James Khatcheressian

2006 Update of Recommendations for the Use of White Blood Cell Growth Factors: An Evidence-Based Clinical Practice Guideline

PURPOSE To update the 2000 American Society of Clinical Oncology guideline on the use of hematopoietic colony-stimulating factors (CSF). UPDATE METHODOLOGY The Update Committee completed a review and analysis of pertinent data published from 1999 through September 2005. Guided by the 1996 ASCO clinical outcomes criteria, the Update Committee formulated recommendations based on improvements in survival, quality of life, toxicity reduction and cost-effectiveness. RECOMMENDATIONS The 2005 Update Committee agreed unanimously that reduction in febrile neutropenia (FN) is an important clinical outcome that justifies the use of CSFs, regardless of impact on other factors, when the risk of FN is approximately 20% and no other equally effective regimen that does not require CSFs is available. Primary prophylaxis is recommended for the prevention of FN in patients who are at high risk based on age, medical history, disease characteristics, and myelotoxicity of the chemotherapy regimen. CSF use allows a modest to moderate increase in dose-density and/or dose-intensity of chemotherapy regimens. Dose-dense regimens should only be used within an appropriately designed clinical trial or if supported by convincing efficacy data. Prophylactic CSF for patients with diffuse aggressive lymphoma aged 65 years and older treated with curative chemotherapy (CHOP or more aggressive regimens) should be given to reduce the incidence of FN and infections. Current recommendations for the management of patients exposed to lethal doses of total body radiotherapy, but not doses high enough to lead to certain death due to injury to other organs, includes the prompt administration of CSF or pegylated G-CSF.

American Society of Clinical Oncology 2006 Update of the Breast Cancer Follow-Up and Management Guidelines in the Adjuvant Setting

PURPOSE To update the 1999 American Society of Clinical Oncology (ASCO) guideline on breast cancer follow-up and management in the adjuvant setting. METHODS An ASCO Expert Panel reviewed pertinent information from the literature through March 2006. More weight was given to studies that tested a hypothesis directly relating testing to one of the primary outcomes in a randomized design. RESULTS The evidence supports regular history, physical examination, and mammography as the cornerstone of appropriate breast cancer follow-up. All patients should have a careful history and physical examination performed by a physician experienced in the surveillance of cancer patients and in breast examination. Examinations should be performed every 3 to 6 months for the first 3 years, every 6 to 12 months for years 4 and 5, and annually thereafter. For those who have undergone breast-conserving surgery, a post-treatment mammogram should be obtained 1 year after the initial mammogram and at least 6 months after completion of radiation therapy. Thereafter, unless otherwise indicated, a yearly mammographic evaluation should be performed. Patients at high risk for familial breast cancer syndromes should be referred for genetic counseling. The use of CBCs, chemistry panels, bone scans, chest radiographs, liver ultrasounds, computed tomography scans, [18F]fluorodeoxyglucose-positron emission tomography scanning, magnetic resonance imaging, or tumor markers (carcinoembryonic antigen, CA 15-3, and CA 27.29) is not recommended for routine breast cancer follow-up in an otherwise asymptomatic patient with no specific findings on clinical examination. CONCLUSION Careful history taking, physical examination, and regular mammography are recommended for appropriate detection of breast cancer recurrence.

Breast Cancer Follow-Up and Management After Primary Treatment: American Society of Clinical Oncology Clinical Practice Guideline Update

PURPOSE To provide recommendations on the follow-up and management of patients with breast cancer who have completed primary therapy with curative intent. METHODS To update the 2006 guideline of the American Society of Clinical Oncology (ASCO), a systematic review of the literature published from March 2006 through March 2012 was completed using MEDLINE and the Cochrane Collaboration Library. An Update Committee reviewed the evidence to determine whether the recommendations were in need of updating. RESULTS There were 14 new publications that met inclusion criteria: nine systematic reviews (three included meta-analyses) and five randomized controlled trials. After its review and analysis of the evidence, the Update Committee concluded that no revisions to the existing ASCO recommendations were warranted. RECOMMENDATIONS Regular history, physical examination, and mammography are recommended for breast cancer follow-up. Physical examinations should be performed every 3 to 6 months for the first 3 years, every 6 to 12 months for years 4 and 5, and annually thereafter. For women who have undergone breast-conserving surgery, a post-treatment mammogram should be obtained 1 year after the initial mammogram and at least 6 months after completion of radiation therapy. Thereafter, unless otherwise indicated, a yearly mammographic evaluation should be performed. The use of complete blood counts, chemistry panels, bone scans, chest radiographs, liver ultrasounds, pelvic ultrasounds, computed tomography scans, [(18)F]fluorodeoxyglucose-positron emission tomography scans, magnetic resonance imaging, and/or tumor markers (carcinoembryonic antigen, CA 15-3, and CA 27.29) is not recommended for routine follow-up in an otherwise asymptomatic patient with no specific findings on clinical examination.

Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update

PURPOSE To update the 2006 American Society of Clinical Oncology guideline on the use of hematopoietic colony-stimulating factors (CSFs). METHODS The American Society of Clinical Oncology convened an Update Committee and conducted a systematic review of randomized clinical trials, meta-analyses, and systematic reviews from October 2005 through September 2014. Guideline recommendations were based on the review of the evidence by the Update Committee. RESULTS Changes to previous recommendations include the addition of tbo-filgrastim and filgrastim-sndz, moderation of the recommendation regarding routine use of CSFs in older patients with diffuse aggressive lymphoma, and addition of recommendations against routine dose-dense chemotherapy in lymphoma and in favor of high-dose-intensity chemotherapy in urothelial cancer. The Update Committee did not address recommendations regarding use of CSFs in acute myeloid leukemia or myelodysplastic syndromes in adults. RECOMMENDATIONS Prophylactic use of CSFs to reduce the risk of febrile neutropenia is warranted when the risk of febrile neutropenia is approximately 20% or higher and no other equally effective and safe regimen that does not require CSFs is available. Primary prophylaxis is recommended for the prevention of febrile neutropenia in patients who are at high risk on the basis of age, medical history, disease characteristics, and myelotoxicity of the chemotherapy regimen. Dose-dense regimens that require CSFs should only be used within an appropriately designed clinical trial or if supported by convincing efficacy data. Current recommendations for the management of patients exposed to lethal doses of total-body radiotherapy, but not doses high enough to lead to certain death as a result of injury to other organs, include the prompt administration of CSFs.

Endocrine Therapy for Hormone Receptor–Positive Metastatic Breast Cancer: American Society of Clinical Oncology Guideline

PURPOSE To develop recommendations about endocrine therapy for women with hormone receptor (HR) -positive metastatic breast cancer (MBC). METHODS The American Society of Clinical Oncology convened an Expert Panel to conduct a systematic review of evidence from 2008 through 2015 to create recommendations informed by that evidence. Outcomes of interest included sequencing of hormonal agents, hormonal agents compared with chemotherapy, targeted biologic therapy, and treatment of premenopausal women. This guideline puts forth recommendations for endocrine therapy as treatment for women with HR-positive MBC. RECOMMENDATIONS Sequential hormone therapy is the preferential treatment for most women with HR-positive MBC. Except in cases of immediately life-threatening disease, hormone therapy, alone or in combination, should be used as initial treatment. Patients whose tumors express any level of hormone receptors should be offered hormone therapy. Treatment recommendations should be based on type of adjuvant treatment, disease-free interval, and organ function. Tumor markers should not be the sole criteria for determining tumor progression; use of additional biomarkers remains experimental. Assessment of menopausal status is critical; ovarian suppression or ablation should be included in premenopausal women. For postmenopausal women, aromatase inhibitors (AIs) are the preferred first-line endocrine therapy, with or without the cyclin-dependent kinase inhibitor palbociclib. As second-line therapy, fulvestrant should be administered at 500 mg with a loading schedule and may be administered with palbociclib. The mammalian target of rapamycin inhibitor everolimus may be administered with exemestane to postmenopausal women with MBC whose disease progresses while receiving nonsteroidal AIs. Among patients with HR-positive, human epidermal growth factor receptor 2-positive MBC, human epidermal growth factor receptor 2-targeted therapy plus an AI can be effective for those who are not chemotherapy candidates.

American Society of Clinical Oncology Endorsement of the Cancer Care Ontario Practice Guideline on Adjuvant Ovarian Ablation in the Treatment of Premenopausal Women With Early-Stage Invasive Breast Cancer

PURPOSE The American Society of Clinical Oncology (ASCO) has policies and procedures for endorsing practice guidelines that have been developed by other professional organizations. METHODS The Cancer Care Ontario (CCO) Guideline on Adjuvant Ovarian Ablation (OA) in the Treatment of Premenopausal Women With Early-Stage Invasive Breast Cancer was reviewed for developmental rigor by methodologists. An ad hoc review panel of experts reviewed the content. RESULTS The ASCO ad hoc OA guideline review panel concurred that the recommendations are clear, thorough, based on the most relevant scientific evidence in this content area, and present options that will be acceptable to patients. According to the CCO guideline: one, OA should not be routinely added to systemic therapy with chemotherapy, tamoxifen, or the combination of tamoxifen and chemotherapy; two, OA alone is not recommended as an alternative to any other form of systemic therapy, except in the specific case of patients who are candidates for other forms of systemic therapy but who, for some reason, will not receive any other systemic therapy (eg, patients who cannot tolerate other forms of systemic therapy or patients who choose no other form of systemic therapy); and three, when chemical suppression using luteinizing hormone-releasing hormone agonists is the chosen method of OA, in the opinion of the Breast Cancer Disease Site Group, monthly injection is the recommended mode of administration. The mode of administration in nearly all of the available trials has been monthly administration. CONCLUSION The ASCO review panel agrees with the recommendations as stated in the CCO guideline, with the qualification that ongoing research studies may alter the recommendations of the panel.

Pazopanib as Second-Line Treatment After Sunitinib or Bevacizumab in Patients With Advanced Renal Cell Carcinoma: A Sarah Cannon Oncology Research Consortium Phase II Trial

BACKGROUND This phase II trial examined the activity and toxicity of second-line treatment with pazopanib after failure of first-line single-agent treatment with sunitinib or bevacizumab in patients with advanced clear cell renal carcinoma. PATIENTS AND METHODS Fifty-five patients with metastatic clear cell renal carcinoma who had previously received first-line treatment with sunitinib (39 patients) or bevacizumab (16 patients) were enrolled. Patients received pazopanib 800 mg orally daily and were evaluated for response after 8 weeks of treatment. Responses were measured using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, and confirmed with repeated scans after 8 weeks. Patients with objective response or stable disease continued treatment until disease progression or unacceptable toxicity occurred. RESULTS Fifteen of 55 patients (27%) had objective response to pazopanib. An additional 27 patients (49%) had stable disease, for a disease control rate of 76%. After a median follow-up of 16.7 months, the median progression-free survival for the entire group was 7.5 months (95% confidence interval, 5.4-9.4 months). Similar progression-free survival was observed regardless of whether previous treatment was with sunitinib or bevacizumab. The estimated overall survival rate for the entire group at 24 months was 43%. CONCLUSION Pazopanib is an active agent for the treatment of advanced clear cell renal carcinoma, even after failure of sunitinib or bevacizumab. Treatment with pazopanib should be considered early in the sequence of therapy for patients with advanced renal cell carcinoma.

Randomized Trial of Long-Term Follow-Up for Early-Stage Breast Cancer: A Comparison of Family Physician Versus Specialist Care

The article by Grunfeld et al in this issue of the Journal of Clinical Oncology is a landmark article for women with breast cancer and their health care providers. It shows conclusively that the health outcomes for women after primary treatment of breast cancer are the same if they are followed by their family physicians or cancer center specialists. Medical, psychosocial, and all other measured outcomes were the same. There really is no other conclusion that can be drawn. This is not one study; this relates to conclusions from years of research. Grunfeld et al previously showed that in Great Britain, follow-up by a generalist physician led to the same health outcomes as did follow-up by a specialist surgeon, with no change in quality of life, better patient satisfaction, and no change in health care expenditures. Another randomized trial in Great Britain showed that twice as many patients preferred simpler, less frequent follow-up by telephone. There is no a priori reason to expect that patients in the United States would choose differently, and Loprinzi et al demonstrated that the demand for medically inappropriate testing can be reduced by patient education about the specificity, sensitivity, and usefulness of the available tests. In fact, this conclusion corresponds with the American Society of Clinical Oncology (ASCO) guidelines for surveillance of breast cancer patients. Data suggest that current follow-up procedures could be improved. Lash and Silliman followed 303 stage I or II breast cancer patients aged 55 years or older diagnosed at five Boston hospitals, with patient interviews and medical record abstracts. Over 4 years, of the 303 women, 279 had some surveillance testing; the most common test was a mammogram (average, 3.9 in 4 years). Younger women, those treated at a breast cancer center with a unified patient chart, and women who worked, were more likely to complete surveillance; those 75 to 90 years old were less likely to complete guideline-approved surveillance. Mille et al at Centre Regional Leon Berard showed that implementation of clinical practice guidelines on follow-up of patients with localized breast cancer standardized care and a one-third decrease in cost per patient. Earle et al showed that patients followed up by a primary care physician and their oncologist were more likely to receive recommended preventive health services than those followed by their oncologists alone; with more and more survivors each year, this will become increasingly important. With all that evidence, why are we still uneasy with allocating surveillance care to primary care physicians, without oncology routine follow-up? There are substantial issues that have not yet been addressed. This study looked at the most important medical events, such as recurrence and new primary cancers. Are there data that show how frequently oncologists or primary care physicians inquire about some of the “softer” but important issues of body image, sexuality, sexual functioning, adaptation back to normal life, cognitive dysfunction, neuropathic pain, bone health, depression, menopause, or the myriad symptoms left after modern treatment? We know these issues are important, and we know we can fix some of them; we just don’t know in everyday practice how frequently they are addressed and controlled. A prospective study of a onepage follow-up check list would give the answers. Do patient outcomes for specific symptoms due to treatment, such as chronic breast pain, sexual function, menopause symptoms, depression, and so on vary between the two groups? The Hospital Anxiety and Depression Scale (HADS) and 36-item short form (SF-36) are good instruments for global function, but are not designed for breast cancer survivor symptoms. Are there data to suggest that any practitioner group is better? We do know that oncologists are not very good at assessing emotional health. For example, in a study of 204 patients and five oncologists, patients reported many more symptoms than their oncologists perceived, and the oncologists had better sensitivity and specificity for physical symptoms than psychosocial. The oncologists had sensitivity rates up to 80% for fatigue, nausea, vomiting, and hair loss, but recognized only 17% of the patients with anxiety and only 6% of those with clinical depression. Do patient outcomes for important issues such as genetic testing and secondary chemoprevention vary between the two groups? No data are provided. Are there data to suggest that oncologists provide good care in this regard? Data from our institution suggest underreferral of patients with potentially detectable genetic changes associated with breast and colorectal cancer for genetic consultation (personal communication, Joann N. Bodurtha, MD, MPH, October 23, 2005) compared with national recommendations, so there is work to be done. Are there data on the diffusion of new knowledge, such as adding letrozole after 5 years of primary treatment with tamoxifen, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 6 FEBRUARY 2

Ovarian Suppression in the Management of Premenopausal Breast Cancer: Methods and Efficacy in Adjuvant and Metastatic Settings

Ovarian suppression has been used to treat hormone-responsive metastatic breast cancer in premenopausal women for over 100 years and is currently under continued evaluation for treatment in the adjuvant setting. In this article, ovarian suppression by surgery, radiation, and pharmacological therapy is discussed, including the risks, benefits, and efficacy of each strategy. The role of ovarian suppression in premenopausal women with early and advanced stages of breast cancer will be reviewed. It is hoped that this review will assist clinicians and their patients in selecting the appropriate therapy if ovarian suppression is indicated.

Randomized Phase II Study of Ramucirumab or Icrucumab in Combination with Capecitabine in Patients with Previously Treated Locally Advanced or Metastatic Breast Cancer

BACKGROUND Icrucumab (ICR) and ramucirumab (RAM) bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. This open-label, randomized phase II study evaluated their efficacy and safety in combination with capecitabine (CAP) in patients with previously treated unresectable, locally advanced or metastatic breast cancer. METHODS Patients were randomly assigned (1:1:1) to receive CAP (1,000 mg/m2 orally twice daily, days 1-14) alone or in combination with RAM (10 mg/kg intravenously [IV], days 1 and 8) (RAM + CAP) or ICR (12 mg/kg IV, days 1 and 8) (ICR + CAP) every 21 days. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), tumor response, safety, and pharmacokinetics. RESULTS Of 153 patients randomized, 150 received treatment. Median PFS (95% confidence interval) was 22.1 (12.1-36.1) weeks on RAM + CAP, 7.3 (6.3-13.0) weeks on ICR + CAP, and 19.0 (12.1-24.3) weeks on CAP (hazard ratios [HRs]: 0.691, p = .1315, RAM + CAP versus CAP; 1.480, p = .0851, ICR + CAP versus CAP). Median OS was 67.4 weeks on RAM + CAP, 62.1 weeks on ICR + CAP, and 71.6 weeks on CAP (HRs: 1.833, p = .0283, RAM + CAP versus CAP; 1.468, p = .1550, ICR + CAP versus CAP). There was no statistically significant difference in PFS or OS between either combination arm and CAP. Treatment-related adverse events more frequent (by ≥10%) on RAM + CAP than on CAP were constipation, decreased appetite, headache, epistaxis, and hypertension. Those more frequent (by ≥10%) on ICR + CAP than CAP were anemia, increased lacrimation, periorbital edema, nausea, vomiting, peripheral edema, facial edema, dehydration, and dyspnea. CONCLUSION Combining RAM or ICR with CAP did not improve PFS in the targeted study population. The Oncologist 2017;22:245-254 IMPLICATIONS FOR PRACTICE: Icrucumab and ramucirumab are recombinant human IgG1 monoclonal antibodies that bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. VEGFR-1 activation on endothelial and tumor cell surfaces increases tumor vascularization and growth and supports tumor growth via multiple mechanisms, including contributions to angiogenesis and direct promotion of cancer cell proliferation. Strong preclinical and clinical evidence suggests key roles for VEGF and angiogenesis in breast cancer growth, invasion, and metastasis. This randomized phase II study evaluated the efficacy and safety of each antibody in combination with capecitabine in patients with previously treated unresectable, locally advanced or metastatic breast cancer.