Cancer Chemotherapy Update

Hospital Pharmacy Volume 40, Number 8, pp 662–670, 736 2005 Wolters Kluwer Health, Inc.

Cancer Chemotherapy Update Leucovorin, Fluorouracil, and Oxaliplatin (FOLFOX 6 and 7) Regimens for Colorectal Cancer J. Aubrey Waddell, PharmD, BCOP and Dominic A. Solimando, Jr., M.A., FAPhA, FASHP, BCOP

The increasing complexity of cancer chemotherapy heightens the requirement that pharmacists be familiar with these highly toxic agents. This column will review various issues related to preparation, dispensing, and administration of cancer chemotherapy. It will also serve as a review of various agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr., President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, E-mail: [email protected]; or J. Aubrey Waddell, Director, Oncology Pharmacy Residency Program, Department of Pharmacy, Walter Reed Army Medical Center, 6900 Georgia Avenue NW, Rm 2P02, Washington, DC 20307; E-mail: [email protected]. The opinions or assertions contained herein are the private views of the author and are not to be construed as official or reflecting the views of the US Department of the Army or the Department of Defense.

Regimen Name: FOLFOX 6 and FOLFOX 7 Origin of Name: Acronym for the three drugs in these regimens: leucovorin (FOLinic acid), Fluorouracil, and OXaliplatin. The numbers 6 and 7 indicate these are the sixth and seventh variations of the regimen developed. USES FOLFOX 61-5 and FOLFOX 71,6-7 are used as adjuvant therapy for resectable colorectal cancer1 and as first-line therapy for advanced colorectal cancer.1-4,6 COMMENTS Several versions of FOLFOX, containing varying doses and schedules of leucovorin, fluorouracil, and oxaliplatin, have been studied. FOLFOX 1, 2, 3, 4, 6, and 7 have all been used in the treatment of colorectal cancer.2-9 FOLFOX 4 has been the most widely

662

Volume 40, August 2005

studied, and is the most commonly used FOLFOX regimen. However, use of the more patient-convenient and oxaliplatin-intense, FOLFOX 6 and FOLFOX 7, regimens is growing—both in clinical trials and routine clinical practice. DRUG PREPARATION A. Leucovorin 1. Use leucovorin injection 10 mg/mL or leucovorin powder for injection, 50, 100, 200, or 350 mg. 2. Reconstitute leucovorin powder for injection with bacteriostatic water for injection or 5% dextrose injection to a concentration of 5, 10, or 20 mg/mL. 3. Dilute with 250 to 500 mL 5% dextrose injection. B. Oxaliplatin 1. Follow institutional policies for preparation of hazardous medications when preparing oxaliplatin. 2. Use oxaliplatin powder for injection, 50 or 100 mg. 3. Reconstitute to a final concentration of 5 or 10 mg/mL with sterile water for injection or 5% dextrose injection. 4. Dilute with 250 to 500 mL 5% dextrose injection. 5. Oxaliplatin is incompatible with chloride. Reconstitution or dilution with a chloridecontaining solution must be avoided. 6. Following dilution, oxaliplatin is stable for only 6 hours at room temperature; reconstituted vials and infusion solutions are stable for 24 hours under refrigeration. C. Fluorouracil 1. Follow institutional policies for preparation of hazardous medications when preparing fluorouracil. 2. Use fluorouracil 50 mg/mL injection. 3. IV bolus – dispense in a syringe; or in 50 to 100 mL of 0.9% sodium chloride injection,

Cancer Chemotherapy Update

Table 1. FOLFOX 6 Regimen1–5 Drug

Dose

Route of Administration

Administered on Day(s)

Total Dose/Cycle

Oxaliplatin

100 mg/m2

IV

1

100 mg/m2

Leucovorin

400 mg/m

IV

1

400 mg/m2

Fluorouracil

400 mg/m2

IV

1

400 mg/m2

Fluorouracil

2,400 to 3,000 mg/m

CIVI over 46 hours

1

2,400 to 3,000 mg/m2

2

2

Cycle repeats every 14 days. CIVI = Continuous intravenous infusion IV = Intravenous

Table 2. FOLFOX 7 Regimen1,6,7 Drug

Dose

Route of Administration

Administered on Day(s)

Total Dose/Cycle

Oxaliplatin

130 mg/m2

IV

1

130 mg/m2

Leucovorin

400 mg/m2

IV

1

400 mg/m2

Fluorouracil

2,400 mg/m

CIVI over 46 hours

1

2,400 mg/m2

2

Cycle repeats every 14 days. CIVI = Continuous intravenous infusion IV = Intravenous

5% dextrose injection, or a saline/dextrose solution for injection. 4. Forty-six hour infusion: a. Dilute in 500 to 1,000 mL of 0.9% sodium chloride injection, 5% dextrose injection, or a saline/dextrose solution for injection. b. Dilute to a final volume of 60 to 150 mL with bacteriostatic 0.9% sodium chloride injection, for administration by an ambulatory infusion pump. DRUG ADMINISTRATION A. Leucovorin Infuse over 2 hours, simultaneously with oxaliplatin. B. Oxaliplatin 1. Infuse over 2 hours, simul-

664


taneously with leucovorin. 2. Oxaliplatin is incompatible with chloride. Infusion through a chloride-containing solution must be avoided. 3. Infusion lines should be flushed with 5% dextrose injection before and after oxaliplatin infusion. C. Fluorouracil 1. When leucovorin is used to modulate the activity of the fluorouracil bolus dose, the fluorouracil is usually given after, or at the midpoint, of the leucovorin infusion. 2. The bolus dose may be administered as a slow push (3 to10 min) or short (5 to 15 min) infusion. 3. The continuous infusion is given over 46 hours and

may be administered by ambulatory infusion pumps. 4. In FOLFOX 7, fluorouracil is administered only by 46-hour infusion. SUPPORTIVE CARE A. Acute Emesis Prophylaxis FOLFOX 6 and FOLFOX 7 are predicted to cause acute emesis in 60% to 90% of The studies patients.10,11 reviewed reported vomiting in 14% to 42% of patients2,3 and nausea or vomiting in 39% to 75% of patients.5,7 Appropriate acute emesis prophylaxis will include a serotonin antagonist and a corticosteroid. One of the following regimens is suggested: 1. Ondansetron 24 mg PO and dexamethasone 20 mg


PO, given 30 minutes before FOLFOX 6 or FOLFOX 7 on day-1 only. 2. Granisetron 2 mg PO and dexamethasone 20 mg PO, given 30 minutes before FOLFOX 6 or FOLFOX 7 on day-1 only. 3. Dolasetron 100 mg PO and dexamethasone 20 mg PO, given 30 minutes before FOLFOX 6 or FOLFOX 7 on day-1 only. 4. Palonosetron 0.25 mg IV and dexamethasone 20 mg PO or IV, given 30 minutes before FOLFOX 6 or FOLFOX 7 on day-1 only. Except for patients who receive palonosetron, the antiemetic therapy should continue for at least 3 days. One of the following regimens is suggested: 1. Ondansetron 8 mg twice a day and dexamethasone 4 mg PO twice a day for 3 days, starting on day-2 of FOLFOX 6 or FOLFOX 7. 2. Granisetron 2 mg once a day, or 1 mg twice a day and dexamethasone 4 mg PO twice a day for 3 days, starting on day-2 of FOLFOX 6 or FOLFOX 7. 3. Dolasetron 100 or 200 mg daily and dexamethasone 4 mg PO twice a day for 3 days, starting on day-2 of FOLFOX 6 or FOLFOX 7. 4. Metoclopramide 0.5 mg/kg PO four times a day + diphenhydramine 25 to 50 mg PO every 6 hours and dexamethasone 4 mg PO twice a day for 3 days, starting on day-2 of FOLFOX 6 or FOLFOX 7. 5. Prochlorperazine 10 mg PO every 4 to 6 hours + diphenhydramine 25 to 50 mg PO every 6 hours and dexamethasone 4 mg PO

twice a day for 3 days, starting on day-2 of FOLFOX 6 or FOLFOX 7. 6. Promethazine 25 to 50 mg PO every 6 hours + diphenhydramine 25 to 50 mg PO every 6 hours and dexamethasone 4 mg PO twice a day for 3 days, starting on day-2 of FOLFOX 6 or FOLFOX 7. Although some groups10 recommend use of an NK1 receptor antagonist (eg, aprepitant) as part of the initial antiemetic regimen, this approach has not been universally adopted. An NK1 antagonist may be used for selected FOLFOX 6 or FOLFOX 7 patients.10 If an NK1 antagonist is used, it should be added to one of the serotonin antagonist/steroid regimens listed above. The following regimen is suggested: Aprepitant 125 mg PO, given 30 minutes before day-1 of FOLFOX 6 or FOLFOX 7 (the day-1 dexamethasone dose should be reduced to 12 mg PO or IV), followed by aprepitant 80 mg PO once each day on days 2 and 3 of FOLFOX 6 or FOLFOX 7. B. Breakthrough Antiemetics10 Patients should receive an antiemetic prescription to treat breakthrough nausea. The following regimens are suggested: 1. Metoclopramide 20 to 40 mg PO every 4 to 6 hours as needed, ± diphenhydramine 25 to 50 mg PO every 4 to 6 hours. 2. Prochlorperazine 10 mg PO every 4 to 6 hours as needed, or prochlorperazine 25 mg rectally every 6 hours as needed. 3. Promethazine 25 to 50 mg PO every 6 hours as needed.

C. Hydration No special precautions are required. D. Hypersensitivity Precautions Type I hypersensitivity reactions to platinum compounds are a recognized phenomenon.12 Oxaliplatin is observed to cause these reactions in 3% to 13% of patients,5,13-16 with the incidence of moderate-tosevere reactions ranging from less than 1% to 7%.13-15 Such reactions usually occur during the second or subsequent cycles,14,15 while one study suggests that the reactions most often occur around cycle 9 or 10.14 The most common symptoms are flushing and swelling of the face and hands, itching, sweating, lacrimation, skin rash, hives, rigors, dyspnea, and fever.14-16 For mild reactions, the oxaliplatin infusion is stopped and an antihistamine and a corticosteroid may be administered. Moderate-to-severe reactions usually require administration of parenteral corticosteroids. One report suggests lengthening the oxaliplatin infusion time from 2 to 6 hours reduces the incidence of hypersensitivity reactions and may be appropriate for some patients. Premedication with corticosteroids and antihistamines does not prevent subsequent hypersensitivity reactions.14 E. Hematopoietic Growth Factors Accepted practice guidelines and pharmacoeconomic analysis suggest that an antineoplastic regimen have a greater than 18% to 40% (depending on institutional cost differences) incidence of febrile neutropenia before prophylactic use of colony stimulating factors is warranted.17-19 Since febrile

Hospital Pharmacy

665


neutropenia was reported in 0% to 5% of patients in the trials of FOLFOX 6 and FOLFOX 7, prophylactic use of colony stimulating factors is not recommended.2,3,5,7 Colony stimulating factors may be considered if a patient experiences febrile neutropenia or grade 4 neutropenia in a prior cycle of FOLFOX 6 or FOLFOX 7. F. Extravasation No special precautions are required.20 G. Diarrhea Diarrhea is a frequent consequence of IV bolus or protracted venous infusion fluorouracil, but it is uncommon for the diarrhea to be severe or dose-limiting. Patients should receive a prescription for an antidiarrheal agent for use at the onset of diarrhea. The standard recommendation is loperamide 4 mg PO at onset of diarrhea, followed by 2 mg PO every 4 hours or after each unformed stool. Patients should be counseled to:21 1. Monitor their bowel movements. 2. Self-treat grade 1 or 2 diarrhea (increase of less than seven stools per day or nocturnal stools) with loperamide and oral rehydration. 3. Seek immediate advice from their physician, pharmacist, or nurse for persistent (greater than 24 hrs) grade 1, 2, or 3 diarrhea (increase of greater than or equal to seven stools per day or incontinence or symptoms of dehydration). H. Neurotoxicity Oxaliplatin causes acute neurotoxicity consisting of coldinduced, or exacerbated, pares-

668


thesias/ dysesthesias and muscle contractions. It also causes chronic neurotoxicity that can impair quality of life. Preclinical data suggest the acute neurotoxicity may be due to oxaliplatin’s effects on voltagedependent sodium channels and/or chelation of intracellular calcium by the oxaliplatin metabolite, oxalate.22 Intravenous infusion of 1 gram each of calcium gluconate and magnesium sulfate before and after the oxaliplatin infusion has been reported to significantly reduce the incidence of acute neurotoxicity.23 MAJOR TOXICITIES Most of the toxicities listed below are presented according to their degree of severity. Higher grades represent more severe toxicities. Although there are several grading systems for cancer chemotherapy toxicities, all are similar. One of the frequently used systems is the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (see http://ctep.info.nih.gov). Oncologists generally do not adjust doses or change therapy for grade 1 or 2 toxicities; but make or consider dosage reductions or therapy changes for grade 3 or 4 toxicities. A. FOLFOX 6 1. Allergic Reactions: (grade 3) 3%.5 2. Cardiovascular: Congestive heart failure 1%;3 pulmonary embolism 1%.3 3. Constitutional: Fatigue (grade 1) 9% to 17%,3 (grade 2) 5% to 22%,2,3 (grade 3) 3% to 5%.2,3 4. Dermatologic: Alopecia (grade 1) 13% to 37%,3,5 (grade 2) 7% to 9%;3,5 cutaneous toxicity (grade

1) 17% to 21%,3 (grade 2) 2% to 5%,3 (grade 3) 1% to 2%;3 hand-foot syndrome (grade 1) 25%,5 (grade 2) 12%,5 (grade 3) 3%,5 (grade 1 or 2) 8%,4 (grade 3 or 4) 1%.4 5. Gastrointestinal: Diarrhea (grade 1) 22% to 28%,3,5 (grade 2) 7% to 22%,2,3,5 (grade 3) 4% to 11%,2,3,5 (grade 4) 1% to 2%,3 (grade 1 or 2) 41%,4 (grade 3 or 4) 6%;4 mucositis (grade 1) 20% to 35%,3,5 (grade 2) 10% to 12%,2,3,5 (grade 3) 5%;2,5 nausea (grade 1) 37% to 39%,3 (grade 2) 10% to 25%,2,3 (grade 3) 3% to 6%,2,3 (grade 1 or 2) 56%,4 (grade 3 or 4) 2%;4 nausea and/or vomiting (grade 1) 40%,5 (grade 2) 28%,5 (grade 3) 7%;5 vomiting (grade 1) 17% to 22%,3 (grade 2) 11% to 17%,2,3 (grade 3) 3% to 4%,2,3 (grade 4) 1%,3 (grade 1 or 2) 29%,4 (grade 3 or 4) 1%.4 6. Hematologic: Anemia (grade 1) 15% to 39%,3,5 (grade 2) 5% to 12%,3,5 (grade 3) 2% to 3%,3 (grade 4) 1%;3 febrile neutropenia 1% to 5%;2,3 neutropenia (grade 1) 5% to 18%,3,5 (grade 2) 14% to 30%,2,3,5 (grade 3) 15% to 31%,2,3,5 (grade 4) 2% to 13%,3,5 (grade 1 or 2) 16%,4 (grade 3 or 4), 44%;4 thrombocytopenia (grade 1) 29% to 59%,3,5 (grade 2) 9% to 29%,2,3,5 (grade 3) 2% to 7%,2,5 (grade 1 or 2) 43%, (grade 3 or 4) 5%.4 7. Neurotoxicity: Any (grade 1) 26% to 45%,3 (grade 2) 29% to 37%,2,3 (grade 3) 20% to 34%.2,3 (grade 1 or


2) 12%,4 (grade 3 or 4) 7%;4 paresthesia (grade 1 or 2) 40%,4 (grade 3 or 4) 6%;4 sensory neuropathy (grade 1) 42%,5 (grade 2) 25%,5 (grade 3) 16%.5 Tournigand et al reported that 13% of grade 3 neurotoxicity patients recovered within 1 month and 31% recovered within 3 Maindraultmonths.3 Goebel et al reported that functional neurologic impairment disappeared in 71% of affected patients 2 to 5 months after oxaliplatin withdrawal.5 8. Treatment-Related Deaths: Hematologic toxicity 1%.3 B. FOLFOX 7 1. Dermatologic: Alopecia (grade 1) 34%;7 hand-foot syndrome (grade 1) 19%,7 (grade 2) 4%,7 (grade 3) 2%.7 2. Gastrointestinal: Diarrhea (grade 1) 53%,7 (grade 2) 13%,7 (grade 3) 11%,7 (grade 3 or 4) 12%;6 mucositis (grade 3 or 4) 7%;6 nausea (grade 3 or 4) 10%;6 nausea and/or vomiting (grade 1) 53%,7 (grade 2) 28%,7 (grade 3) 2%;7 stomatitis (grade 1) 22%,7 (grade 2) 2%.7 4. Hematologic: Anemia (grade 1) 60%,7 (grade 2) 13%;7 neutropenia (grade 1) 32%,7 (grade 2) 15%,7 (grade 3) 11%,7 (grade 4) 2%,7 (grade 3 or 4) 22%;6 thrombocytopenia (grade 1) 49%,7 (grade 2) 11%,7 (grade 3) 11%,7 (grade 3 or 4) 11%.6 5. Neurotoxicity: Any (grade 1) 79%,7 (grade 2) 22%,7 (grade 3 or 4) 14%.6

PRETREATMENT LABORATORY STUDIES NEEDED A. AST/ALT B. Total bilirubin C. Serum creatinine D. CBC with differential RECOMMENDED PRETREATMENT VALUES The minimally acceptable pretreatment CBC values required to begin a cycle of FOLFOX 6 or FOLFOX 7 with full-dose therapy in the protocols reviewed were: A. Absolute neutrophil count (ANC) greater than or equal to 1,500 cells/mcL.2,3,5,7 B. Platelet count greater than or equal to 100,000 cells/mcL.2,3,5,7 C. In clinical practice, a pretreatment ANC of 1,000 cells/mcL and platelet count of 75,000 cells/mcL are usually considered acceptable. DOSAGE MODIFICATIONS A. Renal Function 1. Oxaliplatin a. If CrCL less than or equal to 19 mL/min, consider omitting the drug or changing to another regimen.24 B. Liver Function 1. Oxaliplatin a. Dosage adjustments for elevated AST, ALT, and total bilirubin are not required, but regular assessments of liver function to monitor for oxaliplatin-induced hepatic injury are advised.25,26 2. Fluorouracil a. If total bilirubin greater than 5 mg/dL, omit the drug.27 C. Myelosuppression 1. FOLFOX 6 a. Goldstein et al omitted the fluorouracil bolus

dose from subsequent cycles for ANC less than 500 cells/mcL, platelets less than 50,000 cells/mcL, an episode of febrile neutropenia, or a 1- to 3week treatment delay due to prolonged ANC or platelet recovery. Treatment was then restarted when ANC greater than or equal to 1,500 cells/mcL, platelets greater than or equal to 100,000 cells/mcL, and febrile neutropenia resolved. On the second occurrence of any of these events, the fluorouracil continuous infusion dose was reduced to 2,000 mg/m2 for subsequent cycles. On the third occurrence of any of these events, the oxaliplatin dose was reduced to 75 mg/m2 for subsequent cycles. On the fourth occurrence of any of these events, treatment was discontinued.2 b. Tournigand et al reduced the fluorouracil continuous infusion dose from 3,000 mg/m2 to 2,400 mg/m2 or from 2,400 mg/m2 to 2,000 mg/m2 for any related grade 3 toxicity. Oxaliplatin dose was reduced to 75 mg/m2 for grade 4 neutropenia or grade 3 or 4 thrombocytopenia. c. For thrombocytopenia or neutropenia greater than or equal to grade 2, Maindrault-Goebel et al reduced the oxali-

Hospital Pharmacy

669


platin dose to 75 mg/m2 and the fluorouracil continuous infusion dose from 3,000 mg/m2 to 2,400 mg/m2 or from 2,400 mg/m2 to 2,000 mg/m2. 2. FOLFOX 7 a. For any greater than or equal to grade 3 hematologic toxicity, Taieb et al delayed the next treatment cycle until recovery and reduced the oxaliplatin dose to 100 mg/m2 for subsequent cycles.7 D. Neurotoxicity 1. FOLFOX 6 a. For grade 2 or 3 neurosensory toxicity, Goldstein et al withheld treatment until symptoms resolved and then restarted treatment with the oxaliplatin dose reduced to 75 mg/m2. If symptoms recurred, oxaliplatin was again withheld until resolution and then restarted at a dose of 50 mg/m2. If symptoms recurred again or persisted after a dose delay of greater than 2 weeks, treatment was discontinued. If pseudo-laryngopharyngeal dysesthesia occurred, subsequent doses of oxaliplatin were administered as a 6-hour infusion.2 b. Tournigand et al reduced the oxaliplatin to 75 mg/m2 for grade 2 paresthesia, then further reduced the oxaliplatin dose to 50 mg/m2 if the paresthe-

670


sia persisted. For persistent painful paresthesia or grade 3 neurotoxicity, oxaliplatin was omitted from the regimen.3 c. Maindrault-Goebel et al discontinued oxaliplatin from the regimen for persistent painful or function impairing neurological toxicity greater than or equal to grade 2.5 2. FOLFOX 7 a. Taieb et al discontinued oxaliplatin for greater than or equal to grade 3 sensory peripheral neuropathy.7 E. Other 1. FOLFOX 6 a. Tournigand et al reduced the oxaliplatin dose to 75 mg/m2 for grade 4 diarrhea.3 b. For any nonhematologic or nonneurologic toxicity greater than or equal to grade 3, Maindrault-Goebel et al reduced the oxaliplatin dose to 75 mg/m2 and the fluorouracil continuous infusion dose from 3,000 mg/m2 to 2,400 mg/m2 or from 2,400 mg/m2 to 2,000 mg/m2. 2. FOLFOX 7 a. For any greater than or equal to grade 3 nonhematologic or nonneurologic toxicity, Taieb et al delayed the next treatment cycle until recovery and reduced the oxaliplatin dose to 100 mg/m2 for subsequent cycles.7

REFERENCES 1. National Comprehensive Cancer Network. NCCN colon cancer practice guidelines v.3.2005. Available at:www.nccn.org. Accessed on June 1, 2005. 2. Goldstein D, Mitchell P, Michael M, et al. Australian experience of a modified schedule of FOLFOX with high activity and tolerability and improved convenience in untreated metastatic colorectal cancer patients. Br J Cancer. 2005;92:832–837. 3. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22:229–237. 4. Ducreux M, Adenis A, Bennouna J, et al. Phase III, randomized, open-label study of capecitabine (X) plus oxaliplatin (XELOX) vs. infusional 5-FU/LV plus oxaliplatin (FOLFOX-6) first-line treatment in patients (pts) with metastatic colorectal cancer (MCRC): findings from an interim safety analysis. Abstract 3596 presented at: 2005 ASCO Annual Meeting; May 14-17, 2005. Orlando, Fl. 5. Maindrault-Goebel F, Louvet C, Andre T, et al. Oxaliplatin added to the simplified bimonthly leucovorin and 5fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX 6). Eur J Cancer. 1999; 35:1338-1342. 6. De Gramont A, Cervantes A, Andre T, et al. OPTIMOX study: FOLFOX 7/LV5FU2 compared to FOLFOX 4 in patients with advanced colorectal cancer. J Clin Oncol. 2005:22(suppl 3525): 1209–1214. 7. Taieb J, Artru P, Paye F, et al. Intensive systemic chemotherapy combined with surgery for metastatic colorectal cancer: results of a phase II study. J Clin Oncol. 2005;23:502–509. 8. de Gramont A, Tournigand C, Louvet C, et al. Oxaliplatin, folinic acid, and 5-fluorouracil (folfox) in pretreated patients with metastatic advanced cancer. The GERCOD. Rev Med Interne. 1997;18:769–775. 9. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with and without oxaliplatin as first-line

continued on page 736