March 2014

Independent News on Advances in Hematology/Oncology CLINICALONCOLOGY.COM • March 2014 • Vol. 9, No. 3

Less Cognitive Loss With ReducedIntensity Transplant

SOLID TUMORS HER2 status prompts differing responses to stereotactic radiosurgery ...........................

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CURRENT PRACTICE Ruben Mesa, MD: How I manage essential thrombocythemia .................

Clinical Conundrums ........................

by the

57.6 Average number of hours per week worked by oncologists

52.0 Mean number of outpatients seen per week

44.7 Percent who reported they were burned out

80.4 Percent who reported they were satisfied with their specialty choice

Source: “Burnout and Career Satisfaction Among US Oncologists.” J Clin Oncol.

2014 Jan 27. [Epub ahead of print]

6

12

numbers

Burnout and Career Satisfaction Among U.S. Oncologists

IMAGES in ONCOLOGY

ASH 2013

INSIDE

New Orleans—Reduced-intensity allogeneic hematopoietic cell transplantation (HCT), unlike full-intensity HCT, does not lead to impaired cognitive function, according to a prospective longitudinal study.

The study also was designed to look for factors that might reveal the underlying cause of cognitive loss after transplant, but the study’s hypothesis that short telomere length mediates susceptibility was only partly supported. Telomere length did predict risk for cognitive loss in women but not in men. see HCT, T page 13

Untitled. Is it a deity or psychedelic dancer striking a pose in this rare view of yolk sac tumor?

For more information see page 8.

Vogl, NY...

Adjuvant Bisphosphonates: Does the meta-analysis presented at SABCS change anything?

San Antonio — The 2013 San Antonio Breast Cancer Symposium (SABCS) included two important presentations on adjuSteven Vogl, MD vant bisphosphonates for breast cancer: a plenary lecture by Michael Gnant, MD, of the Medical University of Vienna in Austria; and an oral presentation of data from an Oxford Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) individual patient meta-analysis on the utility of bisphosphonates in preventing

Key Points ✔ ✔ ✔ ✔ ✔

Individual studies and a meta-analysis show benefit of adjuvant zoledronate and clodronate in clearly postmenopausal women, with a reduction in bone metastases and improved survival.

The benefits were demonstrated in subgroup analyses of overall negative studies, making them somewhat suspect.

Oral clodronate seems as effective as IV zoledronate, with much less osteonecrosis of the jaw.

The benefits of adjuvant zoledronate in medically castrated younger women need to be confirmed before this therapy is offered routinely.

Vitamin D supplements for those with low levels may have similar beneficial effects and should be studied.

relapse and death after local treatment for breast cancer by Robert Coleman, MD, of the University of Sheffield, U.K. The point of both presentations was that clodronate orally and zoledronate intravenously each prevent relapse and death in women older than age 55 at diagnosis. The good news is that this effect seems to occur in multiple studies, including the NATAN trial, newly presented at SABCS 2013

by Gunter von Minckwitz, MD, of the German Breast Group. In this trial, every-six-month zoledronate see BISPHOSPHONATES, S page 3

RE VIE WS & COMMENTAR IES

Expert Insights From City of Hope To biopsy or not?

Evaluating three thyroid nodule characteristics ......... 9 John Hosei Yim, MD

Web-based questionnaire improves levels of patient distress ................... 10 Matthew J. Loscalzo, LCSW

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CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • MARCH 2014 • 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

Michael A. Carducci, MD Johns Hopkins Kimmel Cancer Center Baltimore, MD

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Oncology Nursing

Hematologic Malignancies Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Edward Chu, MD University of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

Mayo Clinic Rochester, MN

Mary Lou Bowers, MBA The Pritchard Group Rockville, MD

Syed A. Abutalib, MD

Leonard Saltz, MD

Cancer Treatment Centers of America Zion, Illinois

Cindy O’Bryant, PharmD

Matt Brow

University of Colorado Cancer Center Denver, CO

VP, Public Policy & Reimbursement Strategy McKesson Specialty Health The US Oncology Network Washington, DC

Sara S. Kim, PharmD

Richard Stone, MD

University of Texas, MD Anderson Cancer Center Houston, TX

The Mount Sinai Medical Center New York, NY

Infection Control Susan K. Seo, MD Memorial Sloan-Kettering Cancer Center New York, NY

On the Cover

O

ur cover features the artwork of Marie Sicari, MD, a pathologist, visual artist and performer whose digital art photography project focuses on imagery of human disease.

Dr. Sicari specializes in the fields of anatomic pathology and dermatopathology.

Dr. Sicari’s digital abstract art explores the fantastic imagery of microscopic pathology as a potential tool to access and explore the mind-body-spirit connection. Her work reflects the paradigm shift occurring in medicine toward the inclusion of holistic approaches and the role of creative arts in the healing process.

If you are interested in purchasing this piece or other work from her collection, Dr. Sicari may be reached at www.behance.net/MarieSicari

Community Oncology John W. Finnie, MD Mercy Medical Center St. Louis, MO

Ephraim Casper, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Policy and Management

Pharmacy

Cathy Eng, MD

Gastrointestinal Cancer and Sarcoma

Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

University of Alabama Birmingham, AL

Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

University of Texas, MD Anderson Cancer Center Houston, TX

Shaji Kumar, MD

Gastrointestinal Cancer

Betty Ferrell, RN, PhD

Michele Neskey, MMSc, PA-C

Harry Erba, MD, PhD Maura N. Dickler, MD

Joseph P. DeMarco, PhD Cleveland State University Cleveland, OH

Jennifer R. Brown, MD, PhD Andrew Seidman, MD

Bioethics

University of California, San Diego, CA

Michael J. Fisch, MD, MPH University of Texas, MD Anderson Cancer Center Houston, TX

Genitourinary y Cancer Ronald M. Bukowski, MD Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

Gynecologic y g Cancer Maurie Markman, MD Cancer Treatment Centers of America Philadelphia, PA

Steven Vogl, MD Medical Oncologist New York, NY

Mission Statement Symptom Control and Palliative Care

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.

William S. Breitbart, MD Memorial Sloan-Kettering Cancer Center New York, NY

Lung g and Head and Neck Cancers Edward S. Kim, MD

Steven D. Passik, PhD

Levine Cancer Institute, Carolinas HealthCare Charlotte, NC

Vanderbilt University Medical Center Nashville, TN

Editorial Philosophy 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. 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.

Lung g Cancer,, Emesis Richard J. Gralla, MD Albert Einstein College of Medicine, New York, NY

Joseph V. Pergolizzi Jr., MD Johns Hopkins University School of Medicine Baltimore, MD

Russell K. Portenoy, MD Beth Israel Medical Center New York, NY

Educational review articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

BISPHOSPHONATES continued from page 1

EDITORIAL BOARD COMMENTARY Steven Vogl, MD Medical Oncologist, New York City

reduced relapse by about 17% among women older than 55 years of age. This was a subgroup analysis of a small study that was stopped early for futility and the result was far from statistically significant. NATAN was included in the EBCTCG meta-analysis.

that most of the benefit was observed in postmenopausal women.1 Dr. Paterson noted that younger women were overrepresented in the one totally negative older adjuvant clodronate trial, perhaps accounting for the negative findings (Paterson, personal communication).2 The subgroup analyses presented at SABCS come from a planned analysis of the 3,360-patient AZURE [Adjuvant Zoledronic Acid to Reduce Recurrence] trial, chaired by Dr. Coleman, which was published in The New England Journal of Medicine as an overall negative study.3 I was unaware of the hypothesis that zoledronate benefits only women with low estrogen levels until the AZURE subgroup analysis showed a benefit that

Table 1. Recent Negative Studies of Adjuvant Bisphosphonatesa

was restricted to women more than five years from their last menses. Although this hypothesis has considerable support (Table 2), neither Drs. Gnant nor Coleman—or anyone else—had favored this hypothesis before the AZURE study was analyzed. Both Drs. Gnant and Coleman are smart men, but neither was smart enough to come up with this hypothesis before the AZURE results were available, and so design studies to specifically establish the existence of a benefit restricted to postmenopausal women.

Bisphosphonate Benefit on Bone Mineral Density Is Clear In his SABCS plenary lecture, Dr. Gnant thoroughly reviewed the benefits of bisphosphonates in preventing bone mineral loss and even reversing it in some cases. The activity of these drugs for osteoporosis is clear-cut. It is still not clear, however, which drug to choose, when to begin it, how much to give, how often to give it, when to stop it, or how to modulate the doses and schedule in an effort to balance the benefits with the risks. Although no definite cases of osteonecrosis of the jaw (ONJ) were noted in the ABCSG (Austrian Breast and

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Drug

No. of Patients

Hazard Rate For DFS

P Value

AZURE

Zoledronate

3,359

0.98

0.79

NSABP B-34

Clodronate

3,327

0.91

0.27

GAIN

Ibandronate

3,023

0.95

0.99

NATAN

Zoledronate

693

0.96

0.79

DFS, disease-free survival a

Table data drawn from plenary lecture 2, “Adjuvant Bisphosphonate Therapy in Breast Cancer,” by Michael Gnant, MD, at SABCS SABCS 2013 and revised for publication.

Table 2. Recent Positive or Trending Subgroup Analyses of Adjuvant Bisphosphonates in Women Aged 55 Years and Older

Drug companies have little interest in defining situations in which drugs from which they earn profits should be stopped.

The bad news is that there is not one prospective study that was designed to answer the question, “Do bisphosphonates prevent breast cancer metastases in women over 55?” What we do have is three older clodronate trials, two of which show benefit in overall survival (OS); and three trials of early versus late (after the development of severe osteopenia) zoledronate for aromatase-treated women (the Z-FAST, ZO-FAST and EZOFAST trials), two of which show benefit in disease-free survival (DFS). There also are a bunch of large, prospective, well designed, mostly negative studies looking at the benefits of adjuvant bisphosphonates at preventing relapse and a bunch of variably significant subgroup analyses of these studies showing a benefit in women older than age 55 (Tables 1 and 2).

The hypothesis that bisphosphonates benefit only older women may have started in 2006. Alexander Paterson, MD, from the Tom Baker Cancer Center in Calgary, and Trevor Powles, MD, of the Royal Marsden Hospital in London, reported improved survival from two years of adjuvant clodronate in 2006, and noted in a later American Society of Clinical Oncology educational session

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CLINICAL ONCOLOGY NEWS • MARCH 2014 • CLINICALONCOLOGY.COM

Drug

No. of Patients

Hazard Rate For DFS

P Value

AZURE

Zoledronate

1,041

0.75

0.02

NSABP B-34

Clodronate

2,139

0.68

0.13

GAIN

Ibandronate

1,557

0.75

0.17

NATAN

Zoledronate

233

0.83

0.73

DFS, disease-free survival a

Table data drawn from plenary lecture 2, “Adjuvant Bisphosphonate Therapy in Breast Cancer,” by Michael Gnant, MD, at SABCS SABCS 2013 and revised for publication.

Colorectal Cancer Study Group)-12 zoledronate trial, these were young women, and it is unknown how many of them will develop bone problems later in life.

Painful stress fractures of the proximal femurs are also likely related to bisphosphonate therapy and seem to be reported with increasing frequency. These can be dramatic and disabling. I have personally cared for two patients with such fractures (one with metastatic breast cancer and one with osteoporosis), plus one osteoporosis patient with a metatarsal stress fracture. This suggests a much higher frequency of zoledronateinduced stress fractures than the onein-10,000 quoted by Dr. Coleman for osteoporosis patients.

Drug companies have little interest in defining situations in which drugs from which they earn profits should be stopped. Funding for studies to determine how to give bisphosphonates— which are now generic in any case—for

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The AZURE trial randomized women with positive nodes (98.5% of the study population) or larger breast primary tumors with negative nodes to 19 doses of zoledronate over five years (beginning with a monthly dose for six months) or control, with only 8.7% of control patients eventually getting zoledronate at some schedule for late developing osteoporosis.

For the primary end point of DFS, the untreated control group did trivially better than the zoledronate group: 77.1% versus 76.9% at five years. OS slightly favored zoledronate at five years: 85.4% versus 83.1%, an absolute difference of 33 deaths (adjusted hazard rate [aHR], 0.83; P=0.07). see BISPHOSPHONATES, S page 4

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BISPHOSPHONATES continued from page 3

Subgroup analysis by stratification parameters showed a five-year OS benefit restricted to women more than five years postmenopausal: 84.6% versus 78.7% (aHR, 0.74; P=0.04), a result that was independent of estrogen receptor status, tumor or nodal stage. OS at five years was equivalent among the remainder of the entrants, 85.7% versus 85.1% (aHR, 0.97).

For the end point of invasive disease– free survival, women less than five years postmenopausal at entry did insignificantly worse on zoledronate compared with controls, 74.2% versus 77.2% at five years (aHR, 1.15; P=0.11). Those more than five years postmenopausal did much better with zoledronate: 78.2% versus 71% (aHR, 0.75; P=0.02).

This AZURE subgroup analysis led Drs. Coleman, Gnant and their colleagues to use the EBCTCG to collect data on individual patients randomized to bisphosphonates or not and then combine them into a meta-analysis.

ABCSG-12 Trial: Interesting but Not Practice-Changing Dr. Gnant argued that this trial, which he chaired, shows benefit for zoledronate given every six months for seven doses. I believe he is correct that it shows some

adjuvant ovarian suppression proves efficacious in the SOFT trial, we should not consider the role of adjuvant zoledronate to be established in this population, but should insist on another prospective trial to look at this issue.

Preferably, this trial should focus on a higher-risk, node-positive population, so that the control group will have more recurrences for zoledronate to prevent.

For the moment, the role of adjuvant zoledronate is still uncertain, so premenopausal patients receiving adjuvant therapy for resected breast cancer should not be subjected to the sudden onset of menopausal symptoms just to obtain the possible benefits of adjuvant zoledronate.

I suggest we leave out the unusual situation created in ABCSG-12 (adjuvant pharmaceutical castration) from the discussion of adjuvant bisphosphonates among postmenopausal women (those over 55), since the absolute difference in the number of distant metastases observed was so small.

The Oxford Meta-Analysis This analysis included just over 5,000 women randomized to oral clodronate or not, about 8,300 to intravenous zoledronate or not, and about 4,400 randomized

I suspect Amgen marketing executives would perceive an advantage from the approval of adjuvant zoledronate by the FDA because it will make it easier to market denosumab. benefit, but I am not sure that including it in the argument helps us decide whether to treat with zoledronate to prevent recurrence, and whom to treat.

Briefly, the trial randomized about 1,800 premenopausal, hormone receptor–positive women at low risk of relapse (although 30% had positive nodes), all of whom had three years of ovarian suppression with goserelin and five years of either tamoxifen or anastrozole, to either zoledronate for three years or placebo.

Much has been made of the statistically significant difference in recurrence-free survival.4 Careful reading of the paper shows that only 12 fewer zoledronatetreated patients had first relapse as distant metastasis than placebo patients— the total difference in DFS events was 30 (the rest of the difference is mostly accounted for by 10 more locoregional recurrences, four more contralateral primaries and two more deaths without recurrence in control patients).

The prevention of just 12 instances of distant metastasis among 900 treated patients is a very small number of ultimately lethal events that separate the groups, and suggests that even if

to other amino-bisphosphonates or not (mostly oral ibandronate). There was a nonsignificant reduction in all recurrences (absolute difference 1.1% at 10 years), and a 1.4% reduction in distant recurrences from 22.3% to 20.9% at 10 years ( =0.03). Nearly all of the latter differ(P ence was in bone recurrences: a drop off 1.5% at 10 years, from 8.4% to 6.9%.

Among 11,036 postmenopausal women (or those over the age of 55, since menopausal status was not always available), bisphosphonates reduced distant recurrence by 3.5% at 10 years (from 21.9% to 18.4%), reduced bone recurrence by 2.9% at 10 years (from 8.8% to 5.9%) and reduced non-bone recurrence by 0.9% at 10 years (a nonsignificant reduction from 14.3% to 13.3%). Among premenopausal women, the hazard rate for reduction of bone recurrence was only 0.93, compared with 0.66 among those who were postmenopausal. There was no significant reduction in recurrence in distant non-bone sites in the entire population, and a minor trend for some reduction among older women that was not statistically significant. The benefits seemed about equal for clodronate and

the amino-bisphosphonates, and did not seem to differ according to the intensity of zoledronate administration (monthly “cancer schedules” vs. every three- to 12-month “osteoporosis schedules”).

Bisphosphonates decreased breast cancer mortality by 1.7% at 10 years (from 18.7% to 16.9%; P=0.04), but not mortality from other causes (5.3% for each group). This reduction in mortality was almost entirely among postmenopausal women (hazard rate, 0.83), with allcause mortality decreasing from 23.8% to 21.5% at 10 years (two-sided P=0.007), and breast cancer mortality decreasing from 18.3% to 15.2% at 10 years for those who were postmenopausal.

Tests for heterogeneity and trend of benefit by age were not significant, however, given the smaller numbers of women younger than age 55 on the trials, plus the benefit seen among the “medically castrated” patients in the ABCSG-12 trial. If the ABCSG-12 data showing benefit among “medically castrated” young women are excluded, however, the test for trend in reduction in bone recurrence by age becomes statistically significant, with those aged 55 to 69 having more benefit than those aged 45 to 54, and with a tiny detriment and a hazard rate of 1.03 in those younger than 45 years old.

Dr. Coleman concluded that the 34% reduction in bone recurrence and 17% reduction in risk of breast cancer death among postmenopausal women is statistically and clinically significant, and that it is independent of estrogen receptor status, nodal status, whether or not patients received chemotherapy, and whether the bisphosphonate was clodronate or an amino-bisphosphonate.

He concluded that there were no apparent beneficial effects among premenopausal women, and that there were no significant benefits in terms of deaths not attributed to breast cancer, local or regional recurrence, contralateral breast cancer, or first recurrence in sites other than bone.

I questioned Dr. Dr Coleman Coleman’ss inclusion of the AZURE results—because these generated the hypothesis that all the benefit would

be in women older than age 55—and he said the results are substantially the same when AZURE patients are excluded from the meta-analysis: a hazard rate for bone recurrence of 0.65 in postmenopausal and 1.0 in premenopausal women (Coleman, personal communication).

Our Confidence in Subgroup Analyses Should Be Limited Bisphosphonates are at best marginally effective in preventing breast cancer relapse and death in the entire population of women with the disease. Given this overall result, we do not have sufficient data to conclude that we know with certainty how to define a subpopulation in which bisphosphonates do provide benefit, nor can we be certain how great that benefit is. It remains possible that one subpopulation benefits while another suffers harm from bisphosphonate administration.

Age as a discriminator has obvious advantages—it is easy to measure, criteria are easily agreed on and it has obvious biological relevance. However, more factors than age alone are likely to influence drug activity.

Dr. Gnant argued elegantly that the benefits of adjuvant bisphosphonates on breast cancer recurrence are restricted to low-estrogen environments, and that the ABCSG-12 trial, the AZURE trial and the rest of Dr. Coleman’s meta-analysis confirm this. In his SABCS 2013 plenary lecture, Dr. Gnant reviewed the off-target (non-osteoclast) effects of zoledronate: inhibition of cancer cell adherence, proliferation, migration and invasion; induction of cancer cell apoptosis; stimulation of T γγ δ cell expansion; and inhibition of angiogenesis. Whether one or several of these, or some other action, is responsible for the restricted benefit of zoledronate is unclear. Because ABCSG-12 did not demonstrate an interaction of tamoxifen with zoledronate benefit, the estrogenic action of tamoxifen on bone did not abrogate the activity of zoledronate in preventing breast cancer bone relapse. relapse This suggests to me that the action is on a cell that perceives tamoxifen as an antiestrogen, not as an estrogen—more likely

Bisphosphonate chemical structure.

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CLINICAL ONCOLOGY NEWS • MARCH 2014 • CLINICALONCOLOGY.COM

in an extraosseous site because tamoxifen is known to have estrogenic action in bone. Whether tamoxifen is estrogenic to all cells in bone is unknown (to me, at least).

Age Is Likely a Surrogate for Some Biological Tumor or Host Parameter Breast cancer oncologists have been “burned” in the not too distant past by subgroup analyses defined by age. At various times in the past 40 years, we have been told that adjuvant chemotherapy (both melphalan and CMF [cyclophosphamide, methotrexate and fluorouracil]) worked only in women younger than age 50 and adjuvant tamoxifen worked only in women older than 50— neither proved reproducible.5 I doubt that age alone is the optimal discriminator for zoledronate’s benefit as an adjuvant breast cancer treatment.

Drs. Gnant and Coleman suggested that age is a surrogate for host estrogen levels, and cite as evidence the benefit seen in the ABCSG-12 trial among younger women whose ovarian function has been ablated. This is reasonable, and may be correct. If it is correct, we are a long way from understanding how this works, and how this interaction may be optimized!

We have heard no data on whether bisphosphonates are uniformly helpful in women older than 55 years regardless of HER2 expression or HER2 gene amplification. Perhaps proliferation matters, perhaps gene expression profile matters, perhaps estrogen-receptor level in the cancer cells matters. Once we know that the benefit of bisphosphonate is heterogeneous by a simple measure such as age, we should be very worried that it is really heterogeneous by a more sophisticated biological parameter that is somewhat associated with age, and that some groups may possibly do worse as a result of treatment.

We Need Confirmatory Studies Of Bisphosphonate’s Benefit for Patients Older Than Age 55 A trial randomizing higher risk women to bisphosphonate or not should be designed to demonstrate whether a consequent reduction in distant metastases can be confirmed, and whether the presence and extent of this benefit is uniform across biologic parameters. Clodronate, alas, is not available in the United States. Clodronate given for three years may be preferable because it is easily and orally administered and produced little ONJ in NSABP B-34 (one possible instance among 1,662 women), whereas zoledronate produced much more ONJ in AZURE, although none in ABCSG-12.6 If we choose to use or study zoledronate (since clodronate in not available in the United States), Dr. Gnant suggested giving zoledronate every six months

Every oncologist who treats resected breast cancer needs to consider adjuvant zoledronate and clodronate, regardless of whether or not expert panels like NCCN and authorities like the FDA endorse them in 2014. for only three years, as was done in ABCSG-12 to avoid ONJ and benign stress fractures (toxicities that are probably related to cumulative zoledronate dose).

I agree, as does Dr. Coleman. This would mean seven doses given over three years, compared with the 19 doses given over five years in the AZURE trial.

The German Breast Group has, in the planning stage, a trial of every-six-month zoledronate for women older than age 55 (von Minckwitz, personal communication). The Germans chose five years of zoledronate to avoid the concern that, if their study turns out negative, they just did not give the drug for a sufficient duration. In the early trial of clodronate for two years done by Dr. Powles, the benefits seemed greater during the two years of therapy compared with the subsequent three years.1 This suggests that continued bisphosphonate is needed for continued benefit.

I urge the German group to measure vitamin D levels in their patients, and to randomize those with low levels to observation or to vitamin D supplements to achieve adequate serum level of 25-hydroxy vitamin D. In AZURE, women with adequate vitamin D serum levels had very low relapse rates regardless of whether or not they received zoledronate. In a retrospective series from Toronto, adequate serum levels of 25-hydroxy vitamin D predicted a much lower relapse rate of early breast cancer.

If adequate levels of vitamin D do reduce breast relapses, then it remains to be seen whether the mechanism is similar to the action of bisphosphonates or totally different. Whether either acts entirely in bone is uncertain.

Is There a Commercial Interest?

Dr. Gnant correctly made the point that both clodronate in Europe and Canada and zoledronate worldwide are now generic drugs, with no pharmaceutical company interested in the broad use of either. Generic zoledronate now costs about $157 for a 4-mg dose in the United States, whereas generic clodronate is available in Canada for about $173 per month for a daily 1,600-mg dose.

Amgen, however, is marketing denosumab (Xgeva), an antibody to RANK ligand, as a more conveniently administered subcutaneous drug that has beneficial effects on bone density comparable to those of zoledronate, albeit at 12 times the U.S. price (three times the price before zoledronate went generic). In his plenary lecture, Dr. Gnant cited two already fully accrued studies of

adjuvant denosumab against placebo for resected breast cancer patients in which Amgen has already invested extensively.

I suspect Amgen marketing executives would perceive an advantage from the approval of adjuvant zoledronate by the FDA because it will make it easier to market denosumab. Denosumab and zoledronate are widely—and appropriately—considered equivalent in their bone effects and toxicity. Because it is generic, no company will be marketing the competition—zoledronate!

One almost hopes that some enterprising drug company executive sees an opportunity to file with the FDA for exclusive privileges to market clodronate in the United States for prevention of bone metastases in older women. This would make the drug approved and available, although presumably at a much higher price during the period of exclusive marketing. This strategy recently markedly increased the price of colchicine and quinine, two old drugs with no patent protection.

If zoledronate or clodronate were declared an effective adjuvant for women older than 55 at diagnosis, then in future trials denosumab, and other possible agents, will only have to demonstrate noninferiority, rather than superiority, to an untreated control group.

This is no problem if zoledronate really works in all women older than 55, but it is a big problem if it does not work at all, or works only in some women in that age group. Although properly done noninferiority studies must be very large to exclude small degrees of inferiority (and so are very difficult to complete), they are a catastrophic waste of resources if they correctly demonstrate the noninferiority of one ineffective treatment to another ineffective treatment because neither works. Happily, the two fully accrued denosumab adjuvant trials mentioned by Dr. Gnant are against a placebo control.

Should Any Women Get Adjuvant Zoledronate or Clodronate Now? The short answer is no. However, I think it reasonable to discuss the data now available with very high-risk women more than 5 years postmenopausal or older than 55, especially if they already have severe osteopenia (T scores in hips or lumbar spine less than –2.0) or overt osteoporosis (T scores less than –2.5). Very high-risk women, to my mind, include those with inflammatory or locally advanced cancers, with many positive nodes, with large cancers

that are receptor-negative, or with cancers that fail to demonstrate pathologic complete response (pCR) to neoadjuvant therapy in the groups where pCR is strongly prognostic (i.e., receptor-negative and, to a lesser extent, receptor-positive and HER2-positive).

Unfortunately, relatively few of these very high-risk women were included in AZURE and other trials of adjuvant bisphosphonates, which makes it difficult to have an informed discussion of the potential absolute benefits for an individual patient.

Every oncologist who treats resected breast cancer needs to consider adjuvant zoledronate and clodronate, regardless of whether or not expert panels like the National Comprehensive Cancer Network and authorities like the FDA endorse them in 2014. The consistency of the apparent benefit in relapse reduction among women older than 55 years demonstrated in Dr. Coleman’s metaanalysis is impressive. It merits careful consideration and further study.

References 1. Powles T, Paterson A, McCloskey E, et al.

Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res. 2006;8:R13, PMID: 16542503.

2. Saarto T, Vehmanen L, Virkkunen P, et al.

Ten-year follow-up of a randomized controlled trial of adjuvant clodronate treatment in node-positive breast cancer patients. Acta Oncol. 2004;43:650-656, PMID: 15545185.

3. Coleman RE, Marshall H, Cameron D, et al.

Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med. 2011;365:13961405, PMID: 21995387.

4. Gnant M, Mlineritsch B, Schippinger W, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009;360:679-691, PMID: 19213681.

5. Bonadonna G, Valagussa P, Moliterni A, et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of followup. N Engl J Med. 1995;332:901-906, PMID: 7877646.

6. Paterson AH, Anderson SJ, Lembersky BC, et al. Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo-controlled, randomised trial. Lancet Oncol. 2012;13:734742, PMID: 22704583.

What are your thoughts?

Clinical Oncology News welcomes letters to the editor.

Do you have thoughts on Dr. Vogl’s commentary?

Please send comments to gmiller@mcmahonmed.com

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CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • MARCH 2014 • CLINICALONCOLOGY.COM

How I Manage ...

Essential Thrombocythemia E

ssential thrombocythemia (ET) is classified by the World Health Organization (WHO) as a myeloproliferative neoplasm (MPN) and carries risk for thrombosis, symptomatic burden and potential progression to either myelofibrosis or acute myeloid leukemia (AML). A systemic approach to accurate diagnosis is key as there are many causes of thrombocytosis, both clonal and benign. After an accurate diagnosis of ET, it is pivotal to risk-stratify patients with the goal of reducing the rates of vascular events and alleviating the symptomatic burden. All non–aspirin-allergic patients with ET should be managed with aspirin, and in certain circumstances targeted cytoreduction is required, especially in patients with high-risk disease. Hydroxyurea (HU), anagrelide and interferon-alpha (IFNα) α are important therapeutic options for patients with ET, with their selection and dose generally individualized. Front-line therapy for patients with ET could include either HU or IFNα, and at the moment, this question is the subject of a large international Phase III study. Future therapeutic opportunities include novel agents such as JAK2 and telomerase inhibitors.

How do I approach patients with thrombocytosis?

Thrombocytosis can be a common medical finding with a variety of potential secondary causes including iron deficiency, tissue trauma, prior burns, recent surgery or prior splenectomy. Your first decision is whether the patient seems to have a secondary thrombocytosis or thrombocytosis related to a bone marrow disorder.

Next, among the bone marrow disorders, there are many potential different causes besides ET such as chronic myeloid leukemia, polycythemia vera (PV), primary myelofibrosis, chronic myelomonocytic leukemia (CMML), myelodysplastic syndromes and MPN overlap syndromes. In a patient with undiagnosed thrombocytosis in which an MPN is suspected, it is essential that a bone marrow exam be done for histologic analysis of the marrow, assessment of cytogenetics, baseline karyotype, reticulin fibrosis and assessment of blasts.

Indeed, exclusion of CMML, and refractory anemia with ringed sideroblasts and thrombocytosis, is important. In parallel with the marrow, it is important to obtain molecular mutation analysis. The JAK2 V617F mutation is the most prevalent in patients with essential thrombocythemia.1 Additionally, the recently described calreticulin mutation (CALR) is observed in the majority of patients with JAK2 V617F wild-type ET, and an assay is now available to be used as an important part of the diagnostic workup.2 The third molecular marker, which can be obtained in the absence of JAK2 V617F and CALR mutations, is an MPL mutation present in 1% to 5% of patients with ET.3 Finally, it is important to be certain, based on histology and WHO criteria, that the patient is most accurately characterized as having ET and not an early form of primary myelofibrosis, which can occur without significant fibrosis or splenomegaly.4

What are the risk factors for vascular events in patients with ET? Management of ET really flows from establishing important goals, whether they are to reduce the risk for vascular events, improve symptomatology, delay disease progression or any combination of the above. Risk for vascular events has been studied in retrospective studies in a variety of venues; probably the strongest individual risk factor is a prior vascular event. Vascular events can present in a number of manners, ranging from thrombosis to hemorrhage. Thrombosis may occur in a larger vessel presenting as myocardial infarction or a cerebrovascular accident, or as deep venous thrombosis in the leg, the portal system or the lungs. Increasing age is also a risk factor for vascular events; however, this might be a surrogate marker for comorbidities.

Additional factors include strong cardiovascular risk factors such as significant hypertension, hypercholesterolemia and diabetes. Finally, extreme thrombocytosis, with values greater than 1,500 × 109/L can be associated with an increased risk for hemorrhage. However, it is difficult to precisely quantify this risk. The International Prognostic Score for ET risk model was generated based on retrospective data and has found these factors, as well as potentially leukocytosis, to be relevant in terms of vascular events.5 Finally, an increased risk in vascular events has been seen in certain series among individuals who have JAK2 V617F mutated ET compared with those with wild-type JAK2 disease.6 It is premature to discuss the prognostic implications of CALR mutations in patients with ET.2

What does symptomatic burden imply in patients with ET? Patients with ET have symptoms that

range from fatigue, itching, difficulties with concentration, microvascular symptoms to the spectrum of symptoms we associate with myelofibrosis, such as weight loss, bone pain and night sweats.

Using an Internet-based approach, in 2007 we set out to determine whether patients with MPNs were very symptomatic; this included patients with ET.7 We developed the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF), which to date has been used in almost 2,000 patients and has identified a significant symptomatic burden among subsets of patients with ET, with fatigue and microvascular symptoms being prevalent.8 Subsequently, through cluster analysis we identified that there are significant groups of patients with ET that have a symptomatic burden that is not alleviated by current therapies.9

Why is it important to assess the symptomatic burden of disease in patients with a diagnosis of ET? Assessing the symptomatic burden in the patient with ET is important, however it is equally important to periodically assess the reponse to therapy.

Again, the MPN-SAF is an excellent tool for this purpose; a baseline assessment and any subsequent changes can be used to optimize therapy, consistent with European LeukemiaNet (ELN) guidelines for the response for patients with ET. Similarly, as we look at management for patients with ET, control of their symptomatic burden should be an important part of treatment goals.

What is the most commonly prescribed aspirin dose in patients with ET? The ECLAP (European Collaboration on Low-dose Aspirin in Polycythemia

Ruben A. Mesa, MD Chair, Division of Hematology and Medical Oncology Deputy Director, Mayo Clinic Cancer Center

Vera) study suggests that individuals with a higher risk for PV benefit from low-dose aspirin—in ECLAP the dose was 100 mg per day, although it has been suggested, based on laboratory studies, that the 81 mg per-day regimen would be relatively equivalent in terms of effectiveness.10 This evidence has been extrapolated to ET, and the current ELN guidelines for management of ET suggest that all patients should be on a baby aspirin if they are not aspirinallergic.11 Presently, the data are lacking regarding alternative antiplatelet therapy such as clopidogrel in patients with ET, although certainly it has been used anecdotally for patients without any clear signal of toxicity.

Which patients with ET require cytoreduction?

In my practice, cytoreduction is used for individuals who clearly have highrisk disease, those who have had prior disease-associated events and those who have a significant symptomatic burden that seems related to their platelet count.

Put differently, I avoid cytoreduction in individuals with low-risk asymptomatic disease, particularly if they are of a younger age. If cytoreduction is chosen, my goal for therapy typically is to normalize the platelet count, unless there is an unacceptable toxicity that cannot be overcome in trying to achieve this particular goal. It has been demonstrated that events can still occur in individuals with partial control of their platelet count (i.e., maintained between 450 and 600 × 109/L).

The three front-line therapies for ET are HU, anagrelide and IFNα. HU, when tested in a randomized study against placebo, was superior for high-risk disease and decreasing the risk for vascular events in patients with ET.12 Anagrelide

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • MARCH 2014 • CLINICALONCOLOGY.COM

was approved for the control of thrombocytosis on the basis of single-arm studies. A randomized study of HU versus anagrelide (PT-1 trial), both in the setting of baby aspirin, showed that HU was superior in terms of rates of arterial events, hemorrhage and movement toward myelofibrosis.13 Anagrelide was superior in decreasing the risk for venous events.

HU has limitations that include myelosuppression, mouth and leg ulcers, and increased skin cancers, among other toxicities. Anagrelide can cause vasomotor toxicities, headaches and gastrointestinal disturbances. All things being equal, HU is a preferred front-line therapy and in most cases anagrelide should be reserved as second-line therapy following the failure of HU. IFNα and both long-acting forms of IFNα—pegylated IFN (PEGIFN)-α2a and PEG-IFN-α2b—have shown activity in controlling counts, decreasing risk for vascular events and potentially decreasing fibrosis in individuals with PV.14 Data are limited in patients with ET, although these largely have been positive.15 An important clinical trial is currently under way through the MPD Research Consortium, MPDRC Clinical Trial 111 (Clinicaltrials.gov: NCT01259817), that is randomizing patients to either PEG-IFN-α2a or HU to determine the most efficacious, safest, best tolerated and most effective front-line therapy, in terms of reducing symptom burden for patients with ET. I try to refer patients to this important clinical trial if they have not yet been treated. Anagrelide remains a very helpful therapy and is most often

cytopenias, and increasing blasts in the peripheral blood and the marrow.

Choice and efficacy of therapy for each of these types of progression are in line with management of those individual conditions. Patients who are starting to develop these changes but have not yet reached the diagnostic threshold of either myelofibrosis or AML may still be appropriate candidates for clinical trials or other medication to help delay disease progression. For those moving in the progressive nature from ET to postET myelofibrosis, we will at least consider whether there might be a benefit from IFNα. For those moving progressively from ET to post-ET myelofibrosis, we will consider whether there might be a benefit from IFNα, and allogeneic transplantation should be considered in appropriately selected individuals.

Hematoxylin and eosin stain of bone marrow aspirate in a patient with essential thrombocythemia.

used in my practice for patients who have been intolerant to HU, or IFN, or in combination with either of these two therapies to assist with further targeted cytoreduction.

After front-line therapy for ET fails, what next?

Second-line therapy in ET depends on the results reached with the front-line choice, with the key goals being to prevent vascular events as platelet counts normalize and to delay disease progression. For individuals who have failed all three drugs, clinical trials are a very reasonable consideration. In the experimental space, options include JAK2

AT A GLANCE •

• •

Essential thrombocythemia needs to be distinguished from other chronic myeloid neoplasms and reactive causes of thrombocytosis.

Low-dose aspirin is beneficial across the spectrum of patients with ET, except those who are aspirin-allergic.

HU and IFNα are the preferred front-line therapeutic options for patients with ET.

•

Anagrelide is a helpful therapy frequently used in combination with HU, or as second-line after HU failure.

•

Management of the symptomatic burden is frequently an unmet need in patients with ET.

•

JAK2 inhibitors have demonstrated activity in patients with ET, but to date have not been very successful in acting as monotherapy for control of thrombocytosis.

•

Early studies of telomerase inhibition are promising in patients with ET.

inhibitors and the telomerase inhibitor, imetelstat (Geron). Both of these classes of drugs have demonstrated activity in ET. Alternatively, other options include myelosuppressive drugs such as busulfan; however, the cost is a slightly inferior long-term safety profile compared with front-line therapy. That being said, if the risk for vascular events is very high in the short term, these other long-term risks associated with alkylator therapy may still be worthwhile.

In patients with intolerance to HU from neutropenia, there can be opportunities to combine HU and anagrelide in a way that can be better tolerated by patients. I find very few patients with ET (i.e., >2,000 × 109/L) to be tolerant of a single drug at the doses necessary for adequate control.

How do you suspect and approach patients with progression to primary myelofibrosis or AML? The long-term management of ET requires close observation for the potential of progression. In general, progression occurs in a minority of ET patients.

Certainly less than 50% of patients progress; depending on their age, life expectancy and comorbidities, the rate could be as low as 10% to 15%. There are two main pathways of progression, but they can have different phenotypes. First, the progression to post-ET myelofibrosis is accompanied by progressive weight loss; increased symptomatology; progressive decrease in the blood counts; progressive decrease in toleration for the current dose of cytoreduction; and the development of medullary histologic changes, such as increasing fibrosis and megakaryocytic changes.16 The potential progression toward blast-phase MPN or AML is associated with an increase in cytogenetic abnormalities, progressive

References 1. Nature. 2005;434(7037):1144-1148, PMID: 15793561.

2. N Engl J Med. 2013;369:2379-2390, PMID: 24325356.

3. Blood. 2006;108:3472-3476, PMID: 16868251.

4. Blood. 2009;114:937-951, PMID: 19357394.

5. Blood. 2012;120:5128-5133, PMID: 23033268.

6. Leukemia. 2005;19(10):1847-1849, PMID: 16079890.

7.

Cancer. 2007;109:68-76, PMID: 17123268.

8. Blood. 2011;118:401-408, PMID: 21536863.

9. J Clin Oncol. 2012;30:4098-4103, PMID: 23071245.

10. N Engl J Med. 2004;350:114-124, PMID: 14711910.

11. J Clin Oncol. 2011;29:761-770, PMID: 21205761.

12. N Engl J Med. 1995;332:1132-1136, PMID: 7700286.

13. N Engl J Med. 2005;353:33-45, PMID: 16000354.

14. Blood. 2008;112:3065-3072, PMID: 18650451.

15. J Clin Oncol. 2009;27:5418-5424, PMID: 19826111.

16. Leuk Res. 2007;31:737-740, PMID: 17210175.

Series Editor Syed Abutalib, MD Assistant Director, Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America, Zion, Illinois

Coming Soon How I Manage Lymphoma Following Autologous Transplantation

by Michael R. Bishop, MD University of Chicago

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REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • MARCH 2014 • CLINICALONCOLOGY.COM

Expert Insights From City of Hope Each month, Clinical Oncology News summarizes findings from several recently published, important studies and then asks clinicians from a top 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.

This month we continue with City of Hope. We believe that you will find this Reviews & Commentaries section, both here and with additional commentaries at ClinicalOncology.com, to be a valuable tool.

HER2 Status Prompts Different Stereotactic Radiosurgery Response From Medical Oncology

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atients with HER2-positive breast cancer who were treated with stereotactic radiosurgery (SR) for brain metastases experienced a shorter time to disease progression but had a better overall survival (OS) rate than patients with HER2-negative breast cancer.

Trastuzumab (Herceptin, Genentech), a monoclonal antibody targeting the HER2 receptor, has been successful as adjuvant therapy for the treatment of breast cancer in certain patients. Previous

studies have indicated that patients with HER2-positive breast cancer are at higher risk (by as much as 50%) for brain metastases. The authors of this study, all from New York University Cancer Institute, New York City, compared outcomes of 29 HER2-negative and 28 HER2-positive patients with breast cancer who underwent SR as initial treatment for limited brain metastases. Results of the study, headed by Moses Tam, MD, were published in Medical Oncologyy (2014;31:832835; PMID: 24390418).

Median follow-up was 11.0 months.

EXPERT INSIGHT Rahul Jandial, MD, PhD Co-director, Spine Tumor Program Assistant Professor Division of Neurosurgery, Department of Surgery City of Hope Duarte, California

M

olecular therapies have extended the length and quality of life for patients with breast cancer. In parallel, there has been the unmasking of brain metastases as a point of clinical relapse and as the frontier for opportunities to further improve outcomes for women with breast cancer.

The brain poses unique challenges

that require new drug candidates to traverse the blood–brain barrier; avoid off-target effects on the central nervous system; and potentially work with the current standard-ofcare radiation therapy and, on occasion, neurologic surgery.

Whole-brain radiation is gradually being replaced with radiosurgery to

Time to progression in the HER2-positive group compared with the HER2negative group was seven versus 11 months ((P=0.080). In the HER2-positive group, 14 of 28 patients required additional salvage treatment; six of 29 in the HER2-negative group required additional radiation therapy. Freedom from disease progression at six months and 12 months for patients in the HER2positive group was 64.1% and 36.0%, and for patients in the HER2-negative group was 69.7% and 44.2%, respectively.

The median OS for the HER2-positive

group compared with the HER2-negative group was 22 versus 12 months ( =0.053). OS for patients in the HER2(P positive group at one and two years was 64.7% and 41.6%, and for patients in the HER2-negative group was 48.7% and 14.2%, respectively.

This study showed SR to be an effective treatment for both HER2-positive and HER2-negative disease. There were increased relapses of brain metastatic disease in the HER2-positive group, yet paradoxically those patients showed superior OS.

Increasingly we are finding that brain metastases of breast origin cannot be considered a homogeneous biological entity in terms of radiosurgical response. control brain metastases that are typically smaller than 3 cm and not too numerous (typically, but not strictly, numbering less than four). Focused radiation to the tumor, thus sparing the normal brain from radiosurgery, is better tolerated clinically; can be used on the surgical bed after resections; and in some cases is more effective than whole-brain radiation on radioresistant tumors. Increasingly we are finding that brain metastases of breast origin cannot be considered a homogeneous biological entity in terms of

radiosurgical response. Patients with HER2-positive breast cancer are more likely to develop brain metastases and, based on the data presented by Tam et al, may respond less well to radiosurgery. Future analysis of breast cancer brain metastases stratified based on histology, prior resection or radiation and cranial location should help refine radiosurgical patient selection and surveillance.

Dr. Jandial reported no relevant financial disclosures.

More REVIEWS and COMMENTARIES from City of Hope Find additional, Web-exclusive expert commentaries on important published studies at

ClinicalOncology.com

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • MARCH 2014 • CLINICALONCOLOGY.COM

To Biopsy or Not? Evaluating Three Thyroid Nodule Characteristics From JAMA Internal Medicine

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n analysis has concluded that three characteristics of thyroid nodules found on ultrasound can better identify patients with a low risk for cancer, thereby sparing them a biopsy procedure.

Rebecca Smith-Bindman, MD, and her colleagues undertook a retrospective analysis of patients who had undergone thyroid ultrasound. The authors examined 8,806 patients who had previously had 11,618 consecutive thyroid sonograms, and identified predictors of thyroid cancer.

Using data from the California Cancer

Registry, the authors identified 105 patients who subsequently were diagnosed with thyroid cancer; 369 other patients were used as controls.

Thyroid nodules are quite common; their presence often leads to biopsy when the risk for cancer is possible, although small. Nodules were present in 96.9% of patients found to have cancer and 56.4% of those who did not have thyroid cancer. This study also found that only 1.6% of those with one or more nodules larger than 5 mm harbored cancer. In their report ((JAMA Intern Med 2013;173:17881796, PMID: 23978950), the authors described the following three

EXPERT INSIGHT John Hosei Yim, MD Associate Professor of Surgery Division of Surgical Oncology, Department of Surgery City of Hope Duarte, California

I

n the present study, “Risk of Thyroid Cancer Based on Thyroid Ultrasound Imaging Characteristics, Results of a Population-Based Study,” Dr. Smith-Bindman and her colleagues advocate basing biopsy of thyroid nodules on only three ultrasound imaging characteristics—microcalcifications, size larger than 2 cm and entirely solid composition. The key piece of data for which recommendations are made, some alarming, is that only two of 1,000 patients who had none of the three characteristics identified had thyroid cancer, based on the California Cancer Registry.

It is irresponsible to advocate that imaging surveillance not be performed in patients with nodules that do not meet these simple criteria for biopsy. Any physician who has followed enough patients by ultrasound imaging surveillance of thyroid nodules that do not have microcalcifications, are smaller than 2 cm, and are

not completely solid has had patients who have had thyroid cancer, both on initial biopsy and in follow-up. Yet the implications of this study are that 500 such patients would need to have been seen before this situation would be found. Why the discrepancy? The easiest answer for this is cited in the invited commentary by Drs. Erik K. Alexander and David Cooper ((JAMA Intern Med 2013;173:1796-1797, PMID: 23979653)—the prevalence of thyroid cancer in a population of consecutively evaluated nodules approximates 8% to 15% in other studies while the prevalence in this study was only 1.6%.

More subtle would be the significant numbers of patients with thyroid cancer that were missed in this study for which ultrasound-guided fine-needle aspiration of a thyroid nodule was not performed, which was noted by Drs. Alexander and Cooper.

With respect to comparing ultrasound with diagnostic testing for

characteristics, which were better indicators of thyroid cancer than the mere presence of nodules: microcalcifications (odds ratio [OR], 8.1; 95% confidence interval [CI], 3.8-17.3; P<0.001); size larger than 2 cm (OR, 3.6; 95% CI, 1.7-7.6; P=0.001); and an entirely solid composition (OR, 4.0; 95% CI, 1.7-9.2; P=0.001).

The authors speculated that restricting biopsies to patients who display at least two of these nodule characteristics would reduce the number of unnecessary thyroid biopsies by 90%. The risk for cancer in patients with only one of these characteristics is 18 per 1,000; with two

abnormal characteristics the risk increases to 62 per 1,000; and with all three characteristics, the cancer risk rises to 960 per 1,000.

The researchers concluded that the use of these three nodule characteristics could help identify patients for whom biopsy could be deferred because of their low risk for cancer, and suggest that their findings should be validated using a larger prospective cohort. Adopting uniform interpretation standards for thyroid sonograms will eliminate unnecessary biopsies, and will make progress toward standardizing diagnosis and treatment of thyroid cancer.

It is irresponsible to advocate that imaging surveillance not be performed in patients with nodules that do not meet these simple criteria for biopsy. breast cancer, the supposition that “often a risk of less than 1% or 0.5% is considered sufficiently low that further evaluation is deemed unnecessary” is a fallacy. Mammograms usually are performed with an expectation of a follow-up study regardless of the reading. The Breast Imaging Reporting and Data System (BIRADS) 1 and 2 readings are based on an expectation of a benign biopsy, obviating the need for performing the biopsy. A BIRADS 3 reading carries with it an up to 2% risk for malignancy, for which a follow-up study, usually in three to six months, is recommended, but in no instance would further evaluation be deemed unnecessary.

So how does this study affect the practice of thyroid nodule imaging and biopsy? The American Thyroid Association (ATA) recommends biopsy of nodules based on risk history, clinical characteristics, ultrasound characteristics and size. In general, thyroid nodules that are larger than 1 to 1.5 cm and are not purely cystic or spongiform should be biopsied. In the

presence of multiple nodules, ultrasound characteristics should predominate, but in the absence of suspicion it is reasonable to biopsy the dominant nodule(s).

Perhaps the greatest contribution of this study was to point out the ultrasound characteristics that are suspicious, with degree of suspicion based on OR (in parentheses): microcalcifications (11.6), coarse calcifications (2.1), entirely solid composition (2.0), echogenicity hypoechoic to strap muscle (2.9), halo (2.0), ill-defined or lobulated margins (2.0) and shape taller than wide (2.3). Size should be considered independently because it is not an ultrasound characteristic.

The ATA guidelines state that, based on risk history and clinical characteristics, these suspicious ultrasound features should be evaluated to consider biopsying these nodules, and even to consider biopsying nodules of smaller size without these features.

Dr. Yim reported no relevant financial disclosures.

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REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • MARCH 2014 • CLINICALONCOLOGY.COM

Web-Based Questionnaire Improves Levels of Patient Distress From Journal of Clinical Oncology

C

ancer patients enrolled in a webbased self-reported symptom and quality-of-life (SxQoL) questionnaire benefited when the program included education and intervention modules.

Patients undergoing treatment at the Fred Hutchinson Cancer Research Center in Seattle and Dana-Farber Cancer Institute in Boston enrolled in a study that assessed outcomes for 15 cancer symptoms and QoL issues (Symptom Distress Scale [SDS-15]).

Patients could access the survey using

their home computer or using computers available at the treatment centers.

In the control group (n=378), questions were answered at baseline and at three points during treatment; result summaries were given to the treating physicians. In the intervention group (n=374), patients answered online questions at the same time intervals; in addition, they could access the program and self-report at any time. Based on these responses, education and intervention tips would be displayed, including why and how this issue typically occurs, what can be done to

EXPERT INSIGHT Matthew J. Loscalzo, LCSW Liliane Elkins Professor, Supportive Care Programs Administrative Director, Sheri & Les Biller Patient and Family Resource Center Executive Director, Department of Supportive Care Medicine Professor, Department of Population Sciences City of Hope Duarte, California

T

he Berry et al trial is one of a number of published studies that drives home the growing interest in patient-reported outcomes (PROs) and provides data supporting its importance. Information provided by patients has traditionally been interpreted with the healthy skepticism that is one of the strengths of scientific medicine, but it also creates a trust barrier that has been in plain sight for so long that the process has become invisible. PROs have the potential to transform medicine as patients and their families begin to redefine performance outcomes that are most relevant to them. Although the use of the technology is innovative in this study, the experience and data gleaned are heuristic, which is an important contribution.

There are two main areas of significance to this report that can be useful in planning future studies and in the translation to ongoing cancer care: the usefulness and limitations of patientfriendly automated technologies, and

the value of the data and its real-time connections to services.

The ability of patients to provide ongoing health information from wherever they are is a laudable goal, but to date most systems are passive and patients are only able to access one-dimensional portals. The Berry et al study is beneficial in that this web-based automated program can be updated at home, between clinical encounters. This important advance, however, also brings into sharp relief what was alluded to but not addressed in the report: Even with this technology, there is an insidious chasm in linking PROs in real time to the professionals who are best able to help them—physicians and other health care staff. Coaching or prompting patients to talk with their physician and team, when there are PROs already identifying a serious problem (e.g., pain, depression, suicidal ideation, insomnia), seems to be the wrong message to give to patients, family caregivers and professional

alleviate it and how to address the issue with the clinical team.

In results published in the Journal of Clinical Oncology (2014;32:199-205; PMID: 24344222), Donna L. Berry, PhD, RN, and her co-authors discovered that patients who were enrolled in the control group had a mean change in their SDS-15 score, measured from baseline to the end of the study, of 1.27 (standard deviation [SD] 6.7; i.e., higher distress). Those enrolled in the intervention arm had a mean change in SDS15 score of –0.04 (SD, 5.8; i.e., lower distress). In the intervention group, mean

SDS-15 scores were reduced by 1.21 (95% confidence interval [CI], 0.232.20; P=0.02). The results were most striking for participants older than age 50 years ((P=0.002).

The authors speculated that older patients might especially benefit from coaching in communication and selfcare strategies. They noted that even a small increase or decrease in SDS-15 score reflects a noticeable intensity to patients. The interventions provided in this study added no time to clinic visits and engaged patients more fully in their own care.

This study is also important because it once again drives home the fact that patients have complex psychosocial and physical problems and that, even when they are identified, they may still go untreated. staff. Technology should be used to bring people closer together and not to create data that only has the illusion of communication, coordination and connection. In this situation, we may be asking cancer patients to do too much! The work of L.E. Carlson, PhD, and B.D. Bultz, PhD, in Canada (for instance, J Clin Oncol 2010;28:48844891, PMID: 20940193), as well as that of our own team at City of Hope, have made automated connections that link PROs with clearly assigned actionable items. Although we are not there yet, PROs will eventually be integrated into clinical care everywhere. Once this happens via technology and is linked to actionable items to be managed in new partnerships among professionals and patients, not only will quality be increased and costs be managed, but QoL will be improved for patients, their families and the overworked, committed medical staff.

This study is also important because it once again drives home the fact that patients have complex psychosocial and physical problems and that, even when they are identified, they may still go

untreated. All physical symptoms have negative psychological repercussions and the potential to increase health care costs via unnecessary admissions, lost time at work for patients and their family members, and decreased QoL. Caring professionals may have a lessthan-conscious awareness that their patients are suffering needlessly.

Finally, it is interesting to note that those patients who may have benefited most from the intervention were aged 50 years or older. This is important because of the misperception that technology is primarily for the younger generation—the data and our extensive clinical experience simply does not support this false assumption. It is time to use technology wisely as a bridge to cross the chasm that has separated patients from those in whom they put their trust and their lives.

Mr. Loscalzo and City of Hope license SupportScreen, a biopsychosocial screening instrument for which Mr. Loscalzo and City of Hope receive fees and royalties from external institutions.

Harnessing the Immune System in NSCLC Implications of Emerging Data and Immunotherapeutic Strategies for Personalized Medicine To participate in this FREE CME activity, log on to

Release date: October 1, 2013

www.CMEZone.com

Expiration date: September 30, 2014

Editor

TARGET AUDIENCE

Suresh S. Ramalingam, MD

The target audience for this activity is medical oncologists, hematology/oncology fellows, oncology specialty pharmacists, and other health care professionals involved in the management of individuals with nonsmall cell lung cancer (NSCLC).

Professor of Hematology and Medical Oncology Director, Division of Medical Oncology Emory University School of Medicine Winship Cancer Institute Atlanta, Georgia

EDUCATIONAL OBJECTIVES At the conclusion of this activity, participants should be able to:

Faculty Julie R. Brahmer, MD

1 Review fundamental concepts of antitumor immune responses in NSCLC.

Associate Professor Johns Hopkins University School of Medicine Baltimore, Maryland

2 Evaluate key efficacy and safety data from ongoing clinical trials evaluating immunotherapeutic strategies for NSCLC, including tecemotide (formerly known as L-BLP25), belagenpumatucel-L, melanoma-associated antigenA3 (MAGE-A3) vaccine, immune checkpoint inhibitors, toll-like receptor agonists, and mycobacterial adjuvant-based agents.

John Nemunaitis, MD Executive Medical Director Mary Crowley Cancer Research Centers Dallas, Texas

Roman Perez-Soler, MD Professor of Medicine Chair, Department of Oncology Montefiore Einstein Center for Cancer Care Chief, Division of Medical Oncology Department of Medicine Deputy Director Albert Einstein Cancer Center Bronx, New York

3 Identify effective immunotherapeutic strategies for early- and advanced-stage NSCLC based on patient and disease characteristics.

4 Recall the ongoing clinical trials evaluating immunotherapeutic approaches for NSCLC to aid appropriate patients for study participation.

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CLINICAL ONCOLOGY NEWS • MARCH 2014 • CLINICALONCOLOGY.COM

Prepared by

Syed A. Abutalib, MD

Clinical Conundrums NEJM, JCO, Blood and highlights of oral abstracts from ASH 2013—Part III

4. True

or False.

In a study published in Blood, elevated levels of plasma CXCL9 predicted the onset of chronic graft-versus-host disease (cGVHD) in recipients of allo-HCT.

QUESTIONS

1. True

or False.

On Feb. 12, 2014, the FDA granted accelerated approval to ibrutinib (Imbruvica, Pharmacyclics) for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.

5. True or False. In a

study published in Blood, elderly men have a better outcome than elderly women and more favorable rituximab pharmaTrue or False. In Primum non nocere. cokinetics than all othpatients with high-risk (First, do no harm.) er patients with diffuse myelodysplastic syndrome (MDS), the role of cytoreductive large B-cell lymphoma (DLBCL). therapy before allogeneic hematopoietAll of the following can cause ironic cell transplantation (allo-HCT) is still deficiency anemia (IDA) except: unknown. a. Achlorhydric gastric atrophy b. Active Helicobacter pylori infection True or False. The UKALLXII/ c. Celiac disease ECOG2993 imatinib (Gleevec, Novartis) d. Ascorbic acid intake study conclusively demonstrates that adding imatinib to therapy for patients with Philadelphia chromosome–posiTrue or False. In a study pubtive acute lymphoblastic leukemia (Ph+ lished in Blood, early evaluation of minALL) can obviate the need for allo-HCT imal residual disease (MRD) in NPM in transplant-eligible patients. (nucleophosmin)-ALK (anaplastic (

2.

6.

3.

7.

ANSWERS

1.

True. The most common adverse reactions reported in the CLL clinical trial (occurring in ≥20% of patients) were thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis and dizziness. The recommended dose and schedule of ibrutinib for patients with CLL is 420 mg (three 140-mg capsules) taken orally once daily.

being disease-free at three years. Currently, the data does not support the omission of allo-HCT for treatment of Ph+ ALL despite incorporation of tyrosine kinase inhibitors (i.e., imatinib) in the front-line setting.

Fielding AK, Rowe JM, Buck G, et al. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia.

Blood. 2014;123:843-850, PMID: 24277073.

4. True. CXCL9 is an interferon-γ–γ

lymphoma kinase)–positive anaplastic large cell lymphoma (ALCL) identifies patients with a very high relapse risk and inferior survival.

8. True or False. Posaconazole is

only available in liquid form for patients with hematologic malignancies with prolonged chemotherapy-induced neutropenia and hematopoietic cell transplant recipients with GVHD.

9. True or False. In a study published in The New England Journal of Medicine, idelalisib (Gilead), a well-tolerated oral agent showed activity in heavily pretreated follicular lymphoma (FL).

10. True or False. A study pub-

lished in the Journal of Clinical Oncology analyzed approximately 3,000 patients with CLL and showed that the presence of CD49d is associated with inferior overall survival (OS).

ASH 2013 Oral Abstracts: Highlights—Part III

11. True or False. Hematopoiet-

ic cell transplantation: A retrospective

Such trials should be feasible because of rituximab’s large therapeutic window, in which no significant increase in toxicity has been observed with single doses up to 2,250 mg/m2 (in patients with CLL).

Pfreundschuh M, Müller C, Zeynalova S, et al. Suboptimal dosing of rituximab in male and female patients with DLBCL. Blood. 2014;123:640646, PMID: 24297867.

O’Brien SM, Kantarjian H, Thomas DA, et al.

Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol. 2001;19:2165-2170, PMID: 11304768.

of cytoreductive therapy while awaiting allo-HCT, especially for patients with blast counts between 10% and 15%.

inducible chemokine that binds to CXCR3, its only known receptor. The investigators of this study noted that the clinical utility of CXCL9 as a biomarker for cGVHD needs to be further defined in future studies. In addition, they noted that future investigations should include prospective and serial evaluations of CXCL9 to further define its clinical utility, potentially as a predictive biomarker prior to the onset of cGVHD.

or refractory IDA, screening for celiac disease, autoimmune gastritis, Helicobacter pylori and hereditary forms of IDA is recommended. In young patients with a history suggestive of hereditary iron deficiency with serum ferritin level higher than expected for IDA, mutations involving iron transport and regulation should be considered.

Sekeres MA, Cutler C. How we treat higher-risk myelodysplastic syndromes. Blood. 2014;123:829836, PMID: 24363399.

Kitko CL, Levine JE, Storer BE, et al. Plasma CXCL9 elevations correlate with chronic GVHD diagnosis. Blood. 2014;123:786-793, PMID: 24363401.

Hershko C, Camaschella C. How I treat unexplained refractory iron deficiency anemia. Blood.

2014;123:326-333, PMID: 24215034.

5.

7. True. This is the first observation

American Society of Hematology. FDA approves ibrutinib to treat chronic lymphocytic leukemia. Feb.12, 2014. http://www.hematology.org/ News/2014/12382.aspx. Accessed February 12, 2014.

2. True. Most experts offer some form

3.

False. The UKALLXII/ECOG2993 imatinib study conclusively demonstrates that adding imatinib to therapy for patients with Ph+ ALL improves overall outcomes compared with the historical UKALLXII/ECOG2993 preimatinib study, with over half of patients

False. Elderly women have a better outcome than elderly men, and more favorable rituximab pharmacokinetics, than all other patients with DLBCL. Well-designed prospective trials aimed at optimizing rituximab dose and schedule are warranted in all DLBCL patients.

6. D. In patients with unexplained

of the prognostic impact of MRD measured early—after three weeks of chemotherapy—during treatment in ALKpositive ALCL. It is important to note that patients were treated between 1998 and 2008 with protocols used in the

Assistant Director Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

Australian study showed no adverse effect on neutrophil and platelet recovery or OS resulting from the retrieval of hematopoietic progenitor cells (bone marrow [BM] and peripheral blood progenitor cells [PBPC]) from collection centers with transit times in excess of 24 hours and with some international retrievals requiring up to 90-hour transit times.

12.

True or False. Hematopoietic cell transplantation: The NCIC CTG LY.12 evaluation of rituximab maintenance every two months for one year after autologous HCT (auto-HCT) for aggressive lymphoma showed improved event-free survival (EFS) compared with observation.

13.

True or False. Hematopoietic cell transplantation: A retrospective study showed that transplant-eligible patients with high-risk MDS should proceed directly to allo-HCT.

Berlin-Frankfurt-Münster 95, Linfomi Non-Hodgkin 97, or ALCL 99 trials (Italian and German patients).

Damm-Welk C, Mussolin L, Zimmermann M, et al. Early assessment of minimal residual disease identifies patients at very high relapse risk in NPM-ALK–positive anaplastic large-cell lymphoma. Blood. 2014;123:334-337, PMID: 24297868.

8. False.

The FDA has approved posaconazole delayed-release tablets for the prophylaxis of invasive Aspergillus and Candida infections in patients at high risk for these infections, such as those with hematologic malignancies with prolonged chemotherapy-induced neutropenia and HCT recipients with GVHD. Food and Drug Administration. Product Information Noxafil. November 2013. http://www.accessdata. fda.gov/drugsatfda_docs/label/2013/205053s000lbl. pdf. Accessed February 12, 2014.

9. True. Phosphatidylinositol-3-kinase delta (PI3Kδ) δ mediates B-cell receptor signaling and microenvironmental support signals that promote the growth and survival of malignant B lymphocytes. In this single-group, open-label, Phase II study, 125 patients with indolent non-Hodgkin lymphomas who had not had a response to rituximab and an alkylating agent or had a relapse within six months after receiving those therapies, were administered idelalisib, 150 mg twice daily, until disease progression or the patient withdrew from the

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • MARCH 2014 • CLINICALONCOLOGY.COM

HCT continued from page 1

The association between HCT and cognitive impairment has been demonstrated repeatedly, but the new data provides strong evidence that the risk for cognitive loss is decreased if the intensity of the conditioning of HCT is reduced, according to Alysia Bosworth, a clinical research coordinator in the Department of Population Sciences at City of Hope in Duarte, Calif., who presented the study at the 2013 annual meeting of the American Society of Hematology (ASH).

Given the potentially higher risk for relapse with reduced-intensity conditioning, the improvement in cognitive function could be seen as a tradeoff, but the data from this prospective study—one of the largest to date to evaluate the effect of HCT on cognitive function—at least confirms that the intensity of the conditioning regimen is a factor in cognitive adverse effects.

“These data indicate that full-intensity conditioning for transplant drives the cognitive impairment, but more data are still needed to understand the pathogenesis,” said Smita Bhatia, MD, who is the chair of City of Hope’s Department of Population Sciences and a co-author of the study.

In the study, 242 patients scheduled for HCT and 98 healthy controls

The study suggests a trade-off: Reduced-intensity allogeneic hematopoietic cell transplantation may reduce the risk for cognitive dysfunction, but it also increases the likelihood of relapse. were evaluated with a two-hour battery of standardized neurocognitive tests evaluating function in eight domains, including executive function, processing speed, verbal fluency and working memory. The cognitive tests were repeated six months, one year and two years after HCT in the patients and at the same intervals in the age- and gender-matched controls. At a follow-up of two years, data was available for 125 of the HCT patients and 45 of the controls.

When HCT recipients were compared with controls without regard to conditioning regimen, significant differences were observed in executive function, processing speed, verbal fluency and fine motor dexterity but not in any of the memory domains, such as working or visual memory. The impairments were already present at six months and persisted over the course of follow-up. For example, the highly significant difference ((P=0.0008) in executive function scores between transplant patients and controls persisted throughout the follow-up period.

In contrast, patients treated with reduced-intensity conditioning did not demonstrate the same post-transplant decline observed after full-intensity

conditioning. Scores for executive function, processing speed, verbal speed and visual memory in these patients did not differ significantly from those in controls, but were significantly superior to scores in those who had received fullintensity HCT ((P<0.01 for all) over the two years of follow-up (Figure).

The ages of the patients in this trial ranged from 19 to 71 years, with a median of 49 years. Approximately 60% were men. The most common underlying diseases were acute leukemia and myelodysplastic syndromes, found in 69% of patients. Slightly less than half received full-intensity conditioning. Almost 60% received a transplant from an unrelated donor.

As part of a study design to evaluate the pathogenesis of cognitive loss, baseline telomere length was evaluated in 142 of the HCT patients. Telomere length was shown previously to be a marker of cognitive aging, and chemotherapy and telomeric attrition have been linked. The analysis produced mixed results: Significant shortening of telomeres before HCT was associated with poor cognitive function in women but not in men.

According to Dr. Bhatia, more data is

needed to understand this gender difference and to identify other markers of risk for cognitive loss.

Jeffrey Miller, MD, the associate director of experimental therapeutics at the University of Minnesota in Minneapolis, said this data is reassuring for the older patients most likely to receive reducedintensity conditioning HCT. However, he outlined the complexity of incorporating the results into clinical decisions.

“Reduced-intensity conditioning is allowing us to perform transplants in older patients,” Dr. Miller noted, but “how do we tie together this decision making regarding reduced-intensity conditioning, which gives us a higher rate of relapse, with the reduced risk of cognitive impairment we see in these data?”

In general, he suggested that the opportunity for durable remissions will be a more important consideration for patients who are eligible for a more aggressive conditioning regimen, but he said the risk for cognitive loss may lead some patients—particularly those who already have a cognitive deficit—to consider reduced-intensity conditioning when eligible for either. This data provides an evidence base for that discussion, he said.

—Ted Bosworth Drs. Bosworth, Bhatia and Miller reported that they have no relevant conflicts of interest.

55

T-score

Healthy controls P=0.13

50 Reduced-intensity HCT recipients

P=0.01

45 Full-intensity HCT recipients

Figure. Executive function following hematopoietic cell transplantation.

HCT, hematopoietic cell transplant

study. The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months; the median duration of response was 12.5 months; and the median progression-free survival was 11 months.

Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014 Jan 22. [Epub ahead of print], PMID: 24450858.

10. True. Patients with ≥30% of neoplastic cells expressing CD49d

were considered CD49d-positive. The decrease in OS at five and 10 years among CD49d-positive patients was 7% and 23%, respectively, and the decrease in treatment-free survival was 26% and 25%, respectively.

Bulian P, Shanafelt TD, Fegan C, et al. CD49d is the strongest flow cytometry-based predictor of overall survival in chronic lymphocytic leukemia. J Clin Oncol. 2014 Feb 10. [Epub ahead of print], PMID: 24516016.

11. True. Product should be main-

tained at a temperature between 2 o and 8oC.

Hutchins CJ, Butler JP, McLean A, et al.

Prolonged transportation time of haemopoietic progenitor cells does not impact upon engraftment or overall survival following allogeneic voluntary unrelated donor transplantation. ASH Annual Meeting Abstracts. Blood. 2013;122:694.

A randomized trial of rituximab vs observation following autologous stem cell transplantation (ASCT) for relapsed or refractory CD20positive B cell lymphoma: Final results of NCIC CTG LY.12. ASH Annual Meeting Abstracts. Blood.

2013;122:155.

True. These data need to be 12. False. This evaluation of every- 13. confirmed in larger, prospective clintwo-month rituximab maintenance for one year after auto-HCT for aggressive lymphoma failed to meet the study end point of improved EFS compared with observation.

Crump M, Kuruvilla J, Kouroukis CT, et al.

ical trials.

Oran B, Kongtim P, de Lima M, et al. Prior hypomethylating agents or chemotherapy does not improve the outcome of allogeneic hematopoietic transplantation for high-risk MDS. Blood.

2013;122:305. ■

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