Independent News on Advances in Hematology/Oncology CLINICALONCOLOGY.COM • June 2013 • Vol. 8, No. 6
INSIDE
IMAGES in ONCOLOGY
SOLID TUMORS ASCO Coverage Standard- vs. high-dose radiation for advanced non-small cell lung cancer ............................. 8
Scrambling To Deal With Sequestration Community practices brace for 28% cut to office drug payments Orlando, Fla.–Community oncologists are scrambling to deal with a massive funding cut that leaves cancer specialists at a financial loss every time they administer expensive oncology drugs to Medicare patients in a community clinic. “There is no good way to deal with this cut,” said Ted Okon, the executive director of the Community Oncology Alliance (COA), an organization that represents community cancer centers and their patients. “We’re seeing a variety of reactions on the part of practices but I think most are still in disbelief that this is really happening. Oncologists are a bit like deer in headlights with these cuts.” Many practices are turning away a portion of their Medicare patients. Others are redirecting all Medicare patients to hospitals. Meanwhile, some are sticking to their usual practices, taking in all of their patients and hoping that a solution comes before their practices become untenable. “While we are affected, we haven’t turned down any patients and we haven’t shut down any clinics,” said Lucio Gordan, MD, a medical oncologist at a Florida Cancer Specialists Clinic in Gainesville.
‘On the Spot’ debate: Controversies in breast cancer management ......... 22
HEMATOLOGIC DISEASE How I Manage ... Primary mediastinal large B-cell lymphoma: John Sweetenham, MD ....... 6
ASCO Coverage Imaging to detect relapses in patients with diffuse large B-cell lymphoma ................................ 9
see SEQUESTRATION, N page 21
Counterfeit Chemo CURRENT PRACTICE
A special two-part report on drug fraud in the U.S.
Readers Respond: Letters to the Editor ........... 5
M
Maurie Markman, MD: Interpreting quality-of-life studies ..................................... 10 Clinical Conundrums ......... 25
EDUCATIONAL REVIEW Pathogenesis of a Hereditary Predisposition To Breast Cancer ..... after 28
Lung cancer, close-up. Image courtesy of Science Photo Library
illard Ray Lamb, MD, a physician and part owner of the McLeod Cancer and Blood Center in Johnson City, Tenn., received a fax in September 2007 from Quality Specialty Products (QSP). The message indicated that QSP, a business in Winnipeg, Canada, could provide physicians with substantial discounts on a list of expensive prescription drugs, including chemotherapy medications bevacizumab (Avastin, Genentech/Roche) and rituximab (Rituxan, Biogen Idec/Genentech). For example, QSP was selling a 400-mg vial of Avastin for less than $2,000, whereas an FDAapproved vial of the same drug costs about $2,400. Dr. Lamb, along with physicians and part owners Charles Famoyin, MD, and William Kincaid, MD, and business manager Michael Combs, agreed Mr. Combs should order cancer drugs from QSP. Soon after, patients at McLeod Cancer started receiving chemotherapy treatments from the QSP supply. see COUNTERFEIT, T page 19
RE VIE WS & COMMENTAR IES
Expert Insights From Levine Cancer Institute Anagrelide Effective for Essential Thrombocythemia ....................................... 13 Edward Copelan, MD
Cytarabine Improves Combination Therapy for Mantle Cell Lymphoma ............ 17 Belinda Avalos, MD
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www.CMEZone.com Perspectives in Non-Hodgkins Lymphoma Evolving Paradigms Enter Key word MN111 Expiration Date: August 22, 2013
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Clinical Oncology News wants to publish you! As part of the Clinical Oncology News inaugural writer’s contest, from now until June 30 the magazine will be accepting essays on the topic ‘Change in Medical Oncology or Hematology/Oncology’. Cash prizes!
National literary exposure!
A voice in the marketplace of ideas!
Essays can relate to the topic in any way the author sees fit — how medicine has changed for the worse, how it should be changed for the better, or simply a reflect on the process of change itself. Essays will be judged on their eloquence and persuasiveness and should be a maximum of 3,500 words. Winners will be announced in the August issue. First place will receive $1000, second place $500 and third place $250. All will receive recognition and prominent placement in Clinical Oncology News. Submissions should be emailed as a word document to Clinical Oncology News managing editor Gabriel Miller at gmiller@mcmahonmed.com.
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CLINICAL ONCOLOGY NEWS
CLINICAL ONCOLOGY NEWS • JUNE 2013 • CLINICALONCOLOGY.COM
EDITORIAL BOARD
Solid Tumors Bone Metastases Allan Lipton, MD Milton S. Hershey Medical Center, Penn State University Hershey, PA
Breast Cancer
Prostate Cancer
Charles F. von Gunten, MD University of California, San Diego, CA
Michael A. Carducci, MD AEGON Professor in Prostate Cancer Research, Co-Director, Prostate/GU Cancer and Chemical Therapeutics Programs, Johns Hopkins Kimmel Cancer Center Baltimore, MD
Oncology Nursing Betty Ferrell, RN, PhD City of Hope National Medical Center Duarte, CA
Hematologic Malignancies Jennifer R. Brown, MD, PhD
Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY
Dana-Farber Cancer Institute, Harvard Medical School Boston, MA
Michele Neskey, MMSc, PA-C
Maura N. Dickler, MD
Harry Erba, MD, PhD
University of Texas, MD Anderson Cancer Center Houston, TX
Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY
University of Alabama Birmingham, AL
University of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA
Richard Stone, MD
Leonard Saltz, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY
Gastrointestinal Cancer and Sarcoma
University of Colorado Cancer Center Denver, CO
Sara S. Kim, PharmD The Mount Sinai Medical Center New York, NY
Dana-Farber Cancer Institute, Harvard Medical School Boston, MA
Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH
Gynecologic y g Cancer Maurie Markman, MD Cancer Treatment Centers of America Philadelphia, PA
Levine Cancer Institute, Carolinas HealthCare Charlotte, NC
Lung g Cancer,, Emesis Richard J. Gralla, MD Hofstra North Shore-Long Island Jewish School of Medicine, Monter Cancer Center North Shore University Hospital and Long Island Jewish Medical Center Lake Success, NY
Rhonda M. Gold, RN, MSN The Pritchard Group Rockville, MD
Infection Control Susan K. Seo, MD Memorial Sloan-Kettering Cancer Center New York, NY
Community Oncology John W. Finnie, MD Mercy Medical Center St. Louis, MO
Mission Statement Michael J. Fisch, MD, MPH University of Texas, MD Anderson Cancer Center Houston, TX
T
he mission of Clinical Oncology News is to be an independent source of unbiased, accurate and reliable news combined with in-depth expert analysis about the issues that oncologists and hematologists care about most. We strive to be a valuable source for oncologists and hematologists in providing the best possible care for their patients.
Steven Vogl, MD Medical Oncologist New York, NY
Editorial Philosophy Symptom Control and Palliative Care William S. Breitbart, MD Memorial Sloan-Kettering Cancer Center New York, NY
Lung g and Head and Neck Cancers Edward S. Kim, MD
Mary Lou Bowers, MBA
Cancer Treatment Centers of America Zion, Illinois
Genitourinary y Cancer Ronald M. Bukowski, MD
Policy and Management
Syed A. Abutalib, MD
Ephraim Casper, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY
Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH
Cindy O’Bryant, PharmD
Edward Chu, MD
University of Texas, MD Anderson Cancer Center Houston, TX
Paul J. Ford, PhD
The Pritchard Group Rockville, MD
Pharmacy
Shaji Kumar, MD Mayo Clinic Rochester, MN
Cathy Eng, MD
Joseph P. DeMarco, PhD Cleveland State University Cleveland, OH
Andrew Seidman, MD
Gastrointestinal Cancer
Bioethics
Steven D. Passik, PhD Vanderbilt University Medical Center Nashville, TN
Joseph V. Pergolizzi Jr., MD Johns Hopkins University School of Medicine Baltimore, MD
Russell K. Portenoy, MD Beth Israel Medical Center New York, NY
The Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the magazine. A significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. They then review the articles before they are published. Board members, in their area of specialty, are also consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and review the articles before they go to print. Additionally, all news articles that appear in Clinical Oncology Newss are sent to the sources quoted in each article to review and verify the accuracy of the article’s content. Educational review articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.
CLINICAL ONCOLOGY NEWS
CLINICAL ONCOLOGY NEWS • JUNE 2013 • CLINICALONCOLOGY.COM
Readers Respond: Imaging Safely; 340B Program To the Editor: Re: the article by Maurie Markman, MD, “Diagnostic Imaging in Oncology: A (Potential) Double-Edged Sword” in the March issue of Clinical Oncology News: Radiation is not potentially causing harm; harm has been, and is continuing to be, caused by radiation exposure from diagnostic imaging, in patients stricken with cancer. The harm caused by radiation from diagnostic imaging is directly proportional to the persons owning the radiology equipment. One has to start, as the article did, by not including patients with metastatic cancers, who have a limited life span; those with early cancers; those in which imaging studies should not play a role in treatment decisions; and those in whom no diagnosis of any disease has been confirmed. Let’s go back to basics. Diagnostic imaging is actually a misnomer. Radiology imaging is not able to diagnose anything. The results of radiology imaging project a pattern consistent with a disease process. It is the clinician who should be the diagnostician. For cancers, it is ultimately the pathologist who describes a diagnostic picture. Yet persons with lymphadenopathy are subjected to CT [computed tomography] scans and/or PET [positron emission tomography] scans without the presence of a biopsy. In this clinical situation the premise of primum non nocere is nonexistent. Patients need a lymph node biopsy before the imaging to determine whether the imaging is even necessary. They then undergo repeated scanning, even in the presence of negative biopsies for “clinical follow-up.” Concerning specific disease states, low-grade lymphoma does not require
PET scans as they are mostly non–PET avid. Yet PET scans are repeatedly performed for “staging purposes,” to determine treatment responses and for surveillance. In addition, CT scans are routinely used for surveillance purposes in asymptomatic patients. My understanding of these entities is that treatment is based on specific criteria that involve clinical symptoms, lymph node bulk and end-organ disease. None of these persons need repeated imaging in the face of no symptoms, minimal lymphadenopathy and no end-organ disease. In fact, these people oftentimes go years without needing treatment, either at the time of initial diagnosis or upon recurrence of disease. The national policymakers in oncology, specifically the National Comprehensive Cancer Network and the American Society of Clinical Oncology, do not recommend routine imaging for breast cancer patients in the adjuvant setting of disease. In fact this data has been updated as recently as March 1, 2013, after originally being published in 1994. However, patients are routinely imaged for surveillance and every symptom including a wheeze or a cough generates a PET scan request. Colon cancer requires PET scanning only if there is resectable metastatic disease, or there is a rising carcinoembryonic antigen (CEA) level, with all other tests being negative. CT scans need be performed only yearly for surveillance, and not at all for stage 1 disease or cancers arising in a polyp. Every colon cancer patient gets a request for a PET, with CT scans for initial staging, and then potentially for surveillance purposes. In more
than 30 years of oncology practice, I cannot remember if I ever ordered surveillance CT scans of the chest/abdomen/ pelvis. It is now a commonplace request. For other cancers, for example, head and neck cancers, PET scans are predictive of long-term outcome. A positive scan after initial chemoradiation harbors a poor prognosis, whereas conversely a negative scan harbors a favorable prognosis. However, one PET is enough. Repeated PET scanning offers no beneficial information. Lastly, clinicians utilize PET scans in lieu of biopsies. A clinician may not biopsy a lesion if a PET scan is not positive. This is logically absurd. There are cancers that are not PET avid, and benign entities that may be PET avid. Thus the need for clinical judgment (what’s that?). In conclusion, one must remember that radiologic imaging, of any sort, improves health care outcomes (aka overall survival). They may be predictive or may help in treatment planning, but only the natural history of each individual’s disease affects overall survival. The Stark Amendments left self-referrals for PET scans and CT scans off of their restricted list. This oversight needs to be changed as it directly leads to increased numbers of unnecessary imaging studies, putting patients at risk without impacting the natural history of a disease. When people state that imaging has improved outcomes, they need to be quickly reminded that the pharmaceutical armamentarium available now is vastly superior to even 10 years ago. Dr. Markman had his thoughts in the right place. Now he needs to lead by
example, as his institution is one of the prime examples as to the abovementioned increase in patient risk. Arnold Wax, MD Las Vegas, NV
To the Editor: I appreciated the recent article in Clinical Oncology News by Steven Vogl, MD, regarding the cost of cyclophosphamide (“Vogl, NY: Cyclophosphamide Prices Skyrocket,” March 2013, Clinical Oncology News, page 1). It is both timely and appropriate, and highlights the inconsistencies of the methodology for payment of drugs to private oncologists. The reference to hospitals with 340 designations is also appropriate. I believe the politicians do not really care about this issue as they feel that they are getting benefits from the drug companies, but Sen. Grassley from Iowa may not be too happy about the whole issue as evidenced by his comments in the article in The New York Times. However, on a more serious and practical level, the issue of 340 designations will be making it extremely difficult for private oncologists if the vast majority of practicing oncologists revert to a hospital-based situation. Paradoxically, it may look wonderful on a contractual basis for a few years, but then, guess what? All things may change once you become an employee of the hospital. I look forward to seeing Dr. Vogl at some of the meetings. Keep up the good writing. Paul Donovan, MD Grand Street Medical Associates Kingston, NY
Send us your news Clinical Oncology News appreciates news tips and suggestions for coverage from readers. All submissions will be considered for publication.
Write to managing editor Gabriel Miller at gmiller@mcmahonmed.com
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CLINICAL ONCOLOGY NEWS • JUNE 2013 • CLINICALONCOLOGY.NEWS
How I Manage ...
Primary Mediastinal Large B-Cell Lymphoma P
rimary mediastinal large B-cell lymphoma (PMBCL) is a distinct clinicopathologic entity from diffuse large B-cell lymphoma (DLBCL) and originates in the thymus. It is more common in women than in men and predominantly affects women in their 20s and 30s. Typical presenting features are related to the anatomic site, with a rapidly invasive growth pattern causing cough, dyspnea, chest pain, hoarseness and other symptoms related to local compression such as dysphagia, superior vena cava syndrome or pleural and pericardial effusions.
When do I suspect primary mediastinal large B-cell lymphoma and how is the diagnosis established? The disease is most commonly localized to the mediastinum and supraclavicular lymph nodes and is typically stage I or IIA at presentation, although more advanced presentation is reported, frequently involving extranodal sites such as the lung, kidney and breast. Constitutional (“B”) symptoms are uncommon. Based on presenting features, the most important differential diagnoses include Hodgkin lymphoma (HL), precursor T-cell lymphoblastic lymphoma (T-LBL) and thymoma. Other less common entities with a similar presentation include mediastinal germ cell tumors and primary lung malignancies. The differential diagnosis between PMBCL and thymoma or T-LBL is usually straightforward and based on morphology and immunohistochemistry. The distinction between PMBCL and classical Hodgkin lymphoma (cHL) involving or presenting in the mediastinum is more complex because it is now recognized that these two entities are closely related and share many
Table 1. Key IHC Differences Between PMBCL and cHL PMBCL
cHL
CD45
+
–
CD79a
+
–
Bcl-6
+
–
Oct-2
+
–
MAL
+
–
BOB-1
+
–
EBV
–
+/–
cHL, classical Hodgkin lymphoma; IHC, immunohistochemistry; PMBCL, primary mediastinal large e B-cell B cell lymphoma lymphom ma
immunohistochemical (IHC) and molecular features. Morphologically, PMBCL comprises large tumor cells with abundant, pale cytoplasm and pleomorphic, often multilobulated nuclei, within a background of fine sclerosis that compartmentalizes the neoplastic cells. As a result, the appearance can resemble nodular sclerosis HL. The tumor cells in PMBCL express most B-cell antigens but do not express surface immunoglobulin, and although PMBCL is often CD30-positive, in distinction to cHL, the staining is usually weak and PMBCL is usually negative for CD15. The B-cell transcription factors PAX5, Oct-2, BOB1 and PU.1 are almost always expressed in PMBCL and are negative in HL (Table 1). Most cases of PMBCL also express bcl-6 and MUM1 as well as TRAF1 and nuclear REL.1 Gene expression profiling studies have shown that PMBCL represents a distinct subtype of DLBCL with a favorable outcome and an expression profile very similar to cHL. Also in common with cHL, activation of the JAK/ STAT and NF–κB pathways is commonly seen in PMBCL. In practical terms, the most important differential diagnosis is between PMBCL and cHL and in general, this can be made based on the clinical, morphologic and IHC features, emphasizing the need for close interaction between the clinician and an expert hematopathologist.
Is there a ‘gray zone’ lymphoma associated with PMBCL? A small proportion of cases show features common to PMBCL and cHL and have been labeled as a “gray zone” between PMBCL and cHL. They typically present in the mediastinum but unlike PMBCL, have a male predominance and appear to be very aggressive clinically. Consistent with this, they often comprise sheets of tumor cells, which have an intermediate immunophenotype including CD45, CD20, Oct-2, BOB1 and CD30.2
John W. Sweetenham, MD Senior Director of Clinical Affairs and Executive Medical Director Huntsman Cancer Institute University of Utah Salt Lake City, Utah
The optimal treatment strategy for this group is unknown.
What is the best front-line therapy for PMBCL? The optimal first-line therapy for PMBCL is unclear. Most of the literature regarding this disease comprises single-institution or retrospective studies, many of which are confounded by selection or reporting bias as well as potential diagnostic inaccuracies in view of the emerging data regarding the distinction from cHL. In view of this, no standard of care has emerged for first-line therapy.
superior response and survival rates and were widely adopted as a standard although they have not been the subjects of prospective studies. The rationale for the use of more intensive therapy in this entity has been questioned in recent studies that have suggested that PMBCL, diagnosed using modern criteria, has a favorable prognosis compared with other subtypes of DLBCL.3 In the rituximab era, the apparent benefit of dose-intensive regimens has been questioned. The most definitive analysis to date of the role of rituximab in this disease was undertaken in a subset of patients with PMBCL entered into MInT (Mabthera International Trial).4 This study compared CHOP-like chemotherapy with CHOP-like chemotherapy plus rituximab in 824 young, lowrisk patients with DLBCL, of whom 87 had PMBCL. The addition of rituximab to CHOP-like therapy resulted in an increase in CR rate compared with CHOP-like therapy alone (80% vs. 54%; P=0.015), a marked reduction in disease progression (2% vs. 24%; P<0.001) and an improvement in three-year event-free
In practical terms, the most important differential diagnosis is between PMBCL and cHL and in general, this can be made based on the clinical, morphologic and immunohistochemical features, emphasizing the need for close interaction between the clinician and an expert hematopathologist. In the pre-rituximab era, the use of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy with or without consolidative radiation therapy (RT) produced long-term disease-free survival rates of only 50% to 65%. Several of these studies demonstrated an apparent benefit for consolidative RT, although these data are difficult to interpret because RT was typically restricted to those patients achieving a complete response (CR) or partial response to first-line chemotherapy. In view of the apparently disappointing results reported for CHOP and similar regimens, several groups investigated the use of more aggressive chemotherapy regimens such as VACOP-B (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin) and MACOP-B (methotrexate, leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin), usually with the inclusion of RT. These studies reported apparently
survival (EFS; 78% vs. 52%; P<0.001), although no significant improvement in overall survival (OS) was observed. Approximately 70% of the patients in each arm received consolidative RT but the study was not powered to investigate the effect of radiation on outcomes. The effect of rituximab also was investigated in a prospective study of 76 patients with PMBCL treated with R-CHOP with or without RT, and compared with 45 consecutive historical controls who had received CHOP with or without RT.5 The rate of treatment failure was much lower in patients receiving R-CHOP than in those receiving CHOP (9% vs. 30%; P=0.004) and the five-year failure from progression and EFS also were significantly superior in patients receiving R-CHOP. In this study, a significant difference in fiveyear OS also was observed in patients treated with R-CHOP (89% vs. 69%; P=0.003). This study did not have sufficient statistical power to investigate
HEMATOLOGIC DISEASE
CLINICAL ONCOLOGY NEWS • JUNE 2013 • CLINICALONCOLOGY.COM
the role of RT because most patients received radiation. In the absence of a prospective randomized trial, these two studies represent the best available evidence for the use of CHOP plus rituximab in PMBCL. There are no randomized studies at present comparing R-CHOP with a more doseintensive regimen specifically in PMBCL. Controversy therefore still exists regarding the use of R-CHOP as standard frontline chemotherapy. A recent combined analysis from the National Cancer Institute (NCI) and Stanford University has reported the use of infusional therapy with dose-adjusted (DA) EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide and hydroxydaunorubicin plus rituximab), without mediastinal radiation.6 Fifty-one patients with PMBCL treated in a prospective Phase II study at NCI were analyzed in comparison with a retrospective study of patients receiving the same therapy at Stanford. Patients received six to eight cycles of therapy, depending on response. Those who had more than a 20% reduction of the largest diameter of their tumor between cycles 4 and 6 received a total of eight cycles. Those with less than 20% reduction received only six cycles. With a median of five years of follow-up, the EFS and OS rates were 93% and 97%, respectively. The corresponding five-year EFS and OS rates for the 16 patients in the retrospective group treated at Stanford were both 100%. These results are clearly very impressive, suggesting that DA-EPOCH-R may be considered a new standard of care for patients with PMBCL, especially because these results were achieved without the use of mediastinal RT—a very important consideration given the young, predominantly female population affected by this disease and the potential for late, radiation-induced second malignancies. However, a direct comparison with R-CHOP will be required to confirm the superiority of this regimen.
Is there a role for consolidative radiation therapy in PMBCL? Early studies of the use of CHOP and related regimens in PMBCL included mediastinal RT and reported an apparent benefit for its use, although these studies are difficult to interpret because radiation was typically restricted to patients who responded to first-line therapy. Few systematic studies of the benefit of RT have been reported. In the studies of R-CHOP just cited, most patients received radiation and these studies therefore do not have sufficient statistical power to determine its effect. No major difference in outcome was observed when mediastinal radiation was omitted in responding patients after R-CHOP. In a series from British Columbia, Canada, the routine use of mediastinal radiation was introduced following CHOP after 1998 and CHOP-R
after 2001.3 No difference in progression-free survival or OS was observed for patients treated before or after the introduction of routine mediastinal radiation. The recent combined study from the NCI and Stanford did not include mediastinal radiation after DA-EPOCH-R, reporting excellent long-term outcomes without the potential for late radiationinduced toxicities. In summary, current data do not provide clear evidence of a benefit from consolidative RT. The potential use of functional imaging to identify patients with residual masses who have evidence of active disease and therefore may benefit from consolidative RT is an area of continued active investigation. The International Extranodal Lymphoma Study Group is currently conducting a randomized Phase III trial (NCT01599559) in which patients with PMBCL receive initial rituximab-containing chemotherapy and are reevaluated with positron emission tomography/computed tomography (PET/CT) at completion of therapy. PET-negative patients are randomized to mediastinal RT or no further therapy. This trial is expected to be complete in 2015.
What is the role of PET scan in PMBCL? As with other subtypes of DLBCL, the role of PET or PET/CT scan remains unclear. Although there has been considerable interest in the role of “interim” PET (iPET) to predict long-term outcome in DLBCL, results remain inconclusive and the use of iPET specifically in PMBCL has not been reported to date. In the series from British Columbia, functional imaging with gallium scanning was used at the end of chemotherapy to direct the use of mediastinal RT. Of 54 patients who had functional imaging at the completion of chemotherapy, 43 were negative, only one of whom had received RT. Nine of the remaining 42 nonirradiated patients relapsed. All of the gallium-positive patients received RT and only one relapsed. In contrast, the study from the NCI reported a very poor positive predictive
Series Editor
value (PPV) for post-treatment fluorodeoxyglucose (FDG)-PET/CT of only 17%, although the negative predictive value was 100%. The authors observed a number of patients with initially positive posttreatment PET scans that converted to negative over longer follow-up, suggesting that the inflammatory component of the tumor may be partly responsible for the FDG uptake. Further prospective data are required to clarify the role of posttreatment PET scanning in decision making for RT, also bearing in mind that the predictive value of PET also may relate to the specific chemotherapy regimen.
Is there a role for consolidative autologous stem cell transplantation? Interest in the use of high-dose therapy and autologous stem cell transplantation (ASCT) was generated by early reports of the apparently poor prognosis of PMBCL with conventional chemotherapy and RT regimens. As outcomes for PMBCL have improved, the role of front-line ASCT is doubtful, particularly in patients who achieve CR. Some studies have suggested a possible role for ASCT in patients with a poor response to initial chemotherapy, although these results are difficult to interpret because definitions of responsive and refractory disease are difficult in an entity such as PMBCL where residual masses are common at the completion of induction therapy.7 Prospective evaluation of ASCT in a population with residual FDG-avid disease at the completion of chemotherapy may be a reasonable approach, although the low PPV of PET scan in this situation may limit the utility of ASCT.
Summary Based on the data summarized here, my approach to the management of PMBCL is initially based on accurate diagnosis and distinction from cHL using the morphologic and IHC features described above (Table 1)—it requires close and active interaction with an expert hematopathologist. At present, I treat PMBCL patients with CHOP-R chemotherapy and assess
AT A GLANCE Accurate diagnosis of PMBCL and its distinction from cHL requires close interaction with an expert hematopathologist. The study from the NCI reported a very poor positive predictive value for post-treatment FDG-PET/CT of only 17% although the negative predictive value was 100%. Current data do not provide clear evidence for benefit of consolidative radiation therapy in PMBCL. The results of the recent NCI study with DA-EPOCH-R are intriguing and encouraging.
Syed Abutalib, MD Assistant Director, Hematology and Stem Cell Transplantation Program Cancer Treatment Centers of America, Zion, Ill.
Coming soon How I Manage: MGUS and Smoldering Multiple Myeloma by Robert Kyle, MD
with CT imaging at the midpoint in treatment, to rule out disease progression. I obtain a PET/CT scan six to eight weeks after the completion of chemotherapy for its potential prognostic value, but in the absence of clear radiologic progression of disease, I do nott recommend mediastinal RT. Instead, I favor continued surveillance with CT scanning over the following months and no further therapy unless there is evidence of disease progression, thus avoiding the risk for late radiationinduced toxicity in this predominantly young patient population. The results of the recent NCI study are intriguing and encouraging. The true significance of these results can only be determined in a prospective randomized study, but they are sufficiently encouraging that my management of PMBCL will probably now change, starting with the next patient I see!
References 1. Swerdlow SH, Campo E, Harris NL, et al. (eds.). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue. Lyon, France: IARC; 2008. 2. Harris NL. Shades of gray between large B-cell lymphomas and Hodgkin lymphomas: differential diagnosis and implications. Mod Pathol. 2012;26:S57-S70, PMID: 23281436. 3. Savage KJ, Al-Rajhi N, Voss N, et al. Favorable outcome of primary mediastinal large B-cell lymphoma in a single institution: the British Columbia experience. Ann Oncol. 2006;17:123-130, PMID: 16236753. 4. Rieger M, Osterborg A, Pettengell R, et al. Primary mediastinal B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: results of the Mabthera International Trial Group study. Ann Oncol. 2011;22:664-670, PMID: 20724576. 5. Vassilakopoulos TP, Pangalis GA, Katsigiannis A, et al. Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone with or without radiotherapy in primary mediastinal large B-cell lymphoma: the emerging standard of care. The Oncologist. 2012;17:239-249, PMID: 22282906. 6. Dunleavy K, Pittaluga S, Maeda LS, et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med. 2013;201:1408-1416, PMID: 23574119. 7.
Rodriguez J, Conde E, Gutierrez A, et al. Primary mediastinal large cell lymphoma (PMBL): frontline treatment with autologous stem cell transplantation (ASCT). The GEL-TAMO experience. Hematol Oncol. 2008;26:171-178, PMID: 18432630.
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CLINICAL ONCOLOGY NEWS • JUNE 2013 • CLINICALONCOLOGY.COM
Follow-up Imaging: Little Use in DLBCL Only eight relapses—or 1.5% of patients in postR treatment surveillance—were detected through
outine follow-up imaging is of limited use in determining whether patients with diffuse large B-cell lymphoma (DLBCL) have had a recurrence of disease, according to a recent clinical trial. The findings were reported at a press conference from the 2013 annual meeting of the American Society of Clinical Oncology (ASCO; abstract 8504). “These findings will help physicians develop guidelines for following patients who are in remission from DLBCL and will spare patients the cost and excessive radiation exposure of unnecessary CT [computed tomography] scans,” said Clifford Hudis, MD, the chief of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center in New York City. The results are in line with other studies involving other common malignancies. “Patients with this disease should discuss with their doctors how the findings presented today pertain to their individual care,” said Dr. Hudis. Diffuse large B-cell lymphoma is the most common form of non-Hodgkin lymphoma in adults. In the United States, 20,000 new cases are diagnosed annually. Identifying early relapse is especially important, because the disease can be cured if it recurs, said Carrie A. Thompson, MD, a hematologist at the Mayo Clinic in Rochester, Minn., and the study’s lead investigator. The standard method for following patients in remission from DLBCL is not uniform, but follow-up typically has included physical exam, imaging exams and laboratory tests. Investigators at Mayo Clinic, the University of Iowa, and the Centre Léon Bérard in Lyon, France, looked at posttreatment outcomes, including relapse and death, in 644 newly diagnosed DLBCL patients enrolled in the Molecular Epidemiology Resource (MER) project. The MER is part of the University of Iowa/Mayo Clinic National Cancer Institute Specialized Program of Research Excellence, known as the Lymphoma SPORE. Researchers conducted post-treatment surveillance in 537 patients, and 20% (n=109) experienced recurrence of their disease. The median age of patients was 63 and the median range of follow-up was 59 months (eight to 116). Sixty-eight percent of patients had symptoms at the time of relapse; 55% had abnormal blood tests; and 42% had an abnormal physical exam. Only eight relapses (1.5%) were detected through a planned surveillance scan before symptoms appeared. Dr. Thompson said the findings show the scans are of little value for DLBCL patients in remission who had no
a planned surveillance scan before symptoms of recurrence appeared. other symptoms or abnormal findings. Because so many relapses in this study were accompanied by symptoms, Dr. Thompson said patients should be hypervigilant about reporting them
to their clinicians. Symptoms of DLBCL recurrence include enlarged lymph nodes, night sweats, unexplained fever and unintentional weight loss. “These study findings are important
to help guide physicians in making decisions on how frequently to order scans for patients in remission following treatment for DLBCL,” said Dr. Thompson. “This decision should be discussed with, and tailored for, the individual patient.” —Kate O’Rourke Drs. Thompson and Hudis had no relevant disclosures.
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SOLID TUMORS
CLINICAL ONCOLOGY NEWS • JUNE 2013 • CLINICALONCOLOGY.COM
Standard-Dose Radiation Superior in Stage III NSCLC A
Phase III clinical trial has shown that standard-dose radiotherapy is superior to high-dose radiotherapy in patients with stage III non-small cell lung cancer. The lower-dose radiotherapy improved survival and reduced treatment-associated deaths. The study was presented at the annual meeting of the American Society of Clinical Oncology (ASCO; abstract 7501). “Conventional thinking has been that if one can give higher-dose radiotherapy,
that one can effectively kill the tumor better and prolong survival,” said lead author Jeffrey Bradley, MD, a professor of radiation oncology at Washington University School of Medicine in St. Louis. The researchers randomized 464 patients with NSCLC who received standard chemotherapy with paclitaxel and carboplatin to standard-dose radiotherapy (60 Gy) or high-dose radiotherapy (74 Gy). The investigators halted the trial after an interim analysis revealed that
standard-dose therapy yielded better outcomes. Median survival in patients in the standard-dose arm was 28.7 months compared with 19.5 months in patients in the high-dose arm. At 18 months, overall survival was 67% in the standarddose arm compared with 54% in the high-dose arm. Patients receiving the high radiation dose had increased rates of local recurrence (34% vs. 25%) and distant recurrence (44% vs. 35%). There were 10 deaths in the high-dose arm and
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two deaths in the lower-dose arm. Patients in the high-dose arm had a 56% greater risk for death than patients in the standard-dose arm. “At this point, there is no clear reason for the poorer outcome we experienced in the high-dose arm,” said Dr. Bradley. Possible explanations are increased heart dose, extended therapy duration or unreported toxicity, he said. —Kate O’Rourke The research was supported by Eli Lilly.
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CLINICAL ONCOLOGY NEWS • JUNE 2013 • CLINICALONCOLOGY.COM
Quality-of-Life Studies in Oncology Relevant but often difficult to interpret EDITORIAL BOARD COMMENTARY Maurie Markman, MD Senior Vice President of Clinical Affairs and National Director for Medical Oncology, Cancer Treatment Centers of America, Philadelphia
Q
uality-of-life studies have assumed increasing importance in the oncology arena as patients, payers and government regulators increasingly ask whether a statistically significant improvement in a measurable outcome is also associated with evidence of genuine clinical benefit. A common issue in many cancer studies is whether shrinkage of tumor
masses, delay in the time to subsequent disease progression or even a favorable effect on overall survival (OS) is justified in light of observed toxic effects (e.g., emesis, neuropathy, mucositis, cardiac dysfunction, etc) associated with a particular regimen. Thus, the question to be asked is whether the positive effects of a treatment program are negated by the side effects of the strategy. For example,
does the quality of life (QoL) of a patient population treated with a targeted agent resulting in a median improvement in OS of approximately 10 to 15 days justify an observed, modestly increased risk for grade 3/4 rash and diarrhea?1 Although a relatively straightforward answer may appear on the surface, this may not necessarily always be the case. Consider, for example, the recent report of a well-designed and well-conducted QoL study that accompanied the Phase III randomized trial comparing carboplatin plus paclitaxel (“control arm”) with the same chemotherapy
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CURRENT PRACTICE
CLINICAL ONCOLOGY NEWS • JUNE 2013 • CLINICALONCOLOGY.COM
plus bevacizumab (“experimental regimen”) as primary chemotherapy for advanced epithelial ovarian cancer.2,3 The trial itself revealed a statistically significant improvement in time to disease progression associated with the experimental study arm (median progression-free survival [PFS] 24.1 vs. 22.4 months; P=0.04), with the greatest benefit in PFS observed in the group with “high-risk” disease (median 18.1 vs. 14.5 months; P=0.002) and the suggestion of a modest improvement in OS in this patient subset.2 As expected based on the
well-established toxicity profile of bevacizumab, there were more side effects (e.g., grade ≥2 hypertension, 18% vs. 2%; grade ≥3 thromboembolic event, 7% vs. 3%) but no increase in treatment-related deaths in the bevacizumab-containing treatment arm. Despite the superior survival outcomes, however, the QoL study revealed an overall inferior result for patients managed with the experimental program.3 How does one interpret these data? Do the outcomes indicate that (on average) patients feel worse even if they attain the clinical benefit associated
with a delay in disease progression? Should the results be interpreted to suggest that patients who fail to respond to the treatment are the individuals who actually experience the decrease in QoL that led to this “statistical outcome,” whereas those who do respond achieve a more favorable effect on QoL? Or is it perhaps the very specific subset of patients who experience a particular unique toxicity of the experimental program (e.g., severe hypertension) that produces the negative QoL study result? An answer to these difficult questions in the interpretation of the analysis
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would be helpful and might permit a more appropriate use of the data in clinical practice. There is a second issue to the interpretation of these trials, particularly studies where there may be a major difference in the duration of treatment (e.g., maintenance therapy in the previously discussed trial). When considering this, it is critically important to recognize that there is a highly relevant difference between study participants and non-study patients who may be receiving the identical therapy (as defined in the protocol) at a later point in time. For example, reflect on the fact that research participants do not know the trial results and if they are feeling relatively well but are required to continue “medication/treatment” it should not come as a surprise that “study fatigue” might have a genuinely negative influence on their perception of the quality of their lives. But now consider a different patient who is not in the study but is receiving the identical regimen. This individual has been informed by his or her physician, based on the published peer-reviewed results of this study, that treatment with this specific regimen is associated with a good probability (“statistically significant”) for extended disease-free survival or even OS. Is it not reasonable to conclude that this patient will view the effect of inconvenience or even mild/modest toxicity quite differently from the study patient who was asked to complete the trial-related QoL questionnaire? Nothing in this commentary should be taken to suggest the lack of value associated with QoL studies in oncology. To the contrary, I encourage more widespread use of them in the randomized trial setting. However, the utility of their results will only be strengthened if the oncology research community continues to optimize the “quality” of the data generated and works to improve our understanding of what patients are actually saying when they respond to QoL survey questions.
References Educational ucationall Reviews R i
1. J Clin Oncol. 2007;25:1960-1966, PMID: 17452677. 2. N Engl J Med. 2011;365:2484-2496, PMID: 22204725. 3. Lancet Oncol. 2013;14:236-243, PMID: 23333117.
Comments or feedback on Dr. Markman’s column? Please write to Clinical Oncology News managing editor Gabriel Miller at
gmiller@mcmahonmed.com
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REVIEWS & COMMENTARIES
CLINICAL ONCOLOGY NEWS • JUNE 2013 • CLINICALONCOLOGY.COM
Expert Insights From Levine Cancer Institute Each month, Clinical Oncology News summarizes findings from several recently published, important studies and then asks clinicians from a notable cancer center to offer their perspectives. The cancer center providing the expert commentaries changes every three months. Cancer centers are chosen based on reputation, availability and regional diversity, and we seek to have a mix of academic institutions together with regionally important hospitals with expertise in cancer care. We hope you find this Reviews & Commentaries section to be a valuable tool.
Carolinas’ Levine Cancer Institute Powers Up T he concept of care delivery at Carolinas HealthCare System’s Levine Cancer Institute is to provide patients throughout the Carolinas access to innovative research, state-of-the-art treatment and top-ranked physician expertise. The Institute (see LevineCancerInstitute.org) distributes care evenly across a network of 12 elite cancer programs in North and South Carolina, so that patients living in rural areas are able to fight cancer while still being near their families and homes. Through an advanced technology connection, including webcasted teleconferences and virtual tumor boards, physicians located throughout the Institute are able to collaborate on best practices and treatment guidelines, ensuring that all patients, regardless of location, get the highest quality care and have access to the latest cancer-fighting tools and expertise. The Institute was established in 2010 by its president, Derek Raghavan, MD, PhD, an internationally renowned cancer researcher and medical oncologist who previously served as chairman of the Taussig Cancer Center at Cleveland Clinic. Under the leadership of Dr. Raghavan, the Institute opened its administrative and research headquarters on the campus of Carolinas HealthCare System’s Carolinas Medical Center in Charlotte, N.C., in October 2012. The 171,000-square-foot facility, which serves as the Levine Cancer Institute’s center for communications, research and administration, also houses the technology infrastructure as well as nine cancer clinics, infusion therapy and palliative care centers, a “healing” rooftop garden and a specialized Phase I clinical trials unit, which supports the administration of novel therapies in early stages of development. The Institute has continued to expand its roster of physicians, attracting some of the nation’s top oncologists and empowering them to expand the frontiers of cancer care throughout the Carolinas. Edward S. Kim, MD, chair of solid tumor oncology and investigational therapeutics, came to Levine Cancer Institute from the University of Texas MD Anderson’s Cancer Center in Houston. He is developing a biomarker-based community oncology clinical trials program and has recently established clinical pathways treatment guidelines that have been implemented throughout the Institute’s network. These guidelines cover 15 different tumor sites and are aimed at ensuring that treatment is consistent for all Institute patients, no matter the facility in which they are
State-of-the-art videoconferencing allows personal interaction between Levine Cancer Institute physicians across the Carolinas. Left: Derek Raghavan, MD, PhD. Right: Edward S. Kim, MD.
Text and images provided by Levine Cancer Institute
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Levine Cancer Institute’s Research and Administrative Headquarters in Charlotte, N.C.
being treated. A major benefit of these guidelines will be to bring patients greater access to the latest clinical trials. Edward A. Copelan, MD, formerly of the Cleveland Clinic, is chair of the Department of Hematologic Oncology, Blood Disorders and Bone Marrow Transplantation, and has spent nearly 30 years at the forefront of oncology research. Dr. Copelan is currently leading the Institute’s efforts to develop a 14-bed bone marrow transplant unit at Carolinas HealthCare System’s Carolinas Medical Center, which is expected to open in January 2014. Steve Akman, MD, recently joined the Institute’s network from Wake Forest as medical director of Roper St. Francis Cancer Care in Charleston. The Institute’s collaborative hospital network spanning North and South Carolina is focused on delivering world-class research, innovative care and high-quality treatment to patients living in surrounding rural counties. This extensive reach and access is a key pillar of Dr. Raghavan’s vision for the Institute, which was featured in a two-part story published in the Cancer Letter, an internationally recognized publication for cancer research and drug development.1 Radiation oncologists, together with surgeons and medical oncologists located throughout the Institute’s network, rely on a multidisciplinary approach to providing cancer patients with the best treatment. The Institute’s radiation oncology team works continuously to strengthen radiation safety for patients, and includes board-certified
medical physicists, dosimetrists, licensed radiation therapists and radiation oncology nurses who help the Institute maintain its quality assurance program, which conforms to national accrediting standards. The Institute’s radiation oncology team, led by Michael Haake, MD, was the first nationally to use improved technology for advanced high-dose rate, ultrasound-guided brachytherapy treatment for prostate cancer. The improved brachytherapy drastically reduces recovery time and enables patients to walk out of the hospital just hours after receiving treatment. The Institute focuses not just on treating cancer, but also on addressing all aspects of cancer care through patient survivorship programs. Staff and physicians at the Institute help patients live longer with their cancer, while simultaneously working together to improve the overall quality of life. This integrative oncology approach includes programs and support services, such as genetic counseling, art therapy, patient navigation instruction, wellness and nutrition classes, and Chemo Buddy, which is a program that provides a “friend” for patients receiving chemotherapy. “Levine Cancer Institute: Project PINK” addresses disparities by providing free breast screenings to uninsured patients using a mobile mammography unit. To date, they have treated more than 330 uninsured patients through this program. 1. Cancer Letter. 2013;39(1):1 and 2013;39(2):1.
REVIEWS & COMMENTARIES
CLINICAL ONCOLOGY NEWS • JUNE 2013 • CLINICALONCOLOGY.COM
Anagrelide Also Found Effective for Essential Thrombocythemia From Blood
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recent study demonstrated that anagrelide is noninferior to hydroxyurea as an effective treatment for patients with essential thrombocythemia (ET). In a follow-up to a previously published report (N ( Engl J Med 2005;353:33-45, PMID: 16000354), which used the Polycythemia Vera Study Group (PVSG) classification of ET for patient selection and compared the efficacy of aspirin in combination with either anagrelide or hydroxyurea, the recent study used the World Health Organization (WHO) ET criteria, a factor that, the authors
surmised, may have altered the results slightly. The PVSG criteria included patients with various degrees of reticulin/collagen fibrosis, leading to likely elevation of leukocyte counts. The ANAHYDRET (Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia) study was published in Blood d (2013;121:17201728, PMID: 23315161). In this study, described by Heinz Gisslinger, MD, and colleagues, 253 patients were treated with anagrelide, 1 mg per day, or hydroxyurea, 1,500 mg per day, for one week. The study drug was increased until patients’ platelet counts were normal (≤450 × 109/L) or close to normal (between
EXPERT INSIGHT
T
Edward Copelan, MD
David W. Miller, MD
Chair, Department of Hematologic Oncology and Blood Disorders Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.
Hematology Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.
he risk for major thrombosis or hemorrhage in patients with ET who have risk factors such as age greater than 60 years, prior thrombosis, or platelets greater than 1,500 × 109/L exceeds 10% per year.1,2 Because it was proven to reduce thrombotic events in a randomized controlled trial in 1995,3 cytoreduction with hydroxyurea has been the standard first-line therapy for patients requiring treatment. Lending further support to its use, the UK-PT1 study, comparing hydroxyurea plus aspirin with anagrelide plus aspirin in patients with high-risk ET, demonstrated excess arterial thrombosis, major hemorrhage and progression to myelofibrosis in the anagrelide arm.4 The ANAHYDRET study revisits the comparison of anagrelide and hydroxyurea (without mandatory aspirin) in high-risk ET patients, using updated diagnostic criteria from the WHO-ET5
to distinguish true ET from early prefibrotic primary myelofibrosis or other thrombocythemic entities. This revised classification is less likely to include patients with leukocytosis and excludes those with myelofibrosis, unlike the traditional PVSG-ET diagnostic criteria, which were applied in the UK-PT1 study. The authors attribute the noninferiority of anagrelide versus hydroxyurea in the present study largely to the exclusion of patients with varying degrees of marrow fibrosis, who were included in the UK-PT1 study. The authors may be correct in concluding that significant differences in clinical behavior between patients categorized by WHO-ET and PVSG-ET criteria may account for the difference in outcomes between the two studies. Clinicians also should consider, however, the small number of patients, limited follow-up (730 patient-years compared
450 and 600 × 109/L). Study participants were evaluated at baseline, then weekly during the initial treatment, then monthly up to six months, then every other month for a year and finally quarterly during the three-year follow-up. The authors analyzed platelet count, hemoglobin level, leukocyte count and adverse events (AEs) in the two groups. AEs included major and minor arterial and venous thrombosis, and major and minor bleeding events. There were no relevant differences between the two groups in platelet counts or hemoglobin levels, and no significant differences in AEs between the two groups. In the anagrelide group, leukocyte counts
remained constant at approximately 9 × 109/L; in the hydroxyurea group, leukocyte counts decreased markedly after three months and remained suppressed for the entire study. Thrombotic risks ascribed to anagrelide treatment in the earlier study were not observed in the present study. The authors speculated that the PVSG criteria used in the earlier study led to the inclusion of several study participants with early prefibrotic myelofibrosis rather than ET. They concluded that anagrelide, a platelet-lowering agent, is not inferior to hydroxyurea, a cytoreductive agent, for patients who meet the WHO classification of ET.
The noninferiority design of the trial and the limited statistical power to detect small differences, including some that may be clinically relevant, warrant some caution. with 2,653 patient-years in the UK-PT1 study) and far fewer end point events in the ANAHYDRET study. The noninferiority design of the trial and the limited statistical power to detect small differences, including some that may be clinically relevant, warrant some caution before adopting anagrelide as a standard alternative to hydroxyurea for first-line therapy for prevention of thrombotic complications in WHOET. Additionally, this and other studies have shown a high incidence of side effects, particularly cardiac AEs, with anagrelide. This study does appear to validate the value of differentiation between WHO-ET and early prefibrotic myelofibrosis, which suggests that the risk for myelofibrotic transformation for patients with WHO-ET treated with anagrelide is minimal at worst, and demonstrates that anagrelide is effective in preventing thrombotic/ hemorrhagic events in patients with ET. Its precise role in the management of high-risk patients with ET requires better definition.
References 1. Passamonti F, Rumi E, Arcaini L, et al. Prognostic factors for thrombosis, myelofibrosis, and leukemia in essential thrombocythemia: a study of 605 patients. Haematologica. 2008;93:1645-1651, PMID: 18790799. 2. Besses C, Cervantes F, Pereira A, et al. Major vascular complications in essential thrombocythemia: a study of the predictive factors in a series of 148 patients. Leukemia. 1999;13:150-154, PMID: 10025886. 3. Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med. 1995;332:11321136, PMID: 7700286. 4. Harrison C, Campbell P, Buck G, et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005;353:33-45, PMID: 16000354. 5. Thiele J, Kvasnicka HM, Orazi A, et al. Essential thrombocythaemia. In: Swerdlow SH, Campo E, Lee Harris N, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 2008:48-50.
Drs. Copelan and Miller reported no relevant financial disclosures.
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• With Changing Treatments, New Liability Risks • Drugging the ‘Undruggable’
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REVIEWS & COMMENTARIES
CLINICAL ONCOLOGY NEWS • JUNE 2013 • CLINICALONCOLOGY.COM
Ipilimumab Heightens Melanoma Disease Control Rates on Retreatment From Clinical Cancer Research
P
atients with melanoma can be retreated safely with ipilimumab (Yervoy, Bristol-Myers Squibb), a study has concluded, and disease control rates upon retreatment were significant. Patients who were eligible for this study had stable disease or a documented complete response (CR) or partial response (PR) to their initial
treatment. Patients received an additional four-dose cycle of the study drug they received in their initial treatment. Forty patients were enrolled, although eight were ineligible to participate in the study protocol and were not included in the final evaluation. One patient was retreated with glycoprotein 100 (gp100) peptide vaccine plus placebo, eight patients received ipilimumab plus placebo, and 23 patients were
Asim Amin, MD, PhD Medical Oncology, Melanoma Section Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.
pilimumab is an immunoglobulin G-1 antibody that binds to the immune inhibitory checkpoint CTLA-4 (i.e., cytotoxic T-lymphocyte-associated antigen-4) expressed on activated T cells and blocks it. CTLA-4 inhibition leads to unrestrained activity of the T cells that has been shown to translate into clinical benefit, with improvement in overall survival for patients with advanced melanoma in Phase II/ III studies. Based on the above data, the FDA approved ipilimumab on March 25, 2011, at the following dose: “YERVOY 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of four doses.”1 This dose is based on the Phase III study that compared ipilimumab administered at the dose of 3 mg/ kg for four doses to gp100 peptide vaccine.2 Those individuals who initially experienced clinical benefit with ipilimumab (CR, PR or stable disease) and subsequently progressed were deemed eligible for reinduction with four more doses at 3 mg/kg. Robert et al has now reported the outcome of 31 of 32 eligible patients who received reinduction.3 The best overall response rates were three of 23 (13%) and three of eight (37.5%) in the ipilimumab plus gp100 and ipilimumab plus placebo groups, respectively; disease control rates were 65.2% and 75%. No new types of toxicities were noted and most events were mild to moderate. These are impressive disease control rates. Current labeling does not allow for reinduction. Based on these data,
retreated patients, four of 29 in the ipilimumab plus gp100 arm showed a PR lasting 57, 78, 113 and 814 days. Three of nine patients in the ipilimumab plus placebo arm had a PR lasting 85, 95 and 192 days (the latter of which had a CR of 162 days). There were no responders among patients in the gp100 arm. Additional studies will be needed to define which patients with melanoma would benefit from ipilimumab retreatment.
Despite the numerous questions, the overall improvement in disease control rate in a setting that has previously had dismal outcomes is extremely encouraging.
EXPERT INSIGHT
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retreated with ipilimumab plus gp100 vaccine. Caroline Robert, MD, and coauthors presented their data in Clinical Cancer Research (2013;19:2232-2239, PMID: 23444228). The rates, severity and types of toxicities observed in all 40 patients in this study were similar to those seen in the original treatment study, and the authors found no additional toxicities with ipilimumab retreatment. Of the 40
should reinduction be inducted as standard of care for the patients meeting eligibility? The question of what may be the most optimal dose and schedule is yet to be definitively determined. Several Phase II studies used a higher dose of ipilimumab (10 mg/kg) and incorporated maintenance dosing every three months after an initial induction with four doses.4 The randomized Phase II doseranging study, CA184-022, supported the use of 10 mg/kg dose and showed a dose-dependent effect on efficacy and safety.5 The 24-month survival ranged from 29.8% to 41.8% in the above studies (up to 56.6% for treatment-naive patients in study CA184007). The estimated two-year survival for the ipilimumab-containing arms of
the Phase III (above) study was 24%, compared with the Phase II studies, which incorporated maintenance. This of course is stated with complete cognizance that such comparisons are not valid—yet are provocative! The 3 mg/kg versus 10 mg/kg dose question has been addressed in the CA184-169 study (accrual completed; results awaited) and is being evaluated in the adjuvant study Eastern Cooperative Oncology Group 1609 (ongoing). What may be the most optimal schedule? Reinduction (as was performed in the Phase III study, above) or maintenance as has been exercised in Phase II studies remains an important question. For now, until these questions are answered, reinduction should be considered standard for eligible patients per the Phase III study. This will lead to the more realistic question of treatment cost. Does the “total of four doses” in
the original label really encompass “completion of treatment”? The cost issue will have another layer of complication added if the 10 mg/kg dose wins and more so if maintenance therapy becomes incorporated. The above data also may affect clinical trial designs with newer immune checkpoint inhibitors like anti-PD1. Who would now be eligible to receive the new agent—those patients who were treated with ipilimumab previously and progressed or, alternatively, those patients who progressed after reinduction? Despite the numerous questions, the overall improvement in disease control rate in a setting that has previously had dismal outcomes is extremely encouraging. This class of drugs targeting the immune system continues to transform clinical practice in patients with previously few options.
References 1. www.fda.gov
Study
Design
Patient Population
N
Ipilimumab Dose
CA184-004
Randomized double-blind biomarker study
Previously treated or untreated advanced melanoma
82
3 or 10 mg/kg
CA184-007
Randomized open-label with or without budesonide
Previously treated or untreated advanced melanoma
115
10 mg/kg
CA184-008
Single-arm open-label study
Previously treated advanced melanoma
155
10 mg/kg
CA184-022
Randomized double-blind dose-ranging study
Previously treated advanced melanoma
217
0.3 or 3 or 10 mg/kg
2. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723, PMID: 20525992. 3. http://clincancerres.aacrjournals.org/ content/19/8/2232 4. O’Day SJ, et al. World Meeting of Interdisciplinary Melanoma/Skin Cancer Centers; November 19-21, 2009; Berlin, Germany. Poster 41. 5. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155-164, PMID: 20004617.
Dr. Amin reported no relevant financial disclosures.
REVIEWS & COMMENTARIES
CLINICAL ONCOLOGY NEWS • JUNE 2013 • CLINICALONCOLOGY.COM
Duloxetine Reduces Chemo-Induced Peripheral Neuropathy Pain From JAMA
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uloxetine reduced the pain associated with chemotherapy-induced peripheral neuropathy (CIPN) and may lead to improved quality of life for patients with this painful disorder, a study has concluded. A randomized, double-blind, placebo-controlled Phase III crossover trial, conducted through eight National Cancer Institute–funded research networks, tested the efficacy of this treatment. The results were summarized in JAMA (2013;309:1359-1367, PMID: 23549581). Patients with CIPN were stratified
into two groups by characteristics including pain risk and chemotherapy drug treatment. Patients rated their average neuropathy-based pain using the 11-point validated Brief Pain Inventory-Short Form. The mean pain score of the patients enrolled in the study was 5.8 (SD 1.7). Patients in group A (n=109) were given 30 mg of duloxetine daily for a week, followed by 60 mg of duloxetine daily for an additional four weeks. After a washout period, they were given a daily placebo for five weeks. Patients in group B (n=111) were given placebo first, followed by duloxetine after the crossover.
EXPERT INSIGHT Connie A. Edelen, MD Palliative Medicine Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.
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ainful peripheral neuropathy can occur in 20% to 40% of patients receiving neurotoxic chemotherapy (e.g., taxanes, platinums, vinca alkaloids, bortezomib) and lasts for months to years. These symptoms can be distressing and debilitating enough to require chemotherapy dose reduction or even treatment discontinuation. Prior randomized controlled trials with a variety of agents, including tricyclic antidepressants, selective serotonin reuptake inhibitors and anticonvulsants (such as gabapentin and pregabalin), have not proven effective in reducing pain from CIPN despite their anecdotal use and well-studied benefit in other types of neuropathy.1 This 231-patient study conducted by Cancer and Leukemia Group B is the first large Phase III clinical trial to demonstrate an effective intervention for nerve pain caused by platinum and taxane agents. In this five-week crossover study, the antidepressant duloxetine produced a clinically and statistically significant improvement in
pain control compared with placebo. Secondary outcomes of the study also included improved function and quality of life with the use of duloxetine. Although not all duloxetine-treated patients responded, a majority experienced a decrease in pain relatively quickly, within the first week of therapy. Patients were randomized based on comorbid illness, including diabetes mellitus and peripheral vascular disease, which were thought to be “high risk” for developing severe CIPN pain. Ultimately, there was no difference in duloxetine efficacy between those patients with high or no risk. Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI) and there is growing evidence that these key neurotransmitters suppress the transmission of painful peripheral stimuli. In addition to treatment of depression, duloxetine also has been FDA-approved for pain related to diabetic neuropathy, fibromyalgia and chronic musculoskeletal conditions such as low back pain and arthritis.
Researchers found that the patients taking duloxetine reported a minimal but clinically significant decrease in pain severity. Of the patients treated with duloxetine first, 59% reported a decrease in pain versus 38% of patients in the placebo-first group. The relative risk for experiencing a 30% pain reduction with duloxetine was 1.96 (95% confidence interval [CI], 1.153.35) and for experiencing a 50% pain reduction was 2.43 (95% CI, 1.11-5.30). A secondary finding of the study was that pain interference with daily function was decreased with duloxetine treatment, based on a quality-of-life
survey (Functional Assessment of Cancer Treatment, Gynecologic Oncology Group Neurotoxicity). The authors noted that these results in cancer pain reduction were similar to those experienced by patients with diabetic neuropathy. The drug acts quickly and is generally well tolerated: Reported adverse effects (AEs) were generally mild to moderate and included nausea and fatigue. Patients previously treated with certain types of chemotherapy (e.g., oxaliplatin) appeared more responsive to the duloxetine treatment than those previously treated with other agents (e.g., taxanes).
This practice-changing finding may allow pain relief and improvement in function and quality of life for those patients with cancer who are suffering from this common, debilitating condition. Although generally considered safe and well tolerated, the duloxetine group was noted to have a higher dropout rate, which may have limited the study. These patients had a higher proportion of grade 3 AEs compared with placebo, with the most common reported AEs being fatigue, insomnia and nausea. Exploratory analyses suggested that duloxetine was more effective for patients with CIPN arising from platinum-based chemotherapy than those treated with taxanes. The difference may lie in their mechanisms of action, with platinum drugs causing primary toxicity at the dorsal root ganglion where the sensory nerve cell body is located, whereas taxanes mainly cause axonal damage. Whether other SNRI medications, such as venlafaxine and milnacipran, can produce similar results as duloxetine is an area for future research. Of note, venlafaxine has been reported to reduce the incidence of acute oxaliplatin-induced neuropathic pain compared with placebo in a small trial of 54
patients. As SNRI drugs do not demonstrate significant activity at opioid receptors or sodium ion channels, it also stands to question whether duloxetine may work synergistically with other pain medications. In summary, duloxetine has emerged as an effective and generally well-tolerated intervention for painful CIPN, particularly for platinum-based therapies. Although research for neuroprotective agents remains ongoing, this practice-changing finding may allow pain relief and improvement in function and quality of life for those patients with cancer who are suffering from this common, debilitating condition during and following treatment with neurotoxic agents.
Reference 1. Stubblefield MD, Burnstein HJ, Burton AW, et al. NCCN Task Force Report: Management of Neuropathy in Cancer. J Natl Compr Canc Netw. 2009;7(suppl 5):S1-S26.
Dr. Edelen reported no relevant financial disclosures.
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Adding Lapatinib to Paclitaxel Aids Survival in HER2+ Breast Cancer From the Journal of Clinical Oncology
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reast cancer patients with amplification of the human epidermal growth factor receptor 2 (HER2 ( ) gene who were treated with combination therapy of paclitaxel and lapatinib had improved overall survival (OS) compared with patients treated with paclitaxel plus placebo. In this study, 444 patients from seven countries, primarily in Asia, who were newly diagnosed with HER2positive stage IV metastatic breast cancer (MBC) were assigned to one of two study arms. Most (77%) had undergone
some anticancer treatment; 66% had received chemotherapy; only four had received trastuzumab. Half of the participants received paclitaxel (80 mg/m2 IV weekly for three weeks, every four weeks) and lapatinib (1,500 mg daily). The other group received the same doses of paclitaxel and placebo. Over the course of the study, 263 patients died: 120 (54%) in the lapatinib-paclitaxel group and 143 (64%) in the placebo plus paclitaxel group. Median overall survival (OS) of the lapatinibpaclitaxel group was 27.8 months (95% confidence interval [CI], 23.2-32.2) compared with 20.5 months (95% CI,
EXPERT INSIGHT Gary P. Frenette, MD, PhD Medical Oncology, Breast Section Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.
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he HER2 protein is overexpressed in about 20% of all breast cancers. Inhibition of the HER2 protein— initially in breast cancer and more recently in gastrointestinal malignancies—has been one of the most successful treatment paradigms of targeted therapy to date. The armamentarium of agents directed against this protein has recently grown more prodigious. FDA approval of trastuzumab (1998) has been more recently followed by approval of lapatinib (2007), pertuzumab (2012) and most recently trastuzumab emtansine (2013). Trastuzumab and pertuzumab are both antibodies directed against differing epitopes on the HER2 protein. Trastuzumab binds to the juxtamembrane region of HER2 and inhibits subsequent activation of the MAPK and PI3K/Akt pathways dimerization in a ligand-independent fashion. It likely also works through indirect actions such as antibody-dependent cytotoxicity. Conversely, pertuzumab binds to the dimerization arm of HER2 and blocks ligand-induced dimerization. Trastuzumab emtansine (Kadcyla, Genentech) uses the targeting activity of trastuzumab to deliver the cytotoxic drug mertansine to HER2-amplified breast cancer cells. In the recently published EMILIA study, patients with metastatic or locally advanced unresectable
cancer previously treated with taxanes and trastuzumab were randomized to trastuzumab emtansine versus capecitabine and lapatinib.1 Patients treated with trastuzumab emtansine showed improved progression-free survival (PFS; median 9.6 vs. 6.4 months) and OS (median 30.9 vs. 25.1 months) with an improved safety profile. Lapatinib is unique among the HER2-targeted agents in several respects. It is administered orally and is a small molecule, reversible, dual tyrosine kinase inhibitor of HER2. Lapatinib and capecitabine were initially compared with capecitabine alone in patients with HER2-positive breast cancer that had progressed after trastuzumab-based therapy. The primary end point of the study, time to progression, was dramatically improved in the combined therapy arm (median 8.4 vs. 4.4 months), allowing early reporting of study results. Additionally, the recent LANDSCAPE (Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer) trial showed promising activity for this combination in patients with central nervous system metastases, with a 64% partial response rate and a median time to requiring whole-brain radiotherapy of 8.3 months.2 These encouraging results prompted
17.9-24.3) for the placebo group. The overall response rate was significantly higher in the lapatinib-paclitaxel arm (69%) versus placebo (50%) (odds ratio [OR], 2.30; 95% CI, 1.543.47; P<0.001). Clinical benefit rate improved from 56% to 75% (OR, 2.34; 95% CI, 1.54-3.58; P<0.001). Patients in the lapatinib-paclitaxel group reported more adverse events (AEs) than patients in the placebo plus paclitaxel group, and more serious AEs (30% vs. 14%, respectively). The most common AEs were neutropenia (16% vs. 5%), increased left ventricular ejection fraction (6% vs. 1%) and diarrhea
(5% vs. 0%). Most AEs were transient, reversible and treated by discontinuation of treatment. Zhongzhen Guan, MD, PhD, and coauthors reported their results in the Journal of Clinical Oncology (2013: Mar.18, 10.1200/JCO.2011.40.5241, PMID: 23509322). They concluded that paclitaxel and lapatinib offered improved OS and that no new AEs were described when the two therapies were combined. The authors recommended that, particularly in places where trastuzumab is unavailable, lapatinib and paclitaxel be considered as a firstline treatment for HER2-positive MBC.
There will be an increasing medical and economic imperative to determine which patients benefit from which specific antagonists and which patients require more than a single agent. FDA approval of lapatinib as well as the initiation of several studies that combined both trastuzumab and lapatinib in the metastatic and adjuvant/ neoadjuvant settings. In an attempt to avoid cytotoxic chemotherapy altogether, the EGF104900 study compared lapatinib monotherapy with lapatinib and trastuzumab in patients with HER2 overexpressed breast cancer who had progressed during prior trastuzumab-based treatment.3 The combination arm showed superiority in PFS (median 11.1 vs. 8.1 weeks) and OS (median 14 vs. 9.5 months). In the neoadjuvant setting, the NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) study showed that dual HER2 inhibition with lapatinib and trastuzumab, when combined with chemotherapy, resulted in higher pathologic complete response (pCR) rates compared with monotherapy.4 Specifically, pCR rates with dual inhibition compared with trastuzumab or lapatinib alone were 51.3%, 29.5% and 24.7%, respectively. The ALTTO (Adjuvant Lapatinib and/ or Trastuzumab Treatment Optimisation) trial, investigating the role of dual inhibition versus monotherapy with trastuzumab or lapatinib, was modified in 2011 to discontinue the single-agent lapatinib arm due to inferior PFS during a planned interim analysis.5 Lapatinib has unique features that may make it attractive among the HER2 inhibitors as an agent in monotherapy or dual inhibition therapy. There
will be an increasing medical and economic imperative to determine which patients benefit from which specific antagonists and which patients require more than a single agent. The first chapter of HER2 inhibition has clearly ended and our future will be determined by more sophisticated molecular analysis of tumors and predictive biomarkers that allow us to treat patients with increasing effectiveness and decreasing morbidity.
References 1. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783-1791, PMID: 23020162. 2. Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 2013;14:64-71, PMID: 23122784. 3. Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 2012;30:2585-2592, PMID: 22689807. 4. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379:633-640, PMID: 22257673. 5. http://clinicaltrials.gov/ct2/show/ NCT00490139?term=ALTTO&rank=1.
Dr. Frenette reported no relevant financial disclosures.
REVIEWS & COMMENTARIES
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Cytarabine Improves Combination Therapy for Mantle Cell Lymphoma From the Journal of Clinical Oncology
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he addition of cytarabine to bendamustine plus rituximab (R-BAC) as combination therapy for older patients with mantle cell lymphoma (MCL) was found to be both effective and well tolerated. Most patients diagnosed with this aggressive form of non-Hodgkin lymphoma (NHL) are seniors. This Italybased study, whose lead author was Carlo Visco, MD, focused on first identifying the maximum tolerated dose (MTD) of cytarabine in R-BAC and then evaluating therapeutic efficacy. Results were reported in the Journal of Clinical Oncology (2013;31:14421449, PMID: 23401442). Forty eligible patients who had
confirmed MCL (of which 93% had Ann Arbor stage III/IV disease) and had never been treated (n=20) or had been refractory to treatment or relapsed (n=20) were enrolled. In the first stage, a dose-limiting toxicity study for cytarabine was conducted and 800 mg/m2 was established as the MTD. In stage 2, R-BAC was administered, consisting of rituximab (375 mg/m2 IV) on day 1; bendamustine (70 mg/m2 IV) on days 2 and 3; and cytarabine IV at the MTD on days 2, 3 and 4. This four-day cycle was repeated every 28 days for four to six treatment cycles, as tolerated. The overall response rate (ORR) was evaluated using positron emission tomography (PET). ORR was 90% for all patients (83% complete response
EXPERT INSIGHT Belinda Avalos, MD Vice Chair, Department of Hematologic Oncology and Blood Disorders Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.
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CL is an aggressive form of NHL that predominantly affects patients over the age of 60 years. Encouraging results have been obtained using intensive regimens in younger patients with MCL; however, the same regimens are poorly tolerated in older patients. The treatment approach developed by Visco et al, which avoids exposure to anthracyclines in elderly patients with MCL, makes good sense, as many of these patients have underlying
Jonathan K. Levine, MD Hematology, Medical Oncology Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.
cardiac disease and require multiple cycles of treatment. The addition of cytarabine at a total dose of 2.4 g/m2 per cycle to rituximab and bendamustine led to significant myelosuppression despite growth factor support, but was not associated with central nervous system toxicity. The higher CR rate observed with sequential R-BAC in previously untreated elderly patients with MCL compared with that reported in prior studies using R-CHOP
[CR], 7% partial response [PR]). The ORR was 100% among untreated patients and 80% (70% CR; 10% PR) for refractory or relapsed patients. Patients were tested and observed for adverse events (AEs). Baseline and end-of-treatment evaluations included bone marrow biopsy, flow cytometry, computed tomography and PET scan. Overall, 35 (87%) of the patients experienced transient grade 3 to 4 thrombocytopenia; 23 (57%) reported leukopenia. Relapsed or refractory patients had significantly more AEs than previously untreated patients. Non-hematologic events attributed to R-BAC therapy were generally mild, and included nausea and fatigue (35%), cutaneous rash/ desquamation (15%) and γ-glutamyl
transferase elevation (40%). Five patients reported grade 3 or 4 infections (respiratory, n=1), herpes zoster (n=1), Escherichia coli sepsis (n=1) and febrile neutropenia of unknown origin (n=2). One patient who developed pulmonary edema withdrew, as did another patient who had a myocardial infarction unrelated to the study. The authors concluded that the results of this Phase II study support the use of R-BAC in older or unfit patients with MCL who are not candidates for more intensive regimens. Response to treatment was acceptable and there was a low incidence of severe AEs, with the exception of significant but transient myelosuppression.
The treatment approach developed by Visco et al, which avoids exposure to anthracyclines in elderly patients with MCL, makes good sense. (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone), R-FC (rituximab, fludarabine and cyclophosphamide) and RB (rituximab, bendamustine), together with its stem cell–mobilizing potential, warrant future studies of sequential R-BAC in younger patients with MCL who are being considered for autologous hematopoietic cell transplant. Achieving CR before transplant in this population correlates with long-lasting remissions following transplantation. R-BAC also appears promising in elderly patients with relapsed or refractory MCL, with significantly higher CR rates than previously reported for RB (70% vs. 50%).
An important difference between this study and prior studies is that a post-treatment residual mass of any size that was PET-negative was defined as a CR. It is interesting that despite the superior efficacy of R-BAC reported in this study, the investigators have initiated a multicenter trial of R-BAC using a reduced dose of cytarabine, presumably to lessen hematologic toxicity. Nevertheless, this is a promising approach for elderly patients with MCL and adds to our growing armamentarium of therapies to treat this disease. Drs. Avalos and Levine reported no relevant financial disclosures.
LOOK AHEAD Next month’s issue of Clinical Oncology News will feature in-depth coverage of practice-changing studies from the 2013 ASCO Annual Meeting And coverage of the 17th International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas and Myeloma
—————————— New Columns —————————— The July issue will also feature How I Manage: MGUS and Smoldering Multiple Myeloma by Robert A. Kyle, MD, as well as The Tumor Board by Conrad Simpfendorfer, MD, of Cleveland Clinic, focusing on challenging cases and alternative treatment options in oncology.
Look for it!
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CLINICAL ONCOLOGY NEWS • JUNE 2013 • CLINICALONCOLOGY.COM
Continuous vs. Intermittent Androgen Deprivation in Prostate Cancer From The New England Journal of Medicine
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n international trial comparing intermittent androgen deprivation (IAD) versus continuous androgen deprivation (CAD) in patients with metastatic hormone-sensitive prostate cancer proved inconclusive. Patients with metastatic, hormonesensitive prostate cancer and a prostate-specific antigen (PSA) level before treatment of ≥5 ng/mL were enrolled in the study, the results of which were published in The New England Journal of Medicine (2013:368:1314-1325, PMID:
23550669). The goals of the study were to assess whether IAD was noninferior to CAD for survival, and to compare quality of life between the two groups at three months postrandomization. Treatment consisted of a sevenmonth induction course of luteinizing hormone-releasing hormone agonist along with an anti-androgen agent. PSA levels were measured at months 1, 4, 6 and 7. Patients whose PSA level had dropped and stabilized at ≤4 ng/ mL at months 6 and 7 were considered androgen-dependent and eligible for further study. These patients were additionally
EXPERT INSIGHT Earle F. Burgess, MD Medical Oncology, Genitourinary Section Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.
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astration remains the standard initial treatment for men with metastatic prostate cancer, following the seminal work of Huggins and Hodges in the early 1940s. Although the popularity of orchiectomy has waned since the introduction of gonadotropin-releasing hormone analogues in the 1980s, medical and surgical castration are equally effective options for palliating men with advanced prostate cancer.1 It is well recognized, however, that undesirable effects on health and quality of life accompany castration. Also, preclinical studies have suggested that IAD rather than permanent androgen deprivation might delay the development of androgen independence, so investigators have sought to establish a role for IAD in lieu of castration.2 The SWOG (Southwest Oncology Group) 9346 trial was designed to establish overall noninferiority (or similarity) of IAD to CAD in men with treatment-naive metastatic prostate cancer.3 Although previous studies have suggested IAD may have similar efficacy as CAD in responding patients,4-6 SWOG 9346 failed to confirm this hypothesis. The trial results were statistically inconclusive because the confidence interval for survival included both the predefined upper limit of 1.20 as well as 1.00. As this is the largest reported trial comparing IAD and CAD in men with metastatic prostate cancer, we cannot conclude that IAD is equivalent to CAD.
Because IAD did provide a modest quality of life benefit, it is tempting to extrapolate study findings from an earlier clinical setting, where IAD has been shown to be noninferior to CAD in patients with biochemical relapse after radiotherapy.7 However, compared with the setting of biochemical relapse, the SWOG 9346 results do not exclude up to a 20% increased risk for death with IAD in the metastatic setting. Furthermore, IAD actually trended toward inferiority (hazard ratio for death, 1.10; nonsignificant); thus, without conclusive data to support the noninferiority of IAD, CAD should remain the standard of care in patients with overt metastatic disease. It is worth noting two observations about the study cohorts that could have confounded the trial results. In the intent-to-treat analysis, twice as many patients allocated to the IAD group did not receive any treatment following randomization (6.2% vs. 3.1%), raising the possibility that the noninferiority of IAD may have been established had both study arms contained a balanced number of patients who did not receive the intended treatment. Second, Gleason scores (GS) were unknown for nearly one-third of patients in each arm. Although randomization should have evenly distributed these patients between cohorts, any imbalance in GS distribution would have had an unpredictable effect on the outcome because higher GS increase the risk for
classified according to their performance status and whether the disease at enrollment was minimal (confined to the spine, pelvic bones or lymph nodes) or extensive (present in the ribs, long bones or visceral organs). One group received CAD therapy (n=765); the other group received IAD treatment (n=770). At three months, both groups were tested. If patients in the IAD group showed an elevated PSA level, treatment would be restarted for another three-month cycle or until PSA levels dropped. For the IAD group, determination of whether the cycle of treatment would continue was based on PSA levels.
Median survival for all patients in the CAD group was 5.8 years versus 5.1 years in the IAD group, representing a 10% relative increase in the risk for death. Survival of patients with extensive disease in the CAD group was 4.4 years but was 4.9 years for those receiving IAD treatment. For patients with minimal disease, survival was 6.9 years in the CAD group and 5.4 in the IAD group. Quality-of-life surveys completed by all participants at baseline and at months 3, 9 and 15 showed higher scores for patients enrolled in the IAD group at month 3, but that advantage disappeared in subsequent surveys.
Perhaps a greater question to consider is whether the results of this trial are still relevant to contemporary practice. progression to a castrate-resistant state.8 Perhaps a greater question to consider is whether the results of this trial are still relevant to contemporary practice. The survival curve of the IAD treatment arm trended worse after four years following randomization, and most patients would have evolved to a castrate-resistant state by this time. The trial accrued patients from 1995 to 2008 before widespread use of abiraterone and enzalutamide for castrate-resistant disease, both of which extend survival in this setting.9,10 Given the efficacy of these newer agents, any theoretical, modest difference in survival between IAD and CAD may be overcome by more effective salvage hormonal therapy that is routinely used today in patients with metastatic disease. Based on the SWOG 9346 results, the role of IAD in treatment-naive patients with metastatic prostate cancer remains inconclusive. Notably, clinical interest is now shifting toward subcastrate-level androgen deprivation. Large trials are under way to assess the survival effect of treating this patient population to subcastrate androgen levels (NCT01715285, NCT01809691). If these modern trials of deeper androgen blockade are ultimately positive, perhaps we will learn that IAD will have a greater role only when men with metastatic prostate cancer are taken to subcastrate androgen levels. Until then, in patients with metastatic disease who are most focused on maximizing survival benefit with therapy, CAD remains the standard of care.
References 1. Seidenfeld J, Samson DJ, Hasselblad V, et al. Single-therapy androgen suppression in men with advanced prostate cancer: a systematic
review and meta-analysis. Ann Intern Med. 2000;132:566-577, PMID: 10744594. 2. Sato N, Gleave ME, Bruchovsky N, et al. Intermittent androgen suppression delays progression to androgen-independent regulation of prostate-specific antigen gene in the LNCaP prostate tumour model. J Steroid Biochem Mol Biol. 1996;58:139-146, PMID: 8809195. 3. Hussain M, Tangen CM, Berry DL, et al. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013;368:1314-1325, PMID: 23550669. 4. Calais da Silva FE, Bono AV, Whelan P, et al. Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomised phase 3 study of the South European Uroncological Group. Eur Urol. 2009;55:1269-1277, PMID: 19239153. 5. Mottet N, Van Damme J, Loulidi S, et al. Intermittent hormonal therapy in the treatment of metastatic prostate cancer: a randomized trial. BJU Int. 2012;110:1262-1269, PMID: 22502816. 6. Salonen AJ, Taari K, Ala-Opas M, et al. The FinnProstate Study VII: intermittent versus continuous androgen deprivation in patients with advanced prostate cancer. J Urol. 2012;187:2074-2081, PMID: 22498230. 7.
Crook JM, O’Callaghan CJ, Duncan G, et al. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med. 2012;367:895-903, PMID: 22931259.
8. Benaim EA, Pace CM, Roehrborn CG. Gleason score predicts androgen independent progression after androgen deprivation therapy. Eur Urol. 2002;42:12-17, PMID: 12121723. 9. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005, PMID: 21612468. 10. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197, PMID: 22894553. Dr. Burgess reported no relevant financial disclosures.
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CLINICAL ONCOLOGY NEWS • JUNE 2013 • CLINICALONCOLOGY.COM
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Several months later, nurses at McLeod Cancer noticed that the chemotherapy drugs from QSP had foreign languages on the labels. The nurses voiced their concerns to Drs. Kincaid, Lamb and Famoyin that the drugs were not approved for use in the United States, and the partners agreed to stop ordering from QSP. However, in August 2009, QSP contacted Dr. Kincaid, the president and majority owner of McLeod Cancer, and Mr. Combs again. The men set up a meeting with a QSP representative at a local restaurant in Johnson, during which Dr. Kincaid decided to continue buying drugs from the company. To cover up the purchases, Dr. Kincaid had Mr. Combs ship the drugs to a storage facility across town that Dr. Kincaid partly owned. Mr. Combs and others then took the drugs to McLeod Cancer where they were eventually mixed in with the legitimate supply of medications. McLeod Cancer also continued to receive FDAapproved drugs, which were shipped directly to the cancer center. This arrangement with QSP continued until February 2012. At that time, the FDA had issued its first set of warnings that physicians and medical practices may have purchased a fake version of Avastin 400 mg/16 mL, containing cornstarch, salt, acetone and other chemicals, but none of the drug’s active ingredient bevacizumab. The FDA had also sent letters to 19 medical centers
High-value lifestyle drugs like Viagra paved the way for criminals to target other high-demand medications, including cancer, heart disease, malaria and HIV drugs, and then supply pharmacies, hospitals, doctors and consumers with subeffective, completely ineffective or sometimes deadly versions. throughout the United States that had purchased unapproved medicines, possibly including fake Avastin, from QSP, which also may be known as Montana Healthcare Solutions. McLeod Cancer was on the list of recipients. According to court documents, records from McLeod Cancer show that QSP shipped a variety of non–FDA-approved drugs to Dr. Kincaid’s storage business, including a rituximab knock-off called MabThera. Although MabThera contained the active ingredient in rituximab, it had been manufactured by F. Hoffman-LaRoche Ltd. in Switzerland, not Genentech in the United States and was not approved for sale in the United States. To reach the United States, the drug had traveled through a complex supply chain, which began in India and passed through the United Kingdom on its way to a QSP shipping facility in Chicago. The drugs were then sent to McLeod Cancer in Tennessee. On Dec. 11, 2012, Dr. Kincaid pled guilty to receiving misbranded prescription drugs in interstate commerce with the intent to defraud or mislead the state’s Medicaid program and other health care purchasers. During the time McLeod Cancer was doing business with QSP, it had purchased more than $2 million in unapproved drugs and billed Medicare along with other programs for about $2.5
million. Clinical Oncology News contacted Dr. Kincaid’s lawyer, Mark Slagle, JD, for a comment but received no response. Dr. Kincaid will receive a possible prison sentence of up to three years and a fine of as much as $250,000, according to his plea agreement, issued on Nov. 15, 2012, by the U.S. District Court for the Eastern District of Tennessee at Greeneville. McLeod Cancer has since been shut down.
Scope of the Problem Dr. Kincaid’s case represents just a small piece of a growing problem of misbranded, unapproved cancer drugs entering the legitimate supply chain in the United States and Europe. More than a year after the FDA issued its first caution about QSP, the agency continues to investigate the spread of fake Avastin. As of November 2012, the FDA has sent 155 letters warning medical practices in the United States that their supply may be tainted with fake Avastin or a counterfeit version of Altuzan (Roche). Altuzan is the brand name Avastin is sold under in Turkey, and is not approved for sale in the United States. On Feb. 5, 2013, the FDA alerted U.S. medical practices that it had uncovered two batches of counterfeit Altuzan, at least one of which contained no active ingredients. “Avastin has opened our eyes to the
by the
numbers: counterfeit drugs 147 1,986 484 2.5 million 20%-25% 200,000300,000
Number of U.S. practices or physicians who may have purchased fake Avastin from QSP Number of counterfeiting, illegal diversion and theft incidents worldwide in 2011 Number of incidents recorded in 2003 Number of fake pharmaceutical items seized at European Union borders in 2006 Percentage of medicines in India that are fake Number of people in China who die from, or because of, fake medicines each year Sources: The Partnership for Safe Medicines, European Alliance for Access to Safe Medicines, The Pharmaceutical Security Institute, Wall Street Journal, World Health Organization.
problem of poor drug control, and the U.S.’s increasing vulnerability to counterfeit drugs,” said Bryan Liang, MD, PhD, JD, the vice president of the Partnership for Safe Medicines and the director of the San Diego Center for Patient Safety at the University of California, San Diego School of Medicine and California Western School of Law’s Institute of Health Law Studies. But marketing fake drugs is not a new problem. “Counterfeit medicines are as old as the hills,” said Mark Davison, CEO of Blue Sphere Health Ltd., in Cambridge, England, a company working to combat the production and spread of counterfeit drugs. “People have been knowingly selling ineffective ‘snake oil’ remedies off the back of wagons for hundreds of years.” In the past 15 years, the emergence of high-value lifestyle drugs, most notably Viagra, has helped catalyze the development of this illegal trade. Criminals soon expanded the trade and began targeting other high-demand medications, including cancer, heart disease, malaria and HIV drugs, thus supplying pharmacies, hospitals, doctors and consumers with subeffective, completely ineffective or sometimes deadly versions. “[Counterfeit drugs] is not back-street crime anymore with a few guys in workshops turning out a couple thousand pills and making a few bucks on the side,” said Mr. Davison. “This trade has predominantely become organized crime, and looks very much like traditional networks of prostitution and illegal drug trafficking. We’re seeing some really sophisticated worldwide supply chains of illicit drugs.” One of the biggest cases to hit the United Kingdom and the United States occurred several years ago when counterfeit versions of AstraZeneca’s prostate cancer drug Casodex began popping up in pharmacies and hospitals. Chemists from pharmaceutical companies and the FDA found that the illicit drugs contained varied quantities of Casodex’s active ingredients as well as unknown impurities. The drugs were traced to Kevin Xu, owner of Pacific Orient International Ltd. in China. In July 2007, Mr. Xu was arrested and a year later convicted of conspiring to distribute counterfeit pharmaceutical drugs, including Casodex, misbranding them and smuggling them into the United Kingdom and the United States. Around that same time, investigators in the United Kingdom were on the trail of another man, Peter Gillespie, who also had been selling fake versions of Casodex to U.K. pharmacies. see COUNTERFEIT, T page 20
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Mr. Gillespie owned a wholesaler in the United Kingdom called Consolidated Medical Supplies, which had repackaged and relabeled the drugs and sold them to U.K. wholesalers and pharmacies. On April 8, 2011, Mr. Gillespie was convicted of selling or supplying drugs without authorization and conspiracy to defraud. He was sentenced to eight years in prison. These cases make it clear that fake pharmaceuticals can enter the legal supply chain in the United Kingdom and the United States. “It’s clear that we can’t pretend this type of thing doesn’t happen in the U.S. and U.K,” said Chris Vansteenkiste, the project manager of the Intellectual Property Crime Team at Europol. However, he noted, “The number of similar cases is very, very low.” In fact, the true scale of the problem remains unknown. “The difficulty with this field is that there are no reliable statistics,” Mr. Davison said. “You can see published numbers describing how much damage is caused by fake drugs, and some of them are based on plausible evidence, but they are only estimates. The nature of criminal activity is clandestine so there’s no real way we can really quantify the scope.” Dr. Liang agreed that “because the bad guys don’t give us annual reports, all we have are guesstimates, which indicate that less than 1% of U.S. medications are counterfeit.” However, there are 3.5 to 3.75 billion prescriptions written every year in the United States, so even a tiny percentage has a great effect, he added. Along the same lines, it has been difficult to quantify the extent to which this illegal trade has harmed patients. It is evident, however, that medications containing toxic ingredients can kill
CLINICAL ONCOLOGY NEWS • JUNE 2013 • CLINICALONCOLOGY.COM
The case of the McLeod Cancer and Blood Center, which involved purchases of more than $2 million in unapproved drugs, and payments from Medicare and other programs of about $2.5 million, represents just a small piece of a growing problem of misbranded, unapproved cancer drugs entering the legitimate supply chain in the United States. patients faster than a potentially lifethreatening disease. In 2008, investigators identified fake versions of Baxter’s injectable anticoagulant heparin, which contained a substituted contaminant, over-sulfated chondroitin sulfate, resulting in at least 149 deaths in the United States. In some cases, patients receive a drug that is not FDA-approved (as with MabThera). In other instances, a fake drug may have no active ingredients (as with Avastin) or may contain the active ingredient, but in lesser amounts (e.g., the Casodex case). Also, on occasion, a drug may have 100% of the active ingredient, but storage, transport and other considerations make use unsafe. Despite the difficulty quantifying the scope and perils of the problem, it is clear that the illicit prescription drug trade is “probably the most lucrative illicit trade activity these days, more so than narcotics, cigarettes and faking credit cards, which is attracting the type of people who can exploit those opportunities,” said Mr. Davison, who estimates fake and counterfeit drugs bring in tens of billions of dollars in profits each year.
Beyond the U.S. and Europe Although fake drugs are becoming more of a problem in the United States and Europe, the brunt of this problem is borne in Africa, Asia and Latin America, places that tend to have much more limited regulatory power. “If we go to Africa, there’s a high
proportion of fake malaria drugs, for example, that are probably killing tens of thousands of children a year,” said Amir Attaran, PhD, JD, an associate professor in the Faculties of Law and Medicine at the University of Ottawa, Canada. “It’s a bleak equation.” Fake drugs often seep into the supply chain because a handful of countries are manipulative and dishonest, India being the prime example, he said. In fact, recently India’s Ministry of External Affairs even went so far as to deny ever exporting fake malaria medicines to Africa. “This statement is comparable to the South African government saying that HIV does not cause AIDS. In this instance, a government has taken something so fantastically untrue and pretended it is true for personal gain,” Dr. Attaran said. “The government in India has calculated that it’s good for the country to sell fakes because it’s lucrative and, if it kills people abroad, there’s no legal consequence.” Dr. Attaran couched his concern by noting that overall, in the United States patients are safe. Connie Jung, RPh, PhD, the acting associate director for policy and communication in the Office of Drug Security, Integrity, and Recalls at the FDA’s Center for Drug Evaluation and Research, agreed. “Consumers in the U.S. can be confident about what they’re getting at their local pharmacy.” But, even if the chances of receiving a fake drug are one in a million, when it happens to you, it’s 100%, said Dr. Liang.
“Population information is important but never forget you’re treating the individual patient,” he said. “When my wife had breast cancer, if I knew my colleague had infused her with chemotherapy and had not checked the viability of the medication or was simply interested in making higher profits, it would have ruined her chances. To be cheated like this is a crime against humanity, and it should be treated as such.” —Victoria Stern This is the first article in a two-part special report on fraudulent drugs in the United States. Part II—focusing on the sources of fraud and efforts to prevent it—will be published in the July issue of Clinical Oncology News.
Related coverage online at ClinicalOncology.com Partnership for Safe Medicines Launches Anti-Counterfeit Initiative in China Institute of Medicine Report Recommends National Track-andTrace System
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SEQUESTRATION N continued from page 1
He says the clinic is putting its efforts into advocacy, calling on legislators to take cancer drugs out of the sequestration cuts and supporting H.R. 800, a bill that mandates removal of manufacturer-to-distributor prompt-pay discounts from the calculation of average sales price (ASP) in drug reimbursements. If the sequestration cuts remain unchanged, oncologists believe that the bill will help mitigate the effects of the cuts. Dr. Gordan estimates that Florida Cancer Specialists can continue as usual for “several weeks” before services will need to be cut or Medicare patients sent to hospitals for treatments. “We don’t have a schedule date or time that we’d have to change to hospital care. Obviously, the most expensive drugs would be the most affected because the costs of those drugs are so much higher.” The sequestration reductions have added to the already high stress levels of oncology patients, as well as their physicians, said Dr. Gordan. “We want to treat patients the best way possible. We believe the best quality care is delivered in the community setting. Patients are familiar with us and familiar with our staff. The relationships are built. They know our nurses [and] they know our front staff. This threat adds stress to patients and their families and subsequently the stress becomes ours, which is a natural evolution of things,” he said. Some community oncologists are looking for novel ways to keep their patients in treatment at community centers. In Albuquerque, the physician-owned New Mexico Cancer Center sent letters to 300 affected patients, asking them to come into the office to work with financial advisers to see if they could get supplemental Medicare insurance or find other ways to pay for treatment. Community cancer centers were caught off guard with the sequestration cut, which reduced payments for Part B drugs and to the 6% services payment. The result, after accounting for patient copayments, will be to reduce reimbursement from ASP plus 6% to ASP plus 4.3%,
effectively imposing a 28% cut in payments intended to compensate for the significant operating expenses of procuring, preparing and handling Part B drugs. “Usually, when there are changes to reimbursements, we have a lot of time and guidance to get ready. We were told about this cut in a three- to four-paragraph email from CMS [Centers for Medicare & Medicaid Services] on a Friday afternoon,” said Mr. Okon. The reductions were implemented several weeks later. For many cancer drugs, the cost of storing and administering drugs now exceeds the reimbursement rate from Medicare. “This cut puts many cancer drugs further underwater; that is, reimbursed at less than market cost. We are very concerned about the adverse impact to community oncology practices and their patients, especially seniors covered by Medicare,” he said. Mr. Okon added, “The cut is so severe that it was almost impossible to grasp.” With nearly 50% of cancer patients in the United States covered by Medicare, the effect of the cuts could be “staggering,” said Allen S. Lichter, MD, the CEO of the American Society of Clinical Oncology (ASCO), speaking at the 2013 COA conference. ASCO, the COA, the International Oncology Network/AmerisourceBergen and the US Oncology Network are calling on members of the U.S. House of Representatives to intervene and halt the cut. “This compounds current underpayment for cancer therapies and places community cancer clinics in the untenable position of routinely providing services below their cost,” they said, in a statement released April 1. “When community cancer clinics are forced to close their doors or limit services, access to cancer care is compromised for all cancer patients, especially the vulnerable population of seniors who rely on Medicare.” Many patients are now being redirected to hospitals, which are working with clinics to adapt to the new situation. However, it’s unclear if hospitals have the capacity to absorb these patients long term. Before April 1, 66% of Medicare patients with cancer received their oncology treatment in community clinics
by the
numbers: sequestration effects In a survey by ASCO 80% of respondents said that the sequestration cuts have affected their practices Nearly 50% reported not being able to continue caring for Medicare patients without supplemental insurance 50% reported sending their Medicare patients elsewhere for chemotherapy, primarily to hospital infusion centers Source: ASCO Sequestration Impact Survey.
Many practices are turning away a portion of their Medicare patients. rather than hospitals and many hospitals lack the ability to do oncology infusions. Experts in the oncology field say that it will take time for the true measure of the reductions to be felt. Clinics will not bear the full hit of the financial squeeze for several weeks when the first postsequester claims are filed. It’s expected that the migration of patients to hospitals will increase after those claims are in. In a survey of COA members conducted before the cuts went into effect, respondents said that sequestration slashes to cancer drugs and services would force 72% of community oncology practices to stop seeing new Medicare patients, not treat any Medicare patients without secondary insurance and/or send Medicare patients elsewhere for treatment. The reductions come at a time when community oncology practices are already struggling. Since 2008, more than 1,200 community cancer centers have closed, consolidated or reported financial problems, according to statistics from the COA. Advocates of community oncology argue that the costs of cancer care will rise as patients are redirected to hospitals—exactly the opposite of what the sequestration is supposed to accomplish. One study from Milliman, a Seattlebased employee-benefit consulting and actuarial company, found that chemotherapy delivered in a hospital setting costs the federal government an average of $6,500 more per year than chemotherapy delivered in a community clinic. A similar study from Avalere Health found that treatment for patients receiving chemotherapy in a hospital outpatient department cost on average 24% more than treatment received in a physician’s office. (Both studies are available on the COA website.) Hospital cancer care costs more to patients, as well. The Milliman study found that patients ended up with an average of $650 more in out-of-pocket expenses when they received hospital care. Patients generally travel longer and spend more time away from home when receiving hospital care. Cancer care advocate Daniel Long said on the COA Facebook page that in the days following sequestration, he had to explain to a couple in their 80s that they needed to travel an additional 70 miles— and two more days—to receive care. Speaking at the 2013 COA conference one week before the cuts went into effect, t Matt E. Brow, the vice president of public policy and reimbursement strategy for McKesson Specialty Health, said oncologists need to look at the reimbursement rate for different drug regimens and decide whether they will provide these services under the sequester.
“If you decide to provide those services or drugs in your office for a loss, it should be a conscious decision by your practice in conference with your partner and colleagues,” he said. If centers decide not to provide those drugs, oncologists must be prepared to talk to their patients about why and how they will help them through the displacement, said Mr. Brow. Mr. Okon and other advocates in community oncology are calling on oncologists and patients to contact their legislators to drive the message home about how the cuts are affecting care. Petitions and letters are available on the COA website. Sarah Lyons Walter, a lobbyist who has worked with AmerisourceBergen, urged physicians to be clear with legislators, telling them how the cuts will directly affect patients. “We need to continue to drive home a message about the real-world impact on buyers and beneficiaries because they look at this 2% cut and it’s just a number to them. We need patients and their advocates to be out there reminding them that there are real-world implications to these cuts.” In mid-April, advocates in the oncology community got a boost when Rep. Renee Ellmers (R-N.C.) introduced legislation that would scale back the cuts to cancer clinics. The Cancer Patient Protection Act of 2013, which has 58 bipartisan co-sponsors, exempts chemotherapy drugs administered in offices from the across-the-board budget reductions. The measure also directs Medicare to reimburse physicians for any reduced reimbursements since the sequester took effect on April 1. At press time, the bill was not passed. Congress, however, did approve legislation to give the secretary of the Department of Transportation enough financial flexibility to shift more than $253 million to the air traffic control system to ease flight delays. Sandra M. Swain, MD, the current president of ASCO, said similar financial flexibility should be extended to help people with cancer. “Today, out of concern for public safety, Congress provided the Federal Aviation Administration enhanced flexibility in application of sequestration-related cuts, including reversal of furlough requirements imposed on air traffic controllers. Individuals with cancer deserve no less,” she said in a statement from ASCO. “ASCO, along with others in the oncology community, has called upon the Secretary of Health and Human Services to apply sequestration cuts in a way that protects access to cancer care for America’s elderly.” —Christina Frangou
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CLINICAL ONCOLOGY NEWS • JUNE 2013 • CLINICALONCOLOGY.NEWS
On the Spot With Colleen Hutchinson
Focus on Breast Cancer T
his “On the Spot” column debates breast cancer and mastectomy, specifically surgical resection of the primary tumor for women with metastatic breast cancer and the timing of sentinel lymph node biopsy. In next month’s issue, we will continue the debate and look at the timing of radiation with respect to breast reconstruction; nipple-sparing mastectomy; and
the patenting of genes for diagnostic testing or cancer research. Once you’ve read what these experts have to say, look at your own practices and experience and see how their arguments measure up. Then it’s up to you to determine your own stance, which we’d love you to share with us. Your opinions are an important piece of the puzzle.
Thank you to this month’s contributors for their candid responses and for the time it took to share them. Please feel free to email me at colleen@cmhadvisors.com with any ideas for “On the Spot” debates, thoughts on this month’s column or general feedback, and comment online as well. I always like hearing from you! –Colleen Hutchinson
P ARTICIPANTS Marisa Weiss, MD Founder and President of Breastcancer.org and Director of Breast Radiation Oncology and Breast Health Outreach, Lankenau Medical Center, Wynnewood, Pennsylvania
Tari King, MD Associate Attending Surgeon, Breast Service, Memorial Sloan-Kettering Cancer Center, New York, New York
Seema Khan, MD Professor of Surgery and Bluhm Family Professor of Cancer Research, Northwestern University, Chicago, Illinois
Mary Jane Houlihan, MD Assistant Professor of Surgery, Harvard Medical School, Boston, Massachusetts
Susan Pories, MD Associate Professor of Surgery, Harvard Medical School, Boston, Massachusetts
Cassann Blake, MD Head, Section of Breast Surgical Oncology, Cleveland Clinic Florida, Weston, Florida
Grant Carlson, MD The Wadley R. Glenn Professor of Surgery and Chief of Surgical Services, Emory University Hospital, Atlanta, Georgia
Mehran Habibi, MD Assistant Professor of Surgical Oncology, Johns Hopkins University, Baltimore, Maryland
Larry Norton, MD Deputy Physician-in-Chief for Breast Cancer Programs and Medical Director, Evelyn H. Lauder Breast Center, Memorial SloanKettering Cancer Center, New York, New York
Statement
For the 10% of patients who have breast cancer metastasis at the time of diagnosis, some would say there is tremendous uncertainty and a lack of information regarding definitive treatments in terms of removing the tumor from the breast—for example, does tumor removal improve long-term outcome or is mortality dictated by metastasis? In these patients, the preferred option is to immediately operate versus the watch-and-wait approach of deferring surgery and seeing how the patient does on systemic therapy.
Cassann Blake, MD: Agree. Studies have shown that removal of the primary breast cancer either has no impact on survival or improves survival. Given that surgery to remove the primary tumor is a low-morbidity procedure and does not worsen survival, it is a reasonable discussion to have with stage IV breast cancer patients.
My preferred approach is watch and wait to see how the patient responds to systemic therapy, which offers the logical first course of therapy to temporize progression of metastatic disease. Mortality in stage IV breast cancer could be a multifactorial process that, for some patients, involves the status of the primary breast cancer if they have shown a response to systemic therapy. It is hopeful that robust accrual to the ECOG-E2108 trial (Phase III Randomized Study of Early Local Therapy Comprising Surgery versus Standard Palliative Therapy for the Intact Primary Tumor in Patients with Stage IV Breast Cancer) will provide definitive results to guide multidisciplinary breast teams on who would best benefit from local therapy in the metastatic setting.
Larry Norton, MD: Fence. Right now, pending clinical trial data, I would say that it depends on the situation, in particular whether the local disease or the metastatic disease is most threatening to life and/or quality of life. And indeed, we do not know if local surgical therapy is indicated at all in such cases. From a theoretical point of view, arguments can be made either way, so it is critical that we address these issues in the context of clinical trials that also assess biomarkers.
Tari King, MD: Disagree. New insights into cancer biology have resulted in a shift in our approach to systemic treatment for breast cancer, with an increased focus on biologic subtypes and targeted therapy. Given the documentation of improved survival for women with stage IV breast cancer and the anticipation that survival for this group will continue to improve with newer targeted systemic agents, the question of whether or not surgery for the primary tumor impacts survival in this setting is increasingly important. At last count, at least 19 retrospective studies have addressed this question, with the majority concluding that surgery, or local therapy with radiation, is associated with improved survival. Although all of these studies are inherently biased by their retrospective nature, the consistency of the results has led to the opening of five prospective randomized trials designed to definitively answer the question of whether local-regional treatment can further improve outcomes for patients with metastatic disease. Two of these trials (Turkish and Danish groups) randomize patients to surgery or no surgery prior to systemic therapy and the other three trials, including the U.S. trial (ECOG), randomize patients after assessing response to primary systemic therapy. If the tumor functions as a see ON THE SPOT, T page 24
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CLINICAL ONCOLOGY NEWS • JUNE 2013 • CLINICALONCOLOGY.COM
ON THE SPOT continued from page 22
source of new metastatic deposits, treating it early in the course would intuitively seem to have greater benefit, yet the retrospective studies examining the timing of surgery are very limited and the results are inconsistent. Given the lack of level 1 evidence that surgery—at any time—improves survival, in my opinion the preferred option is to encourage patients to enroll in prospective trials so that we can definitively answer this important question.
Mary Jane Houlihan, MD: On the fence. Most women who present with stage IV disease will die of their disease within 24 to 30 months, and in most women, there is little to no role for mastectomy. However, there is a small subset of women with limited metastatic disease who are young, healthy, and have a primary tumor that is completely resectable, who would benefit from mastectomy and axillary surgery as part of a multidisciplinary approach. For these women, it is unlikely that we are curing them; however, their life expectancy may be prolonged.
Mehran Habibi, MD: I agree with surgery in the setting of oligometastatic disease. There is no prospective randomized study to date on this reported. We are currently part of a multicenter study looking into this subject, but the recruitment is slow. The reason is the patient self-selection bias. It means that if the patients that are presenting with the metastatic breast cancer are responding to the medical therapy or having a stable disease, most of them opt to have the surgery on the breast lesion. Retrospective and animal studies as well as in other tumors may suggest that removing the index tumor may have a positive effect on the immune system and help with the cancer therapy. I usually offer surgery to patients with breast cancer and oligometastatic disease or those with good response to the systemic therapy.
Marisa Weiss, MD: Disagree. Systemic therapy is the mainstay of treatment for metastatic disease, as it’s the only form of therapy that addresses all areas of tumor involvement. Interval symptomatic and imaging re-evaluation are done to monitor response. Surgery has a limited role.
Grant Carlson, MD: Agree. Approximately 5% of women with breast cancer will present with systemic metastases at diagnosis. Modern systemic therapy has markedly improved survival in patients with systemic disease. Local treatment in this setting is controversial and is currently being examined in randomized trials. Metaanalysis of retrospective reviews has shown a significant survival benefit for treating the primary cancer independent of age, tumor extent and site of metastatic disease. There are several possible mechanisms why
removing the primary would affect survival. Surgical treatment of the primary may reduce the patient’s tumor burden and reduce the levels of circulating tumor cells. The primary tumor may have immunosuppressive effects that can be reversed by removal. Local control can also significantly impact quality of life. I prefer for patients in this setting to be treated with systemic therapy and wait a period of time to assess primary tumor response prior to local treatment. In patients with large ulcerative tumors that are resectable, I prefer local treatment at the onset.
contemporary series of primary SLN biopsy. In some subsets, the false-negative rate was unacceptably high; in women who had a single SLN examined, the falsenegative rate was 30%. Therefore, among women who start neoadjuvant therapy with a known positive axillary node, SLN biopsy can be offered but with readiness to change the plan to axillary dissection if only one or two SLNs are identified at surgery. Preoperative discussion with the radiation oncologist in terms of how surgical axillary management will affect the radiotherapy decisions is also helpful.
Seema Khan, MD: Disagree. The existing literature supporting surgical resection of the primary tumor for women with metastatic breast cancer is entirely retrospective and biased. Several trials are ongoing worldwide (including ECOG 2018 in the U.S. and Canada), and practitioners who have access to a trial should offer such a patient trial participation. Outside of a trial, immediate surgery still does not make sense, since there is little chance that a tumor that does not respond to distant sites will behave differently if the primary site is resected. Therefore, the only logical plan requires initial systemic therapy for distant disease; this will also lead to a response at the primary site in the majority of cases and will avoid a delay in the initiation of systemic therapy, with its proven life-prolonging potential. Once it is clear that distant disease is controlled, surgery for the primary tumor can be considered, with a careful explanation to the patient that although this may aid local control, there is so far no good evidence that survival will be altered. Personally, I reserve primary tumor resection for women whose distant disease is well controlled, but the primary site is progressing despite effective systemic therapy.
Dr. Norton: Agree, with the qualification that I interpret the term “accurate” as referring to clinical utility. Yes, neoadjuvant systemic therapy often downstages the axilla, but as we increasingly rely on tumor biology rather than anatomy for prognostication, prediction and clinical decision making, the absolute count of involved axillary lymph nodes has become less important.
Susan Pories, MD: Disagree. Patients with widespread metastatic disease at the time of presentation will not benefit from surgery and should be treated with systemic therapy. Patients with oligometastatic disease, with only one site of metastasis, can be considered for surgery if they have a good response to systemic therapy.
Statement
Regarding the timing of SLN biopsy, SLN assessment after neoadjuvant therapy is as accurate as performing the procedure prior to chemotherapy treatment.
Dr. Khan: Agree. For women who present without evidence of nodal metastases, that is, axillary nodes appear normal clinically, the effectiveness of SLN biopsy following neoadjuvant systemic therapy is well established, and is essentially equivalent to the accuracy of SLN biopsy in the primary surgical setting. The controversy at the moment relates to the use of SLN biopsy following neoadjuvant systemic therapy in women who present with involved axillary nodes. Here, the recent ACOSOG Z1071 trial suggests that use of SLN biopsy following chemotherapy is also reasonably accurate, but there are caveats and areas of concern. The overall false-negative rate in that study was just over 12%, substantially higher than what we are used to seeing in
Dr. Houlihan: Disagree. Studies remain controversial; however, it appears that mapping is better when the sentinel node biopsy is performed before neoadjuvant chemotherapy. False-negative rates of up to 25% have been reported after neoadjuvant chemotherapy. These results may lead to incomplete treatment in the setting of a mastectomy: no axillary dissection and possible post-mastectomy radiation therapy in certain cases.
Dr. Pories: Agree. For patients who are undergoing neoadjuvant therapy, the axilla should be assessed with ultrasound, and any suspicious lymph nodes should be biopsied with either fine needle aspiration or core biopsy under ultrasound guidance. Patients with positive biopsies will need to have full axillary dissections at the time of their definitive breast surgery. Those patients who do not have clinically positive nodes at the time of presentation and negative axillary ultrasounds can have SLN biopsy at the time of surgery.
Dr. King: Agree and disagree. The question of whether or not SLN biopsy is accurate after neoadjuvant therapy depends on the patient population in question. In the setting of clinically node-negative disease, multiple single-institution series and the NSABP B27 prospective randomized trial clearly demonstrated that SLN biopsy after neoadjuvant chemotherapy is associated with acceptable false-negative rates (less than 10% in most series) and allows node-negative patients, or those that were downstaged to node-negative status, the opportunity to avoid axillary node dissection without an increase in rates of local-regional recurrence. In the setting of clinically node-positive disease, however, the results are not as convincing. Recent data from the ACOSOG Z1071 trial, presented last December at the San Antonio Breast Cancer Symposium (abstract S2-1), demonstrated that SLN biopsy following neoadjuvant therapy in patients with a clinically positive axilla was associated with a false-negative rate of 12.6% when two or more SLN were removed, but exceeded 20% when only one SLN was removed. These results are difficult to interpret in light of the study design, which specified a false-negative rate of 10% as a predefined study end point and are even more difficult to apply in clinical practice, given that some patients actually only have one SLN. In light of these findings, I don’t believe SLN biopsy after neoadjuvant
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CLINICAL ONCOLOGY NEWS • JUNE 2013 • CLINICALONCOLOGY.COM
Clinical Conundrums
Prepared by
Syed A. Abutalib, MD Assistant Director Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois
Clinical Hematology Review: Highlights from NEJM, Blood, JCO and ASCO
5. True
QUESTIONS
or False. In newly diagnosed chronic myeloid leukemia (CML), additional measurement of the transcript level at six months adds useful clinical information to the three-month result in patients treated with ponatinib (Iclusig, Ariad) and hydroxyurea.
1. True or False. In an
elegant study reported in The New England Journal of Medicine by Julia E. Maxson, PhD, of the Knight Cancer Institute at Oregon Health & Science University in Portland, mutations in colony-stimulating factor 3 receptor (CSF3R) are present in all patients with newly diagnosed chronic neutrophilic leukemia (CNL).
Primum non nocere. (First, do no harm.)
2. True or False. Ruxolitinib (Jakafi,
Incyte Pharmaceuticals/Novartis) demonstrated clinical activity in patients with CNL harboring CSF3R proximal membrane mutations.
3. True or False. Two simultaneous-
ly published studies in Blood d described a critical first step by providing a description and characterization of the immune response to protamine, with potentially important clinical implications for patients undergoing cardiopulmonary bypass (CPB) surgery.
4. True or False. Protamine adminis-
tration in the setting of cardiac surgery is associated with a very high incidence of anti–PF4-heparin antibodies.
6. True or False. A
Spanish study demonstrated that in intermediate-risk acute myeloid leukemia (AML), patients with NPM1 mutation and those with either absence of FLT3-ITD or with a low FLT3-ITD/ FLT3 wild type ratio of <0.5 had similar leukemia-free survival (LFS) and overall survival (OS).
7. True or False. At the 2013 annu-
al meeting of the American Society of Clinical Oncology (ASCO), Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute in Boston, reported substantial clinical activity of idelalisib (formerly known as GS-1101, Gilead) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL).
8. True or False. The PI3K pathway is not affected in CLL.
chemotherapy in clinically node-positive patients is as accurate as SLN biopsy before chemotherapy.
Dr. Blake: Agree. The accuracy of performing SLN biopsy on a locally advanced breast cancer patient is similar whether done before or after neoadjuvant chemotherapy. The ACOSOG trial has shown an acceptable 12.6% false-negative rate in the post-neoadjuvant chemotherapy SLN biopsy patient. My practice has evolved from routinely performing SLN biopsy before neoadjuvant chemotherapy to offering it after neoadjuvant chemotherapy in a patient with a clinically negative axilla by exam, mammogram, ultrasound and breast MRI [magnetic resonance imaging] at presentation. I will, at times, proceed with a pre-neoadjuvant chemotherapy SLN biopsy in a patient with a benign fine needle aspiration in a clinically suspicious lymph node, based on my assessment of the imaging and presentation of the breast cancer.
Dr. Weiss: Disagree. The most accurate lymph node assessment is usually accomplished prior to treatment intervention.
Dr. Habibi: Agree. I have always believed that if we
9. True or False. In a population-
based data analysis from nine U.S. population-based cancer registries (19752008), the incidence of therapy-related acute myeloid leukemia (t-AML) was reported to be eight times higher than expected compared with the general population.
10. True
or False. The Spanish MDS (myelodysplastic syndrome) cooperative group was able to segregate chronic myelomonocytic leukemia (CMML) patients into four prognostic risk groups based on French–American– British classification system (FAB) and World Health Organization subtypes, CMML-specific cytogenetic risk classification, and red blood cell (RBC) transfusion dependence or hemoglobin levels in terms of OS (P ( <0.001) and risk of AML evolution (P ( <0.001), with the predictive capability confirmed in an external validation cohort.
11.
True or False. Targeting ectonucleoside triphosphate diphosphohydrolase (CD39) represents a promising therapeutic antithrombotic strategy that might be able to break the link between antithrombotic potency and bleeding.
12.
True or False. Positive CD30 expression defines a unique subgroup of diffuse large B-cell lymphoma (DLBCL) with unfavorable clinical outcome.
are doing neoadjuvant chemo and getting the benefit of the therapy to, for example, convert a mastectomy to a partial mastectomy, then why not use the same benefit when it comes to the nodal evaluation? Classic level 1 to 2 axillary dissection is associated with a significant lymphedema in around 15% of patients and with associated local numbness and paresthesia, which is bothersome to the patients. When you add the effect of radiation to this, especially now that even patients with less than three to four nodes are undergoing radiation, this can potentially impact up to 30% of patients negatively without an impact on survival. I favor doing SLN biopsy after neoadjuvant chemotherapy if the patient presents with negative axilla or if she has a complete clinical response after neoadjuvant chemotherapy.
Dr. Carlson: Disagree. Full axillary lymph node dissection is the standard therapy for node-positive breast cancer treated with neoadjuvant chemotherapy. Forty percent of patients will convert to nodenegative in this setting, causing many surgeons to consider SLN biopsy to reduce potential morbidity. The literature cites a false-negative rate (FNR) for SLN biopsy in this setting of 5% to 30%, but these studies were retrospective in nature, limited by small patient numbers, and employed varying SLN biopsy techniques. At the San Antonio Breast Cancer
13. True or False. In a European
collaborative study, the poor-prognosis subgroup of patients with stage II amyloid light-chain (AL) amyloidosis was identified with a median OS of only three months.
ANSWERS
1.
False. Dr. Maxson and colleagues identified activating mutations in the gene encoding the receptor for CSF3R in 16 of 27 patients (59%) with CNL or atypical CML. These mutations segregate within two distinct regions of CSF3R and lead to preferential downstream kinase signaling through SRC family–TNK2 or JAK kinases and differential sensitivity to kinase inhibitors. These mutations represent a potentially useful criterion for diagnosing these neoplasms. Maxson JE, Gotlib J, Pollyea DA, et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med. 2013;368:1781-1790, PMID: 23656643.
see CONUNDRUMS, S page 26
Symposium, the results of the ACOSOG Z1071 trial found a 92.7% SLN identification and a FNR in patients with two or more SLN examined of 12.6%. The FNR was significantly lower with the use of both blue dye and radioactive colloid (10.6%) and when three or greater SLNs were examined. The conclusion of this trial was that SLN surgery was useful in node-positive patients treated with neoadjuvant therapy. Surgical technique using dual tracers and removing a minimum of two SLNs was recommended to reduce the FNR. The SENTINA trial examined accuracy of SLN before or after neoadjuvant chemotherapy. It found that systemic treatment significantly impaired the tracer uptake and SLN detection rate. The SLN identification rate was 80.1% and FNR of SLN biopsy in patients receiving neoadjuvant chemotherapy for clinically positive axillary nodal disease was 14.2%. The study concluded that SLN biopsy was not reliable in patients who convert from node-positive to node-negative. In contrast to the ACOSOG trial, the SENTINA trial did not require biopsy confirmation of node-positive disease and didn’t use dual tracer. Efforts to reduce the FNR after neoadjuvant chemotherapy include pre-treatment axillary ultrasound, use of dual tracers during SLN biopsy and removal of at least two SLNs. The use of post-mastectomy radiation therapy adds further controversy to this issue.
25
26
CURRENT PRACTICE
CONUNDRUMS continued from page 25
2. True. The association between the
CSF3R mutations was found in a large sequencing of the “usual suspects” of cancer signaling. The work described in this study went from identification of the CSF3R mutation in CNL and atypical (BCR-ABL1–negative) CML, through in vitro studies, to a successful clinical application with inhibition of the JAK-activating mutation. The study highlights the power of genetic screening to uncover new potential drug targets and provides a rationale for using drugs that are already available for other indications. Maxson JE, Gotlib J, Pollyea DA, et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med. 2013;368:1781-1790, PMID: 23656643. Radich J. Genetically informed therapy in leukemia. N Engl J Med. 2013;368:1838-1839, PMID: 23656651.
3. True. Protamine sulfate, derived
from salmon sperm, is used to reverse the anticoagulant activity of unfractionated heparin and as a stabilizer in neutral protamine Hagedorn (NPH), a longacting formulation of insulin. Notably, following exposure to protamine, especially with CPB surgery, protamineinduced thrombocytopenia (PIT) and thrombosis may develop. Cuker A, Cines DB. Protamine-induced thrombocytopenia? Blood. 2013;121:2818-2819, PMID: 23580634. Lee GM, Welsby IJ, Phillips-Bute B, Ortel TL, Arepally GM. High incidence of antibodies to protamine and protamine/heparin complexes in patients undergoing cardiopulmonary bypass. Blood. 2013;121:2828-2835, PMID: 23422751. Bakchoul T, Zöllner H, Amiral J, et al. Anti– protamine-heparin antibodies: incidence, clinical relevance, and pathogenesis. Blood. 2013;121:28212827, PMID: 23325832.
4. False. Protamine administration
in the setting of cardiac surgery is associated with a very high incidence (25%50%) of subsequent, but transient, formation of anti–protamine-heparin antibodies. Heparin administration is associated with anti–PF4-heparin. A high proportion of patients tested positive for anti–protamine-heparin antibodies at day 10 after cardiac surgery, but clinically relevant events were observed in only a few patients. More work is needed in this area to define epitopes; elucidate the role of heparin; validate clinical assays to identify patients at potential risk, especially during CPB; and understand the clinical ramifications and management of this response. Bakchoul T, Zöllner H, Amiral J, et al. Anti– protamine-heparin antibodies: incidence, clinical relevance, and pathogenesis. Blood. 2013;121:28212827, PMID: 23325832.
CLINICAL ONCOLOGY NEWS • JUNE 2013 • CLINICALONCOLOGY.COM
5. False. In the study published in
Blood d by Pratap Neelakantan, MD, from Imperial College and Hammersmith Hospital in London, England, the question of whether the prognostic value of the three-month transcript level could be improved by combining the threeand six-month results was addressed. The study concluded that additional measurement of the transcript level at six months adds very little useful clinical information to the threemonth result. The imatinib (Gleevec, Novartis)- and dasatinib (Sprycel, Bristol-Myers Squibb)-treated patients who met the three-month landmark but failed the six-month landmark had outcomes identical to those of patients who met both landmarks, whereas the patients who failed the first landmark but met the second one had prognoses similar to those who failed both landmarks. The investigators concluded that the prognosis for patients starting tyrosine kinase inhibitors (imatinib and dasatinib in this trial) can be established accurately by assessing the transcript level only at three months and so clinical decisions at this time point can be made with confidence. Neelakantan P, Gerrard G, Lucas C, et al. Combining BCR-ABL1 transcript levels at 3 and 6 months in chronic myeloid leukemia: implications for early intervention strategies. Blood. 2013;121:2739-2742, PMID: 23380743.
6.
True. Among NPM1-mutated patients, wild-type FLT3 and low FLT3-ITD/FLT3 wild type ratio (<0.5) subgroups showed similar OS, relapse risk and LFS, whereas high FLT3-ITD/ FLT3 wild type ratio (≥0.5) patients had a worse outcome. In wild-type NPM1 AML, FLT3-ITD subgroups showed comparable outcomes, with higher risk for relapse and shorter OS than wildtype FLT3 patients. Allogeneic hematopoietic cell transplantation in CR1 was associated with a reduced relapse risk in all molecular subgroups with the exception of NPM1 mutated AML with absent or low-ratio FLT3-ITD. The investigators concluded that the effect of FLT3 burden is modulated by NPM1 mutation, especially in patients with a low ratio. Pratcorona M, Brunet S, Nomdedéu J, et al. Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy. Blood. 2013;121:2734-2738, PMID: 23377436.
7. True. In this Phase I study, 54
patients with relapsed or refractory CLL were treated continuously for up to 48 weeks with idelalisib. Patients had received a median of five prior therapies (range, two to 14), and 70% of patients were refractory to their most recent prior regimen. The median
progression-free survival (PFS) was 17.1 months and the median duration of response was 18 months. The drug was well tolerated. Three Phase III trials studying the efficacy of idelalisib currently are enrolling patients with previously treated CLL, and all three trials involve testing the drug in combination with other agents, specifically ofatumumab (NCT01659021; Arzerra, Genmab), rituximab (NCT01539512; Rituxan, Biogen Idec/Genentech), and a combination of rituximab and bendamustine (NCT01569295). Brown JR, Furman RR, Flinn I, et al. Final results of a phase I study of idelalisib (GS-1101) a selective inhibitor of PI3K delta in patients with relapsed or refractory CLL. J Clin Oncol. 2013;suppl: abstract 7003).
8. False. The PI3K pathway is hyper-
active in CLL. Idelalisib is the first drug that selectively inhibits PI3K delta isoform and is designed to reduce proliferation, enhance apoptosis and inhibit homing and retention of malignant B cells. Brown JR, Furman RR, Flinn I, et al. Final results of a phase I study of idelalisib (GS-1101) a selective inhibitor of PI3K delta, in patients with relapsed or refractory CLL. J Clin Oncol. 2013;suppl: abstract 7003).
9. False. t-AML is a rare but highly
fatal complication of cytotoxic chemotherapy. Despite major changes in cancer treatment, data describing t-AML risks over time are sparse. Among 426,068 adults initially treated with chemotherapy for first primary malignancy (nine U.S. population-based cancer registries, 1975-2008), 801 cases of t-AML were identified, at a rate 4.70 times higher than expected relative to the general population ((P<0.001). Morton LM, Dores GM, Tucker MA, et al. Evolving risk of therapy-related acute myeloid leukemia following cancer chemotherapy among adults in the United States, 1975-2008. Blood. 2013;121:2996-3004, PMID: 23412096.
10. True. This study reported a
new CMML-specific prognostic scoring system (CPSS) in a large series of 558 patients with external validation in an independent series of 274 patients. The CPSS is easily applicable and may prove most valuable for assessing prognosis, planning therapy and designing future clinical trials in patients with CMML. Such E, Germing U, Malcovati L, et al. Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia. Blood. 2013;121:3005-3015, PMID: 23372164.
11. True. The enzyme CD39 degrades
adenosine 5’-diphosphate (ADP), a main platelet-activating/recruiting agent. Investigators from the Baker IDI Heart & Diabetes Institute in Melbourne, Australia, constructed single-chain antibody (scFv, specific for activated GPIIb/IIIa)
for targeting CD39. In a mouse carotid artery thrombosis model, targeted-CD39 (activated GPIIb/IIIa-specific scFv) concentrated at the thrombus site without prolonged bleeding time. Delayed targeting of CD39 via scFv to activated platelets provides strong antithrombotic potency yet prevents bleeding, thereby promoting CD39 for clinical use. Hohmann JD, Wang X, Krajewski S, et al. Delayed targeting of CD39 to activated platelet GPIIb/IIIa via a single-chain antibody: breaking the link between antithrombotic potency and bleeding? Blood. 2013;121:3067-3075, PMID: 23380744.
12. False. In a retrospective analysis
on behalf of the International DLBCL Rituximab-CHOP Consortium Program, greater than 20% immunohistochemical expression of CD30-positive cells was associated with superior OS and PFS regardless of cell of origin stratification in a cohort of 903 patients with de novo DLBCL treated with the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) regimen. However, considering the group of CD30-positive DLBCL as a distinct entity is premature at this point. Hu S, Xu-Monette ZY, Balasubramanyam A, et al. CD30 expression defines a novel subset of diffuse large B-cell lymphoma with favorable prognosis and distinct gene expression signature: a report from The International DLBCL Rituximab-CHOP Consortium Program Study. Blood. 2013;121:27152724, PMID: 23343832. Chan WC. CD30, another useful predictor of survival in DLBCL? Blood. 2013;121:2582-2583, PMID: 23557969.
13. False. They reported treatment
outcomes of 346 patients with stage III (not stage II) AL amyloidosis from the United Kingdom, Italy, Germany and Greece. Median OS was seven months with OS rates at three, six, 12 and 24 months of 73%, 55%, 46% and 29%, respectively; 42% died before the first response evaluation. Amino-terminal fragment of brain-type natriuretic peptide (NT-proBNP) greater than 8,500 ng/L and systolic blood pressure (SBP) less than 100 mm Hg were the only factors that independently affected OS and identified an especially poor-prognosis subgroup of patients with a median OS of only three months. Outcome and organ function of stage III AL amyloidosis without very elevated NT-proBNP and low SBP are improved by a very good hematologic response to chemotherapy. Wechalekar AD, Schonland SO, Kastritis E, et al. A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood. 2013;121:3420-3427, PMID: 23479568.
Insia F. Rizvi, MBBS, assisted in the preparation of this manuscript.
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Perspectives in Non-Hodgkin’s Lymphoma: Evolving Treatment Paradigms MM111 Release Date: August 22, 2012 Expiration Date: August 22, 2013 The goal of this activity is to provide hematologists-oncologists, medical oncologists, specialty nurses, and other relevant health care professionals with up-to-date, clinically useful information on the management of non-Hodgkin’s lymphoma. FACULTY • Julie M. Vose, MD, MBA, Nebraska Medical Center • John P. Leonard, MD, Weill Medical College of Cornell University • Jonathan W. Friedberg, MD, University of Rochester Medical Center
Perspectives on Breast and Ovarian Cancers: Integrating Data, Improving Outcomes
Cases and Conversations: Individualizing Therapy in Metastatic Breast Cancer MM112 Release Date: October 22, 2012 Expiration Date: October 22, 2013 The goal of this activity is to educate community oncologists on recent evidence in the individualized management of metastatic breast cancer. FACULTY • Linda T. Vahdat, MD, Weill Cornell Medical Center • Adam Brufsky, MD, PhD, University of Pittsburgh Cancer Institute • William J. Gradishar, MD, Northwestern University
MN122 Release Date: October 31, 2012 Expiration Date: October 31, 2013 The goal of this activity is to provide general oncologists with a concise summary of the most clinically important findings in breast and ovarian cancer research in the previous year. FACULTY • • • •
Stefan Glück, MD, PhD, FRCPS, University of Miami Ruth O’Regan, MD, Emory University Robert A. Burger, MD, Fox Chase Cancer Center Samer I. Schuman, MD, FACS, FACOG, University of Miami
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