This article is more than 5 years old. Information may no longer be current.
Validating keratinocyte growth factor for alleviating oral mucositis
More data are needed before physicians can justify the costly and inconveniently administered agent.
Mucositis is a significant complication of chemotherapy and radiation therapy. Patients at highest risk for mucositis include those undergoing therapy for head and neck cancers, acute leukemias and patients receiving hematopoietic stem cell transplants. Irritation and ulceration of the mouth and throat can result in significant pain and suffering, increased risk of infection and inability to eat or take oral medications. Unfortunately, therapies to treat mucositis are limited to pain relief, prevention or treatment of secondary infections, and treatment of dehydration and malnutrition.
Effective therapies for the prevention of mucositis are even more limited. Specialized low-level laser therapy has been shown to reduce the incidence of mucositis in patients who received hematopoietic stem cell transplants (HSCT), but this therapy is not widely available. Cryotherapy is intended to reduce chemotherapy concentration in mouth tissue by having the patient hold ice chips in the mouth before, during and after drug administration. This technique has been reported effective in patients receiving fluorouracil (by bolus administration) and melphalan. Both of these agents have fairly short elimination half-lives (about 60 to 90 minutes) that make this technique feasible.
Novel therapy
Palifermin (Kepivance, Amgen), the first available keratinocyte growth factor, was approved by the FDA for use in reducing the incidence and duration of severe mucositis in patients with hematopoietic malignancies receiving myelotoxic therapy and requiring stem cell support. The approval was based on a phase-3 trial in 212 patients receiving a HSCT regimen (total body irradiation/etoposide/cyclophosphamide) that usually causes a high degree of mucositis. Despite a statistically significant difference in the incidence and duration of grade-3 or -4 mucositis, most patients (.60%) treated with palifermin still had severe mucositis, and the rest of the patients had less severe mucositis. Although there is the possibility of reduced but not eliminated costs of opioids and parenteral nutrition, palifermin continues to be an extremely expensive medication.
 Lisa K. Lohr |
Stiff and colleagues have published an additional review of the data of the original palifermin trial, documenting the effect of the drug on patients’ subjective reports of mucositis and validating their patient self-assessment tool.
Preventing 5-FU mucositis
Another group of researchers recently published data from a study of palifermin in the prevention of mucositis in patients with colorectal cancer receiving bolus fluorouracil chemotherapy. This group enrolled 65 patients with advanced, Duke’s Stage D colorectal cancer and randomized them to receive placebo (n=36) or 40 mg/kg daily of IV palifermin (n=28) for three days before each of two cycles of chemotherapy. All patients received the same chemotherapy regimen: IV leucovorin (20 mg/m2/day daily for five days) followed by IV bolus fluorouracil (425 mg/m2 daily for five days) every 28 days. Mucositis was evaluated with the five-point WHO scale and diarrhea was graded according to the NCI Common Toxicity Criteria on days one, four, eight, 12, 15 and 28. Results from this trial are shown in the table.
Although there were small reductions in the more serious grade-3 mucositis (oral ulcers, inability to tolerate solid food), the greatest effect of palifermin was in reducing the less serious grade-2 mucositis (erythema and ulcers, with the ability to eat solid food).
A more important parameter for this type of agent is the avoidance of grade-3 or -4 mucositis. From the data presented in this trial, either the palifermin effect is small or the study was underpowered to detect these differences. From the data reported, 11% of patients developed grade-3 or -4 mucositis without treatment, but with palifermin 4% of patients developed it. Thus, if 100 patients were treated with palifermin only seven would actually be protected from grade-3 or -4 mucositis. Since this is an extremely expensive medication that would require additional clinic visits for IV administration, the cost-effectiveness must be considered very carefully.
There were no statistically significant differences in the incidence of grade-2 or higher diarrhea. Overall, palifermin was well tolerated, with a modest increase in the frequency of oral-related adverse events, as well as transient increases in the amylase and lipase levels.
|
|
Palifermin and chemotherapy
In addition, consideration should be paid to the context of this study and the applicability to current practice. Patients with advanced, metastatic, Duke’s D colorectal cancer were treated with a five-day bolus fluorouracil chemotherapy regimen.
The current accepted chemotherapy regimens for this disease include fluorouracil, leucovorin and oxaliplatin (FOLFOX); fluorouracil, leucovorin and irinotecan (Camptosar, Pfizer; collectively, FOLFIRI); and cetuximab (Erbitux; ImClone, Bristol-Myers Squibb) with oxaliplatin and capecitabine (Xeloda, Roche; collectively, CAPOX). The fluorouracil in the FOLFOX and FOLFIRI regimens is administered by bolus and continuous infusion for 48 hours. The capecitabine in the CAPOX regimen is administered twice daily for 14 days. Since palifermin was not studied with any of these chemotherapy regimens, it is not known whether there would be any beneficial effect to this costly treatment.
In summary, palifermin is a unique agent that has been highly touted to help prevent mucositis from cancer treatments. Unfortunately, much of the promise of this very costly and inconveniently administered agent has yet to be demonstrated. A careful cost-benefit analysis should be undertaken before it is used.
For more information:
- Lisa K. Lohr, PharmD, BCPS, is a Clinical Pharmacy Specialist in Oncology at Fairview University Medical Center in Minneapolis and is the section editor for Pharmacology in Hem/Onc Today’s Editorial Board.
- Rosen LS, Abdi E, Davis ID, et al. Palifermin reduces the incidence of oral mucositis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy. J Clin Oncol. 2006;24:10.1200/JCO.2005.04.1152.
- Stiff PJ, Emmanouilides C, Bensinger WI, et al. Palifermin reduces patient-reported mouth and throat soreness and improves patient functioning in the hematopoietic stem-cell transplantation setting. J Clin Oncol. 2006;24:10.1200/JCO.2005.02.8340.
- Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med. 2004;351:2590-2598.