February 2011 - Journal of Oncology Navigation & Survivorship

© 2011 Green Hill Healthcare Communications, LLC

Journal of Oncology ™

The Official Journal of the Academy of Oncology Nurse NavigatorsNAVIGATION & SURVIVORSHIP

®

FEBRUARY 2011 • VOL. 2, NO. 1

MAINTENANCE THERAPY FOR NON–SMALL CELL LUNG CANCER:A Value-Based Approach to Improve Patient Care and Outcomes

PROGRAM TURNS CANCER SURVIVORS INTO PEER NAVIGATORS

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Announcingthe first and only monoclonal antibody indicated for use inHER2+ metastatic gastric and gastroesophageal junction (GEJ) cancer

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to drive outcomes in HER2+ metastatic gastric/GEJ cancer

Boxed WARNINGS Herceptin administration can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving Herceptin with anthracycline-containing chemotherapy regimens. In a pivotal adjuvant breast cancer trial, one patient who developed CHF died of cardiomyopathy

Evaluate cardiac function prior to and during treatment. Discontinue Herceptin for cardiomyopathy

Herceptin can result in serious and fatal infusion reactions and pulmonary toxicity. Discontinue Herceptin for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome

Exposure to Herceptin during pregnancy can result in oligohydramnios, in some cases complicated by pulmonary hypoplasia and neonatal death

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Indication Herceptin is indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, who have not received prior treatment for metastatic disease.

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Additional Important Safety Information Exacerbation of chemotherapy-induced neutropenia has also occurred

Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy

The most common adverse reactions associated with Herceptin were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia

Please see brief summary of full Prescribing Information, including Boxed WARNINGS and additional important safety information, on the following pages.

Reference: 1. Herceptin Prescribing Information. Genentech, Inc. October 29, 2010.

HER2+ metastatic gastric/GEJ cancer

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Final Median Overall Survival Analysis1

Updated Median Overall Survival Analysis1‡

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13.5

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Herceptin plus chemotherapy* (n=298)

Chemotherapy alone* (n=296)

Hazard Ratio = 0.7395% CI: 0.60-0.91

P=0.0038

Hazard Ratio = 0.8095% CI: 0.67-0.97 11.7

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In the ToGA trial†:

• The final overall survival analysis demonstrated a 13.5-month median OS with Herceptin + chemotherapy (cisplatin and either capecitabine or 5-fluorouracil) vs an 11.0-month median OS with chemotherapy alone1

• The updated overall survival analysis demonstrated a 13.1-month median OS with Herceptin + chemotherapy (cisplatin and either capecitabine or 5-fluorouracil) vs an 11.7-month median OS with chemotherapy alone1

• Herceptin should be administered until disease progression or unacceptable toxicity in HER2+ metastatic gastric and GEJ cancer

Herceptin plus chemotherapy* extended median overall survival (OS) in HER2+ metastatic gastric and GEJ cancer1

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*Chemotherapy was cisplatin and either capecitabine or 5-FU. ‡ The updated analysis was conducted one year after the final analysis. No P value

was associated with the updated analysis in the Herceptin Prescribing Information because there was no preplanned statistical testing for OS after the final analysis.

†Trastuzumab in gastric cancer.

©2010 Genentech USA, Inc. So. San Francisco, CA All rights reserved. 10581800 11/10

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HERCEPTIN® (trastuzumab)Brief Summary For full Prescribing Information, see package insert.

WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY Cardiomyopathy Herceptin administration can result in sub clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving Herceptin with anthracycline containing chemotherapy regimens. Evaluate left ventricular function in all patients prior to and during treatment with Herceptin. Discontinue Herceptin treatment in patients receiving adjuvant therapy and withhold Herceptin in patients with metastatic disease for clinically significant decrease in left ventricular function. [see Warnings and Precautions and Dosage and Administration]Infusion Reactions; Pulmonary Toxicity Herceptin administration can result in serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during or within 24 hours of Herceptin administration. Interrupt Herceptin infusion for dyspnea or clinically significant hypotension. Monitor patients until symptoms completely resolve. Discontinue Herceptin for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. [see Warnings and Precautions] Embryo-Fetal Toxicity Exposure to Herceptin during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. [see Warnings and Precautions, Use in Specific Populations]

INDICATIONS AND USAGE Adjuvant Breast Cancer Herceptin is indicated for adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature [see Clinical Studies] breast cancer • as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel • with docetaxel and carboplatin • as a single agent following multi-modality anthracycline based therapy. Metastatic Breast Cancer Herceptin is indicated: • In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer • As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease. Metastatic Gastric Cancer Herceptin is indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, who have not received prior treatment for metastatic disease. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Cardiomyopathy Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: Cardiomyopathy]. Herceptin can also cause asymptomatic decline in left ventricular ejection fraction (LVEF). There is a 4−6 fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving Herceptin as a single agent or in combination therapy compared with those not receiving Herceptin. The highest absolute incidence occurs when Herceptin is administered with an anthracycline. Withhold Herceptin for 16% absolute decrease in LVEF from pre-treatment values or an LVEF value below institutional limits of normal and 10% absolute decrease in LVEF from pretreatment values [see Dosage and Administration]. The safety of continuation or resumption of Herceptin in patients with Herceptin-induced left ventricular cardiac dysfunction has not been studied. Cardiac Monitoring Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended: • Baseline LVEF measurement immediately prior to initiation of Herceptin • LVEF measurements every 3 months during and upon completion of Herceptin • Repeat LVEF measurement at

4 week intervals if Herceptin is withheld for significant left ventricular cardiac dysfunction [see Dosage and Administration] • LVEF measurements every 6 months for at least 2 years following completion of Herceptin as a component of adjuvant therapy. In Study 1, 16% (136/844) of patients discontinued Herceptin due to clinical evidence of myocardial dysfunction or significant decline in LVEF. In Study 3, the number of patients who discontinued Herceptin due to cardiac toxicity was 2.6% (44/1678). In Study 4, a total of 2.9% (31/1056) patients in the TCH arm (1.5% during the chemotherapy phase and 1.4% during the monotherapy phase) and 5.7% (61/1068) patients in the AC-TH arm (1.5% during the chemotherapy phase and 4.2% during the monotherapy phase) discontinued Herceptin due to cardiac toxicity. Among 32 patients receiving adjuvant chemotherapy (Studies 1 and 2) who developed congestive heart failure, one patient died of cardiomyopathy and all other patients were receiving cardiac medication at last follow-up. Approximately half of the surviving patients had recovery to a normal LVEF (defined as

50%) on continuing medical management at the time of last follow-up. Incidence of congestive heart failure is presented in Table 1. The safety of continuation or resumption of Herceptin in patients with Herceptin-induced left ventricular cardiac dysfunction has not been studied.Table 1 Incidence of Congestive Heart Failure in Adjuvant Breast Cancer Studies

Incidence of CHF Study Regimen Herceptin Control 1 & 2a ACb Paclitaxel+ Herceptin 2% (32/1677) 0.4% (7/1600) 3 Chemo Herceptin 2% (30/1678) 0.3% (5/1708) 4 ACb Docetaxel+ Herceptin 2% (20/1068) 0.3% (3/1050) 4 Docetaxel+Carbo+ Herceptin 0.4% (4/1056) 0.3% (3/1050)a Includes 1 patient with fatal cardiomyopathy.b Anthracycline (doxorubicin) and cyclophosphamideTable 2 Incidence of Cardiac Dysfunctiona in Metastatic Breast Cancer Studies

Incidence NYHA I−IV NYHA III−IV Study Event Herceptin Control Herceptin Control 5 Cardiac (AC)b Dysfunction 28% 7% 19% 3% 5 Cardiac (paclitaxel) Dysfunction 11% 1% 4% 1% 6 Cardiac Dysfunctionc 7% N/A 5% N/Aa Congestive heart failure or significant asymptomatic

decrease in LVEF.b Anthracycline (doxorubicin or epirubicin) and

cyclophosphamide.c Includes 1 patient with fatal cardiomyopathy.In Study 4, the incidence of NCI-CTC Grade 3/4 cardiac ischemia/infarction was higher in the Herceptin containing regimens: (AC-TH: 0.3% (3/1068) and TCH 0.2% (2/1056)) as compared to none in AC-T. Infusion Reactions Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion included nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia. [see Adverse Reactions] In postmarketing reports, serious and fatal infusion reactions have been reported. Severe reactions which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, were usually reported during or immediately following the initial infusion. However, the onset and clinical course were variable including progressive worsening, initial improvement followed by clinical deterioration, or delayed post-infusion events with rapid clinical deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction. Interrupt Herceptin infusion in all patients experiencing dyspnea, clinically significant hypotension, and intervention of medical

therapy administered, which may include: epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen. Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered in all patients with severe infusion reactions. There are no data regarding the most appropriate method of identification of patients who may safely be retreated with Herceptin after experiencing a severe infusion reaction. Prior to resumption of Herceptin infusion, the majority of patients who experienced a severe infusion reaction were pre-medicated with antihistamines and/or corticosteroids. While some patients tolerated Herceptin infusions, others had recurrent severe infusion reactions despite pre-medications. Embryo-Fetal Toxicity Herceptin can cause fetal harm when administered to a pregnant woman. In post-marketing reports, use of Herceptin during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise women of the potential hazard to the fetus resulting from Herceptin exposure during pregnancy and provide contraception counseling to women of childbearing potential. [see Use in Specific Populations, Patient Counseling Information]. Pulmonary Toxicity Herceptin use can result in serious and fatal pulmonary toxicity. Pulmonary toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions [see Warnings and Precautions]. Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity. Exacerbation of Chemotherapy-Induced Neutropenia In randomized, controlled clinical trials the per-patient incidences of NCI CTC Grade 3−4 neutropenia and of febrile neutropenia were higher in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received Herceptin and those who did not. [see Adverse Reactions] HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy because these are the only patients studied and for whom benefit has been shown. Due to differences in tumor histopathology, use FDA-approved tests for the specific tumor type (breast or gastric/gastroesophageal adenocarcinoma) to assess HER2 protein overexpression and HER2 gene amplification. Tests should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Several FDA-approved commercial assays are available to aid in the selection of breast cancer and metastatic gastric cancer patients for Herceptin therapy. Users should refer to the package inserts of specific assay kits for information on the Intended Use, and the validation and performance of each assay. Limitations in assay precision make it inadvisable to rely on a single method to rule out potential Herceptin benefit. Treatment outcomes for adjuvant breast cancer (Studies 2 and 3) and for metastatic breast cancer (Study 5) as a function of IHC and FISH testing are provided in Tables 8 and 10. Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic gastric cancer should be performed using FDA-approved tests specifically for gastric cancers due to differences in gastric vs. breast histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers. Study 7 demonstrated that gene amplification and protein overexpression were not as well correlated as with breast cancer. Treatment outcomes for metastatic gastric cancer (Study 7), based on HER2 gene amplification (FISH) and HER2 protein overexpression (IHC) test results are provided in Table 12.

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ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Cardiomyopathy [see Warnings and Precautions] • Infusion reactions [see Warnings and Precautions] • Embryo-fetal Toxicity [see Warnings and Precautions] • Pulmonary toxicity [see Warnings and Precautions] • Exacerbation of chemotherapy-induced neutropenia [see Warnings and Precautions] The most common adverse reactions in patients receiving Herceptin in the adjuvant and metastatic breast cancer setting are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Adverse reactions requiring interruption or discontinuation of Herceptin treatment include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity [see Dosage and Administration]. In the metastatic gastric cancer setting, the most common adverse reactions ( 10%) that were increased ( 5% difference) in the Herceptin arm as compared to the chemotherapy alone arm were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. The most common adverse reactions which resulted in discontinuation of treatment on the Herceptin-containing arm in the absence of disease progression were infection, diarrhea, and febrile neutropenia. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adjuvant Breast Cancer Studies The data below reflect exposure to Herceptin across three randomized, open-label studies, Studies 1, 2, and 3, with (n= 3355) or without (n= 3308) trastuzumab in the adjuvant treatment of breast cancer. The data summarized in Table 3 below, from Study 3, reflect exposure to Herceptin in 1678 patients; the median treatment duration was 51 weeks and median number of infusions was 18. Among the 3386 patients enrolled in Study 3, the median age was 49 years (range: 21 to 80 years), 83% of patients were Caucasian, and 13% were Asian.Table 3 Adverse Reactions for Study 3, All Gradesa:

Table 3 (cont’d) Adverse Reactions for Study 3, All Gradesa:

a The incidence of Grade 3/4 adverse reactions was <1% in both arms for each listed term.

b Higher level grouping term.

The data from Studies 1 and 2 were obtained from 3206 patients, of whom 1635 received Herceptin; the median treatment duration was 50 weeks. The median age was 49 years (range: 24−80); 84% of patients were White, 7% Black, 4% Hispanic, and 4% Asian. In Study 1, only Grade 3−5 adverse events, treatment-related Grade 2 events, and Grade 2−5 dyspnea were collected during and for up to 3 months following protocol-specified treatment. The following non-cardiac adverse reactions of Grade 2−5 occurred at an incidence of at least 2% greater among patients randomized to Herceptin plus chemotherapy as compared to chemotherapy alone: arthralgia (31% vs. 28%), fatigue (28% vs. 22%), infection (22% vs. 14%), hot flashes (17% vs. 15%), anemia (13% vs. 7%), dyspnea (12% vs. 4%), rash/desquamation (11% vs. 7%), neutropenia (7% vs. 5%), headache (6% vs. 4%), and insomnia (3.7% vs. 1.5%). The majority of these events were Grade 2 in severity. In Study 2, data collection was limited to the following investigator-attributed treatment-related adverse reactions: NCI-CTC Grade 4 and 5 hematologic toxicities, Grade 3−5 non-hematologic toxicities, selected Grade 2−5 toxicities associated with taxanes (myalgia, arthralgias, nail changes, motor neuropathy, sensory neuropathy) and Grade 1−5 cardiac toxicities occurring during chemotherapy and/or Herceptin treatment. The following non-cardiac adverse reactions of Grade 2−5 occurred at an incidence of at least 2% greater among patients randomized to Herceptin plus chemotherapy as compared to chemotherapy alone: arthralgia (11% vs. 8.4%), myalgia (10% vs. 8%), nail changes (9% vs. 7%), and dyspnea (2.5% vs. 0.1%). The majority of these events were Grade 2 in severity. Safety data from Study 4 reflect exposure to Herceptin as part of an adjuvant treatment regimen from 2124 patients receiving at least one dose of study treatment [AC-TH: n = 1068; TCH: n = 1056]. The overall median treatment duration was 54 weeks in both the AC-TH and TCH arms. The median number of infusions was 26 in the AC-TH arm and 30 in the TCH arm, including weekly infusions during the chemotherapy phase and every three week dosing in the monotherapy period. Among these patients, the median age was 49 years (range 22 to 74 years). In Study 4, the toxicity profile was similar to that reported in Studies 1, 2, and 3 with the exception of a low incidence of CHF in the TCH arm. Metastatic Breast Cancer Studies The data below reflect exposure to Herceptin in one randomized, open-label study, Study 5, of chemotherapy with (n=235) or without (n=234) trastuzumab in patients with metastatic breast cancer, and one single-arm study (Study 6; n=222) in patients with metastatic breast cancer. Data in Table 4 are based on Studies 5 and 6. Among the 464 patients treated in Study 5, the median age was 52 years (range: 25−77 years). Eighty-nine percent were White, 5%

Black, 1% Asian and 5% other racial/ethnic groups. All patients received 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly. The percentages of patients who received Herceptin treatment for 6 months and

12 months were 58% and 9%, respectively. Among the 352 patients treated in single agent studies (213 patients from Study 6), the median age was 50 years (range 28−86 years), 86% were White, 3% were Black, 3% were Asian, and 8% in other racial/ethnic groups. Most of the patients received 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly. The percentages of patients who received Herceptin treatment for 6 months and

12 months were 31% and 16%, respectively.Table 4 Per-Patient Incidence of Adverse Reactions Occurring in 5% of Patients in Uncontrolled Studies or at Increased Incidence in the Herceptin Arm (Studies 5 and 6)

Herceptin Single + Paclitaxel Herceptin ACb

Agenta Paclitaxel Alone + ACb Alone n = 352 n = 91 n = 95 n = 143 n = 135

Body as a Whole Pain 47% 61% 62% 57% 42% Asthenia 42% 62% 57% 54% 55% Fever 36% 49% 23% 56% 34% Chills 32% 41% 4% 35% 11% Headache 26% 36% 28% 44% 31% Abdominal pain 22% 34% 22% 23% 18% Back pain 22% 34% 30% 27% 15% Infection 20% 47% 27% 47% 31% Flu syndrome 10% 12% 5% 12% 6% Accidental injury 6% 13% 3% 9% 4% Allergic reaction 3% 8% 2% 4% 2%Cardiovascular Tachycardia 5% 12% 4% 10% 5% Congestive 7% 11% 1% 28% 7% heart failureDigestive Nausea 33% 51% 9% 76% 77% Diarrhea 25% 45% 29% 45% 26% Vomiting 23% 37% 28% 53% 49% Nausea and vomiting 8% 14% 11% 18% 9% Anorexia 14% 24% 16% 31% 26% Heme & Lymphatic Anemia 4% 14% 9% 36% 26% Leukopenia 3% 24% 17% 52% 34%Metabolic Peripheral edema 10% 22% 20% 20% 17% Edema 8% 10% 8% 11% 5%Musculoskeletal Bone pain 7% 24% 18% 7% 7% Arthralgia 6% 37% 21% 8% 9%Nervous Insomnia 14% 25% 13% 29% 15% Dizziness 13% 22% 24% 24% 18% Paresthesia 9% 48% 39% 17% 11% Depression 6% 12% 13% 20% 12% Peripheral neuritis 2% 23% 16% 2% 2% Neuropathy 1% 13% 5% 4% 4%Respiratory Cough increased 26% 41% 22% 43% 29% Dyspnea 22% 27% 26% 42% 25% Rhinitis 14% 22% 5% 22% 16% Pharyngitis 12% 22% 14% 30% 18% Sinusitis 9% 21% 7% 13% 6%Skin Rash 18% 38% 18% 27% 17% Herpes simplex 2% 12% 3% 7% 9% Acne 2% 11% 3% 3% < 1%Urogenital Urinary tract infection 5% 18% 14% 13% 7%

a Data for Herceptin single agent were from 4 studies, including 213 patients from Study 6.

b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide.

1 Year Herceptin Observation Adverse Reaction (n= 1678) (n=1708)

CardiacHypertension 64 (4%) 35 (2%)Dizziness 60 (4%) 29 (2%)Ejection Fraction Decreased 58 (3.5%) 11 (0.6%)Palpitations 48 (3%) 12 (0.7%)Cardiac Arrhythmiasb 40 (3%) 17 (1%)Cardiac Failure Congestive 30 (2%) 5 (0.3%)Cardiac Failure 9 (0.5%) 4 (0.2%)Cardiac Disorder 5 (0.3%) 0 (0%)Ventricular Dysfunction 4 (0.2%) 0 (0%)Respiratory Thoracic Mediastinal DisordersCough 81 (5%) 34 (2%)Influenza 70 (4%) 9 (0.5%)Dyspnea 57 (3%) 26 (2%)URI 46 (3%) 20 (1%)Rhinitis 36 (2%) 6 (0.4%)Pharyngolaryngeal Pain 32 (2%) 8 (0.5%)Sinusitis 26 (2%) 5 (0.3%)Epistaxis 25 (2%) 1 (0.06%)Pulmonary Hypertension 4 (0.2%) 0 (0%)Interstitial Pneumonitis 4 (0.2%) 0 (0%)Gastrointestinal DisordersDiarrhea 123 (7%) 16 (1%)Nausea 108 (6%) 19 (1%)Vomiting 58 (3.5%) 10 (0.6%)Constipation 33 (2%) 17 (1%)Dyspepsia 30 (2%) 9 (0.5%)Upper Abdominal Pain 29 (2%) 15 (1%)Musculoskeletal & Connective Tissue DisordersArthralgia 137 (8%) 98 (6%)Back Pain 91 (5%) 58 (3%)Myalgia 63 (4%) 17 (1%)Bone Pain 49 (3%) 26 (2%)Muscle Spasm 46 (3%) 3 (0.2%)

1 Year Herceptin Observation Adverse Reaction (n= 1678) (n=1708)

Nervous System DisordersHeadache 162 (10%) 49 (3%)Paraesthesia 29 (2%) 11 (0.6%)Skin & Subcutaneous Tissue DisordersRash 70 (4%) 10 (0.6%)Nail Disorders 43 (2%) 0 (0%)Pruritis 40 (2%) 10 (0.6%)General DisordersPyrexia 100 (6%) 6 (0.4%)Edema Peripheral 79 (5%) 37 (2%)Chills 85 (5%) 0 (0%)Aesthenia 75 (4.5%) 30 (2%)Influenza-like Illness 40 (2%) 3 (0.2%)Sudden Death 1 (0.06%) 0 (0%)InfectionsNasopharyngitis 135 (8%) 43 (3%)UTI 39 (3%) 13 (0.8%)Immune System DisordersHypersensitivity 10 (0.6%) 1 (0.06%)Autoimmune Thyroiditis 4 (0.3%) 0 (0%)

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Metastatic Gastric Cancer The data below are based on the exposure of 294 patients to Herceptin in combination with a fluoropyrimidine (capecitabine or 5-FU) and cisplatin (Study 7). In the Herceptin plus chemotherapy arm, the initial dose of Herceptin 8 mg/kg was administered on Day 1 (prior to chemotherapy) followed by 6 mg/kg every 21 days until disease progression. Cisplatin was administered at 80 mg/m2 on Day 1 and the fluoropyrimidine was administered as either capecitabine 1000 mg/m2 orally twice a day on Days 1-14 or 5-fluorouracil 800 mg/m2/day as a continuous intravenous infusion Days 1 through 5. Chemotherapy was administered for six 21-day cycles. Median duration of Herceptin treatment was 21 weeks; median number of Herceptin infusions administered was eight.

Table 5 Study 7: Per Patient Incidence of Adverse Reactions of All Grades (Incidence 5% between Arms) or Grade 3 /4 (Incidence >1% between Arms) and Higher Incidence in Herceptin Arm

Herceptin +FC FC (N = 294) (N = 290) N (%) N (%)

Body System/ All Grades All GradesAdverse Event Grades 3 / 4 Grades 3/ 4

Investigations Neutropenia 230 (78) 101 (34) 212 (73) 83 (29) Hypokalemia 83 (28) 28 (10) 69 (24) 16 (6) Anemia 81 (28) 36 (12) 61 (21) 30 (10) Thrombocytopenia 47 (16) 14 (5) 33 (11) 8 (3)Blood And Lymphatic System Disorders Febrile Neutropenia _ 15 (5) _ 8 (3)Gastrointestinal Disorders Diarrhea 109 (37) 27 (9) 80 (28) 11 (4) Stomatitis 72 (24) 2 (1) 43 (15) 6 (2) Dysphagia 19 (6) 7 (2) 10 ( 3) 1 ( 1)Body as a Whole Fatigue 102 (35) 12 (4) 82 (28) 7 (2) Fever 54 (18) 3 (1) 36 (12) 0 (0) Mucosal Inflammation 37 (13) 6 (2) 18 (6) 2 (1) Chills 23 (8) 1 ( 1) 0 (0) 0 (0)Metabolism And Nutrition Disorders Weight Decrease 69 (23) 6 (2) 40 (14) 7 (2)Infections And Infestations Upper Respiratory Tract Infections 56 (19) 0 (0) 29 (10) 0 (0) Nasopharyngitis 37 (13) 0 (0) 17 (6) 0 (0)Renal And Urinary Disorders Renal Failure and Impairment 53 (18) 8 (3) 42 (15) 5 (2)Nervous System Disorders Dysgeusia 28 (10) 0 (0) 14 (5) 0 (0)

The following subsections provide additional detail regarding adverse reactions observed in clinical trials of adjuvant breast, metastatic breast cancer, metastatic gastric cancer, or post-marketing experience. Cardiomyopathy Serial measurement of cardiac function (LVEF) was obtained in clinical trials in the adjuvant treatment of breast cancer. In Study 3, the median duration of follow-up was 12.6 months (12.4 months in the observation arm; 12.6 months in the 1-year Herceptin arm); and in Studies 1 and 2, 23 months in the AC-T arm, 24 months in the AC-TH arm. In Studies 1 and 2, 6% of patients were not permitted to initiate Herceptin following completion of AC chemotherapy due to cardiac dysfunction (LVEF < 50% or 15 point decline in LVEF from baseline to end of AC). Following initiation of Herceptin therapy, the incidence of new-onset dose-limiting myocardial dysfunction was higher among patients receiving Herceptin and paclitaxel as compared to those receiving paclitaxel alone in Studies 1 and 2, and in patients receiving Herceptin monotherapy compared to observation in Study 3 (see Table 6, Figures 1 and 2).

Table 6a Per-patient Incidence of New Onset Myocardial Dysfunction (by LVEF) Studies 1, 2, 3 and 4

LVEF <50% and Absolute Decrease Absolute from Baseline LVEF Decrease

LVEF 10% 16% <20% and <50% decrease decrease 10% 20%

Studies 1 & 2b AC TH 22.8% 18.3% 11.7% 33.4% 9.2% (n=1606) (366) (294) (188) (536) (148)

AC T 9.1% 5.4% 2.2% 18.3% 2.4% (n=1488) (136) (81) (33) (272) (36)

Study 3 Herceptin 8.6% 7.0% 3.8% 22.4% 3.5% (n=1678) (144) (118) (64) (376) (59)

Observation 2.7% 2.0% 1.2% 11.9% 1.2% (n=1708) (46) (35) (20) (204) (21)

Study 4c TCH 8.5% 5.9% 3.3% 34.5% 6.3% (n=1056) (90) (62) (35) (364) (67)

AC TH 17% 13.3% 9.8% 44.3% 13.2% (n=1068) (182) (142) (105) (473) (141)

AC T 9.5% 6.6% 3.3% 34% 5.5% (n=1050) (100) (69) (35) (357) (58)

a For Studies 1, 2 and 3, events are counted from the beginning of Herceptin treatment. For Study 4, events are counted from the date of randomization.

b Studies 1 and 2 regimens: doxorubicin and cyclo-phosphamide followed by paclitaxel (AC T) or paclitaxel plus Herceptin (AC TH).

c Study 4 regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC T) or docetaxel plus Herceptin (AC TH); docetaxel and carboplatin plus Herceptin (TCH).

Figure 1 Studies 1 and 2: Cumulative Incidence of Time to First LVEF Decline of 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event

Time 0 is initiation of paclitaxel or Herceptin + paclitaxel therapy.

Figure 2 Study 3: Cumulative Incidence of Time to First LVEF Decline of 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event

Time 0 is the date of randomization.

Figure 3 Study 4: Cumulative Incidence of Time to First LVEF Decline of 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event

Time 0 is the date of randomization.

The incidence of treatment emergent congestive heart failure among patients in the metastatic breast cancer trials was classified for severity using the New York Heart Association classification system (I−IV, where IV is the most severe level of cardiac failure) (see Table 2). In the metastatic breast cancer trials the probability of cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracyclines. In Study 7, 5.0% of patients in the Herceptin plus chemotherapy arm compared to 1.1% of patients in the chemotherapy alone arm had LVEF value below 50% with a 10% absolute decrease in LVEF from pretreatment values. Infusion Reactions During the first infusion with Herceptin, the symptoms most commonly reported were chills and fever, occurring in approximately 40% of patients in clinical trials. Symptoms were treated with acetaminophen, diphenhydramine, and meperidine (with or without reduction in the rate of Herceptin infusion); permanent discontinuation of Herceptin for infusional toxicity was required in <1% of patients. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and asthenia. Infusional toxicity occurred in 21% and 35% of patients, and was severe in 1.4% and 9% of patients, on second or subsequent Herceptin infusions administered as monotherapy or in combination with chemotherapy, respectively. In the post- marketing setting, severe infusion reactions, including hypersensitivity, anaphylaxis, and angioedema have been reported. Anemia In randomized controlled clinical trials, the overall incidence of anemia (30% vs. 21% [Study 5]), of selected NCI-CTC Grade 2-5 anemia (12.5% vs. 6.6% [Study 1]), and of anemia requiring transfusions (0.1% vs. 0 patients [Study 2]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. Following the administration of Herceptin as a single agent (Study 6), the incidence of NCI-CTC Grade 3 anemia was < 1%. In Study 7 (metastatic gastric cancer) on the Herceptin containing arm as compared to the chemotherapy alone arm the overall incidence of anemia was 28% compared 21% and of NCI CTC Grade 3/4 anemia was 12.2% compared to 10.3%. Neutropenia In randomized controlled clinical trials in the adjuvant setting, the incidence of selected NCI-CTC Grade 4−5 neutropenia (2% vs. 0.7% [Study 2]) and of selected Grade 2−5 neutropenia (7.1% vs. 4.5% [Study 1]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. In a randomized, controlled trial in patients with metastatic breast cancer, the incidences of NCI-CTC Grade 3/4 neutropenia (32% vs. 22%) and of febrile neutropenia (23% vs. 17%) were also increased in patients randomized to Herceptin in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. In Study 7 (metastatic gastric cancer) on the Herceptin containing arm as compared to the chemotherapy alone arm, the incidence of NCI CTC Grade 3/4 neutropenia was 36.8% compared to 28.9%; febrile neutropenia 5.1% compared to 2.8%. Infection The overall incidences of infection (46% vs. 30% [Study 5]), of selected NCI-CTC Grade 2−5 infection/febrile neutropenia (22% vs. 14% [Study 1]) and of selected Grade 3−5 infection/febrile neutropenia (3.3% vs. 1.4%) [Study 2]), were higher in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. The most common site of infections in the adjuvant setting involved the upper respiratory tract, skin, and urinary tract. In Study 4, the overall incidence of infection was higher with the addition of Herceptin to AC-T but not to TCH [44% (AC-TH), 37% (TCH), 38% (AC-T)]. The incidences of NCI-CTC Grade 3−4 infection were similar [25% (AC-TH), 21% (TCH), 23% (AC-T)] across the three arms. In a randomized, controlled trial in treatment of metastatic breast cancer, the reported incidence of febrile neutropenia was higher (23% vs. 17%) in patients receiving Herceptin in combination with myelo-suppressive chemotherapy as compared to chemo-therapy alone. Pulmonary Toxicity Adjuvant Breast Cancer Among women receiving adjuvant therapy for

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breast cancer, the incidence of selected NCI-CTC Grade 2−5 pulmonary toxicity (14% vs. 5% [Study 1]) and of selected NCI-CTC Grade 3−5 pulmonary toxicity and spontaneous reported Grade 2 dyspnea (3.4% vs. 1% [Study 2]) was higher in patients receiving Herceptin and chemotherapy compared with chemotherapy alone. The most common pulmonary toxicity was dyspnea (NCI-CTC Grade 2−5: 12% vs. 4% [Study 1]; NCI-CTC Grade 2−5: 2.5% vs. 0.1% [Study 2]). Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving Herceptin compared with 0.3% of those receiving chemotherapy alone. Fatal respiratory failure occurred in 3 patients receiving Herceptin, one as a component of multi-organ system failure, as compared to 1 patient receiving chemotherapy alone. In Study 3, there were 4 cases of interstitial pneumonitis in Herceptin-treated patients compared to none in the control arm. Metastatic Breast Cancer Among women receiving Herceptin for treatment of metastatic breast cancer, the incidence of pulmonary toxicity was also increased. Pulmonary adverse events have been reported in the post-marketing experience as part of the symptom complex of infusion reactions. Pulmonary events include bronchospasm, hypoxia, dyspnea, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, and acute respiratory distress syndrome. For a detailed description, see Warnings and Precautions. Thrombosis/Embolism In 4 randomized, controlled clinical trials, the incidence of thrombotic adverse events was higher in patients receiving Herceptin and chemotherapy compared to chemotherapy alone in three studies (3.0% vs. 1.3% [Study 1], 2.5% and 3.7% vs. 2.2% [Study 4] and 2.1% vs. 0% [Study 5]). Diarrhea Among women receiving adjuvant therapy for breast cancer, the incidence of NCI-CTC Grade 2−5 diarrhea (6.2% vs. 4.8% [Study 1]) and of NCI-CTC Grade 3−5 diarrhea (1.6% vs. 0% [Study 2]), and of Grade 1−4 diarrhea (7% vs. 1% [Study 3]) were higher in patients receiving Herceptin as compared to controls. In Study 4, the incidence of Grade 3−4 diarrhea was higher [5.7% AC-TH, 5.5% TCH vs. 3.0% AC-T] and of Grade 1−4 was higher [51% AC-TH, 63% TCH vs. 43% AC-T] among women receiving Herceptin. Of patients receiving Herceptin as a single agent for the treatment of metastatic breast cancer, 25% experienced diarrhea. An increased incidence of diarrhea was observed in patients receiving Herceptin in combination with chemotherapy for treatment of metastatic breast cancer. Renal Toxicity In Study 7 (metastatic gastric cancer) on the Herceptin-containing arm as compared to the chemotherapy alone arm the incidence of renal impairment was 18% compared to 14.5%. Severe (Grade 3/4) renal failure was 2.7% on the Herceptin-containing arm compared to 1.7% on the chemotherapy only arm. Treatment discontinuation for renal insufficiency/failure was 2% on the Herceptin-containing arm and 0.3% on the chemotherapy only arm. In the postmarketing setting, rare cases of nephrotic syndrome with pathologic evidence of glomerulopathy have been reported. The time to onset ranged from 4 months to approximately 18 months from initiation of Herceptin therapy. Pathologic findings included membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis. Complications included volume overload and congestive heart failure. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Among 903 women with metastatic breast cancer, human anti-human antibody (HAHA) to Herceptin was detected in one patient using an enzyme-linked immunosorbent assay (ELISA). This patient did not experience an allergic reaction. Samples for assessment of HAHA were not collected in studies of adjuvant breast cancer. The incidence of antibody formation is highly dependent on the sensitivity and the specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Herceptin with the

incidence of antibodies to other products may be misleading. Post-Marketing Experience The following adverse reactions have been identified during post approval use of Herceptin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Infusion reaction [see Warnings and Precautions] • Oligohydramnios or oligohydramnios sequence, including pulmonary hypoplasia, skeletal abnormalities, and neonatal death [see Warnings and Precautions] • Glomerulopathy [see Adverse Reactions] DRUG INTERACTIONS In Study 5, the mean serum trough concentration of trastuzumab was consistently elevated approximately 1.5-fold, when administered in combination with paclitaxel as compared to trough concentrations of trastuzumab when administered in combination with an anthracycline and cyclophosphamide. In other pharmacokinetic studies, where Herceptin was administered in combination with paclitaxel, docetaxel or doxorubicin, Herceptin did not alter the plasma concentrations of these chemotherapeutic agents, or the metabolites that were analyzed. In a drug interaction substudy conducted in patients in Study 7, the pharmacokinetics of cisplatin, capecitabine and their metabolites were not altered when administered in combination with Herceptin. USE IN SPECIFIC POPULATIONS Pregnancy: Category D [see Warnings and Precautions, Nonclinical Toxicology] Herceptin can cause fetal harm when administered to a pregnant woman. In post-marketing reports use of Herceptin during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. These case reports described oligohydramnios in pregnant women who received Herceptin either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after Herceptin was stopped. In one case, Herceptin therapy resumed after the amniotic fluid index improved, and oligohydramnios recurred. Monitor women exposed to Herceptin during pregnancy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of IV hydration in management of oligohydramnios due to Herceptin exposure is not known. Advise women of the potential hazard to the fetus resulting from Herceptin exposure during pregnancy. Encourage pregnant women with breast cancer who are using Herceptin to enroll in MotHER-the Herceptin Pregnancy Registry: phone 1-800-690-6720. [see Patient Counseling Information]. No teratogenic effects were observed in offspring from reproduction studies in cynomolgus monkeys at doses up to 25 times the recommended weekly human dose of 2 mg/kg trastuzumab. In mutant mice lacking HER2, embryos died in early gestation. Trastuzumab exposure was reported at delivery in offspring of cynomolgus monkeys treated during the early (Days 20-50 of gestation) or late (Days 120-150 of gestation) fetal development periods, at levels of 15 to 28% of the maternal blood levels. Nursing Mothers It is not known whether Herceptin is excreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Trastuzumab was present in the breast milk of lactating cynomolgus monkeys given 12.5 times the recommended weekly human dose of 2 mg/kg of Herceptin. Infant monkeys with detectable serum levels of trastuzumab did not have any adverse effects on growth or development from birth to 3 months of age; however, trastuzumab levels in animal breast milk may not accurately reflect human breast milk levels. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from Herceptin, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of trastuzumab and the importance of the drug to the

mother. Pediatric Use The safety and effectiveness of Herceptin in pediatric patients has not been established. Geriatric Use Herceptin has been administered to 386 patients who were 65 years of age or over (253 in the adjuvant treatment and 133 in metastatic breast cancer treatment settings). The risk of cardiac dysfunction was increased in geriatric patients as compared to younger patients in both those receiving treatment for metastatic disease in Studies 5 and 6, or adjuvant therapy in Studies 1 and 2. Limitations in data collection and differences in study design of the 4 studies of Herceptin in adjuvant treatment of breast cancer preclude a determination of whether the toxicity profile of Herceptin in older patients is different from younger patients. The reported clinical experience is not adequate to determine whether the efficacy improvements (ORR, TTP, OS, DFS) of Herceptin treatment in older patients is different from that observed in patients <65 years of age for metastatic disease and adjuvant treatment. In Study 7 (metastatic gastric cancer), of the 294 patients treated with Herceptin 108 (37%) were 65 years of age or older, while 13 (4.4%) were 75 and over. No overall differences in safety or effectiveness were observed. OVERDOSAGE There is no experience with overdosage in human clinical trials. Single doses higher than 8 mg/kg have not been tested. PATIENT COUNSELING INFORMATION • Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Boxed Warning Cardiomyopathy]. • Advise pregnant women and women of childbearing potential that Herceptin exposure can result in fetal harm [see Warnings and Precautions and Use in Specific Populations]. • Advise women of childbearing potential to use effective contraceptive methods during treatment and for a minimum of six months following Herceptin [see Warnings and Precautions]. • Advise nursing mothers treated with Herceptin to discontinue nursing or discontinue Herceptin, taking into account the importance of the drug to the mother [see Use in Specific Populations]. • Encourage women who are exposed to Herceptin during pregnancy to enroll in MotHER- the Herceptin Pregnancy Registry (1-800-690-6720) [see Warnings and Precautions and Use in Specific Populations].

HERCEPTIN® [trastuzumab]Manufactured by:Genentech, Inc.A Member of the Roche Group1 DNA WaySouth San Francisco, CA 94080-4990

Initial US Approval: September 1998Revision Date: October 29, 2010Herceptin® is a registered trademark of Genentech, Inc.HER0000097200©2010 Genentech, Inc.

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8 FEBRUARY 2011 • VOLUME 2, ISSUE 1 AONNONLINE.ORG

Journal of Oncology ™

The Official Journal of the Academy of Oncology Nurse Navigators

NAVIGATION & SURVIVORSHIP®

PUBLISHING STAFFPu bl is h er

Philip [email protected]

ed it o r ia l d ir ec t o rChristin Melton

[email protected]

as s o c iat e ed it o rDawn Lagrosa

[email protected]

dir ec t o r , c l ien t s er v ic esJohn W. Hennessy

[email protected]

Pr o du c t io n Man ag erStephanie Laudien

bu s in es s Man ag erBlanche Marchitto

c ir c u l at io n dePar t Men [email protected]

FEBRUARY 2011 • VOL. 2, NO. 1TABLE OF CONTENTS

Journal of Oncology Navigation & Survivorship, ISSNapplied for; (online) is published 6 times a year byGreen Hill Healthcare Communications, LLC, 241Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831.Telephone: 732.656.7935. Fax: 732.656.7938. Copy -right ©2011 by Green Hill Health care Com -munications, LLC. All rights reserved. Journal ofOncology Navigation & Survivorship logo is a trademarkof Green Hill Healthcare Communications, LLC. Nopart of this publication may be reproduced or transmit-ted in any form or by any means now or hereafterknown, electronic or mechanical, including photocopy,recording, or any informational storage and retrievalsystem, without written permission from the publisher.Printed in the United States of America.

EDITORIAL CORRESPONDENCE should be ad -dressed to EDITORIAL DIRECTOR, Journal ofOncology Navigation & Survivorship (JONS), 241Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831.E-mail: [email protected]. YEARLY SUB-SCRIPTION RATES: United States and possessions:individuals, $50.00; institutions, $90.00; single issues,$5.00. Orders will be billed at individual rate until proofof status is confirmed. Prices are subject to change with-out notice. Correspondence regarding permission toreprint all or part of any article published in this jour-nal should be addressed to REPRINT PERMIS-SIONS DEPART MENT, Green Hill HealthcareCommunications, LLC, 241 Forsgate Drive, Suite205C, Monroe Twp, NJ 08831. The ideas and opinionsexpressed in JONS do not necessarily reflect those ofthe editorial board, the editorial director, or the pub-lisher. Publication of an advertisement or other productmention in JONS should not be construed as anendorsement of the product or the manufacturer’sclaims. Readers are encouraged to contact the manu-facturer with questions about the features or limitationsof the products mentioned. Neither the editorial boardnor the publisher assumes any responsibility for anyinjury and/or damage to persons or property arising outof or related to any use of the material contained in thisperiodical. The reader is advised to check the appropri-ate medical literature and the product information cur-rently provided by the manufacturer of each drug to beadministered to verify the dosage, the method andduration of administration, or contraindications. It isthe responsibility of the treating physician or otherhealthcare professional, relying on independent experi-ence and knowledge of the patient, to determine drugdosages and the best treatment for the patient. Everyeffort has been made to check generic and trade names,and to verify dosages. The ultimate responsibility, how-ever, lies with the prescribing physician. Please conveyany errors to the editorial director.

REVIEW ARTICLE

12 Maintenance Therapy for Non–Small Cell Lung Cancer: A Value-Based Approach to Improve Patient Care and OutcomesThis 2-part series evaluates the risks and benefits of maintenance therapycompared with retreating upon disease progression for patients with stageIIIB or IV non–small cell lung cancer.

COMMENTARIES

18 Maintenance Therapy in Non–Small Cell Lung Cancer:Personalized PerspectivesBy Corey J. Langer, MD

26 Nursing and Patient Management Considerations forMaintenance Therapy in Non–Small Cell Lung Cancer By Beth Eaby-Sandy, CRNP

FEATURE

28 Program Turns Cancer Survivors into Peer NavigatorsBy Dawn LagrosaA study that matched survivors of breast cancer with women just diagnosedwith the disease produced some surprising results and offers a model for peernavigation programs nationwide.

ABOUT THE COVERThe vibrant depiction of a cancer cell on the cover is No. 15 in a series of cancer cellimages created by artist Angela Canada Hopkins. After her father succumbed to can-cer in June 2001, she decided the best way to overcome her new “enemy” was byembracing it through her art. Each painting begins with a slide of a cancer cell, whichCanada Hopkins then deconstructs and reinterprets using triumphant colors and boldbrush strokes. Each canvas telegraphs a message of hope to cancer sufferers, cancer sur-vivors, and their loved ones. Canada Hopkins is a full-time artist and resides inLoveland, Colorado, with her husband, James.

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LEADERSHIP COUNCILLinda Fleisher, MPH, PhD(c)Fox Chase Cancer CenterCheltenham, Pennsylvania

Sharon Gentry, RN, MSN, AOCN, CBCNDerrick L. Davis ForsythRegional Cancer CenterWinston-Salem, North Carolina

Pamela Matten, RN, BSN, OCNSt. Joseph HospitalOrange, California

Nicole Messier, RNVermont Cancer CenterBurlington, Vermont

Elaine Sein, RN, BSN, OCN, CBCNFox Chase Cancer Center PartnersRockledge, Pennsylvania

Lillie Shockney, RN, BS, MASJohns Hopkins Breast CenterJohns Hopkins UniversitySchool of MedicineBaltimore, Maryland

Tricia Strusowski, MS, RNHelen F. Graham Cancer CenterChristiana Care Health SystemNewark, Delaware

Jay R. Swanson, RN, BSN, OCNSt. Elizabeth Cancer InstituteLincoln, Nebraska

EXECUTIVE DIRECTORSean T. [email protected]

O n behalf of the Academy of Oncology Nurse Navigators(AONN) leadership council, I am excited to introduce theJournal of Oncology Navigation & Survivorship (JONS), a pub-

lication designed to meet the needs of oncology nurse and patientnavigators. Each issue will feature topics related to patient navigationand survivorship care, offering original research, best practices, inter-views, case reports, study highlights, and more. Our goal is to enhance the value of your AONN membership by

giving you additional tools to improve care for your patients at every stage. JONS alsooffers a platform for you to share your research and views on navigation and survivor-ship issues with your colleagues.In the past 2 years, we have seen widespread adoption of patient navigation and sur-

vivorship care in oncology. Although the US healthcare system is in flux, with an agingpopulation and uncertain healthcare policies, the looming shortage of oncologists andongoing need to reduce medical spending will drive greater reliance on models of pa -tient care like patient navigation. Additionally, the American College of Surgeons’Commission on Cancer expects to begin implementing new standards in the comingyear that will likely foster an increase in the number of centers, hospitals, and commu-nity clinics recognizing patient navigation and survivorship care as essential services.This is a critical time for navigation; everyone involved benefits by working together

to define the reach and practices of this evolving profession. The individual and collec-tive efforts of AONN members to strengthen and grow this academy of dedicated oncol-ogy professionals are instrumental in ensuring that we have a voice in shaping the futureof navigation and survivorship. As nurse and patient navigators assume a more central role in the delivery of cancer

care, you will need more information and guidance. JONS reflects the academy’s commit-ment to stay on top of those needs and reinforces our support for evidence-based practices. This publication belongs to you. We welcome your manuscript submissions, ideas, and

assistance in making JONS the resource AONN members need and deserve. We areinterested in articles from AONN members and other medical professionals on an arrayof topics, including navigation and survivorship, for all cancer types and in all patientpopulations. You are invited to submit perspectives, studies, or reviews about programmodels, psychosocial issues, long-term management, community outreach, patient edu-cation, tracking processes, or any topic you feel supports AONN’s efforts to improve carefor patients with cancer. For authorship guidelines or to submit a manuscript for consideration, visit us at

www.AONNonline.org/submit-manuscript. Please direct any comments, inquiries, orrequests to join our editorial advisory board to Christin Melton, the journal’s editorialdirector, at [email protected].

Thank you for being an active supporter of the academy.

Sean T. WalshExecutive DirectorAcademy of Oncology Nurse Navigators (AONN)

AN EXPANDED RESOURCE FORNAVIGATING CANCER CARE

MISSION STATEMENT

The Journal of OncologyNavigation and Survivorship(JONS) promotes reliance on evidence-based practices in navigating patients withcancer and their caregiversthrough diagnosis, treatment,and survivorship. JONS alsoseeks to strengthen the roleof nurse and patient naviga-tors in cancer care by servingas a platform for these profes-sionals to disseminate originalresearch findings, exchangebest practices, and find support for their growing community.

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Conference Overview

All clinical and nonclinical professionals involved or interestedin patient navigation and survivorship. This conference will enhance the skills and knowledge of:• Oncology Nurse Navigators• Patient Navigators • Oncology Nurses &

Nurse Practitioners

• Administrators • Oncology Social Workers • Case Managers • Practice Managers

Who Should Attend

• Navigation and Survivorship Program Planning and Implementation

• Best Practices• Collaborative Navigation• Psychosocial Care and Distress Management• Compassion Fatigue• Tumor-site Focused Breakouts/Workshops

Topics Include

Register Online atwww.AONNonline.org/conference

NAVIGATING PATIENTS ACROSS THECONTINUUM OFCANCERCARETM

AONN’s second annual conference will further advance nav-igation and survivorship in cancer care through the addition ofa variety of sessions, topics, and networking events. Attendeeswill receive a thorough understanding of the state of navigationand survivorship in today’s evolving healthcare system.

CURRENT MEMBERS - $295(Save $200 off full registration of $495.)

NEW MEMBERS - $335(Registration includes member dues.)

NONMEMBERS - $495

CONFERENCE LOCATIONSan Antonio Marriott Rivercenter Hotel

101 Bowie StreetSan Antonio, TX 78205-3901

Phone: 210.223.1000

Second Annual Navigation and Survivorship ConferenceSeptember 16-18, 2011 - San Antonio, Texas

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Second Annual Navigation and Survivorship ConferenceSeptember 16-18, 2011 - San Antonio, Texas

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Rev iew


DisclosureLoretta Fala participated in

the development of this article. She has no financial

relation ships to disclose.

MAINTENANCE THERAPY FOR NON–SMALL CELL LUNG CANCER:A Value-Based Approach to Improve Patient Care andOutcomes, Part I of II

L ung cancer is the most common type of can-cer in the United States.1,2 An estimated221,520 people (115,750 men and 105,770

women) will be diagnosed with cancer of the lungand bronchus in 2010, and only 15.8% of patientswith lung cancer survive 5 years or more after diag-nosis.3 Lung cancer accounts for more cancerdeaths in the United States than any other type ofcancer.4 Advances in surgical techniques and com-bined therapies have helped increase the 1-yearrelative survival for patients with lung cancer to42% in 2002-2005, from 35% 2 decades earlier in1975-1979.2 Although the 5-year survival rate isgreater than 50% for early-stage disease, unfortu-nately only 15% of lung cancers are detected whenthe disease is still localized.2According to the National Cancer Institute,

lung cancer costs the American public an esti-mated $10.3 billion a year and is the thirdcostliest cancer after breast cancer and colorec-tal cancer.5 Furthermore, lung cancer tops thelist in terms of lost productivity, accounting for$36.1 billion in lost lifetime earnings—lost pro-ductivity costs 3 times greater than those associ-ated with breast cancer or colorectal cancer.5The financial burden of cancer may continue toexpand with the aging of the US population,improved survival, and the increasing cost ofcancer treatments.5The median age at diagnosis of lung cancer is 71

years.3 As the baby boom generation (people bornbetween 1946 and 1964) reaches age 65 and olderover the next 2 decades,6 the number ofAmericans in this age-group is expected toincrease by 36% from 2010 to 2020.7 Because lungcancer is widespread and carries a dire prognosis,urgency prevails in the search for better therapiesand improved outcomes for patients. Efforts areparticularly robust in non–small cell lung cancer(NSCLC), which accounts for 85% of all cases.4For patients with advanced NSCLC, mainte-

nance therapy may help control the disease andextend a patient’s life.8 Administered after induc-

tion chemo therapy and generally in lower dosesthan initial chemotherapy, maintenance therapyoften involves standard chemotherapy (an agentused in the initial treatment plan therapy oranother drug), or it may include a combination oftherapies, including vaccines, hormones, or otherdrugs.8 Decisions about maintenance therapyinclude consideration of the associated benefits,risks, and costs, as well as patient-specific factorsand preferences. Two chemotherapy agents haverecently received US Food and Drug Admin -istration (FDA) approval for the maintenancetherapy of patients with advanced NSCLC.Recent advances have also yielded a number of

novel agents that target specific molecular path-ways in tumor cells, and research on these discov-eries is ongoing. The molecular/genetic profilingof NSCLC can now be used to characterizetumors by their expression of specific markers.These molecular profiles hold promise for theirpotential in predicting a response, or resistance,to specific standard or novel therapies and inidentifying a benefit from a new or standardagent, based on clinical trial evidence.9

MAINTENANCE THERAPY BRINGS A NEW TREATMENT APPROACH FORADVANCED NSCLC

Maintenance therapy, a relatively new para-digm in the treatment of NSCLC, constitutesa shift from the past paradigm of treatingrecurrent disease.10 However, maintenancetherapy has been used for years in the treat-ment of patients with acute lymphocyticleukemia and acute myeloid leukemia tolower the risk of disease recurrence, and it isalso being studied in a number of other can-cers.8 His tologic information about the lungcarcinoma is particularly useful for tailoringmaintenance therapy toward improving out-comes for patients with NSCLC.11 Molecu -

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AONNONLINE.ORG JOURNAL OF ONCOLOGY NAVIGATION & SURVIVORSHIP 13

Rev iew

larly targeted agents, including those thatinhibit epidermal growth factor receptor(EGFR) and vascular endothelial growth fac-tor, also represent a crucial inroad into per-sonalized therapy for patients with lung cancer.9Maintenance therapy has been shown to pro-

long progression-free survival (PFS) and overallsurvival (OS) in the appropriate patients, based onrandomized, controlled studies of 2 agents—peme-trexed and erlotinib.12-14

PemetrexedIn July 2009, pemetrexed was the first drug to beFDA-approved for maintenance therapy of ad -vanced or metastatic lung cancer.15 Pemetrexed, afolate analog metabolic inhibitor, received thisnew indication specifically for patients with non-squamous NSCLC that has not progressed after 4cycles of platinum-based first-line chemotherapy.16Pemetrexed is also indicated for initial treatmentin combination with cisplatin, as well as after priorchemotherapy as a single agent in patients withlocally advanced or metastatic nonsquamousNSCLC.16Based on a randomized, double-blind, phase 3

international study (N = 663), patients withstage IIIB or IV NSCLC (without progress after4 cycles of platinum-based chemotherapy) whowere treated with pemetrexed showed a signifi-cant improvement in PFS: 4.3 months (95%confidence interval [CI], 4.1-4.7) compared with2.6 months (95% CI, 1.7-2.8) in the placebo group(hazard ratio [HR], 0.50; 95% CI, 0.42-0.61; P <.001).13 The pemetrexed group also showed asignificantly greater OS: 13.4 months (95% CI,11.9-15.9) versus 10.6 months (95% CI, 8.7-12.0)in the placebo group (HR, 0.79; 95% CI, 0.65-0.95; P = .012). No pemetrexed-associated mortal-ities occurred.13 Grade 3 or higher adverse eventswere more frequent in the pemetrexed group thanin the placebo group, and included fatigue (5% vs1%) and neutropenia (3% vs 0%).13 The mostcommon any-grade adverse reactions comparedwith placebo were nausea (19% vs 6%) andanorexia (19% vs 5%).16

ErlotinibIn April 2010, the FDA approved an expandedindication for erlotinib, a tyrosine kinaseinhibitor (TKI), as a maintenance treatment forpatients with locally advanced or metastaticNSCLC whose disease has not progressed after

4 cycles of platinum-based first-line chemothera-py.17,18 Erlotinib is also indicated for the treatmentof locally advanced or metastatic NSCLC afterfailure of at least 1 prior chemotherapy regimen.18Results from a randomized, double-blind, inter-

national phase 3 study (N = 889) showed a signifi-cant median PFS of 12.3 weeks for patients in theerlotinib group versus 11.5 weeks for the placebogroup (HR, 0.71; 95% CI, 0.62-0.82; P <.001).14 Inpatients with EGFR-positive immunohistochem-istry treated with erlotinib, compared with EGFR-positive patients receiving placebo, PFS was alsosignificantly longer in the erlotinib group (12.3weeks) versus the placebo group (11.1 weeks; HR,0.69; 95% CI, 0.58-0.82; P <.001).14 The study alsoshowed an improvement in OS of 1 month witherlotinib versus placebo as maintenance therapy(HR, 0.81; 95% CI, 0.70-0.95; P = .009).18Serious adverse events were reported in 11% of

the patients in the erlotinib group compared with8% in the placebo group; the most common seri-ous adverse events were pneumonia (2% witherlotinib vs <1% with placebo).14 The most com-mon grade 3 or higher adverse events includedrash (9% in the erlotinib group vs 0% in theplacebo group) and diarrhea (2% in the erlotinibgroup vs 0% in the placebo group).14 The mostcommon any-grade adverse reactions comparedwith placebo were rash (49.2% vs 5.8%) and diar-rhea (20.3% vs 4.5%).18

MAINTENANCE THERAPY: BENEFITS,RISKS, AND COSTS

Maintenance therapy is associated with severalpotential benefits, including preventing therecurrence of cancer, slowing disease growth,and prolonging life.8 However, these benefitsmust be weighed against potential risks, whichinclude increased side effects, more frequentdoctor visits, and drug resistance.8 Maintenancetherapy may also be associated with highertreatment costs.8 In addition, the data on thesurvival benefits associated with maintenancetherapy are limited,8 as are data on the quality oflife associated with maintenance therapy8,19—inparticular, the cumulative toxicity of prolongedchemotherapy.19 Other study limitations includethe variability in measurable end points such asthe definition of progression (in PFS) and fre-quency of response assessment; additionally, the

Maintenancetherapy has beenshown to prolongprogression-freesurvival and overallsurvival in theappropriate patients,based onrandomized,controlled studies of2 agents—pemetrexed anderlotinib.

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use of multiple agents in the poststudy settingmay confound the impact of maintenance treat-ment.19 Although patients receiving maintenancetherapy may not have the opportunity of a reprievefrom chemotherapy during the “wait-and-see” peri-od, this period is often accompanied by anxietyabout disease progression or recurrence.19The rising cost of cancer care persists as a

major healthcare challenge. The AmericanSociety of Clinical Oncology (ASCO) encour-ages members to discuss the cost of care direct-ly with patients.10 Although maintenancechemotherapy for advanced NSCLC is associat-ed with increased costs, it may decrease costsrelated to palliative radiotherapy and hospitaladmissions resulting from deteriorating per-formance status.12 Furthermore, the concept ofextended survival—in terms of additionalmonths, or even weeks of life—may representan immeasurable benefit for patients and theirloved ones.

THE IMPORTANCE OF HISTOLOGY ANDMOLECULAR BIOMARKERS

Lung cancer is classified as either non–small cellor small cell, based on its biology, therapy, andprognosis.4 The 5-year survival rate for NSCLCis 17%, compared with a lower survival rate of6% for small-cell lung cancer.2 NSCLC is catego-rized into 2 types: nonsquamous carcinoma (ade-nocarcinoma, large-cell carcinoma, and others)and squamous cell carcinoma.4 Squa mous celllung carcinoma accounts for 25% of lung cancersin the United States, whereas large cell carcino-ma (nonsquamous) accounts for 10% to 20% ofall lung cancers.20Identifying the histologic subtype of NSCLC

is an essential step in selecting the appropriatetherapy, and it may also be particularly usefulwhen augmented by molecular testing.21 Forexample, the detection of the bronchoalveolarsubtype of NSCLC adenocarcinoma may suggesta specific treatment strategy, particularly if it car-ries specific mutations in the EGFR tyrosinekinase domain, suggesting it will respond totreatment with an EGFR TKI.21Several of the key predictive molecular bio-

markers in the treatment of NSCLC include4:• Presence of the EGFR exon 19 deletion orexon 21 L858R mutation is associated with a

treatment benefit from EGFR TKI therapy• High levels of ERCC1 expression are associ-ated with a poor response to platinum-basedchemotherapy

• The presence of KRAS mutations is associat-ed with a lack of benefit from platinum/vinorelbine chemotherapy or from EGFRTKI therapy

• High levels of RRM1 expression are associat-ed with a poor response to gemcitabine-basedchemotherapy.

Patients with EGFR mutations exon 19 dele-tion and L858R mutation have shown a signifi-cantly better response to erlotinib or gefitinib(both EGFR TKI agents), with initial retrospec-tive studies suggesting that an estimated 90% ofpatients with a tumor response to these agentshad mutations, whereas patients without aresponse did not have these mutations.4According to the National Compre hen sive

Cancer Network (NCCN) practice guidelinesfor NSCLC, pathologic evaluation should beperformed to classify the lung cancer, determineits extent of invasion, determine the status ofsurgical margins, and identify molecular abnor-malities that may predict the benefit of, or resist-ance to, EGFR TKI therapy.4 Pre operative assess-ment may include bronchial brushings orwashings, fine-needle aspiration biopsy, coreneedle biopsy, endobronchial biopsy, trans-bronchial biopsy, as well as sampling of mediasti-nal lymph nodes to stage the disease and helpdetermine therapeutic options. In traoperative(lobectomy or pneumonectomy) evaluation mayinclude determining the surgical resection mar-gin status, diagnosing any incidental nodulesfound during the surgery, or checking the statusof regional lymph nodes.4 Postoperative patholo-gy provides information necessary for classifyingthe tumor type, stage, and prognostic factors.Accord ing to NCCN guidelines, the surgicalpathology report should use the histologic classi-fications established by the World HealthOrganization for lung carcinomas.4Adequate tissue sampling may provide the key

to identifying the treatment most appropriate fora specific patient and improving the likelihoodof identifying an effective treatment as early aspossible.21 Refinements in histology and theevolving role of molecular testing will undoubt-edly play a role in predicting responses to partic-ular treatments for NSCLC.21

Althoughmaintenance

chemotherapy foradvanced NSCLC is

associated withincreased costs, it

may decrease costsrelated to palliative

radiotherapy andhospital admissions.

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Rev iew

CLINICAL PRACTICE GUIDELINES FORMAINTENANCE THERAPY

The NCCN practice guidelines for NSCLC, whichwere updated in March 2010, added a new sectionwith recommendations on maintenance therapy(Table). Although ASCO released a clinical prac-tice guideline update on chemotherapy for stage IVNSCLC, the guideline went to press in 2009 with-out the opportunity of a comprehensive data reviewon recent data supporting the indication/use ofpemetrexed for maintenance therapy in patientswith advanced NSCLC.22 In this 2009 update,ASCO included an announcement that an updatewould be forthcoming on consideration of relevantdata on the use of pemetrexed in maintenancetherapy. Results of 2 studies evaluating erlotinib asmaintenance therapy were also anticipated by theASCO review committee at the time of the 2009guideline publication.22In June 2010, the National Institute for Health

and Clinical Excellence, based in London, issuedguidance to the National Health Service, UnitedKingdom, recommending pemetrexed for themaintenance treatment of NSCLC.23 The guidancestates that pemetrexed is recommended as anoption for maintenance therapy in people withlocally advanced or metastatic NSCLC other thanpredominantly squamous cell histology if the can-cer has not progressed immediately after platinum-based chemo therapy in combination with gem -citabine, paclitaxel, or docetaxel.23,24 It also statesthat people who have received pemetrexed in com-bination with cisplatin as first-line therapy cannotreceive pemetrexed maintenance treatment.23,24

MAINTENANCE THERAPYCONSIDERATIONS

Treatment considerations include the stage of thecancer and invasion status, the type of cancer, thepatient’s performance status, patient-specific prefer-ences, the costs of treatment, as well as otherpatient- and agent-specific factors. Evidence-basedclinical practice guidelines can be a valuable decision-support resource for clinicians.Selecting the appropriate patient population, as

characterized by histologic (nonsquamous) ormolecular (EGFR mutation) profile, is a guidingfactor in selecting the appropriate maintenancetherapy.19 Furthermore, the use of a well-character-

ized tumor profile as a tool for selecting the appro-priate patients for maintenance therapy mayimprove the therapeutic index, and therebyimprove the survival benefit in these patients.19 Inaddition, identifying predictive biomarkers for specific agents used in maintenance therapy mayhelp to improve the benefits and reduce risks.Pemetrexed is a maintenance therapy option forpa tients with nonsquamous histology.4 Moreover, amolecular-based strategy may be important forselecting the appropriate subgroup of patients bestsuited for maintenance therapy with erlotinib.19The risks and benefits of maintenance therapy

must be considered and weighed, along with thesafety, efficacy, and tolerability of the agents used inthis setting. Similarly, the risks associated withdelaying additional therapy must also be consid-ered: a delay strategy may be associated with a faster

Table NCCN Guideline Recommendations (March 2010) for NSCLC Maintenance Therapy

Continuation Maintenance Therapya Switch Maintenance Therapyb

Continue with biologic agents (giveninitially in combination with conven-tional chemotherapy) until disease pro-gression or unacceptable toxicity (perclinical trial design that led toapproval):• Bevacizumab may be continuedbeyond 4-6 cycles of platinum-doublet chemotherapy given withbevacizumab (Category 1)

• Cetuximab may be continued beyond4-6 cycles of therapy with cisplatin,vinorelbine, and cetuximab(Category 1)

• Pemetrexed may be continued after4-6 cycles of therapy with cisplatinand pemetrexed for patients withnonsquamous cell carcinoma(Category 2B)

Initiation of pemetrexed orerlotinib after first-line chemo -therapy (4-6 cycles) in patientswithout disease progression, basedon 2 recent studies demonstratinga benefit in progression-free sur-vival and overall survival:• Pemetrexed may be initiatedafter 4-6 cycles of first-line plat-inum-doublet chemotherapy inpatients with nonsquamous cellcarcinoma (Category 2B)

• Erlotinib may be initiated after4-6 cycles of first-line platinum-doublet chemotherapy(Category 2B)

• Docetaxel may be initiated after4-6 cycles of first-line platinum-doublet chemotherapy(Category 3)

• No randomized trial data are available to support continuing mainte-nance of conventional cytotoxic agents beyond 4-6 therapy cycles.

• Pemetrexed is not recommended for patients with squamous cell carcinoma.

• Close follow-up without therapy is a reasonable alternative to switch maintenance.

aContinuation maintenance = use of at least 1 of the agents administered as first-line therapy.bSwitch maintenance = initiation of an agent that was not included as part of the first-line treatment regimen.NCCN indicates National Comprehensive Cancer Network; NSCLC, non–small cell lungcancer.Data adapted from reference 4. Refer to that source for definitions of evidence categories.

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disease progression and shorter survival time thanimmediate additional therapy.25,26 Extendingchemotherapy, particularly with a third-generationregimen, has been shown to improve PFS substan-tially and OS modestly.26

CONCLUSION

Maintenance therapy represents a new treatmentparadigm for patients with advanced NSCLC,given its potential for improved survival. Ideally,the agent selected for maintenance therapy shouldbe well-tolerated by the patient, have minimal sideeffects/cumulative toxicities, and demonstrateimproved patient outcomes.19 The histology of thecarcinoma is an important tool in tailoring mainte-nance therapy for a specific patient. In addition,molecular profiling can help characterize tumorsand predict response or resistance after standard ornovel therapies.27 Mole cular tests will continue toplay an important role in redefining patients withNSCLC into specific subgroups that may respondto different optimal treatment pathways.22

The risks and benefits of maintenance therapymust be considered and addressed with the patient.Similarly, the risks and benefits of a delayed/wait-and-see treatment approach must likewise beweighed carefully. The future holds promise, basedon recent advances that foster targeted, personal-ized treatment approaches with the potential toimprove response and survival for patients withadvanced NSCLC. g

References1. National Cancer Institute, National Institutes of Health.

Common cancer types. www.cancer.gov/cancertopics/typescommoncancers. Accessed September 21, 2010.

2. American Cancer Society. Cancer Facts & Figures 2010.Atlanta, GA: American Cancer Society; 2010.

3. National Cancer Institute, National Institutes of Health.Surveillance, Epidemiology, and End Results. SEER stat factsheets: lung and bronchus. http://seer.cancer.gov/statfacts/html/lungb.html. Accessed September 20, 2010.

4. National Comprehensive Cancer Network. NCCN ClinicalPractice Guidelines in Oncology. Non-small cell lung cancer,V.2.2010. March 5, 2010. www.nccn.org/professionals/physician_gls/PDF/nscl.pdf. Accessed September 15, 2010.

5. Wang BH. The financial burden of cancer—NCI benchmarks.April 23, 2010. http://benchmarks.cancer.gov/2010/04/the-financial-burden-of-cancer/. Accessed September 20, 2010.

6. Vincent GK, Velkoff VA. The Next Four Decades, the OlderPopulation in the United States: 2010 to 2050. Current PopulationReports, P25-1138. Washington, DC: US Census Bureau; May2010.

7. US Department of Health and Human Services, Ad -ministration on Aging. A Profile of Older Amer icans: 2007.www.agingcarefl.org/aging/AOA-2007profile.pdf. AccessedAugust 27, 2010.

8. American Society of Clinical Oncology. Explaining mainte-

nance therapy. Cancer.net. Updated February 22, 2010.www.cancer.net/patient/All+About+Cancer/Cancer.Net+Feature+Articles/Treatments%2C+Tests%2C+and+Procedures/Explaining+Maintenance+Therapy. Accessed September20, 2010.

9. Herbst RS, Lippman SM. Molecular signatures of lung cancer—toward personalized therapy [editorial]. N Engl J Med. 2007;356:76-78.

10. Peck P. Maintenance pemetrexed extends NSCLC survivalby three months. Medpage Today. May 30, 2009. www.medpagetoday.com/tbprint.cfm?tbid=14437. Accessed Sep -tember 22, 2010.

11. Lilly receives fourth FDA approval for ALIMTA—firstchemotherapy approved as maintenance therapy for non-squamous non-small cell lung cancer. Medical News Today.July 8, 2009. www.medicalnewstoday.com/articles/156659.php. Accessed September 22, 2010.

12. Eaton KD. Maintenance chemotherapy in non-small cell lungcancer. J Natl Compr Canc Netw. 2010;8:815-821.

13. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance peme-trexed plus best supportive care versus placebo plus best support-ive care for non-small-cell lung cancer: a randomized, double-blind, phase 3 study. Lancet. 2009;374:1432-1440. EpubSeptember 18, 2009.

14. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as mainte-nance treatment in advanced non-small-cell lung cancer: amulticentre, randomized, placebo-controlled phase 3 study.Lancet Oncol. 2010;11:521-529. Epub May 20, 2010.

15. Riley K. FDA approves first maintenance drug therapy foradvanced lung cancer [press release]. July 6, 2009. US Food andDrug Administration. www.fda.gov/News/Events/Newsroom/PressAnnouncements/ucm170515.htm. Accessed Sept ember22, 2010.

16. Alimta (pemetrexed disodium) [package insert]. Indianapolis,IN: Eli Lilly and Company; 2010.

17. Waknine Y. FDA approves use of erlotinib as maintenance ther-apy for advanced non-small cell lung cancer [press release].April 20, 2010. www.medscape.com/viewarticle/720446.Accessed September 22, 2010.

18. Tarceva (erlotinib) [package insert]. Melville, NY: OSIPharmaceuticals Inc; and South San Francisco, CA:Genentech; 2010.

19. Owonikoko TK, Ramalingam SS, Belani CP. Maintenancetherapy for advanced non-small cell lung cancer: current status,controversies, and emerging consensus. Clin Cancer Res.2010;16:2496-2504.

20. Cleveland Clinic. Lung cancer overview. Reviewed October 23,2008. http://my.clevelandclinic.org/disorders/Lung_Cancer/hic_Lung_Cancer.aspx. Accessed September 23, 2010.

21. Neal JW. Histology matters: individualizing treatment in non-small cell lung cancer [editorial]. Oncologist. 2010;15:3-5. EpubJanuary 19, 2010.

22. Azzoli CG, Baker S Jr, Temin S, et al. American Society ofClinical Oncology clinical practice guideline update onchemotherapy for stage IV non-small-cell lung cancer. J ClinOncol. 2009;27:6251-6266.

23.NICE recommends pemetrexed for the maintenance treat-ment of non-small-cell lung cancer [press release]. MedicalNews Today. June 23, 2010. www.medicalnewstoday.com/articles/192709.php. Accessed September 22, 2010.

24.National Institute for Health and Clinical Excel lence(NICE). Final appraisal determination—pemetrexed for themaintenance treatment of non-small cell lung cancer. March2010. www.nice.org.uk/nicemedia/live/12091/48303/48303.pdf. Accessed Septem ber 22, 2010.

25. Belani CP, Liao J. Maintenance therapy for non-small cell lungcancer [comment]. Lancet. 2010;375:281-282; comment onStinchcombe T, West H comment in: Lancet. 2009;374:1398-1400.

26.Soon YY, Stockler MR, Askie LM, Boyer MJ. Duration ofchemotherapy for advanced non-small-cell lung cancer: asystematic review and meta-analysis of randomized trials. J Clin Oncol. 2009;27:3277-3283. Epub May 26, 2009.

27.Herbst RS, Heymach JV, Lippman SM. Molecular origins ofcancer. N Engl J Med. 2008;359:1367-1380.

TON1110_4_TON1110_FINAL 2/24/11 4:35 PM

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TON1110_4_TON1110_FINAL 2/24/11 4:36 PM

Rev iew


C o m m e n t a r y

Maintenance therapy has begun to emerge as atreatment standard for patients with non–smallcell lung cancer (NSCLC) whose disease has notprogressed after 4 to 6 cycles of frontline chemo -therapy. But some caveats still apply. Althoughit may be suitable for fit, motivated patients whoare highly symptomatic at the time of presenta-tion, it is not yet clear if maintenance therapyshould be routine. Based on the phase 3 data, use of pemetrexed is

certainly justified in patients whose advancedNSCLC has stabilized or improved after 4 ormore cycles of frontline therapy with a platinat-ing agent, plus either gemcitabine or a taxane.Pemetrexed is particularly well tolerated and con-venient, al though its “maintenance” benefits areconfined to nonsquamous histology and its utilityis as yet unproven in patients who have receivedpemetrexed and/or bevacizumab as part of theirfirst-line treatment.Similarly, erlotinib has yielded a survival advan-

tage compared with placebo in the maintenancesetting, although the extent of its benefit seems lesspronounced compared with pemetrexed.

Prolonged Initial ChemotherapyProlonged treatment with initial chemotherapy(eg, 6 vs 3 cycles or indefinite treatment vs 4cycles) has shown no overall survival (OS) bene-fit1-3; neither have prior maintenance studies ofattenuated dosing or single agents yielded a sur-vival benefit, although “intriguing trends” in timeto progression have been observed in underpow-ered efforts.4,5Switching to a new compound for maintenance

therapy demonstrated some benefit in the well-designed study by Fidias and colleagues, whichevaluated immediate versus delayed docetaxelupon disease progression after first-line carbo-platin/gemcitabine.6 Pro gres sion-free survival(PFS) improved from 2.7 months in the delayedarm to 5.7 months with maintenance (P <.001),and median OS trended better (12.3 vs 9.7months; P = .085). In addition, a recent meta-

analysis documented a 30% reduction in diseaseprogression using maintenance therapy with athird-generation regimen compared with mainte-nance with older regimens.7

Determining the Optimal MaintenanceTherapy AgentThe study by Fidias and colleagues laid the ground-work for pemetrexed as maintenance afterchemotherapy,6 which was evaluated in a recentphase 3 study by Ciuleanu and colleagues.8Patients were randomized 2:1 to pemetrexed orintravenous placebo. Disease progression wasreduced by 40% (P <.001) overall and by 53% inpatients with nonsquamous histology (P <.001),and deaths were reduced by 21% (P = .012) and30% (P = .002), respectively. Pemetre xed wasreasonably well-tolerated and devoid of cumula-tive toxicity. Benefits were particularly pro-nounced in patients with nonsquamous histology(they had a more than 5-month survival advan-tage); there was no PFS or OS advantage in thosewith squamous histology.8Although this was the first randomized, double-

blind, placebo-controlled trial to show a signifi-cant survival benefit for maintenance treatment,one still needs to exercise caution in basing clini-cal decisions on this study. Maintenance therapy is unrealistic for many

patients due to early disease progression, comor-bidities, and patient desire to stop treatment.Pemetrexed is of no value to patients with squa-mous histology and is unproven in patients whohave received first-line pemetrexed or bevacizu -mab. Furthermore, the survival improvement inthe Ciuleanu study would be more impressive hadthere been mandatory crossover to pemetrexed atthe time of disease progression in the control arm;unlike the Fidias trial, mandatory crossover wasnot instituted in this trial. It is noteworthy that<20% of enrollees in the control arm receivedpemetrexed at the time of disease progression,although a majority received a standard second-line treatment.

Maintenance Therapy in NSCLC: Personalized PerspectivesBy Corey J. Langer, MDDirector of Thoracic Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia

DisclosureThe author acknowledges

grant/research support fromBristol-Myers Squibb,Genentech, ImClone,

Eli Lilly and Company,OSI, and Pfizer.

He is on the speaker’sbureau for Genentech,

ImClone-BMS, Eli Lillyand Company, and OSI,

and is a scientific advisor toAbbott, Abraxis, Amgen,

AstraZeneca, Bayer-Onyx,Biodesix, Bristol-Myers

Squibb, Caris DX,Clarient, Genentech,

ImClone, Eli Lilly andCompany, Morphotek,

Novartis, Pfizer, and sanofi-aventis.

TON1110_4_TON1110_FINAL 2/24/11 4:36 PM


Rev iew

Many patients look forward to the prospect of atherapeutic holiday. If patients are closely moni-tored once they have completed first-line therapy,there is often enough time to implement second-line treatment when disease progresses beforesymptoms have taken over. Finally, cost is the 800-lb gorilla in the room. Recent analyses of peme-trexed maintenance suggest a minimum incremen-tal cost of >$120,000 per life-year saved.9A recent phase 2 study evaluated pemetrexed

plus bevacizumab for maintenance after 6 initialcycles of carboplatin, pemetrexed, and bevacizu -mab.9 Median PFS was 9.3 months and medianOS was 14 months.10 Many practitioners areusing this regimen increasingly in bevacizumab-eligible patients. These encouraging findingshave led to a large, planned randomized phase 3trial in the Eastern Cooperative Oncology Group(ECOG) 5508, which just opened and will ran-domize 1282 patients to bevacizumab, peme-trexed, or to a combination of bevacizumab andpemetrexed after 4 cycles of initial therapy withpaclitaxel/carboplatin/bevacizumab. In addition,a separate phase 3 trial, POINT-BREAK, willcompare this regimen to the “winning” arm ofECOG 4599 (a combination of paclitaxel, carbo-platin, and bevacizumab), which yielded a signif-icant and clinically meaningful survival advan-tage in this setting compared with chemotherapyalone. Finally, in Europe, pemetrexed mainte-nance is being compared with “observation” inpatients who have stabilized or responded to a“standard” pemetrexed/cisplatin regimen.

Erlotinib MaintenanceErlotinib has shown value as a maintenance agentin 2 key studies. The Sequential Tarceva® inUnresectable NSCLC (SATURN) trial foundthat erlotinib reduced the risk of progression by29% (P <.001) and offered a 1-month OS benefit(P = .0088).11 In the Assessment of Treatmentwith Lisinopril And Survival (ATLAS) trial,maintenance therapy with erlotinib plus beva-cizumab improved PFS by 39%, or by approxi-mately 1 month (P = .0012), but no OS differencewas shown.12 Moreover, toxicity associated withthis approach is not trivial.

ConclusionsDocetaxel, pemetrexed, and erlotinib are eachapproved in the second-line setting, and all have

shown a PFS benefit as maintenance therapy andat least a trend toward improved survival, if not astatistically significant increase in survival. Todate, both pemetrexed and erlotinib are US Foodand Drug Administration–approved for mainte-nance therapy. At the end of the day, treatmentshould be individualized for all patients, takinginto account not only clinical outcomes butpatients’ personal preferences, disease burden, andcomorbidities.g

References1. Socinski MA, Schell MJ, Peterman A, et al. Phase III trialcomparing a defined duration of therapy versus continuoustherapy followed by second-line therapy in advanced-stageIIIB/IV non-small-cell lung cancer. J Clin Oncol. 2002;20:1335-1343.

2. von Plessen C, Bergman B, Andresen O, et al. Palliativechemotherapy beyond three courses conveys no survival orconsistent quality-of-life benefits in advanced non-small-celllung cancer. Br J Cancer. 2006;95:966-973.

3. Smith IE, O’Brien ME, Talbot DC, et al. Duration ofchemotherapy in advanced non-small-cell lung cancer: a ran-domized trial of three versus six courses of mitomycin, vinblas-tine, and cisplatin. J Clin Oncol. 2001;19:1336-1343.

4. Belani CP, Barstis J, Perry MC, et al. Multicenter, randomizedtrial for stage IIIB or IV non-small-cell lung cancer using week-ly paclitaxel and carboplatin followed by maintenance weeklypaclitaxel or observation. J Clin Oncol. 2003;21:2933-2939.

5. Brodowicz T, Krzakowski M, Zwitter M, et al. Cisplatin andgemcitabine first-line chemotherapy followed by maintenancegemcitabine or best supportive care in advanced non-small celllung cancer: a phase III trial. Lung Cancer. 2006;52:155-163.

6. Fidias P, Dakhil S, Lyss A, et al. Phase III study of immediatecompared with delayed docetaxel after front-line therapy withgemcitabine plus carboplatin in advanced non-small cell lungcancer. J Clin Oncol. 2009;27:591-598.

7. Soon YY, Stockler MR, Askie LM, Boyer MJ. Duration ofchemotherapy for advanced non-small-cell lung cancer: a sys-tematic review and meta-analysis of randomized trials. J ClinOncol. 2009;27:3277-3283.

8. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenancepemetrexed plus best supportive care versus placebo plus bestsupportive care for non–small-cell lung cancer: a randomized,double-blind, phase 3 study. Lancet. 2009;374:1432-1440.

9. Klein R, Wielage R, Muehlenbein C, et al. Cost-effectivenessof pemetrexed as first-line maintenance therapy for advancednonsquamous non-small cell lung cancer. J Thorac Oncol.2010;5:1263-1272.

10.Patel JD, Hensing TA, Rademaker F, et al. Phase II study ofpemetrexed and carboplatin plus bevacizu mab with mainte-nance pemetrexed and bevacizumab as first-line therapy fornonsquamous non–small-cell lung cancer. J Clin Oncol.2009;27:3284-3289.

11.Capuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as mainte-nance treatment in advanced non–small-cell lung cancer: amulticentre, randomized, placebo-controlled phase III study.Lancet Oncol. 2010;11:521-529.

12.Miller VA, O’Connor P, Soh C, et al. A randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) compar-ing bevacizumab (B) therapy with or without erlotinib aftercompletion of chemotherapy with B for first-line treatment oflocally advanced, recurrent, or metastatic non-small cell lungcancer (NSCLC). Presented at 2009 ASCO Annual Meeting.J Clin Oncol. 2009;27(18 suppl):LBA8002.

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Improving outcomes for patients with non–small cell lung cancer (NSCLC) is particular-ly relevant because NSCLC accounts for 85%

of all cases of lung cancer.1 In the appropriatepatients with advanced NSCLC, maintenancetherapy may help control the disease and extendpatients’ lives. Maintenance therapy is relative-ly new in NSCLC treatment, representing achange from the past approach of retreatmentupon disease progression.2 Two chemotherapyagents previously approved by the US Foodand Drug Administration (FDA) for the treat-ment of advanced NSCLC—pemetrexed anderlotinib—recently received FDA ap proval for anew indication for maintenance therapy ofadvanced NSCLC. Pemetrexed, a folate analog metabolic inhibitor,

was granted FDA approval for maintenance thera-py of advanced or metastatic lung cancer in July2009.3 This new indication for pemetrexed isspecifically for patients with nonsquamousNSCLC that has not progressed after 4 cycles ofplatinum-based first-line chemotherapy.4 Pem -etrex ed is also indicated as initial treatment in pa -tients with locally advanced or meta static non-squamous NSCLC, in combination with cisplatin,and after prior chemotherapy as a single agent.4Erlotinib, an endothelial growth factor receptor

(EGFR) tyrosine kinase inhibitor (TKI), receivedFDA approval in April 2010 for an expanded indi-cation as a maintenance treatment in patientswith locally advanced or metastatic NSCLCwhose disease has not progressed after 4 cycles of platinum-based first-line chemotherapy.5,6Erlotinib is also indicated to treat locallyadvanced or metastatic NSCLC after failure of atleast 1 prior chemotherapy regimen.6Identifying the appropriate patients as charac-

terized by histology (nonsquamous) or molecular(EGFR mutation) profile is an important consid-eration when selecting the appropriate mainte-nance therapy.7 Using predictive biomarkers totarget specific agents for maintenance therapy

may help improve benefits and reduce risks bytailoring a specific treatment to the appropriatepatient.7 For example, pemetrexed is an optionfor maintenance therapy in patients with non-squamous histology.1,4 In addition, a molecular-based strategy may be useful in selecting theappropriate patients best suited for maintenancetherapy with erlotinib.7 Progression-free survival(PFS) was significantly longer in patients withEGFR-positive immunohistochemistry who weretreated with erlotinib as maintenance therapycompared with EGFR-positive patients whoreceived placebo, based on a randomized, place-bo-controlled study.8In addition to histology and genetic markers,

maintenance therapy decisions involve a numberof other important considerations, including thelatest clinical data, evidence-based clinical prac-tice guidelines, and the patient’s performancestatus and personal preferences. Although mainte-nance therapy may slow the growth of disease andextend life, the benefits of treatment must beweighed against the potential toxicities and otherside effects associated with extended treatment.Costs and resource utilization associated withmaintenance therapy must also be considered.

NSCLC: BURDEN AND ECONOMICIMPACT

Lung cancer claims the lives of more Americansthan any other type of cancer.1 Moreover, lungcancer imposes a substantial economic burden onour healthcare system. The estimated annualcosts to the American public as well as lost pro-ductivity costs associated with lung cancer werepreviously outlined in the first part of this article.9Treatment costs associated with lung cancer, as

well as treatment failure costs, are also substan-tial. A retrospective, case-control cohort studythat followed patients for 2 years from the firstdiagnosis of lung cancer showed that the monthly

MAINTENANCE THERAPY FOR NON–SMALL CELL LUNG CANCER:A Value-Based Approach to Improve Patient Care andOutcomes, Part II of II

Using predictivebiomarkers totarget specific

agents formaintenance

therapy may helpimprove benefits

and reduce risks.

DisclosureLoretta Fala participated in

the development of this article. She has no financial

relation ships to disclose.

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cost per patient was $11,496 for initial treatment,$3733 per month for secondary treatment, and$9399 for terminal care treatment.10 Failure of ini-tial treatment was associated with increased costs:patients who experienced treatment failureincurred an additional $10,370/month in initialtreatment phase costs and $8779/month afterstarting the secondary and/or terminal care phaseof treatment.10 Moreover, treatment failure wasassociated with incremental costs of $19,149/month and $74,697 across the study period.10 Thestudy authors concluded that improvements inprevention or treatment of lung cancer, includingnew therapies or adjuvant chemotherapy, mightreduce healthcare resource utilization and costs,and that strategies aimed at reducing hospitaliza-tions and preventing or delaying treatment failuremay offset the associated cost burden.10More than 68% of all patients diagnosed with

lung cancer are 65 years of age or older.11 Theburden and cost of NSCLC may continue to growas the baby boom generation (people bornbetween 1946 and 1964) reaches the age of 65years and older over the next 20 years.12

MAINTENANCE THERAPY AGENTSFOR THE TREATMENT OF ADVANCEDNSCLC

Maintenance therapy, sometimes also referred to asconsolidation therapy or early second-line thera-py,7 is a relatively new approach to improving out-comes in patients whose disease either respondedto initial chemotherapy or was stable followingthat, and is intended to improve survival withoutadversely affecting quality of life.13 Aside fromimproving outcomes, the optimal maintenancetreatment should be well-tolerated by patients andassociated with few or no cumulative toxicities.7The National Comprehensive Can cer Network

(NCCN) has established specific recommenda-tions for the use of pemetrexed in maintenancetherapy, as well as for the use of erlotinib.1 Theseguidelines also include recommendations for sev-eral other agents, including docetaxel, bevacizu -mab, and cetuximab.1

PemetrexedBased on phase 3 study results, patients whoreceived maintenance therapy with pemetrexedshowed a significantly greater PFS (1.7 months

longer), compared with the placebo group, and asignificantly greater overall survival (OS) dura-tion (2.8 months longer), compared with theplacebo group.14 Specific findings from the studywere previously highlighted in Part I of this arti-cle.9 Moreover, in patients with nonsquamoushistology treated with pemetrexed, the OS was5.2 months longer than in the placebo arm.14The most common any-grade ad verse reactions

associated with pemetrexed included nausea(19%) and anorexia (19%).14 The pemetrexedgroup had a greater frequency of grade 3 or high-er adverse events than the placebo group, includ-ing fatigue (5%) and neutropenia (3%).14Another study that compared the combination

of cisplatin plus pemetrexed with cisplatin plusgemcitabine in chemotherapy-naïve patientswith advanced NSCLC demonstrated superiorefficacy and reduced toxicity in the group receiv-ing cisplatin plus pemetrexed.15

ErlotinibBased on a phase 3 study, patients who receivedmaintenance therapy with erlotinib showed agreater PFS (0.8 weeks longer) and an improvedOS (1 month longer), compared with the placebogroup.6,8 In patients with EGFR-positive immuno-histochemistry treated with erlotinib, comparedwith EGFR-positive patients receiving placebo,PFS was significantly greater (1.2 months longer)in the erlotinib group, compared with the placebogroup, in patients with EGFR-positive immuno-histochemistry treated with erlotinib.8 Specificstudy results were previously highlighted.9The most common any-grade ad verse reactions

associated with erlotinib were rash (49.2%) anddiarrhea (20.3%).6 The most common seriousadverse event was pneumonia (2%), and themost common grade 3 or higher adverse eventsincluded rash (6%) and diarrhea (2%).8

OTHER AGENTS INCLUDED INCLINICAL PRACTICE GUIDELINES

DocetaxelAlthough docetaxel, a microtubule inhibitor, doesnot have a specific FDA approval for mainte-nance therapy in NSCLC, this agent is indicatedas a single agent for locally advanced or metastat-ic NSCLC after failure on platinum therapy; andwith cisplatin for unresectable, locally advanced,

Aside fromimproving outcomes,the optimalmaintenance treat -ment should be well-tolerated by patientsand associated withfew or no cumulativetoxicities.

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or metastatic untreated NSCLC.16 Based on aphase 3 randomized study that assessed the effica-cy and safety of docetaxel administered eitherimmediately after gemcitabine or at disease pro-gression, immediate docetaxel was associated witha significantly greater PFS (5.7 months) comparedwith delayed docetaxel (2.7 months), and imme-diate docetaxel was associated with a greatermedian OS (12.3 months) compared with delayeddocetaxel (9.7 months).17 However, the differencein median OS was not statistically significant(P = .0853). There was no significant differencein quality of life between the immediate anddelayed docetaxel groups.17Based on studies of docetaxel as monotherapy

for NSCLC patients previously treated with plat-inum-based chemotherapy (n = 176), the mostcommon grade 3/4 adverse reactions included neu-tropenia (65%), leuko penia (49%), and pul-monary effects (21%).16 The most common any-grade adverse reactions include neutropenia(84%); leukopenia (84%); anemia (91%); asthe-nia (53%); pulmonary effects (41%); infection(34%); nausea (34%); fluid retention (34%); neu-rosensory effects (34%); stomatitis (26%); diarrhea(23%); and vomiting (22%).16In chemotherapy-naïve advanced NSCLC

patients receiving docetaxel in combination withcisplatin (n = 406), the most common grade 3/4adverse reaction was neutropenia (74%).16 Themost common any-grade adverse reactionsincluded neutropenia (91%); anemia (89%);alopecia (75%); asthenia (74%); nausea (72%);vomiting (55%); fluid retention (54%); diarrhea(47%); neurosensory effects (47%); anorexia(42%); infection (35%); peripheral edema(34%); and fever (33%).16

BevacizumabBevacizumab, a monoclonal antibody thatinhibits vascular endothelial growth factor, isindicated for the treatment of nonsquamousNSCLC, with paclitaxel and carboplatin for thefirst-line treatment of unresectable, locallyadvanced, recurrent, or metastatic disease.18According to the NCCN clinical practice guide-lines, the criteria for bevacizumab therapyinclude a performance status of 0-1, nonsqua-mous histology, and no history of hemoptysis.1Adding bevacizumab to chemo therapy with

paclitaxel plus carboplatin has shown a signifi-cant im provement in median OS (12.3 months),

compared with chemotherapy alone (10.3months), based on a randomized 3-year study ofpatients with recurrent or advanced NSCLC (N= 878) conducted by the Eastern CooperativeOncology Group.19 An increased risk of treat-ment-related deaths were ob served in the grouptreated with bevacizumab plus paclitaxel and car-boplatin, and the rate of clinically significantbleeding was 4.4% in this arm.19 Other adverseevents included grade 4 neutropenia (24%),grade 3/4 hemorrhage (4.5%), hemoptysis(1.9%), and hypertension (6%).1 According tothe NCCN guidelines, caution is advised whenchemotherapy regimens with a high risk forthrombocytopenia and/or possible bleeding arecombined with bevacizumab.1Further studies are needed to determine

whether bevacizumab maintenance is associatedwith a survival benefit compared with the combi-nation of chemotherapy and bevacizumab with-out maintenance bevacizumab.20

CetuximabCetuximab, a monoclonal antibody that targetsEGFR, is indicated for the treatment of specifichead and neck cancers and colorectal cancers;however, this agent does not have an indicationfor the treatment of NSCLC.21 Cetuximab use isnot recommended for patients with colorectalcancer whose tumors have KRAS mutations incodon 12 or 13.21According to a study of patients (N = 1125)

with advanced NSCLC (stage IIIB or IV; majoritywere stage IV), patients treated with cetuximab incombination with vinorelbine and cisplatinshowed no difference in PFS and a significantlyimproved OS (11.3 months) compared withpatients receiving vinorelbine and cisplatin alone(10.1 months).1,22 Treatment-related deaths weresimilar in both groups.22 Patients receiving cetux-imab had increased grade 3/4 febrile neutropenia(22%) and grade 3 acne-like rash (10%).1,22

EVIDENCE-BASED PRACTICEGUIDELINES

For the NCCN NSCLC clinical practice guide-lines (updated in March 2010), a new sectionwith maintenance therapy recommendations wasadded.1 These recommendations categorizedmaintenance therapy into 2 types: continuation

Addingbevacizumab to

chemo therapy withpaclitaxel plus

carboplatin hasshown a significant

im provement inmedian survival(12.3 months),compared with

chemotherapy alone(10.3 months).

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maintenance therapy and switch maintenancetherapy. Con tinuation maintenance therapyrefers to the use of at least 1 of the agents admin-istered as first-line therapy.1 Switch maintenancetherapy refers to the initiation of an agent thatwas not included as part of the first-line treat-ment regimen.1 Based on 2 recent studies demon-strating a benefit in PFS and OS, the guidelinesnow recommend initiation with pemetrexed orerlotinib for switch maintenance therapy inpatients without disease progression (Category2B recommendation).1Highlights of the NCCN guideline recommen-

dations for continuation maintenance therapyand switch maintenance therapy were outlinedpreviously in the first part of this article.9Information about the American Society ofClinical Oncology (ASCO) guideline update, aswell as recent guidance from the NationalInstitute for Health and Clinical Excellence arealso highlighted in that article.

THE ROLE OF HISTOLOGY ANDMOLECULAR BIOMARKERS INMAINTENANCE THERAPY

It is important to identify the histologic subtypeof NSCLC (ie, squamous cell vs nonsquamouscell) when selecting maintenance therapy.23Histologic information may be particularly usefulwhen augmented by molecular testing.23Detecting the bronchoalveolar subtype ofNSCLC adenocarcinoma may suggest a specifictreatment approach, particularly if it is associatedwith specific mutations in the EGFR tyrosinekinase domain, which indicates it may respond totreatment with an EGFR TKI.23 However, it isimportant to point out within this NSCLC sub-type, there are also variabilities in histology andmolecular information.23 Several predictive molecular biomarkers play

a key role in NSCLC treatment,1 and these bio-markers and associated characteristics were sum-marized in Part I.9 Initial retrospective studiessuggest that approximately 90% of patients witha tumor response to erlotinib and gefitinib (bothEGFR TKI agents) had EGFR mutations E19deletion and L858R mutation, whereas patientswithout a response to these 2 agents did notcarry these mutations.1 The NCCN guidelinesrecommend that pathological evaluation be per-

formed to classify the lung cancer, determine itsextent of invasion, determine the status of surgi-cal margins, and identify molecular abnormali-ties that may predict the treatment response, orresistance to, EGFR TKI therapy.1

OTHER MAINTENANCE THERAPYCONSIDERATIONS

The potential benefits of maintenance therapy—preventing cancer recurrence, slowing diseasegrowth, and prolonging life—must be weighedagainst the potential risks—increased sideeffects and potential for toxicities, drug resist-ance, and more frequent doctor visits. Anotherconsideration is that maintenance therapy doesnot provide the patient with a chemotherapybreak, also referred to as a wait-and-see period.7Data on the quality of life associated with main-tenance therapy are limited, including data oncumulative toxicity associated with extendedchemotherapy.7 Although maintenance therapyincreases chemotherapy costs and may increaseoverall costs, it may conversely decrease costsassociated with palliative radiotherapy and hos-pital admissions resulting from performancestat us deterioration.20 The value of maintenance therapy is the

subject of ongoing discussion among clini-cians, particularly in light of its cost andpotential toxicity.24 Pemetrexed administeredin 6 cycles at the average wholesale price of$3000 per cycle would total $18,000.24 Thewholesale acquisition cost for erlotinib main-tenance treatment would be $4000 per month¥ a mean PFS of 3 months, for a total treat-ment cost of $12,000.24Some of the challenges surrounding cost of

added survival were presented at the 2010ASCO meeting by Scott Ramsey, MD, PhD, ofthe Fred Hutchinson Cancer Research Centerin Seattle.24,25 Ramsey asserted that mainte-nance therapy was unlikely to be cost-effec-tive, based on a ratio that considers both theprice over standard care and the months of OSbenefit. However, he acknowledged that phar-macogenomic strategies may improve the cost-effectiveness of therapy and that the cost oftesting will be a factor. Ramsey claimed thatmany new oncology agents do not meet thecriteria for cost-effectiveness and that many

It is important toidentify the histologicsubtype of NSCLC(ie, squamous cell vsnonsquamous cell)when selectingmaintenancetherapy.

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economic analyses do not meet the guidelines foreconomic evaluation.24,25 Guideline-driven phar-macoeconomic studies may shed light on whethermaintenance therapy is the most cost-effective.

The rationale in favor of maintenance ther-apy was presented at the 2010 ASCO meetingby Tracey Evans, MD, of the AbramsonCancer Center, University of Pennsylvania, inPhiladelphia.26 According to Evans, “mainte-nance therapy for advanced NSCLC isabsolutely a standard of care” that should beconsidered for all patients, particularly basedon clinical data showing prolonged survival andtolerability.26 An opposing point of view waspresented by Tom Stinchcombe, MD, of theLineberger Comprehensive Cancer Center, atthe University of North Carolina at ChapelHill.27 According to Stinchcombe, maintenancetherapy is not necessarily a standard of care forevery patient but rather an option to be consid-ered, which depends on toxicities as well as thepatient’s disease burden, extent of symptoms,performance status, and preferences.27 He main-tained that a treatment-free interval is still anoption in this incurable disease setting.27

CONCLUSION

Maintenance therapy, a relatively new approachin the treatment of patients with advancedNSCLC, has the potential to extend survival andimprove outcomes. Key considerations for tailor-ing treatment for the appropriate patients includethe histology of the carcinoma, genetic biomark-ers, the extent of disease invasion, and thepatient’s performance status and preferences. Thebenefits of maintenance therapy must be weighedagainst the potential toxicities and other sideeffects associated with extended treatment.Selecting the appropriate therapy for the appro-priate patients and involving patients in the deci-sion process are important aspects of the treat-ment plan. Strategies for managing side effectswarrant careful consideration. Optimally, theagent selected for maintenance therapy should bewell-tolerated by the patient, demonstrateimproved patient outcomes, and have minimalside effects/cumulative toxicities.7

Recent clinical data and evidence-based guide-lines are valuable decision-making tools for clini-cians. However, data assessing quality of life, cost-

effectiveness, and cumulative toxicity of mainte-nance therapy are lacking. Costs and resource uti-lization associated with maintenance therapymust be balanced against the risks and costs ofnot treating or of deteriorating performance sta-tus. A delay strategy may be associated with ashorter survival time and a faster disease progres-sion than immediate additional therapy.28,29 Inany case, the prospect of extended survival of sev-eral months, or even weeks, particularly if treat-ment is well-tolerated, represents an importantmilestone for patients with advanced NSCLC. g

References1. National Comprehensive Cancer Network. NCCN Clinical

Practice Guidelines in Oncology™. Non-small cell lung can-cer, V.2.2010. March 5, 2010. www.nccn.org/professionals/physician_gls/PDF/nscl.pdf. Accessed September 15, 2010.

2. Peck P. Maintenance pemetrexed extends NSCLC survival by3 months. Medpage Today. May 30, 2009. www.medpagetoday.com/tbprint.cfm?tbid=14437. Accessed September 22, 2010.

3. Riley K. FDA approves first maintenance drug therapy foradvanced lung cancer [press release]. July 6, 2009. US Foodand Drug Administration. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm170515.htm. Accessed Sep -tember 22, 2010.

4. Alimta (pemetrexed disodium) [package insert]. Indian -apolis, IN: Eli Lilly and Company; 2010.

5. Waknine Y. FDA approves use of erlotinib as maintenancetherapy for advanced non-small cell lung cancer [pressrelease]. April 20, 2010. www.medscape.com/viewarticle/720446. Accessed September 22, 2010.

6. Tarceva (erlotinib) [package insert]. Melville, NY: OSIPharmaceuticals Inc; and South San Francisco, CA:Genentech; 2010.

7. Owonikoko TK, Ramalingam SS, Belani CP. Maintenancetherapy for advanced non-small cell lung cancer: currentstatus, controversies, and emerging consensus. Clin CancerRes. 2010;16:2496-2504.

8. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib asmaintenance treatment in advanced non-small-cell lungcancer: a multicentre, randomized, placebo-controlledphase 3 study. Lancet Oncol. 2010;11:521-529. Epub May20, 2010.

9. Maintenance therapy for non-small-cell lung cancer: a value-based approach to improve patient care and outcomes, part I ofII. Value-Based Cancer Care. 2010;1:24-26.

10.Kutikova L, Bowman L, Change S, et al. The economicburden of lung cancer and the associated costs of treatmentfailure in the United States. Lung Cancer. 2005;50:143-154.Epub August 19, 2005.

11.National Cancer Institute, US National Institutes ofHealth. Surveillance, Epidemiology, and End Results. SEERstat fact sheets: lung and bronchus. http://seer.cancer.gov/statfacts/html/lungb.html. Accessed September 20,2010.

12.Vincent GK, Velkoff VA. The Next Four Decades, the OlderPopulation in the United States: 2010 to 2050. CurrentPopulation Reports, P25-1138. Washington, DC: USCensus Bureau; May 2010.

13.American Society of Clinical Oncology. Explaining main-tenance therapy. Cancer.net. Updated February 22, 2010.www.cancer.net/patient/All+About+Cancer/Cancer.Net+Feature+Articles/Treatments%2C+Tests%2C+and+Proced

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ures/Explaining+Maintenance+Therapy. Accessed September20, 2010.

14.Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenancepemetrexed plus best supportive care versus placebo plusbest supportive care for non–small-cell lung cancer: a ran-domized, double-blind, phase 3 study. Lancet. 2009;374:1432-1440. Epub September 18, 2009.

15. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III studycomparing cisplatin plus gemcitabine with cisplatin pluspemetrexed in chemotherapy-naive patients withadvanced-stage NSCLC. J Clin Oncol. 2008;26:3543-3551.

16. Taxotere (docetaxel) [package insert]. Bridgewater, NJ:sanofi-aventis US, LLC; 2010.

17. Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study ofimmediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advancednon-small-cell lung cancer. J Clin Oncol. 2009;27:591-598.Epub December 15, 2008.

18. Avastin (bevacizumab) [package insert]. South SanFrancisco, CA: Genentech, Inc; 2009.

19.Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatinalone or with bevacizumab for non–small-cell lung cancer.N Engl J Med. 2006;355:2542-2550.

20.Eaton KD. Maintenance chemotherapy in non-small celllung cancer. J Natl Compr Canc Netw. 2010;8:815-821.

21.Erbitux (cetuximab) [package insert]. Branchburg, NJ:ImClone Systems Inc; 2010; and Princeton, NJ: Bristol-Myers Squibb Company; 2010.

22.Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus

chemo therapy in patients with advanced non–small-celllung cancer (FLEX): an open-label randomized phase IIItrial. Lancet. 2009;373:1525-1531.

23.Neal JW. Histology matters: individualizing treatment innon-small cell lung cancer [editorial]. Oncologist. 2010;15:3-5. Epub January 19, 2010.

24.Hayes E. Will maintenance sell in NSCLC? Experts weighcosts against benefits. Pharmaceutical Ap provals Monthly.August/September 2010.

25.Ramsey S. Cost effectiveness in lung cancer trials and treat-ment. Presented at the 2010 American Society of ClinicalOncology Meeting—Education Session. June 4-8, 2010;Chicago, IL.

26.Evans TL. Maintenance therapy for advanced NSCLC isstandard of care. Presented at the 2010 American Society ofClinical Oncology Meeting—Education Session. June 4-8,2010; Chicago, IL.

27.Stinchcombe T. Maintenance therapy for advancedNSCLC is not standard of care. Presented at the 2010American Society of Clinical Oncology Meeting—Education Session. June 4-8, 2010; Chicago, IL.

28.Belani CP, Liao J. Maintenance therapy for non-small celllung cancer [comment]. Lancet. 2010;375:281-282; com-ment on Stinchcombe T, West H comment in: Lancet.2009;374:1398-1400.

29.Soon YY, Stockler MR, Askie LM, Boyer MJ. Duration ofchemotherapy for advanced non-small-cell lung cancer: asystematic review and meta-analysis of randomized trials. J Clin Oncol. 2009;27:3277-3283. Epub May 26, 2009.

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DisclosureThe author is on the speaker’s bureau for

Genentech, Eli Lilly andCompany, and Merck.

Significant ad van ces in treat ing non–small celllung cancer (NSCLC) have been made over thepast 10 years; nevertheless, survival im provementin this disease pales compared with many othersolid tumors. Because maintenance chemo -therapy offers improved survival in NSCLC,patients and doctors are justifiably excited.

Nursing ConsiderationsIn my dealings with patients, there seem to be 2distinct responses to maintenance treatment. Onthe one hand, patients are very happy that theycan continue receiving some sort of therapy,because they feel that they are continuing thefight. Before the data supporting maintenancechemo therapy for NSCLC, we would stop therapyafter 4 to 6 cycles and give a treatment break, andmany patients were worried that they weren’tdoing anything to treat their disease during thistime. Con versely, I have also encountered manypatients who are yearning for a break in therapy.Suggesting maintenance chemotherapy, whichpromises more toxicity similar to what the patientis already experiencing, leaves them bewildered.But because the treatment offers a survival advan-tage, patients usually will continue with it becausethey want to live longer. However, they frequentlyask when there will be a break, and this often givesthem the realization that they will be receivingthis treatment for the rest of their lives. It is important for oncology treatment pro -

viders to have a detailed discussion withpatients about the pros and cons of maintenancetherapy for NSCLC. These patients have a ter-minal illness with average survival of around ayear. Doctors and nurses must allow pa tients theautonomy to make decisions about receivingmaintenance therapy, along with possible breaksto have a vacation or spend time with family.Maintenance therapy can continue indefinitely,which can leave a patient feeling that his/herlife is a constant schedule of treatments and cancause tremendous emotional stress.

Managing ToxicitiesAs maintenance therapy becomes a more widelyused treatment option for patients with NSCLC, itis important to weigh its toxicities. Pemetrexed,which is US Food and Drug Administration(FDA)-approved in the maintenance setting, anddocetaxel, which has a recommendation (al -though not an FDA approval) for maintenancetherapy, are both cytotoxic chemo therapy agentsand pose concerns different from other approvedmaintenance therapies. Common side effects ofchemotherapeutic agents, including risk for myelo-suppression, fatigue, and nausea, are a concern forpatients receiving maintenance therapy, especiallybe cause there is no defined end date to it unlessthere is disease progression or unacceptable toxici-ty. So patients may end up taking these drugs with-out a break for up to a year or more.In the pemetrexed maintenance study, ane-

mia occurred in 15% of patients in the peme-trexed maintenance arm versus 6% in the placeboarm.1 Patients receiving pemetrexed may thereforerequire more frequent blood transfusions and pos-sibly colony-stimulating factors such as darbepoe -tin or erythropoietin. Managing fatigue canbecome difficult for these patients, and consid-ering that they are dealing with a terminal ill-ness, fatigue must be taken into serious accountin terms of its effect on the patient’s quality oflife. Nausea was also reported in 19% ofpatients in the pemetrexed arm versus 6% inthe placebo arm.1The targeted therapies erlotinib (in the switch

maintenance setting) and bevacizumab and cetux-imab (in the continuation maintenance setting)do not typically induce the same side effects aschemotherapy but rather carry their own set ofunique toxicities. The toxicities from these agentscan also interfere with a patient’s quality of life andmust be considered and addressed before embark-ing on maintenance therapy.Rash was the most common side effect in

patients receiving erlotinib in the maintenance

C o m m e n t a r y

Nursing and Patient Management Considerations forMaintenance Therapy in Non–Small Cell Lung CancerBy Beth Eaby-Sandy, CRNPOutpatient Thoracic Oncology Nurse Practitioner, University of Pennsylvania Health System, Philadelphia

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trial. Grade 3/4 rash, causing interference withactivities of daily living, was 6%.2 Because goodrandomized data on treating this rash have notemerged, management strategies have focused onbest-practice recommendations. Depending onseverity, papulopustular rash can be treated withtopical steroids or antibiotics, oral antibiotics,and even oral steroids in severe cases.3 Thesemedications can be used in combination or sepa-rately depending on the grade of rash. Althoughit is rarely life-threatening, rash can be uncom-fortable and disfiguring at times. In the cetux-imab continuation trial, rash was present inapproximately 70% (382/548) of patients, with10% experiencing grade 3/4 rash.Rates of grade 3/4 diarrhea in both the cetux-

imab and erlotinib maintenance trials were 4%and 2%, respectively.2,4 It is usually easily con-trolled with loperamide and sometimes re quires aprescription-strength anti diarrheal. Concern fordehydration may be an issue given that this patientpopulation is often elderly, so prompt assessmentand ensuring fluid intake are important. Bevacizumab is only approved for the use of

nonsquamous NSCLC because of bleeding risk.The most common side effects of bevacizumabinclude hypertension and proteinuria,5 andassessing for these on each visit is recommended.Standard antihypertensives will usually controlbevacizumab-associated hypertension; pro tein -uria often improves on holding the bevacizumabdose. In rare NSCLC cases, bevacizumab has the

potential to cause fatal pulmonary hemorrhage,so it is essential that practitioners assess forhemoptysis and permanently discontinue beva-cizumab if hemoptysis occurs. In summary, the improvement in survival for

metastatic NSCLC by continuing a maintenancetherapy after first-line treatment is modest, but itis certainly an advance. Conversations withpatients about the schedule, toxicities, and bene-fits of therapy must be unbiased and thorough.Patients need to be able to voice their concernsand have ample opportunity to shape their treat-ment regimen because of their limited prognosisand possible effect of maintenance treatment onquality of life. g

References1. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenancepemetrexed plus best supportive care versus placebo plusbest supportive care for non-small-cell lung cancer: a ran-domized, double-blind, phase 3 study. Lancet. 2009;74:1432-1440.

2. Cappuzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib asmaintenance treatment in advanced non-small-cell lungcancer: a multi-center, randomized, placebo-controlledphase 3 study. Lancet Oncol. 2010;11:521-529.

3. Lynch T, Kim E, Eaby B, et al. Epidermal growth factorreceptor (EGFR) inhibitor-associated rash: an evol ving par-adigm in clinical management. Oncologist. 2007;12:610-621.

4. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab pluschemotherapy in patients with advanced non-small-celllung cancer (FLEX): an open-label randomized phase IIItrial. Lancet. 2009;373:1525-1531.

5. Sandler A, Gray R, Perry MC, et al. Paclitaxel–carboplatinalone or with bevacizumab for non–small-cell lung cancer.N Engl J Med. 2007;355:2542-2550.

Conversations withpatients about theschedule, toxicities,and benefits oftherapy must beunbiased andthorough.

—Beth Eaby-Sandy, CRNP

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Unlike a patient navigator, whose primary roleis to ease the patient’s journey through the med-ical system, the main role of the program’s peernavigators is to ease the patient’s journey into thenew psychosocial realm of living with cancer.After training, the peer navigators provided newpatients with emotional support and informa-tion for up to 6 months. The study found thatpatients experienced less-than-expected de -clines in some QOL measures and improvementin others. QOL for the navigators was neitherhelped nor hindered. The investigators believe cancer survivors rep-

resent a “largely untapped reservoir of wisdomand experience about coping with illness.” The

program offers one way to harness this valuableresource to provide meaningful benefit to newpatients.

GOING FROM SURVIVOR TO NAVIGATORSuccess of a peer navigation program hinges onfinding the right individuals to serve as peer nav-igators. For the pilot study, WomenCARE, acommunity-based nonprofit organization thatprovides free psychosocial support to women withcancer, referred promising candidates from itssupport groups. Local clinicians referred othersurvivors, and some were recruited using newspa-per and radio advertisements. Eligible candidateshad received a diagnosis of breast cancer an aver-

PROGRAM TURNSCANCER SURVIVORSINTO PEERNAVIGATORSBy Dawn Lagrosa

In the first year after a breast cancer diagnosis, women typically experience signifi-cant deterioration in their overall quality of life (QOL), but a program that connectsnew patients with breast cancer survivors following diagnosis seems to halt the

decline. The pilot program, sponsored by Stanford University and WomenCARE,recruited and trained breast cancer survivors to act as peer navigators.

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age of 4.5 years earlier, had completed treatment,and were in remission.The investigative team—Janine Giese-Davis,

PhD, Caroline Bliss-Isberg, PhD, KristinCarson, Path Star, Jessica Donaghy, Matthew J.Cordova, PhD, Nita Stevens, MFT, LynneWittenberg, MPH, Connie Batten, MFT, andDavid Spiegel, MD—rigorously screened theapplicants to ensure that every-one selected for the programwas a good listener, emotional-ly stable, and willing to complywith the program’s protocols. First, candidates attended a

full-day training course, whichfocused on listening skills andincluded an hour of medicalinstruction from an oncologist.Following this, they attendedmonthly meetings. At each ses-sion, Star, the program’s co-coor-dinator and matchmaker, and Stevens, a profes-sional therapist, worked to improve navigators’listening skills through instruction, group discus-sion, and role playing. A trained clinician sup-plied medical information and re mained on callduring the program to answer any questions.“We put them through a listening exercise to

see how they naturally listen when they try tohelp somebody with a problem,” Star said.Becoming a better listener required the naviga-tors to learn to separate their personal judg-ments, needs, and medical viewpoints from theirinteraction with the patient. As a final and firmcaveat, the peer navigators were instructednever to second-guess the patient’s oncologistsor offer medical advice.During each monthly session, investigators

monitored the peer navigators for signs of emo-tional distress. Anyone with emotional issueswas not matched with a patient. Following thestudy’s pilot phase, it was decided to requireeach navigator to attend 2 monthly meetingsbefore being matched. “If they were not going toadhere to coming once a month for supervision,then we didn’t want them out there alone beinga peer counselor; it is just too dangerous foreverybody. We might have had [a patient] whowas suicidal or traumatized, or the peer coun-selor might get more traumatized as they wentalong trying to be a good listening ear,” saidGiese-Davis, University of Calgary Faculty of

Medicine, who was the program’s key scientificinvestigator. She stressed the importance ofreinforcing to the navigators their need for regu-lar supervision.

THE PEER–PATIENT RELATIONSHIPIn all, 42 patients with newly diagnosed breastcancer were matched with 39 peer navigators.

Before matching patients with anavigator, investigators askedthem to prioritize a list of naviga-tor qualities. Some preferred anavigator who had the samediagnosis or treatment regimen;others asked for a “good listener”or indicated an age or religiouspreference. Using what wasknown about the navigatorsfrom training sessions, the inves-tigators did their best to optimizethe matches.

Either party could initiate contact, whichoccurred 1 to 4 times each week. Most exchangeswere by telephone, but some occurred face-to-face or via e-mail. After each meeting, navigatorsand patients described the interaction using aform designed by the investigators. Data showed that navigators were more likely

than patients to initiate contact. Most often, theexchanges involved “expression of feelings,” fol-lowed by “active coping,” a term the investigatorsdid not define for the participants and thus was notrestricted to the physiological effects of cancer,such as treatment response (Figure, page 31).

The study’s initial design did not establish abreaking point for the peer–patient relationship,but the parties were required to assess and re -negotiate their arrangement after 3 months toallow anyone dissatisfied with their partner torequest a new one. In the study’s initial phase,the relationships typically dissolved between 4.5 and 6 months. As the study progressed, the investigators set

81% Common diagnosis

76% Similar treatmentprotocol

67% Specific treatmentconcern

PATIENTS’TOP 3 QUALITIES FOR A PEER NAVIGATOR

The peer navigators were instructednever to second-guess the patient’soncologists or offer medical advice.

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6 months as an official end point of the arrange-ment. “This takes most people through most oftheir treatment, which was our goal,” saidWittenberg, who is with the Department ofPsychiatry and Behavioral Sciences at StanfordUniversity School of Medicine. Giese-Davisadded that 6 months was generally enough timefor the peer counselors to navigate the personinto a support group or to other resources.

The provision to renegotiate at 3 months waskept in place, but the investigative team decidedthey would also telephone navigators andpatients 2 weeks after being matched to askwhether they were satisfied with their partner orwanted to be rematched. “Some women do notwant to offend each other and admit that they areunhappy with their match, so we gave themopportunities to tell us,” said Giese-Davis.

At the end of 6 months, patients and naviga-tors were not restricted from continuing a rela-tionship. Giese-Davis said, “Some of those peercounselors continued as sort of friends or infor-mal peer counselors.”

MEASURING RESULTSInvestigators used standardized questionnaires toassess the emotional status of patients and naviga-tors and to evaluate their perceptions about theirmedical team and breast cancer resources.Assessments were administered at baseline andrepeated at 3, 6, and 12 months. After the study,the investigators also conducted separate focusgroups with the peer navigators to discuss theirviews on the program.

For patients, being matched with a peer navi-gator correlated with a decrease in trauma symp-toms—most notably arousal—and improve-

ments in emotional well-being and cancer self-efficacy. Over time, the patients felt less need forbreast cancer resources, which the investigatorssurmised was likely because their informationalneeds had been met. Although peer navigationdid not correlate with significant improvementin the patients’ depression symptoms or socialwell-being, it might have contributed to lesspsychosocial deterioration.

As the pilot program progressed, some peernavigators showed signs of trauma, and theinvestigators decided they needed to take stepsto protect their mental health. Bliss-Isberg,Cabrillo College, Aptos, California, a co-princi-pal investigator, offered her perspective as a 4-time cancer survivor: “When you are navigat-ing someone else when you are a survivor your-self, you need support and you need both profes-sional and peer support yourself because it cantrigger a lot of stuff you are not aware of.”

During the subsequent randomized clinicaltrial of this intervention, the group brought in atrauma specialist to help the peer counselorsrecognize signs of trauma in themselves and thewomen they were navigating. “We are hopingthat was helpful, but we don’t know the answerto that yet,” said Giese-Davis.

Although the program appeared to have nolasting adverse effects on the emotional healthof the peer navigators, the investigators weresurprised to see no improvement in navigators’self-efficacy and QOL scores. Although the nav-igators’ scores remained relatively flat over thecourse of the program, the investigators believethey did benefit from participating. “One of thewonderful things for the navigators is that it setsa landmark—they are no longer a person living

Although peer navigation didnot correlate with significantimprovement in the patients’depression symptoms or socialwell-being, it might have contributed to less psychosocialdeterioration.

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with cancer.…They are a survivor, and thatmark of becoming a navigator is crucial forthat,” explained Star.

The investigators said one unexpected find -ing was how increasingly dissatisfied the navi -gators became over the course of the study intheir interactions with medical professionals.Wittenberg said when asked about this in thefocus groups, the navigators indicated that they“noticed these changes as they were further outfrom treatment and had less frequent contactwith their medical team.”

“The ones who were approximately 2 yearsout were just far enough out that they [were]now going to their family physician instead ofthe oncology center,” added Giese-Davis.

The investigators offered a few hypotheses forthe navigators’ growing dissatisfaction, includ-ing the possibility that they missed the level ofattention they had received as cancer patients.Another possibility is that the navigators’ grow-ing medical knowledge made them more awareof apparent gaps in knowledge among membersof their assigned patient’s treatment team.

Bliss-Isberg suggested that the navigators’ dis-cussions with medical staff “revealed how muchart oncologists have to utilize, as well as the sci-ence.” She explained that when an oncologistdescribes a treatment plan, for example, “thewell-informed patient has learned enoughthrough reading, the Internet, and contact withothers [to see] what the oncologist does notknow.” Bliss-Isberg said no matter how mar-velous an oncologist is, it is like any profession.“The more you learn, the more you learn thatthere are holes in the knowledge base of thatprofession.” Wittenberg said patients spoke totheir navigators about negative experiences theyhad with their medical team, and this mighthave influenced navigators’ perceptions of theirown medical care.

FUTURE OF THE PROGRAMPeer navigation is a useful complement to theservices that patient and nurse navigators pro-vide. As cancer survivors, peer navigators offerpatients new to the cancer experience a perspec-tive on the journey to wellness that cliniciansoften cannot.

“Once you have had cancer, you have some-thing in common with everyone who has hadcancer,” said Bliss-Isberg. The support provided

by properly trained peer navigators and themodel of survivorship they represent “is some-thing that someone who hasn’t had cancer andhasn’t survived can’t offer,” she added.

For those interested in starting a peer naviga-tion program, the investigational team stressedhow critical initial training and ongoing supportare to a program’s success. “We are not taughthow to communicate; we are not taught how tolisten,” said Star. “Of all the things we do in ourtraining, the listening exercise for people to seewhat their style of listening is…is such an impor-tant piece.” They also stressed the need to makesure peer navigators understand how important itis that they do not undermine the clinicians bysecond-guessing their decisions or offering theirown medical advice.

The study investigators believe strongly in thevalue of peer counseling and hope that theirfindings will help shape future peer navigationprograms. Bliss-Isberg said she hopes changes inthe US healthcare system and the growing needfor health services make this “the perfect timefor peer support to take hold” in the country.

For complete findings, see an initial analy-sis of the study that appeared in the March2006 issue of Psycho-Oncology. A subanalysison the effects of the patients’ and navigators’marital status on distress and well-being was published in The Breast Journal (Sept/Oct2010). g


For More InformationTo learn more about the program and the trainingtechniques used, contactJanine Giese-Davis, PhD,lead scientific investigator, [email protected], (403) 698-8175; LynneWittenberg, MPH, peernavigator project coordina-tor, at [email protected],(831) 238-6939; orCaroline Bliss-Isberg, PhD,co-principal investigator, at [email protected],(408) 334-5162.

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ACTIVE COPING

Figure Perception and Frequency of Topics Discussed

TOPIC CATEGORIES

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, %

EMPOWER-MENT

FEELINGS REQUESTEDINFO

REQUESTEDRESOURCES

SOCIAL/SEXUALITY

NAVIGATORS

PATIENTS

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February 2011 - Journal of Oncology Navigation & Survivorship

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