This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sørbye, H. Articles by Dahl, O. Search for Related Content PubMed PubMed Citation Articles by Sørbye, H. Articles by Dahl, O. Social Bookmarking                            What's this?

Multicenter Phase II Study of Nordic Fluorouracil and Folinic Acid Bolus Schedule Combined With Oxaliplatin As First-Line Treatment of Metastatic Colorectal Cancer

From the Department of Oncology and Section of Oncology, Institute of Medicine, Haukeland University Hospital, Bergen; Department of Oncology, Ullevål University Hospital; The Norwegian Radium Hospital, Oslo; Division of Hematology and Oncology, Rogaland Central Hospital, Stavanger, Norway; Departments of Oncology, Radiology, and Clinical Immunology, Uppsala University Hospital, Uppsala; and Radiumhemmet, Karolinska Hospital, Stockholm, Sweden

Address reprint requests to H. Sørbye, MD, PhD, Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway; e-mail: half{at}helse-bergen.no

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: This Nordic multicenter phase II study evaluated the efficacy and safety of oxaliplatin combined with the Nordic bolus schedule of fluorouracil (FU) and folinic acid (FA) as first-line treatment in metastatic colorectal cancer.

PATIENTS AND METHODS: Eighty-five patients were treated with oxaliplatin 85 mg/m² as a 2-hour infusion on day 1, followed by a 3-minute bolus injection with FU 500 mg/m² and, 30 minutes later, by a bolus injection with FA 60 mg/m² every second week. The same doses of FU and FA were also given on day 2.

RESULTS: Fifty-one of 82 assessable patients achieved a complete (n = 4) or partial (n = 47) response, leading to a response rate of 62% (95% CI, 52% to 72%). Nineteen patients showed stable disease, and 12 patients had progressive disease. Thirty-eight of the 51 responses were radiologically confirmed 8 weeks later (confirmed response rate, 46%; 95% CI, 36% to 58%). The estimated median time to progression was 7.0 months (95% CI, 6.3 to 7.7 months), and the median overall survival was 16.1 months (95% CI, 12.7 to 19.6 months) in the intent-to-treat population. Neutropenia was the main adverse event, with grade 3 to 4 toxicity in 58% of patients. Febrile neutropenia developed in seven patients. Nonhematologic toxicity consisted mainly of neuropathy (grade 3 in 11 patients and grade 2 in another 27 patients).

CONCLUSION: Oxaliplatin combined with the bolus Nordic schedule of FU+FA (Nordic FLOX) is a well-tolerated, effective, and feasible bolus schedule as first-line treatment of metastatic colorectal cancer that yields comparable results compared with more complex schedules.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Fluorouracil (FU) plus folinic acid (FA, leucovorin) has an established role in the treatment of advanced colorectal cancer and has, until the year 2000, been considered the standard combination for most patients. A wide variety of FU regimens with either a low dose or high dose of FA have been used. FU has been given as a bolus injection, a continuous infusion, or a combination of both (the de Gramont schedule), as well as according to chronomodulated schedules [1]. However, a plateau seems to have been reached with FU at response rates up to 30% with a variety of modulators. An adequate meta-analysis has elicited a statistically significant survival advantage of limited clinical relevance (1 month) for continuous infusion when compared with bolus administration of FU in first-line treatment of colorectal cancer patients [2]. However, a subgroup analysis showed that when FU was modulated by FA, no significant difference was found when comparing patients assigned to continuous infusion or FU bolus. High-dose continuous schedules and hybrid regimens are commonly used in Europe, with consistently higher response rates and longer progression-free survival (PFS) and overall survival (OS) times than the bolus regimens.

Modulated bolus regimens have been the reference treatment in the United States and in the Nordic countries. Given the limited difference in therapeutic benefit and the greater institutional burden of administering continuous schedules, bolus injection may be an easier and cheaper way to administer FU. The Nordic FU+FA schedule was developed to be an active but, at the same time, a highly tolerable and practical palliative bolus regimen. The Nordic FU+FA regimen consists of a short (3 minutes) bolus injection of 500 mg/m² FU followed by a bolus injection of 60 mg/m² FA 30 minutes later and results in response rates of 25% and a median survival of 10 months [3]. Trials using oxaliplatin in combination with different infused FU regimens and FA as first-line treatment of metastatic colorectal cancer have consistently demonstrated a doubling in response rate and a significant increase in PFS when compared with infused FU+FA alone [4-6]. OS has been between 16 and 20 months. In first-line therapy, most phase III data have been obtained using combinations with infused FU regimens. In phase III studies combining oxaliplatin with FU, FU has been administered using the de Gramont approach (usually 2-hour bolus FA, FU bolus, and 22-hour continuous FU infusion given for 2 consecutive days) or as a chronomodulated 12-hour infusion over 4 days. These schedules are time consuming and require infusion pumps. In two consecutive compassionate-use studies of oxaliplatin conducted in North America with more than 5,000 patients, the majority preferred a bolus FU schedule to combine with oxaliplatin, even though infusion schedules were available [7]. By adding oxaliplatin to the Nordic bolus schedule in a pilot compassionate-use study, we obtained a high confirmed response rate (63%) [8]. Therefore, we decided to investigate, in a formal phase II Nordic multicenter study, whether these preliminary results could be confirmed.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Patient Selection
All patients had prior histologically confirmed adenocarcinoma of the colon or rectum, with nonresectable metastatic disease. No prior treatment with chemotherapy other than adjuvant FU-based chemotherapy completed at least 6 months before study entry was allowed. The patients were required to have bidimensionally measurable disease (defined as the presence of at least one index lesion capable of two-dimensional measurement by abdominal computed tomography scan or chest x-ray outside any irradiated volume and above 2 cm in greatest diameter). Eligibility criteria also included age between 19 and 75 years, a WHO performance status of 0 to 2, absolute neutrophil count more than 1.5 x 10⁹/L, platelet count more than 100 x 10⁹/L, serum creatinine less than 1.5 x upper normal limit (UNL), bilirubin less than 2 x UNL, and AST or ALT less than 3 x UNL, unless with known liver metastasis where no upper limits were set. Alkaline phosphatase was measured with either the International Federation of Clinical Chemistry method (normal range, 80 to 285 U/L) or a Scandinavian recommended method (p/nitrophenylphosphate + H₂O phosphate + p/nitrophenol photometrically measured at 410 nmol/L; normal range, 0.8 to 4.6 ukat/L). The study was approved by the ethical committees in each country and was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent.

Treatment Protocol
The study patients were given the Nordic FU+FA bolus schedule combined with oxaliplatin (Nordic FLOX) as first-line treatment. Patients received oxaliplatin 85 mg/m² as a 2-hour infusion on day 1, followed by a 3-minute bolus injection with FU 500 mg/m² and, 30 minutes later, by a bolus injection with FA 60 mg/m². FU and FA were given on days 1 and 2. The treatment was repeated every second week. Treatment was delayed if neutrophils were less than 1.5 x 10⁹/L, if platelets were less than 100 x 10⁹/L, and if there were any persisting mucositis, diarrhea, or any grade 2 toxicity. If treatment was delayed longer than 4 weeks, the patient was withdrawn from the study. The dose of FU was reduced by 20% in subsequent cycles for the following toxicities: febrile neutropenia, grade 4 thrombocytopenia, grade 3 to 4 gastrointestinal toxicity, and failure of hematologic recovery to neutrophils more than 1.5 x 10⁹/L and platelets more than 100 x 10⁹/L within 2 weeks of the scheduled start of the next treatment. A second 20% dose reduction of FU was made if the above toxicities recurred. If the toxicities then recurred, the patients continued treatment with oxaliplatin as monotherapy. No dose reductions were performed for FA. The oxaliplatin dose was only modified for neurologic toxicity. In case of persisting paresthesias between cycles, the next oxaliplatin dose was reduced by 25%. A second 25% dose reduction was possible if no improvement took place. If, after that, no improvement took place, the patients continued treatment on FU as monotherapy. Oxaliplatin was also discontinued if paresthesia was associated with functional impairment. No dose modifications were made for cold dysesthesias. Neither FU nor oxaliplatin doses were allowed to be escalated during cycles subsequent to dose reduction. Ondansetron 8 mg was routinely given on days 1 and 2 of each schedule. Subjective symptoms, body weight, physical examination, performance status, CBCs, and all adverse reactions were recorded before starting the next treatment cycle. Measurable lesions were reassessed by abdominal computed tomography scan and chest x-ray after every fourth cycle or every second month in patients without treatment until progression was documented. Treatment was continued until disease progression, the occurrence of unacceptable toxicity, secondary surgery, or patient's own withdrawal.

Study End Points
Response was calculated according to WHO criteria [9]. A complete response (CR) required complete disappearance of all objective evidence of disease. A partial response (PR) was defined as a reduction of more than 50% in the sum of the products of the greatest perpendicular dimensions of measurable, bidimensional lesions. Progressive disease (PD) was defined as enlargement of existing, measurable lesions by more than 25% in sum of the products of the greatest perpendicular dimensions or the development of new metastatic lesions. Stable disease was defined as any measurement that did not fulfil the criteria for CR, PR, or PD. Toxicity grades were evaluated according to National Cancer Institute common toxicity criteria, version 2 [10], except in the case of neurotoxicity. For neurotoxicity, the following commonly used oxaliplatin-specific scale was used [11]: grade 1, paresthesias and/or dysesthesias of short duration with complete resolution before the next cycle; grade 2, paresthesias and/or dysesthesias persisting between two cycles without functional impairment; and grade 3, paresthesias interfering with function.

Statistical Analyses
The analysis was performed with the SPSS statistics package (version 11.01, SPSS Inc, Chicago, IL) and with StatXact 5 for Windows (Cytel Software, Cambridge, MA). The primary end point was response rate. The secondary efficacy criteria were time to progression (TTP) and OS. In the analysis, CR and PR were analyzed together as objective responses. All end points were first analyzed by univariate analyses using the following covariates: performance status, sex, primary tumor site (colon v rectum), number of organs involved (one, two or three organs), surgery of primary tumor (yes v no), WBC count (< 10 x 10⁹/L v 10 x 10⁹/L), platelets (< 400 x 10⁹/L v 400 x 10⁹/L), hemoglobin (< 11 g/dL v 11 g/dL), and alkaline phosphatase (< 300 v 300 U/L). End points were then subsequently analyzed by multivariate analyses using the covariates with P < .25 from the univariate analyses [12]. Alkaline phosphatase values above 4.8 ukat/L were set to be more than 300 U/L in the univariate and multivariate analyses. For response rate, the univariate analyses were performed using cross tabulations with linear by linear association tests, and the multivariate analysis was performed using multinomial logistic regression. For the end points of TTP and OS, the univariate analyses were performed using the Kaplan-Meier method with log-rank (Mantel-Haenszel) tests, and the multivariate analysis was performed using the Cox regression. All statistical tests were two-tailed using the 5% significance level.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Patient Characteristics
Eighty-five patients were enrolled onto this study from December 12, 2000, to August 15, 2001. The demographic and baseline disease characteristics are listed in Table 1. Eighty-two patients were assessable for response, and three patients (4%) were ineligible. One patient had no measurable lesions, one went to surgery after being reconsidered for surgical resection and found to be operable, and one patient left the study after two cycles because of renal toxicity. Three patients with rapid clinical deterioration before the start of therapy who died from rapid PD before the first radiologic evaluation (two patients died the day after the first cycle, and one died after the third cycle) were analyzed as having PD at their date of death. The median carcinoembryonic antigen level was 39 µg/L (range, 1 to 11,800 µg/L). All 85 patients were assessable for toxicity assessment.

View larger version (7K): [in this window] [in a new window]   Fig 1. Kaplan-Meier curve of (A) time to progression and (B) overall survival.

View larger version (18K): [in this window] [in a new window]   Fig 2. Kaplan-Meier curves of overall survival as a function of (A) alkaline phosphatase levels (Alp), (B) platelet count (Tpk), (C) resected primary tumor, and (D) performance status (PS).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

Data on oxaliplatin combined with a strict FU bolus schedule (intravenous push) as first-line treatment in metastatic colorectal cancer are sparse. Oxaliplatin (130 mg/m²) has been administered together with daily x 5 bolus FU and FA (Mayo Clinic regimen) in first-line treatment of colorectal cancer patients [13]. The response rate was 45%, and the PFS was 3.9 months, but the regimen was highly toxic and unfeasible because of a high level of myelosuppression and gastrointestinal toxicity. In the Intergroup N9741 study, a similar treatment arm was closed because of excessive toxicity [14]. Ravaioli et al [15] used a modified Machover schedule consisting of oxaliplatin 130 mg/m² every third week combined with FU 350 mg/m² and FA 20 mg/m² as a daily bolus for 5 days, every 21 days. Because of toxicity, the FU dose had to be reduced to 300 mg/m². Ravaioli reported a response rate of 40%, a PFS of 5.9 months, and a median survival of 14 months. During revision of this article, a study from Hochster et al [11] was published using fortnightly oxaliplatin combined with weekly bolus FU and low-dose leucovorin (bFOL) as first-line therapy for 42 patients with metastatic colorectal cancer. The bFOL schedule exhibited a confirmed response rate of 63%, a median TTP of 9.0 months, and a median survival of 15.9 months. The Nordic FLOX combination was well tolerated, safe, and as effective as other infused and bolus schedules, and a bolus schedule may offer the advantage of increasing convenience and lower cost by the use of rather low doses of FA. The main dose-limiting toxicity was cumulative sensory peripheral neuropathy. Grade 2 to 3 neuropathy was seen in 54% of patients, usually first appearing after eight to 10 courses of treatment and probably more reflecting the number of courses given. In the future, an intermittent strategy with a treatment break after eight courses may prove favorable [16]. Grade 3 to 4 neutropenia was reported in 58% of the patients, but only seven patients exhibited neutropenic fever. The main consequence of neutropenia (and of a low-grade thrombocytopenia) was delay in treatment, which occurred in 28% of the treatment cycles, usually for 1 week. Grade 3 diarrhea was seen in six patients, and grade 4 diarrhea was seen in two patients. In the modified Machover schedule with oxaliplatin, grade 3 to 4 diarrhea was observed in 29% of the patients, and grade 3 to 4 neutropenia was observed in 20% [15]. The bFOL schedule reported 29% grade 3 to 4 diarrhea, 22% grade 2 diarrhea, and 10% grade 3 to 4 hematologic toxicity [11]. Incidences of grade 3 to 4 diarrhea were reported in 35% of the constant-rate treatment arm patients and 29% of the chronomodulated arm patients in the study by Levi et al [6], 43% of patients in the chronomodulated study by Giacchetti et al [4], and 12% of patients in the study by de Gramont et al [5]. The incidence of grade 1 to 2 diarrhea after Nordic FLOX was similar to the de Gramont schedule. Grade 3 to 4 neutropenia was reported in 3% of the constant rate arm and 8% of the chronomodulated arm in the Levi study, in 2% of patients in the Giachetti study, and in 42% of patients in the de Gramont study. Neurotoxicity grade 2 to 3 was reported by Levi in the constant arm (31%) and in the chronomodulated arm (16%), by Giacchetti (46%), and by de Gramont (47%). The toxicity profile of the bolus administration of FU+FA with oxaliplatin in the current study, therefore, compares favorably in many aspects. The recently published toxicity analysis of more than 5,000 patients demonstrated that the use of bolus FU schedules in combination with oxaliplatin was safe [7].

The patient populations in the present study showed a higher number of poor prognostic factors than usually seen in phase II and III studies and in the pilot study of Nordic FLOX [4-6,8,15]. Our present study population had a high number of organs involved, many with lower performance status, several patients with unresected primary tumors, and many patients with increased alkaline phosphatase, WBC, or platelet levels.

Kohne et al [12] have shown that performance status, WBC count, alkaline phosphatase, and the number of metastatic sites predict survival in patients with FU-based treatment for metastatic colorectal cancer. The median survival times for the low-, intermediate-, and high-risk groups were 14.7, 10.5, and 6.4 months, respectively. In our study, increased alkaline phosphatase and platelet levels and an unresected primary tumor were poor parameters for survival. Patients with normal alkaline phosphatase and platelet levels at baseline had a median survival of 22.8 months, whereas it was 10.4 months if both levels were elevated. Our results indicate that both good- and poor-risk patients benefit from adding oxaliplatin to FU-based chemotherapy. A new observation was the finding that presence of the primary tumor had a negative impact on survival. This group may have unfavorable characteristics such as, for example, a larger metastatic burden. Simultaneous presence of primary tumor and metastases may reflect a more aggressive cancer. However, in some cancers, there is a complex interaction between the primary tumor and its metastases, and a benefit of surgery of the primary can not be excluded. Because the present trend in the United States and Europe has changed recently towards not resecting an asymptomatic colorectal primary in patients with metastatic disease, future studies should account for the presence of the primary tumor as a possible confounding factor.

Oxaliplatin is usually given as a 2-hour infusion. Only a few studies have tried to give the oxaliplatin infusion in 30 minutes without an increase in observed toxicity [17-18]. If oxaliplatin could be given in 30 minutes without compromising effect or toxicity, the Nordic FLOX schedule will constitute an even more attractive regimen suitable for outpatient practice. In conclusion, the Nordic FLOX regimen is a well-tolerated, effective, and simple bolus schedule suitable for first-line treatment of metastatic colorectal cancer.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank R. Eikeland (Clinical Cancer Research Office, Haukeland University Hospital, Bergen, Norway) for data managing, T. Wentzel-Larsen (Center for Clinical Research, Haukeland University Hospital) for statistical help, G. Frykholm (Department of Oncology, St. Olavs Hospital, Trondheim, Norway) and R. Pedersen (Department of Oncology, University Hospital of Northern Norway, Tromsø, Norway) for their contributions to referral of patients, and Sanofi-Wintrop Sweden for data monitoring.

	NOTES

 
Supported by The Norwegian Cancer Society, The Swedish Cancer Society, and Sanofi Winthrop.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
1. Ragnhammar P, Hafstrom L, Nygren P, et al: A systematic overview of chemotherapy effects in colorectal cancer. Acta Oncol 40:282-308, 2001[Medline]

2. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer: Meta-Analysis Group ini Cancer. J Clin Oncol 16:301-308, 1998[Abstract/Free Full Text]

3. Glimelius B, Jakobsen A, Graf W, et al: Bolus injection (2-4 min) versus short term (10-20 min) infusion of 5-fluorouracil in patients with advanced colorectal cancer: A prospective randomised trial. Eur J Cancer 34:674-678, 1998

4. Giacchetti S, Perpoint B, Zidani R, et al: Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18:136-147, 2000[Abstract/Free Full Text]

5. 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 18:2938-2947, 2000[Abstract/Free Full Text]

6. Levi F, Zidani R, Misset JL, et al: Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. Lancet 350:681-686, 1997[CrossRef][Medline]

7. Ramanathan RK, Clark JW, Kemeny NE, et al: Safety and toxicity analysis of oxaliplatin combined with fluorouracil or as a single agent in patients with previously treated advanced colorectal cancer. J Clin Oncol 21:2904-2911, 2003[Abstract/Free Full Text]

8. Sørbye H, Dahl O: Nordic 5-flurorouracil/leucovorin bolus schedule combined with oxaliplatin (Nordic FLOX) as first-line treatment of metastatic colorectal cancer. Acta Oncol 42:827-831, 2003

9. WHO: WHO Handbook for Reporting Results of Cancer Treatment. WHO Offset Publication No. 48, World Health Organization, Geneva, Switzerland, 1979

10. National Cancer Institute: National Cancer Institute common toxicity criteria. http://ctep.cancer.gov/reporting/ctc.html

11. Hochster H, Chachoua A, Speyer J, et al: Oxaliplatin with weekly bolus fluorouracil and low-dose leucovorin as first-line therapy for patients with colorectal cancer. J Clin Oncol 21:2703-2707, 2003[Abstract/Free Full Text]

12. Kohne CH, Cunningham D, Di Costanzo F, et al: Clinical determinants of survival in patients with 5-fluorouracil-based treatment for metastatic colorectal cancer: Results of a multivariate analysis of 3825 patients. Ann Oncol 13:308-317, 2002[Abstract/Free Full Text]

13. Comba AZ, Blajman C, Richardet E, et al: A randomised phase II study of oxaliplatin alone versus oxaliplatin combined with 5-fluorouracil and folinic acid (Mayo Clinic regimen) in previously untreated metastatic colorectal cancer patients. Eur J Cancer 37:1006-1013, 2001

14. Morton RF, Goldberg RM, Sargent DJ, et al: Oxaliplatin or CPT-11 combined with 5FU/leucovorin in advanced colorectal cancer: An NCCTG/CALGB study. Proc Am Soc Clin Oncol 20:125a, 2001 (abstr 495)

15. Ravaioli A, Marangolo M, Pasquini E, et al: Bolus fluorouracil and leucovorin with oxaliplatin as first-line treatment in metastatic colorectal cancer. J Clin Oncol 20:2545-2550, 2002[Abstract/Free Full Text]

16. Maughan TS, James RD, Kerr DJ, et al: Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: A multicentre randomised trial. Lancet 361:457-464, 2003[CrossRef][Medline]

17. Chollet P, Bensmaine MA, Brienza S, et al: Single agent activity of oxaliplatin in heavily pretreated advanced epithelial ovarian cancer. Ann Oncol 7:1065-1070, 1996[Abstract/Free Full Text]

18. Pfeiffer P, Hahn P, Jensen HA: Short-time infusion of oxaliplatin in combination with capecitabine in patients with advanced colorectal cancer. Proc Am Soc Clin Oncol 22:360, 2003 (abstr 1445)

Submitted May 29, 2003; accepted October 17, 2003.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				D. L. Nielsen, P. Pfeiffer, and B. V. Jensen Six cases of treatment with panitumumab in patients with severe hypersensitivity reactions to cetuximab Ann. Onc., April 1, 2009; 20(4): 798 - 798. [Full Text] [PDF]

				C. Qvortrup, M. Yilmaz, D. Ogreid, A. Berglund, L. Balteskard, J. Ploen, T. Fokstuen, H. Starkhammar, H. Sorbye, K. Tveit, et al. Chronomodulated capecitabine in combination with short-time oxaliplatin: a Nordic phase II study of second-line therapy in patients with metastatic colorectal cancer after failure to irinotecan and 5-flourouracil Ann. Onc., June 1, 2008; 19(6): 1154 - 1159. [Abstract] [Full Text] [PDF]

				P. Pfeiffer, D. Nielsen, J. Bjerregaard, C. Qvortrup, M. Yilmaz, and B. Jensen Biweekly cetuximab and irinotecan as third-line therapy in patients with advanced colorectal cancer after failure to irinotecan, oxaliplatin and 5-fluorouracil Ann. Onc., June 1, 2008; 19(6): 1141 - 1145. [Abstract] [Full Text] [PDF]

				B. Glimelius, H. Sorbye, L. Balteskard, P. Bystrom, P. Pfeiffer, K. Tveit, R. Heikkila, N. Keldsen, M. Albertsson, H. Starkhammar, et al. A randomized phase III multicenter trial comparing irinotecan in combination with the Nordic bolus 5-FU and folinic acid schedule or the bolus/infused de Gramont schedule (Lv5FU2) in patients with metastatic colorectal cancer Ann. Onc., May 1, 2008; 19(5): 909 - 914. [Abstract] [Full Text] [PDF]

				H. Sorbye, C.-H. Kohne, D. J. Sargent, and B. Glimelius Patient characteristics and stratification in medical treatment studies for metastatic colorectal cancer: A proposal for standardization of patient characteristic reporting and stratification Ann. Onc., October 1, 2007; 18(10): 1666 - 1672. [Abstract] [Full Text] [PDF]

				Y. Yamada, A. Ohtsu, N. Boku, Y. Miyata, Y. Shimada, T. Doi, K. Muro, M. Muto, T. Hamaguchi, K. Mera, et al. Phase I/II Study of Oxaliplatin with Weekly Bolus Fluorouracil and High-Dose Leucovorin (ROX) As First-Line Therapy for Patients with Colorectal Cancer. Jpn. J. Clin. Oncol., April 1, 2006; 36(4): 218 - 223. [Abstract] [Full Text] [PDF]

				P. Pfeiffer, H. Sorbye, H. Ehrsson, T. Fokstuen, J. P. Mortensen, L. Baltesgard, K. M. Tveit, D. Ogreid, H. Starkhammar, I. Wallin, et al. Short-time infusion of oxaliplatin in combination with capecitabine (XELOX30) as second-line therapy in patients with advanced colorectal cancer after failure to irinotecan and 5-fluorouracil Ann. Onc., February 1, 2006; 17(2): 252 - 258. [Abstract] [Full Text] [PDF]

				Y. Yildirim, Z. Akcali, and O. Ozyilkan Controversy in Folinic Acid Administration After Fluorouracil J. Clin. Oncol., June 1, 2005; 23(16): 3862 - 3862. [Full Text] [PDF]

				H. Sorbye and B. Glimelius In Reply: J. Clin. Oncol., June 1, 2005; 23(16): 3862 - 3863. [Full Text] [PDF]

				P. Comella, B. Massidda, G. Filippelli, S. Palmeri, D. Natale, A. Farris, F. De Vita, F. Buzzi, S. Tafuto, L. Maiorino, et al. Oxaliplatin plus high-dose folinic acid and 5-fluorouracil i.v. bolus (OXAFAFU) versus irinotecan plus high-dose folinic acid and 5-fluorouracil i.v. bolus (IRIFAFU) in patients with metastatic colorectal carcinoma: a Southern Italy Cooperative Oncology Group phase III trial Ann. Onc., June 1, 2005; 16(6): 878 - 886. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sørbye, H. Articles by Dahl, O. Search for Related Content PubMed PubMed Citation Articles by Sørbye, H. Articles by Dahl, O. Social Bookmarking                            What's this?