Source: www.medscape.com
Author: Nick Mulcahy

In its first issuance since 2002, the American Society of Clinical Oncology (ASCO) has released an updated guideline on the use of protectants for chemotherapy and radiation therapy. The update provides new guidance on the use of palifermin, the only new protectant approved by the US Food and Drug Administration since 2002, as well as new or deleted recommendations for amifostine and dexrazoxane.

The updated guideline, published online November 17 in the Journal of Clinical Oncology, also addresses the concern that protectant agents could compromise tumor response and survival.

Palifermin, a recombinant keratinocyte growth factor, was approved for prophylaxis against severe mucositis associated with hematopoietic stem-cell transplantation in hematologic malignancies. It represents “an advance for the field,” write the guideline authors, cochaired by Martee L Hensley, MD, from Memorial Sloan-Kettering Cancer Center, in New York City, and Lynn M. Schuchter, MD, from the University of Pennsylvania, in Philadelphia.

Because of the growing body of evidence on amifostine use in the prevention of esophagitis, the ASCO panel of experts decided to add a new section on this topic in the chemoradiotherapy setting for non–small-cell lung cancer. Updates on amifostine also include guidance on its use for both chemotherapy and radiation-therapy toxicities.

With regard to dexrazoxane, the panel made only 1 change from the previous guidelines: guidance on its use in patients receiving high-dose anthracycline therapy has been deleted because of insufficient data. However, the panel highlighted its previous and ongoing recommendation that this agent not be used routinely in either the adjuvant or metastatic settings with initial doxorubicin-based chemotherapy.

The literature review on which the guidelines are based identified 744 potential randomized controlled trials. In the end, only 39 reports met the inclusion criteria and underwent data extraction. The majority of the reports (33) were for amifostine.

Using Palifermin to Prevent Oral Mucositis
According to the guideline, palifermin “is recommended to decrease severe mucositis in autologous stem-cell transplantation for hematologic malignancies with total-body irradiation-conditioning regimens.” The guideline recommends that clinicians “consider” the drug for patients undergoing myeloablative allogeneic stem-cell transplantation with total-body irradiation-conditioning regimens. However, the guideline stops short of recommending prophylactic use of this agent in the non–stem-cell transplantation setting because of insufficient evidence.

Mucositis is a new topic for the guideline. Considered by patients to be the worst complication of stem-cell transplantation, oral mucositis is characterized by mouth and oropharyngeal pain and impaired swallowing.

Oral mucositis is a frequent complication of both high-dose chemotherapy and radiation therapy, notes the guideline. In its least severe form, related mucosal erythema and ulceration are associated with few or no symptoms. However, oral mucositis can be severe enough to cause significant mucosal bleeding or tissue inflammation and edema that requires endotracheal intubation to protect a compromised airway. Palliation of pain generally requires intravenous narcotics.

An Array of Considerations Regarding Amifostine
As the protectant agent with the most studies reviewed by the panel, amifostine understandably has the most updates in the new guideline.

Amifostine can be considered for prevention of cisplatin-associated nephrotoxicity, reduction of grade 3 or 4 neutropenia, and to decrease acute and late xerostomia with fractionated radiation therapy alone for head and neck cancer, according to the guideline. However, with regard to reducing neutropenia, the authors note that clinicians can “reasonably” consider alternatives, such as using myeloid growth factor or reducing chemotherapy dose.

Furthermore, the panel does not recommend amifostine — either because of insufficient evidence or because of negative results — for “protection against thrombocytopenia, prevention of platinum-associated neurotoxicity or ototoxicity or paclitaxel-associated neuropathy, prevention of radiation-therapy–associated mucositis in head and neck cancer, or prevention of esophagitis during concurrent chemoradiotherapy for non–small-cell lung cancer.”

Recommendations on Dexrazoxane Largely Unchanged
Although continuing its previous recommendation that dexrazoxane not be used routinely in either the adjuvant or metastatic settings with initial doxorubicin-based chemotherapy, the panel suggests that clinicians consider “use with metastatic breast cancer and other malignancies for patients who have received more than 300 mg/m2 doxorubicin who may benefit from continued doxorubicin-containing therapy.” Because of the risk for cardiac toxicity with this agent, cardiac monitoring should continue in patients receiving doxorubicin.

The panel made no changes with regard to dexrazoxane, other than to delete a previous statement about potential use in patients receiving high-dose anthracyclines; with no new data on this topic, the panel said its clinical relevance appears limited.

Protectants Do Not Increase or Decrease Survival
The ASCO panel notes in the updated guideline that there is a “concern” that “chemotherapy and radiation therapy protectant agents may compromise tumor response and survival.”

However, their literature review provides no such evidence. “In all of the studies reviewed, for those studies reporting overall survival, disease-free survival, progression-free survival, or local control rate, no significant differences were found between patients receiving these agents and those not receiving them,” write the panel.

Nonetheless, there was a trend toward “higher objective response rates among patients with metastatic breast cancer initiating anthracycline treatment, compared with those assigned to anthracycline plus dexrazoxane,” they note. “Such a trend toward higher response rates was not observed among patients in studies where dexrazoxane treatment was delayed until after cumulative doxorubicin doses of 300 mg/m2,” they add.

According to the panel, patients should understand that protective agents have not been shown to increase or decrease disease-free or overall survival.

Source:
J Clin Oncol,  Published online November 17, 2008.

Note:
The panel members and authors have disclosed the following relevant financial relationships to the subjects under consideration. Consultant or advisory roles: Tarun Kewalramani, Amgen; Neal J. Meropol, Amgen; J. Tate Thigpen, Bristol-Myers Squibb; Andy Trotti III, GlaxoSmithKline, Viventia. Stock ownership: J. Tate Thigpen, Medimmunie; Andy Trotti III, Amgen.

Clinical Context
ASCO first published evidence-based guidelines for the use of protectants for chemotherapy and radiation therapy in 1999, and the last update was provided in 2002. Since then, a new protectant, palifermin, was approved by the US Food and Drug Administration for mucositis associated with stem-cell transplantation in hematologic malignant tumors, and growing evidence has been available on amifostine for esophagitis in chemoradiation therapy for non–small-cell lung cancer.

Other agents considered in the 2008 guidelines are dexrazoxane and mesna.

This is a review of the updated recommendations and the evidence supporting them by an expert panel of clinicians, researchers, health service experts, and other experts who met once, communicated though teleconference and email, and used trials since 2002 to compile the guidelines.

Study Highlights
The investigators searched the databases Medline, preMedline, and the Cochrane Library as well as libraries of panel members. 744 potential randomized controlled trials were identified, of which 39 reports met inclusion criteria. 2 studies of palifermin, 2 studies of dexrazoxane, 31 studies of amifostine, and no trials of mesna since 2002 were used for the panel guidelines.

Overall, many trials failed to document allocation concealment, and the majority lacked a placebo group.
In addition, tools used for assessment of symptoms varied across studies.

Dexrazoxane:
All but 1 recommendation remained unchanged from 2002. The guideline pertaining to use in patients receiving high-dose anthracycline was deleted because of lack of data.

There was no change in recommendation not to use for patients with breast cancer receiving initial doxorubicin-based chemotherapy.

Use should be considered for patients with breast cancer who receive more than 300 mg/m² of doxorubicin in the metastatic setting and in the adjuvant setting being considered for chemotherapy.
The dosage and administration, monitoring strategy, and other recommendations remain unchanged.

Amifostine:
There is no change in recommendations for the use of amifostine for nephrotoxicity and neutropenia.
Alternative strategies such as myeloid growth factor support or chemotherapy reduction may be considered to ameliorate neutropenia.

The 2008 ASCO panel recommends against using amifostine for protection against thrombocytopenia in patients receiving chemotherapy or radiation therapy and for the prevention of platinum-associated neurotoxicity or ototoxicity because of insufficient data.

Amifostine may be considered for decreasing the incidence of acute and late xerostomia in patients undergoing fractionated radiation therapy alone for head and neck cancer, but not for routine use in concurrent platinum-based chemoradiotherapy for head and neck cancer.
Data are insufficient to support use to prevent mucositis associated with radiation for head and neck cancer and to prevent esophagitis in patients receiving concurrent chemoradiotherapy for head and neck cancer.

Data are insufficient to support its use for preventing taxane-associated neuropathy. There is no change in dosage and administration since 2002. Common toxicities include acute hypotension, nausea, and fatigue.

Palifermin:
Palifermin is recommended in patients undergoing autologous or myeloablative allogeneic stem-cell transplantation for hematologic malignant tumor with a total-body irradiation-conditioning regimen to reduce severe mucositis, but not for chemotherapy regimens alone. There are insufficient data to support use for non–stem-cell transplantation or for the treatment of solid tumors.

Palifermin should be administered intravenously at 60 μg/kg/day for 3 days preceding conditioning treatment and 60 μg/kg/day for 3 days beginning on the day of stem cell infusion. It should be administered within 24 hours of the initiation of the conditioning regimen.

Mesna:
There is no change in recommendations for use with standard or high-dose ifosfamide, administration by the oral route, use with cyclophosphamide, and surveillance in patients receiving these agents.
No new data from randomized clinical trials on mesna were identified since 2002 to warrant any change to the 2002 recommendations.

Pearls for Practice
The protectants covered in the 2002 ASCO guidelines are dexrazoxane, amifostine, and mesna; palifermin has been introduced since then. The 2008 ASCO recommendations cover palifermin dosage and administration and indications; other recommendations for protectants have been modified or deleted owing to insufficient evidence.