Faster FOLFOX: Oxaliplatin Can Be Safely Infused at a Rate of 1 mg/m²/min

Abstract

Purpose:

Oxaliplatin at a dose of 85 mg/m² traditionally has been administered over 120 min in the standard FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) regimen. CapeOx (capecitabine plus oxaliplatin), in which the dose of oxaliplatin is 130 mg/m², has also been infused over 120 min. Maintenance of a prolonged infusion time has been largely based on the concern for a potential hypersensitivity reaction (HSR) if administered too quickly.

Methods:

We first performed a retrospective review of our institutional experience to assess whether HSR rates were similar in FOLFOX and CapeOx by using computerized pharmacy records between January 1, 2011, and December 31, 2013. We then instituted a new policy to infuse all nonresearch doses of oxaliplatin at a set rate of 1 mg/m²/min (85 mg/m² given over 85 min; 68 mg/m² over 68 min, etc). The incidence of HSRs with the new infusion rate was actively monitored.

Results:

Of 2,097 patients who previously received oxaliplatin over 120 min, 1,936 received a dose of 85 mg/m² (± 10%), and 161 received a dose of 130 mg/m². The incidence of HSRs in the 85 mg/m² group was 11% versus 7% in the 130 mg/m² group (P = .13). Then between December 1, 2014, and June 4, 2015, 667 patients received oxaliplatin at a rate of 1 mg/m²/min for all doses. The incidence of HSRs in patients treated at this fixed infusion rate was 8%.

Conclusion:

Infusing oxaliplatin at a rate of 1 mg/m²/min does not increase the rate of HSRs and does not compromise patient safety. This infusion rate is safe for use in routine practice.

INTRODUCTION

Oxaliplatin is a third-generation platinum compound that has efficacy in colorectal cancer as well as other gastrointestinal tumors, including gastroesophageal, biliary and pancreatic, and ovarian cancers.^1-3 Similar to other platinum compounds, oxaliplatin interacts with DNA to form intra- and interstrand DNA cross linking that can affect DNA base pairing, replication, and gene transcription and cause cell death.⁴ The drug has a number of adverse effects, but the most common associated with discontinuation are cold-sensitive, dysesthesia, and peripheral neurotoxicities. Oxaliplatin, like other platinum compounds, can cause hypersensitivity reactions (HSRs) that often are unpredictable but are typically associated with repeat exposure. The reactions usually are not severe; < 1% of allergic reactions are life threatening.⁵ Typically, the reactions are characterized by pruritus and erythema but can also include dyspnea, wheezing, chest discomfort, hypoxia, hypotension, and anaphylaxis.

Oxaliplatin at a dose of 85 mg/m² is administered over 120 min in the standard FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) regimen. An alternative regimen is CapeOx (capecitabine plus oxaliplatin) in which the dose of oxaliplatin is 130 mg/m², also infused over the same 120-min interval. Clinicians have hesitated to shorten the length of oxaliplatin infusions largely based on concern for HSRs if infused too quickly. In the CapeOx regimen, the standard infusion rate of the drug is approximately 50% faster, yet studies have not reported higher rates of infusion reactions with the CapeOx regimen compared with FOLFOX dosed at 85 mg/m².^6,7 Shortening oxaliplatin infusion duration would shorten overall treatment time, decompress crowded chemotherapy units, and improve patient satisfaction.

We postulated that the incidence and severity of oxaliplatin infusion reactions would not be substantially different based on different infusion times at our institution. To evaluate this, we retrospectively examined the incidence of HSRs to oxaliplatin in 2,097 unique patients who had previously received oxaliplatin over 120 min. Of these, 1,936 received a dose of 85 mg/m² (± 10%), and 161 received a dose of 130 mg/m². Our plan was to implement a pilot program that used the faster infusion rate for all oxaliplatin treatments if no contraindications were identified in the retrospective review. We report the results of these investigations.

METHODS

For the initial part of the analyses, we obtained institutional review board approval to review records of all patients who received oxaliplatin at Memorial Sloan Kettering Cancer Center (MSKCC) between January 1, 2011, and December 31, 2013. These records were identified through computerized pharmacy records. The pharmacy’s institutional adverse drug reporting program was used to identify all HSRs. The number of HSRs were described by relative frequency tables and then analyzed by χ² test. Subsequently, in a second analysis based on the initial results, we established an institutional quality improvement project in which all patients received oxaliplatin at an infusion rate of 1 mg/m²/min. The original institutional review board waiver was amended to review charts of patients who received oxaliplatin at an infusion rate of 1 mg/m²/min for an additional 6 months through June 30, 2015.

HSRs were prospectively reported and recorded but graded retrospectively according to Common Terminology Criteria for Adverse Events (version 4.0).⁸ Criteria for categorizing mild, moderate, and severe reactions were those used by the MSKCC in-house reporting system, which are defined as follows: A mild reaction resolves with no medications administered, with no harm caused to the patient; a moderate reaction resolves with the administration of prescription medications, with no harm caused to the patient; and a severe reaction is the occurrence of severe bronchospasm or hypotension, hypoxia (oxygen saturation ≤ 89%), use of epinephrine, a situation the physician believes to be serious or potentially life threatening, and/or a reaction that contributes to permanent disability or death (Table 1).

Table 1.

Common Terminology Criteria for Adverse Events (version 4.0) Infusion-Related Reactions

Adverse Event	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Infusion-related reaction	Mild transient reaction; infusion interruption not indicated; intervention not indicated	Therapy or infusion interruption indicated but responds promptly to symptomatic treatment (eg, antihistamines, NSAIDs, narcotics, IV fluids); prophylactic medication indicated for ≤ 24 h	Prolonged (ie, not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms after initial improvement; hospitalization indicated for other clinical sequelae	Life-threatening consequences; urgent intervention indicated	Death

Abbreviations: IV, intravenous; NSAIDs, nonsteroidal anti-inflammatory drugs.

RESULTS

We identified 2,097 unique patients who had previously received oxaliplatin over 120 min. Of these, 1,936 received a dose of 85 mg/m² (± 10%), and 161 received a dose of 130 mg/m². Figure 1 represents the incidence of HSRs in these groups. Eleven (7%) of 161 patients experienced an HSR at 130 mg/m², and 213 (11%) of 1,936 patients experienced an HSR at 85 mg/m². This difference was not statistically significant (P = .11, χ² test; Appendix Table A1, online only).

FIG 1.

Incidence of hypersensitivity reactions (HSRs) from oxaliplatin administered over 120 min.

Because we did not find a significant difference in the rate of HSRs between the two doses, with the higher dose having a 1.5-fold faster infusion, we concluded that oxaliplatin could be safely infused at an accelerated rate. For simplicity, we rounded 130 mg/m² over 120 min to a rate of 1 mg/m²/min. Then between December 1, 2014, and June 4, 2015, 667 unique patients received oxaliplatin, with all doses given at a rate of 1 mg/m²/min. The incidence of HSRs was 8%. The majority of HSRs (70%) were grade 2. The incidence of grade 1, 3, and 4 HSRs was 5%, 21%, and 4%, respectively (Table 2).

Table 2.

Incidence of Grades of Oxaliplatin HSRs in 85 mg/m², 130 mg/m², and Universal Rate of 1 mg/m²

	Oxaliplatin Infusion, No. (%)
HSR	85 mg/m2 (n = 1,936)	130 mg/m2 (n = 161)	1 mg/m2 (n = 667)
Total incidence of HSRs	213 (11)	11 (7)	53 (8)
Grade 1	1 (0.05)	0 (0)	3 (5)
Grade 2	194 (10)	10 (6)	37 (70)
Grade 3	16 (0.8)	1 (0.6)	11 (21)
Grade 4	0 (0)	0 (0)	2 (4)

Abbreviation: HSR, hypersensitivity reaction.

DISCUSSION

Oxaliplatin is widely used for the treatment of many types of malignancies and is particularly used in gastrointestinal malignancies in both the metastatic and the adjuvant setting. The infusion rates of most drugs are usually set empirically before the start of phase I studies. Once set, they often are not revisited and so are maintained through phase II and III studies, then onto the product label, and then into clinical practice. Such was the case for oxaliplatin. On the basis of the initial studies from the early clinical development of oxaliplatin, the infusion rate of 85 mg/m² was initially set, somewhat arbitrarily, at 120 min. When capecitabine was subsequently studied in combination with oxaliplatin at 130 mg/m² every 3 weeks, oxaliplatin was still infused over 120 min despite that the dose was roughly 50% higher. Thus, patients who received the 130 mg/m² dose over 120 min received it at a rate roughly 1.5 times faster than those who received a 85 mg/m² dose over the same time interval.

In the MOSAIC (Adjuvant Treatment of Colon Cancer) trial, in which > 1,100 patients received oxaliplatin at 85 mg/m², the reported incidence of HSRs was 10.3%.⁹ In the large phase III adjuvant trial of capecitabine plus oxaliplatin, the HSR rate did not reach the threshold for toxicity reporting and, thus, was not a factor of clinical concern.^6,7

In our 6-month pilot, 667 unique patients received oxaliplatin at the standard infusion rate of 1 mg/m²/min. Thus, standard 85 mg/m² doses were given over 85 min; if a dose reduction to 68 mg/m² was used, it was infused over 68 min. The total rate of HSRs was not different from that seen during the previous time period when the standard, longer (120-min) infusion rates were used. The shorter infusions times, of course, led to shorter treatment times in the chemotherapy suite.

The data are strengthened by the fact that this was a prospective pilot study during which vigilance for the presence of even mild HSRs was high. Computerized pharmacy records were used to capture all patients treated with oxaliplatin during the 6-month study period, and medical records of all patients treated with oxaliplatin during that time were reviewed for any grade of HSR reported.

In summary, the data strongly indicate that the established standard practice of a 120-min infusion for oxaliplatin is unnecessary and that a change to 1 mg/m²/min does not compromise patient safety. This faster infusion rate has been established as standard practice at MSKCC, and at the time of this writing, it has been used for > 6 months, with careful safety monitoring. We have noted no compromise in patient safety. Widespread use of a faster infusion time, and thus decreased treatment time, would improve patient satisfaction as well as allow for treatment of more patients due to shorter occupancy of chemotherapy chairs and lower associated costs.

Appendix

Table A1.

Incidence of HSRs in Oxaliplatin Administered Over 120 Min

	Oxaliplatin Infusion (Over 120 Min), No. (%)
	85 mg/m2 (n = 1,936)	130 mg/m2 (n = 161)
Incidence of HSRs	213 (11)	11 (7)

Abbreviation: HSR, hypersensitivity reaction.

AUTHOR CONTRIBUTIONS

Conception and design: Andrea Cercek, Leonard B. Saltz

Collection and assembly of data: Andrea Cercek, Vivian Park, Leonard B. Saltz

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Faster FOLFOX: Oxaliplatin Can Be Safely Infused at a Rate of 1 mg/m²/min

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or jop.ascopubs.org/site/misc/ifc.xhtml.

Andrea Cercek

Consulting or Advisory Role: Bayer, Baxter

Research Funding: Bayer

Vivian Park

No relationship to disclose

Rona Yaeger

Consulting or Advisory Role: GlaxoSmithKline

Research Funding: Genentech (Inst), Novartis (Inst), GlaxoSmithKline (Inst)

Diane Reidy-Lagunes

Honoraria: Novartis

Consulting or Advisory Role: Ipsen, Pfizer, Novartis

Research Funding: Novartis

Nancy E. Kemeny

No relationship to disclose

Zsofia K. Stadler

Stock or Other Ownership: Alimera Sciences (I), Avalanche Biotechnologies (I)

Consulting or Advisory Role: Alimera Sciences (I), Avalanche Biotechnologies (I), Allergan (I), Bausch & Lomb (I), Genentech (I), Regeneron (I), Optos (I)

Neil H. Segal

Honoraria: MedImmune

Consulting or Advisory Role: Bristol-Myers Squibb, Pfizer, AstraZeneca, MedImmune, MacroGenics, Imugene, Kymab, Amgen, Calithera Biosciences

Research Funding: MedImmune, Bristol-Myers Squibb, Pfizer, Genentech, Merck

Anna Varghese

No relationship to disclose

Leonard B. Saltz

Consulting or Advisory Role: Genentech, Eli Lilly, McNeil-PPC (I), AbbVie

Research Funding: Taiho Pharmaceutical