sons 1980; 14–15.

30. Brookmeyer R, Crowley JJ. A confidence interval for the medican survival time. Biometrics 1982; 38: 29–41.[ISI]

31. Sorbye H, Bruserud Y, Dahl O. Oxaliplatin-induced haematological emergency with an immediate severe thrombocytopenia and haemolysis. Acta Oncol 2001; 40: 882–883.[CrossRef][ISI][Medline]

32. Ilson DH, Ajani J, Bhalla K et al. Phase II trial of paclitaxel, fluorouracil, and cisplatin in patients with advanced carcinoma of the esophagus. J Clin Oncol 1998; 16: 1826–1834.[Abstract/Free Full Text]

33. Ilson DH, Saltz L, Enzinger P et al. Phase II trial of weekly irinotecan plus cisplatin in advanced esophageal cancer. J Clin Oncol 1999; 17: 3270–3275.[Abstract/Free Full Text]

34. Ross P, Nicolson M, Cunningham D et al. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 2002; 20: 1996–2004.[Abstract/Free Full Text]

35. Clark PI. Medical research council randomised trial of surgery with or without pre-operative chemotherapy in resectable cancer of the oesophagus (MRC Upper GI Tract Cancer Group). European Society of Medical Oncology 2000; 11 (Suppl 4): Kluwer Academic Publishers, 4.

36. Khushalani NI, Leichman CG, Proulx G et al. Oxaliplatin in combination with protracted-infusion fluorouracil and radiation: report of a clinical trial for patients with esophageal cancer. J Clin Oncol 2002; 20: 2844–2850.[Abstract/Free Full Text]





This Article
Abstract
Full Text (PDF)
All Versions of this Article:
16/8/1320    most recent
mdi249v1
E-letters: Submit a response
Alert me when this article is cited
Alert me when E-letters are posted
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Mauer, A. M.
PubMed
PubMed Citation
Articles by Mauer, A. M.