Compassionate-use oxaliplatin with bolus 5-fluorouracil/leucovorin in heavily pretreated patients with advanced colorectal cancer.Objectives: The efficacy of a concomitant oxaliplatin/bolus 5-fluorouracil/leucovorin regimen in 123 heavily pretreated patients with advanced colorectal cancer colorectal cancer
Malignant tumour of the large intestine (colon) or rectum. Risk factors include age (after age 50), family history of colorectal cancer, chronic inflammatory bowel diseases, benign polyps, physical inactivity, and a diet high in fat. was evaluated. Patients with an Eastern Cooperative Oncology Group The Eastern Cooperative Oncology Group (ECOG) was established in 1955 as one of the first cooperative groups launched to perform multi-center cancer clinical trials. A cooperative group is a large network of researchers, physicians, and health care professionals at public and performance status of 0 to 2 and radiographically progressive cancer which failed to respond to between two and five prior treatment modalities were consented and enrolled.
Methods: Patients received oxaliplatin on day 1 of weeks 1, 3, and 5 of an 8-week cycle. 5-fluorouracil/leucovorin was administered on day 1 of weeks 1 through 6.
Results: Grade 3 to 4 toxicities were as follows: diarrhea 30%; vomiting 11%; hematologic hematological, hematologic
pertaining to or emanating from blood cells.
total and differential white cell counts, hematocrit estimation, erythrocyte count. <3%; peripheral neuropathy Peripheral Neuropathy Definition
The term peripheral neuropathy encompasses a wide range of disorders in which the nerves outside of the brain and spinal cord—peripheral nerves—have been damaged. 2.5%. Of the 101 patients evaluable for response, 7% achieved a partial response (median duration 4.25 mo), 1 patient achieved a minor response (7 mo), and 31% had stable disease (median duration 6.08 mo). The median time to progression was 3.6 months.
Conclusion: This regimen in heavily pretreated patients with disseminated colorectal cancer is of modest benefit, often at the expense of considerable gastrointestinal toxicity. It appears that the use of oxaliplatin/bolus 5-fluorouracil/leucovorin is more toxic than oxaliplatin/infusional 5-fluorouracil and possibly less effective.
Key Words: bolus bolus /bo·lus/ (bo´lus)
1. a rounded mass of food or pharmaceutical preparation ready to swallow, or such a mass passing through the gastrointestinal tract.
2. a concentrated mass of pharmaceutical preparation, e. 5-fluorouracil/leucovorin, colorectal cancer, compassionate use compassionate use Pharmacology The use of an agent to treat Pts for whom conventional therapies have failed, or for whom no other drug exists; CU refers to the use of an agent on humanitarian grounds before it has received regulatory–FDA–approval study, diarrhea, oxaliplatin, pretreated
In the United States United States, officially United States of America, republic (2005 est. pop. 295,734,000), 3,539,227 sq mi (9,166,598 sq km), North America. The United States is the world's third largest country in population and the fourth largest country in area. , 135,400 new cases of colorectal cancer will be diagnosed in 2001. Of these, 20 to 25% will have already disseminated beyond the colon at the time of initial presentation, most commonly, though not exclusively, to the liver. In spite of advances made in screening, diagnostic, and surgical technique over the last decade, colorectal cancer remains the third leading cause of cancer-related deaths in the USA, with an annual mortality rate exceeding 50,000. (1)
Following its introduction into clinical practice over 40 years ago, 5-fluorouracil (5-FU) had been the standard chemotherapeutic agent chemotherapeutic agent An agent used to treat CA, administered in 'regimens'-one or more 'cycles' that combine 3 or more agents over wks; CAs are toxic to any cell with a high rate of proliferation–the CA itself, the GI tract–causing N&V, for treating patients with advanced colorectal carcinoma. However, as a single-agent, 5-FU was found to be only modestly beneficial, with response rates rarely exceeding 15%. (2) Several attempts have been made to increase the efficacy of 5-FU, including the addition of modulating compounds, manipulation of dosage and administration schedules, and combining 5-FU with other chemotherapeutic agents This is a list of specific pharmacologic agents that are known to be of use in the treatment of cancer, otherwise known as chemotherapeutic agents. This list is organized by "type" of agent, though the subsections are not necessarily definitive and are subject to revision. such as cisplatin cisplatin /cis·plat·in/ (sis´plat-in) DDP; a platinum coordination complex capable of producing inter- and intrastrand DNA crosslinks; used as an antineoplastic.
n. and methotrexate methotrexate, drug used in halting the growth of actively proliferating tissues. Introduced in the 1950s, it is used in the treatment of leukemia, psoriasis, and non-Hodgkin's lymphoma. . (3) Although these methods have succeeded in increasing the efficacy of 5-FU in terms of objective response rate, the survival of patients with advanced colorectal cancer remains quite low, rarely exceeding 12 months. Even with the introduction of new agents into the treatment armamentarium ar·ma·men·tar·i·um
n. pl. ar·ma·men·tar·i·ums or ar·ma·men·tar·i·a
The complete equipment of a physician or medical institution, including drugs, books, supplies, and instruments. such as irinotecan and capecitabine, the median survival of patients with metastatic Metastatic
The term used to describe a secondary cancer, or one that has spread from one area of the body to another.
Mentioned in: Coagulation Disorders
pertaining to or of the nature of a metastasis. disease remains only in the range of 14.8 months. (4)
Oxaliplatin (OXP OXP Office XP (Microsoft)
OXP Open Expose (German online photo album)
OXP Oxford Paper Company ) is a relatively new 1,2-diaminocyclohexane (DACH DACH Division of Adult and Community Health (US CDC)
DACH Deutschland, Austria & Switzerland
DACH Darnal Army Community Hospital
DACH Department of the Army Chaplains Fund
DACH Department of the Army, Chief of Chaplains ) platinum compound that has demonstrated antitumor an·ti·tu·mor also an·ti·tu·mor·al
Counteracting or preventing the formation of malignant tumors; anticancer.
Adj. 1. activity in a variety of neoplasms. (5,6) Of particular interest has been its antitumor activity in advanced colorectal carcinoma, which has been studied extensively by European investigators over the last 8 years. (6-17) Its postulated primary mechanism of action is similar to that of cisplatin, with the formation of intrastrand DNA adducts between two adjacent guanine guanine (gwä`nēn), organic base of the purine family. It was reported (1846) to be in the guano of birds; later (1879–84) it was established as one of the major constituents of nucleic acids. residues or adjacent guanine and adenine adenine (ăd`ənĭn, –nīn, –nēn), organic base of the purine family. Adenine combines with the sugar ribose to form adenosine, which in turn can be bonded with from one to three phosphoric acid units, yielding the three residues. (7) Since intrastrand adducts are capable of blocking both DNA replication DNA replication is the process of copying a double-stranded DNA molecule. This process is important in all known life forms and the general mechanisms of DNA replication are not the same in prokaryotic and eukaryotic organisms. and transcription, this can be lethal to a proliferating carcinoma. Preclinical trials have demonstrated the antitumoral superiority of oxaliplatin to cisplatin. (18) Indeed, one of the preclinical observations that spawned oxaliplatin's clinical development was the significant in vitro in vitro /in vi·tro/ (in ve´tro) [L.] within a glass; observable in a test tube; in an artificial environment.
In an artificial environment outside a living organism. antitumor effect in cisplatin-resistant cell lines. (7,8,18,19)
Early evidence of oxaliplatin activity in combination with 5-FU was provided by clinical studies employing various infusional and chronomodulated OXP/5-FU and leucovorin (LV) schedules. (15-17)
Oxaliplatin entered phase II and phase III Noun 1. phase III - a large clinical trial of a treatment or drug that in phase I and phase II has been shown to be efficacious with tolerable side effects; after successful conclusion of these clinical trials it will receive formal approval from the FDA testing in the United States in 1998, through a multi-center compassionate use program sponsored by Sanofi-Synthelabo. The Kentuckiana Cancer Institute, PLLC PLLC Professional Limited Liability Company
PLLC Polk Life and Learning Center (Bartow, FL)
PLLC Partners of Limited Liability Corporation , participated in this program and consistently placed eligible, heavily pretreated patients with advanced colorectal cancer (CRC (Cyclical Redundancy Checking) An error checking technique used to ensure the accuracy of transmitting digital data. The transmitted messages are divided into predetermined lengths which, used as dividends, are divided by a fixed divisor. ) on a regimen of oxaliplatin with weekly bolus 5-FU/LV (Roswell Park regimen). The results of this treatment program on 123 patients are reported herein.
Materials and Methods
Between September 25, 1998 and May 1, 2001 a total of 123 advanced CRC patients were consented and enrolled in a compassionate use study in which OXP 85 mg/[m.sup.2] was administered in combination with the Roswell Park 5-FU/LV regimen. (3) Patients were required to have Eastern Cooperative Oncology Group performance status (ECOG-PS) 0 to 2 and have radiographically progressive CRC at the time of protocol entry. All had progressed through at least one prior 5-FU and irinotecan-containing regimen. Patients received OXP 85 mg/[m.sup.2] as a two-hour infusion on day 1 of weeks 1, 3, and 5 of an 8-week cycle. 5-FU 500 mg/[m.sup.2] and LV 500 mg/[m.sup.2] were administered on day 1 of weeks 1 through 6 via bolus infusion following oxaliplatin administration. Treatment was planned for four cylces of therapy, or a total duration of 32 weeks. The protocol was approved by the Institutional Review Board of Jewish Hospital/University of Louisville, and all patients gave written informed consent before enrollment. Patients with confirmed progressive disease at any point during the study received no further treatment on the protocol. All patients were followed for survival through May 31, 2001.
Response and Toxicity Analysis
Of the 123 patients accrued, only those receiving at least two eight-week treatment cycles and with adequately documented, measurable and/or evaluable disease evaluable disease Medtalk A condition that cannot be measured directly by tumor size but can be evaluated by other methods specific to a particular clinical trial were eligible for tumor response assessment. All patients were evaluable for treatment-related toxicities. Response evaluation was undertaken with every two cycles of treatment (ie, 16 wk) or at the discretion of the treating physician upon suspicion of disease progression. Responses were recorded per World Health Organization guidelines and toxicities were reported in accordance with National Cancer Institute common toxicity criteria Common Toxicity Criteria (CTC) is a standardised classification of side effects used in assessing drugs for cancer therapy. Most US drug trials base their observations on this system which has a range of grades from 0-5, 5 usually equating to death. Currently version 3. . (20,21)
Of the 123 registered patients, 101 were eligible for response. The remaining 22 patients were removed from the study before completion of the first treatment cycle due to either disease progression or the occurrence of significant treatment-related toxicities which prompted the patients to decline further treatment. Patient and disease characteristics at the time of study enrollment are summarized in Table 1.
The population of heavily pretreated advanced CRC patients included 65 men and 58 women, the majority of whom (92%) had an ECOG ECOG Eastern Cooperative Oncology Group performance status of 0 or 1 at the time of enrollment. The principal metastatic sites in this patient population were the liver, lungs, and bone, in descending order of frequency. Seventy-five percent of patients had an elevated serum CEA CEA carcinoembryonic antigen.
CEA (Carcinoembryonic antigen) level at the time of enrollment.
The grade 3 to 4 toxicity profile of oxaliplatin and concomitant bolus 5-FU/LV in the 123 intent-to-treat patients is presented in Table 2. The most prevalent adverse effects resulting from this treatment schedule were gastrointestinal (GI). Nearly a third (30%) of patients reported grade 3 to 4 diarrhea (9% required hospitalization and dose reduction) and 10% reported grade 3 to 4 vomiting. Although peripheral neuropathy is a known limiting toxicity for oxaliplatin, the most frequent neuropathies observed were grade 1 or 2. (6) Laryngopharyngeal dysesthesias are also frequently encountered in conjunction with oxaliplatin, yet only one patient reported such sensations. The subgroup of patients experiencing grade 3 to 4 GI toxicity was scrutinized for commonalities. No significant correlation was found between toxicity and the patient's history of prior radiotherapy, performance status upon enrollment, or their number of previous chemotherapeutic regimens.
One hundred and one patients were evaluable for objective tumor response (Table 3). An overall response rate of 6.9% was achieved with 7 partial responses of at least 2 months' duration. In addition, there was one minor response lasting 7 months, and 31 patients with disease stabilization. These 31 patients had radiographic radiographic (rā´dēōgraf´ik),
adj relating to the process of radiography, the finished product, or its use. evidence of progression of disease at the time of enrollment and then demonstrated disease stabilization with a median duration of 6.08 months. Seventy-seven of the evaluable patients had serial CEA levels available. Twenty-seven (35%) had a greater than 25% reduction, while seven (9%) achieved greater than 50% CEA reduction.
Patients were assessed for time to progression and overall survival through May 31, 2001 (32 months after the accrual of the first patient and 30 days after the accrual of the last patient). The median time to progression of all evaluable patients was 3.6 months from receiving the first dose of OXP/5-FU/LV. Sixty percent of patients were removed from the study before finishing their second treatment cycle. Of those, 83% were removed due to disease progression; 17% withdrew from the study in response to experiencing significant toxicities, most commonly gastrointestinal. The median overall survival of all patients accrued to the study was 6.5 months.
This analysis of 123 patients with advanced, heavily pretreated colorectal cancer, enrolled into a Sanofi-Synthelabo sponsored compassionate-use program with oxaliplatin with bolus 5-fluorouracil/leucovorin represents the first large scale US experience with this new generation platinum compound. Phase II trials evaluating oxaliplatin either alone or in combination with 5-FU in patients with colorectal cancer have appeared in the European literature European literature refers to the literature of Europe.
European literature includes literature in many languages; among the most important are English literature, Spanish literature, French literature, Polish literature, German literature, Italian literature, Greek since 1993. (22-28) Although phase I testing of oxaliplatin had been performed with various dosing schedules, a consensus emerged recommending either 130 mg/[m.sup.2] every three weeks, or 85 mg/[m.sup.2] every 2 weeks for phase II trials. (23,24) When combined with 5-FU in the relapsed setting, de Gramont et al (25) championed the use of OXP 85 to 100 mg/[m.sup.2] every two weeks, together with biweekly bolus/infusional 5-FU (de Gramont regimen). These authors have reported objective response rates in the range of 20 to 58%, which were significantly higher than the 10% response rate when oxaliplatin was administered as a single agent in this patient population. (24)
In 1999, Brienza et al (15) published a European multi-center compassionate use program experience of oxaliplatin with bolus/infusion 5-FU in 206 5-FU pretreated patients with advanced CRC. The majority of their patient population had received only one (53%) or two (23%) prior chemotherapy regimens and almost all received some form of infusional 5-FU together with oxaliplatin. A response rate of 25.5% in 98 evaluable patients was reported, and although the incidence of grade 3 to 4 hematologic and peripheral neurotoxicity neurotoxicity /neu·ro·tox·ic·i·ty/ (noor?o-tok-sis´it-e) the quality of exerting a destructive or poisonous effect upon nerve tissue. was in line with previously reported European data, a somewhat higher incidence of grade 3 to 4 diarrhea (28% of patients) was noted. Interestingly, despite their improved response rate, the median time to progression in their 98 evaluable patients was 4.1 months, as compared with 3.6 months in our patient population.
Alternatively, Levi et al (26,29) reported the use of oxaliplatin together with 5-FU and leucovorin using a chronomodulated approach, again reporting response rates in the range of 29 to 55%. (27) These response rates are markedly better than those achieved in our patient population (6.9%) using a similar oxaliplatin dose but a bolus-only administration of 5-FU. This difference may in part be secondary to the multiple prior chemotherapeutic regimens that our patient population had received before entering into the oxaliplatin study (89% having received two or more previous regimens), thus reflecting patients with more inherently resistant tumors. In addition, the use of a bolus-only administration of 5-FU rather than a bolus/continuous infusion (de Gramont regimen) or a chronomodulated continuous infusion in conjunction with oxaliplatin may result in a diminished therapeutic efficacy of the combined regimen.
The toxicity profile of oxaliplatin with bolus 5-FU/LV (Roswell Park schedule) in our heavily pretreated population was characterized by significant diarrhea and nausea (grade 3-4 in 30% and 10% of patients, respectively). The former contributed to hospitalization as well as dose reduction for 9% of patients.
European phase II and III studies employing OXP 85 mg/[m.sup.2] together with the de Gramont regimen report grade 3 to 4 diarrhea in only 5 to 12%. However, they do report a higher incidence of neutropenia Neutropenia Definition
Neutropenia is an abnormally low level of neutrophils in the blood. Neutrophils are white blood cells (WBCs) produced in the bone marrow that ingest bacteria. (15-42%) and thromobocytopenia (2.5-7%) as well as peripheral neuropathy (18-28%). (25,28) In light of the comparable oxaliplatin dosing in our patient cohort, we attribute the different toxicity profile to the bolus administration of 5-FU, although the decreased incidence of peripheral neuropathy was unexpected.
Indeed, the controversy between bolus and continuous infusion 5-FU when used as a single agent in advanced colorectal cancer is longstanding in the oncologic literature. (30,31) Although a high response rate and a more favorable toxicity profile versus bolus schedules have been shown with the infusional administration of 5-FU when used as a single agent, this failed to translate into a significant overall survival benefit in a randomized ran·dom·ize
tr.v. ran·dom·ized, ran·dom·iz·ing, ran·dom·iz·es
To make random in arrangement, especially in order to control the variables in an experiment. study of 179 previously untreated patients. (30) In addition, although a metaanalysis of seven randomized trials demonstrated a slight improvement in overall survival in favor of an infusional schedule, this disappeared when studies using leucovorin modulation were included. (31)
With regard to combined OXP/5-FU/LV regimens, European investigators have limited themselves to infusional 5-FU regimens, and no formal randomized comparison exists with oxaliplatin-containing 5-FU bolus-only regimens. Hochster et al (32) have reported preliminary data utilizing oxaliplatin with weekly bolus 5-FU and low-dose leucovorin every 3 of 4 weeks in an ongoing single arm study in newly diagnosed advanced colorectal cancer patients. An objective response rate greater than 50% was reported in that patient population, with nausea and diarrhea being the most pronounced toxicities reported to date (grade 3-4 toxicity in 15% and 22%, respectively). In a phase III setting, de Gramont et al (28) demonstrated a statistically significant improvement in response rate (51% versus 22%, P < 0.001) and median progression-free survival (9.0 versus 6.2 mo, P < 0.001) of oxaliplatin with bolus/infusion 5-FU (de Gramont regimen) and leucovorin as compared with 5-FU/LV alone in the first line treatment of patients with advanced colorectal cancer. However, no improvement in overall survival could be demonstrated (16.2 mo versus 14.7 mo). Although both of these studies revealed improved responses over our experience, our patient population had failed two to five prior treatment modalities, again suggesting an inherently resistant disease process.
We conclude from our experience in 123 heavily pretreated colorectal cancer patients that the combination of oxaliplatin with weekly bolus-only 5-FU and leucovorin has only modest therapeutic benefit. The GI toxicity profile resulting from this dosing schedule is significantly worse than reported with bolus/infusion 5-FU (de Gramont) regimens in conjunction with oxaliplatin, and quite possibly results in lower objective response rate. This study therefore supports the use of the de Gramont regimen, even in the US setting. However, further studies are needed to clarify the optimal dose and scheduling of oxaliplatin and 5-FU in colorectal cancer.
Table 1. Patient and disease characteristics (a) Total Percentage Characteristics (n = 123) (%) Sex Male 65 53 Female 58 47 Race White 115 93 African-American 7 6 Asian 1 1 PS (ECOG) 0-1 113 92 2-3 10 8 Primary tumor Colon 88 72 Rectum 32 26 Pseudomyxoma peritonei 3 2 Metastatic sites Liver only 33 27 Lung only 7 6 Other 5 4 Multiple sites 78 63 Elevated CEA (> 2X the upper normal limit) 92 75 Number of prior chemotherapeutic regimens 1 14 11 2 70 57 3 26 21 4+ 13 11 Prior radiation 24 20 (a) PS (ECOG), Eastern Cooperative Oncology Group performance status; CEA, carcinoembryonic antigen. Table 2. Toxicity (a) Toxicity Grade 3-4 (%) (b) Gastrointestinal Nausea 9.8 Vomiting 10.7 Diarrhea 30.3 Hematological Neutropenia 1.6 Thrombocytopenia 2.5 Peripheral neuropathy 2.5 Dehydration 6.6 Fatigue 4.1 Laryngopharyngeal dysesthesias 0.8 (a) Based on National Cancer Institute common toxicity criteria. (b) n = 123. Table 3. Response to treatment for 101 evaluable patients (a) Antitumor response: patient's best response on study (%) Response TTP in months: CR PR MR SD PD rate (%) mean (min-max) 0 6.9 0.9 30.7 61.4 6.9 3.6 (0.6-11.8) Survival in months: mean CEA (min-max) response (b) (%) 6.5 (0.3-24.5) 35 (a) CR, complete response; PR, partial response; MR, minimal response; SD, stable disease; PD, progressive disease; TTP, time to progression; CEA, carcinoembryonic antigen. (b) CEA response = 25% or greater reduction in serum CEA levels.
Accepted April 7, 2004.
1. American Cancer Society American Cancer Society,
n.pr established in 1913, this national volunteer-based health organization is committed to the elimination of cancer through prevention and treatment and to diminishing cancer suffering through advocacy, scholarship, research, . Cancer facts and figures, 2001. Atlanta, ACS (Asynchronous Communications Server) See network access server. , 2001 (publication no. 5008.01).
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1. inhibiting or preventing development of neoplasms; checking maturation and proliferation of malignant cells.
2. an agent that so acts. activity. Seminars in Oncology 1998;25:Suppl 5:4-12.
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Malignant tumour of the ovaries. Risk factors include early age of first menstruation (before age 12), late onset of menopause (after age 52), absence of pregnancy, presence of specific genetic mutations, use of fertility drugs, and personal history of breast cell line and its use in evaluation of platinum analogues. Cancer Res 1987;47:414-418.
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13. Balconi G, Pang Y, Broggini M, et al. Cis-dichlorodiammineplatinum induced DNA DNA: see nucleic acid.
or deoxyribonucleic acid
One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. interstrand cross-links in primary cultures of human ovarian cancer. Br J Cancer 1971;64:288-292.
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15. Brienza S, Bensmaine M, Soulie P, et al. Oxaliplatin added to 5-FU-based therapy in the treatment of 5-FU-pretreated patients with advanced colorectal carcinoma (ACRC ACRC Advanced Cisco Router Configuration
ACRC Asthma Clinical Research Center
ACRC American Civil Rights Coalition
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tr.v. pro·tract·ed, pro·tract·ing, pro·tracts
1. To draw out or lengthen in time; prolong: disputants who needlessly protracted the negotiations.
2. continuous 5-FU infusion in patients with pretreated advanced colorectal carcinoma. Ann Oncol 2001;12:519-524.
17. Maindrault-Goebel F, Louvet C, Andre T, et al. Oxaliplatin added to the simplified bimonthly bi·month·ly
1. Happening every two months.
2. Happening twice a month; semimonthly.
1. Once every two months.
2. Twice a month; semimonthly.
n. pl. leucovorin and 5-Fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX FOLFOX 5-Fluorouracil, Leucovorin and Oxaliplatin (chemo treatment) 6). Eur J Cancer 1999;35:1338-1342.
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20. WHO handbook for reporting results of cancer treatment. Geneva Geneva, canton and city, Switzerland
Geneva (jənē`və), Fr. Genève, canton (1990 pop. 373,019), 109 sq mi (282 sq km), SW Switzerland, surrounding the southwest tip of the Lake of Geneva. (Switzerland), World Health Organization Offset Publication, 1979, p 48.
21. Cancer Therapy Evaluation Program Common Toxicity Criteria, Version 2.0 DCTC DCTC Denver Center Theatre Company (Denver, CO, USA)
DCTC Developing Communities and Tackling Crime , NCI See Liberate. , NIH "Not invented here." See digispeak.
NIH - The United States National Institutes of Health. , DHHS DHHS Department of Health & Human Services (US government)
DHHS Dana Hills High School (Dana Point, California)
DHHS Deaf and Hard of Hearing Services
DHHS Deaf and Hard of Hearing Services . March 1998.
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Inherent cycle of approximately 24 hours in length that appears to control or initiate various biological processes, including sleep, wakefulness, and digestive and hormonal activity. modulated rate. Eur J Cancer 1993;29A:1280-1284.
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25. Andre T, Bensmaine MA, Louvet C, et al. Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil fluorouracil: see metabolite. infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J Clin Oncol 1999;17:3560-3568.
26. Levi F, Zidani R, Misset JL. Randomized multicenter trial of chronotherapy chron·o·ther·a·py
1. Medical treatment administered according to a schedule that corresponds to a person's daily, monthly, seasonal, or yearly biological clock.
2. with oxaliplatin, fluorouracil, and folinic acid folinic acid /fo·lin·ic ac·id/ (fo-lin´ik) leucovorin; the 5-formyl derivative of tetrahydrofolic acid; it can act as a coenzyme carrier in certain folate-mediated reactions and is used, as the calcium salt leucovorin calcium, in the in metastatic colorectal cancer. Lancet 1997;350:681-686.
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RELATED ARTICLE: Key Points
* Oxaliplatin and bolus 5-FU/leucovorin does exhibit modest benefit in heavily pretreated patients with colorectal cancer.
* Oxaliplatin and bolus 5-FU/leucovorin causes considerable toxicity, primarily gastrointestinal, in the heavily pretreated colorectal cancer patient.
* It appears that the use of a biweekly oxaliplatin with weekly bolus 5-FU/leucovorin regimen in the management of advanced colorectal cancer is considerably more toxic than oxaliplatin/infusional 5-FU regimens, and quite possibly less effective.
Renato V. LaRocca, MD, Shawn D. Glisson, MD, Jeffrey B. Hargis, MD, Rodney E. Kosfeld, MD, Karen E. Leaton, RN, OCN OCN Open College Network
OCN Open Computer Network
OCN Operating Company Number (NANPA)
OCN Oncology Certified Nurse
OCN Of Course Not
OCN Orange County News Channel
OCN Optical Carrier Level N , Rebecca M. Hicks, and Falguni Amin-Zimmerman, MD
From the Kentuckiana Cancer Institute, PLLC, and the Radiation Oncology radiation oncology
The branch of radiology that deals with the use of ionizing radiation to treat cancers.
radiation oncology Department, University of Louisville See also
1. ^ 
2. ^  URL accessed on June 8 2006
3. , James Graham Brown For the cricketer, see .
James Graham Brown (August 18 1881 — March 20 1969) was a businessman and real estate developer best known as the builder of the Brown Hotel in Louisville, Kentucky and for his philanthropy. Cancer Center.
This multicenter phase II/III compassionate use program was funded by Sanofi-Synthelabo.
Reprint requests to Falguni Amin-Zimmerman, MD, Radiation Oncology Department, University of Louisville, James Graham Brown Cancer Center, 529 South Jackson Street, Louisville, KY 40202.