Black Box Warning And Important Safety Information

Diagnosing/Staging Guidelines

The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (www.nccn.org) contains detailed decision trees on the evaluation and treatment of colorectal cancer. The guidelines follow the American Joint Committee on Cancer (AJCC) system, also known as the TNM (tumor/node/metastasis) system.

Health care professionals should base treatment decisions for colorectal cancer on pathologic staging using the TNM classification. The following is a summary of the staging guidelines outlined by the NCCN. More specifically, you will find:

Stage Grouping
TNM Definitions

Stage Grouping

	Primary Tumor (T)	Regional Lymph Nodes (N)	Distant Metastasis (M)
Stage 0	Tis	N0	M0
Stage I	T1	N0	M0
	T2	N0	M0
Stage IIA	T3	N0	M0
Stage IIB	T4	N0	M0
Stage IIIA	T1-T2	N1	M0
Stage IIIB	T3-T4	N1	M0
Stage IIIC	Any T	N2	M0
Stage IV	Any T	Any N	M1

TNM Definitions

Primary Tumor (T)

TX:	Primary tumor cannot be assessed
T0:	No evidence of primary tumor
Tis:	Carcinoma in situ: intraepithelial or invasion of lamina propria*
T1:	Tumor invades submucosa
T2:	Tumor invades muscularis propria
T3:	Tumor invades through the muscularis propria into the subserosa, or into non-peritonealized pericolic or perirectal tissues
T4:	Tumor directly invades other organs or structures, and/or perforates visceral peritoneum†

* Tis includes cancer cells confined within the glandular basement membrane (intraepithelial) or lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa.

† Direct invasion in T4 includes invasion of other segments of the colorectum by way of the serosa; for example, invasion of the sigmoid colon by a carcinoma of the cecum. Tumor that is adherent to other organs or structures macroscopically is classified T4. However, if no tumor is present in the adhesion microscopically, the classification should be pT3. The V and L substaging should be used to identify the presence or absence of vascular or lymphatic invasion.

Regional Lymph Nodes (N)

NX:	Regional lymph nodes cannot be assessed
N0:	No regional lymph node metastasis
N1:	Metastasis in 1 to 3 regional lymph nodes
N2:	Metastasis in 4 or more regional lymph nodes

Note: A tumor nodule in the pericolorectal adipose tissue of a primary carcinoma without histologic evidence of residual lymph node in the nodule is classified in the pN category as a regional lymph node metastasis if the nodule has the form and smooth contour of a lymph node. If the nodule has an irregular contour, it should be classified in the T category and also coded as V1 (microscopic venous invasion) or as V2 (if it was grossly evident), because there is a strong likelihood that it represents venous invasion.

Distant Metastasis (M)

MX:	Distant metastasis cannot be assessed
M0:	No distant metastasis
M1:	Distant metastasis

To view the Colon and/or Rectal Cancer Treatment Guidelines for Patients – Version IV, February 2005 visit the NCCN Web site.

INDICATIONS

ELOXATIN, used in combination with infusional 5-FU/LV, is indicated for:

Adjuvant treatment of stage Ill colon cancer patients who have undergone complete resection of the primary tumor
Treatment of advanced carcinoma of the colon or rectum

Important Safety Information

Anaphylactic-like reactions to ELOXATIN have been reported and may occur within minutes of ELOXATIN administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms, and discontinuation of ELOXATIN therapy may be required.

ELOXATIN should not be administered to patients with a history of known allergy to ELOXATIN or other platinum compounds. Hypersensitivity and anaphylactic/anaphylactoid reactions to ELOXATIN have been reported and were similar in nature and severity to those reported with other platinum compounds (ie, rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension). These reactions occur within minutes of administration and should be managed with appropriate supportive therapy. Drug-related deaths from this reaction have been reported
ELOXATIN may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant while receiving ELOXATIN. It is not known whether ELOXATIN or its derivatives are excreted in human milk
ELOXATIN has been associated with pulmonary fibrosis (<1% of study patients), which may be fatal. The combined incidence of cough and dyspnea was 7.4% (<1 % grade 3, no grade 4) in the ELOXATIN plus 5-FU/LV arm compared to 4.5% (no grade 3, 0.1% grade 4) in the 5-FU/LV alone arm in the adjuvant colon cancer study. In this study, one patient died from eosinophilic pneumonia in the ELOXATIN combination arm. The combined incidence of cough, dyspnea, and hypoxia was 43% (7% grade 3 and 4) in the ELOXATIN plus 5-FULV arm compared to 32% (5% grade 3 and 4) in the irinotecan plus 5-FU/LV arm in patients with previously untreated colorectal cancer. In case of unexplained respiratory symptoms, ELOXATIN should be discontinued until pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis
ELOXATIN is associated with two types of primarily peripheral sensory neuropathy: an acute, reversible type of early onset and a persistent type (>14 days). In patients with advanced colorectal cancer, paresthesias occurred in 77% (all grades) and 18% (grade 3/4) of previously untreated patients. In previously treated patients, acute neuropathy occurred in 56% (all grades) and 2% (grade 3/4) of patients; persistent neuropathy occurred in 48% (all grades) and 6% (grade 3/4) of patients. In patients with stage II and Ill colon cancer, paresthesia was seen in 92% (all grades) and 13% (grade 3/4) of patients; 21% (all grades) and 0.5% (grade 3/4) of patients had residual paresthesia at 18-month follow-up
Hepatotoxicity, as evidenced in the adjuvant study by increase in transaminases and alkaline phosphatase, was observed more commonly in the ELOXATIN combination arm. The incidence of increased bilirubin was similar on both arms. Changes noted on liver biopsies include: peliosis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive lesions. Hepatic vascular disorders should be considered and, if appropriate, investigated in case of abnormal liver function test results or portal hypertension not explained by liver metastases
Monitoring of white blood cell count with differential, hemoglobin, platelet count, and blood chemistries (including ALT, AST, bilirubin, and creatinine) is recommended before each ELOXATIN cycle
The safety and effectiveness of ELOXATIN plus 5-FU/LV in patients with renal impairment have not been evaluated. Since the primary route of platinum elimination is renal, this combination should be used with caution in patients with preexisting renal impairment. Clearance of these products may be decreased by coadministration of potentially nephrotoxic compounds, although this has not been specifically studied
The incidence of diarrhea, dehydration, hypokalemia, leukopenia, fatigue, and syncope was higher in patients ≥ 65 years old
Extravasation may result in local pain and inflammation that may be severe and lead to complications, including necrosis. Injection site reaction, including redness, swelling, and pain, has been reported
There have been reports of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients receiving ELOXATIN plus 5-FU/LV while on anticoagulants. Patients receiving ELOXATIN plus 5-FU/LV and requiring oral anticoagulants may require closer monitoring
The most common adverse reactions in patients with stage II or Ill colon cancer receiving adjuvant therapy were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue, and stomatitis. The most common adverse reactions in patients with advanced colorectal cancer were peripheral sensory neuropathy, fatigue, neutropenia, nausea, emesis, and diarrhea

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Eloxatin.com Registration | Colorectal Cancer Symptoms | Colorectal Cancer Treatment | Colorectal Cancer Side Effects

ELOXATIN, used in combination with infusional 5-FU/LV, is indicated for

Adjuvant treatment of stage III colon cancer patients who have undergone complete resection of the primary tumor. The indication is based on an improvement in disease-free survival, with no demonstrated benefit in overall survival after a median follow-up of 4 years
Treatment of advanced carcinoma of the colon or rectum

Clinical Safety Considerations

ELOXATIN should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.

ELOXATIN should not be administered to patients with a history of known allergy to ELOXATIN or other platinum compounds. Hypersensitivity and anaphylactic/anaphylactoid reactions to ELOXATIN have been reported and were similar in nature and severity to those reported with other platinum compounds (ie, rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension). These reactions occur within minutes of administration and should be managed with appropriate supportive therapy. Drug-related deaths from this reaction have been reported
ELOXATIN may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant while receiving ELOXATIN. It is not known whether ELOXATIN or its derivatives are excreted in human milk
ELOXATIN has been associated with pulmonary fibrosis (<1% of study patients), which may be fatal. The combined incidence of cough and dyspnea was 7.4% (<1% grade 3, no grade 4) in the ELOXATIN plus 5-FU/LV arm compared to 4.5% (no grade 3, 0.1% grade 4) in the 5-FU/LV alone arm in the adjuvant colon cancer study. In this study, one patient died from eosinophilic pneumonia in the ELOXATIN combination arm. The combined incidence of cough, dyspnea, and hypoxia was 43% (7% grade 3 and 4) in the ELOXATIN plus 5-FU/LV arm compared to 32% (5% grade 3 and 4) in the irinotecan plus 5-FU/LV arm in patients with previously untreated colorectal cancer. In case of unexplained respiratory symptoms, ELOXATIN should be discontinued until pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis
ELOXATIN is associated with two types of primarily peripheral sensory neuropathy: an acute, reversible type of early onset and a persistent type (>14 days). In patients with advanced colorectal cancer, paresthesias occurred in 77% (all grades) and 18% (grade 3/4) of previously untreated patients. In previously treated patients, acute neuropathy occurred in 56% (all grades) and 2% (grade 3/4) of patients; persistent neuropathy occurred in 48% (all grades) and 6% (grade 3/4) of patients. In patients with stage II and III colon cancer, paresthesia was seen in 92% (all grades) and 13% (grade 3/4) of patients; 21% (all grades) and 0.5% (grade 3/4) of patients had residual paresthesia at 18-month follow-up
Hepatotoxicity, as evidenced in the adjuvant study by increase in transaminases and alkaline phosphatase, was observed more commonly in the ELOXATIN combination arm. The incidence of increased bilirubin was similar on both arms. Changes noted on liver biopsies include: peliosis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive lesions. Hepatic vascular disorders should be considered and, if appropriate, investigated in case of abnormal liver function test results or portal hypertension not explained by liver metastases
Monitoring of white blood cell count with differential, hemoglobin, platelet count, and blood chemistries (including ALT, AST, bilirubin, and creatinine) is recommended before each ELOXATIN cycle
The safety and effectiveness of ELOXATIN plus 5-FU/LV in patients with renal impairment have not been evaluated. Since the primary route of platinum elimination is renal, this combination should be used with caution in patients with preexisting renal impairment. Clearance of these products may be decreased by coadministration of potentially nephrotoxic compounds, although this has not been specifically studied
The incidence of diarrhea, dehydration, hypokalemia, leukopenia, fatigue, and syncope was higher in patients 65 years old
Extravasation may result in local pain and inflammation that may be severe and lead to complications, including necrosis. Injection site reaction, including redness, swelling, and pain, has been reported
There have been reports of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients receiving ELOXATIN plus 5-FU/LV while on anticoagulants. Patients receiving ELOXATIN plus 5-FU/LV and requiring oral anticoagulants may require closer monitoring
The most common adverse reactions in patients with stage II or III colon cancer receiving adjuvant therapy were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue, and stomatitis. The most common adverse reactions in patients with advanced colorectal cancer were peripheral sensory neuropathy, fatigue, neutropenia, nausea, emesis, and diarrhea