UPDATES IN CANCER FOR CLINICIANS

WINTER 2014

Progress in Hematologic Cell Transplantation

has been associated with lower myeloid leukemia in first remission.1 rates of relapse in acute myeloid With a median follow up of leukemia and better overall surviving patients exceeding five outcomes. These studies utilized years, the non-relapse mortality fixed oral doses of busulfan, of patients receiving IV busulfan which is associated with up to (IV Bu) was only 12 percent at twentyfold variations in plasma one year and 18 percent at five Edward Copelan, MD, (left) levels. Low plasma levels are years, comparable to reports using Chair of the Department of Hematologic associated with graft rejection and allegedly safer reduced intensity Oncology and Blood Disorders leukemia relapse and high levels regimens, and significantly better with toxicity and transplant-related than the TBI group in the study. Belinda Avalos, MD (right) Vice Chair of the Department of mortality. Improved methods Survival and leukemia free survival Hematologic Oncology and Blood of administration, including the (57 percent at five years for IV Disorders intravenous route and dose Bu) were significantly higher and adjustment of busulfan based on late relapse significantly less Initial studies demonstrating plasma levels, represent important frequent with IV Bu compared a cure of acute leukemia with advances which result in much to TBI. A supportive prospective allogeneic transplantation less variation in plasma levels cohort study in patients with were conducted by Nobel and less toxicity. Drs. Copelan various diagnoses, including Laureate E. Donnall Thomas. and Avalos pioneered the use of AML, and shorter follow up and Total body irradiation (TBI) with busulfan preparative regimens an accompanying commentary cyclophosphamide as preparative and advances in its administration. by Richard Champlin, of MD therapy was used. The principal investigators and Anderson, supported and This regimen has remained the lead authors of the plenary paper applauded the results of the standard for 50 years. Regimens in the December 5th issue of study reported by Drs. Copelan substituting busulfan for irradiation Blood, describe for the first time and Avalos. Dr. Champlin labeled have been used at many centers the superiority of intravenous the study the “answer to an because of the relative ease of busulfan compared to TBI in a age-old question.” The results administration and lower rates of study of 1,230 patients from more are viewed by most experts as some delayed effects, including than 100 institutions worldwide practice-changing; in addition hypothyroidism, infertility and who reported to the Center for to ease of administration and certain second malignancies. In International Blood and Marrow fewer complications, non-relapse randomized studies, however, TBI Transplant Research with acute mortality, late relapse, leukemia-

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LEARN MORE ABOUT LEVINE CANCER INSTITUTE Stereotactic Radiation Incorporating Approaches for Message from The SELECT Palliative Medicine Primary and CarolinasHealthCare.org/UpdatesInCancerV4 the President Lung Cancer Study into Clinical Pathways Oligometastatic Malignancies Message from the President of Levine Cancer Institute

system-wide resources, such as that produces a mathematical availability of patient navigation, result of little real importance. This patient support teams, survivorship edition of Updates in Cancer for activities, e-genetic counseling, Clinicians will illustrate how our cancer trials, units to support patients team is approaching the whole at home and improved oncology issue of value in healthcare, as well palliative medicine. In this fashion, as several other important game- Derek Raghavan, MD, PhD we can structure our System’s changing initiatives. I hope you find President, Levine Cancer Institute approach to patient care, and base it to be of interest. Let us know if our decision process on the best you require reprints of any of our available evidence and outcomes. There is no question that every Similarly, we are focusing on value published work. patient, caregiver and health in our academic activities. REFERENCES: professional will increasingly I have participated actively in the 1.Oberlander J and Perreira K: Implementing become involved in the “business” writing of the ASCO Guidelines on Obamacare in a Red State – Dispatch from of healthcare in 2014. It’s a pity, in Choosing Wisely, published in North Carolina. New Engl. J. Med., 2013, one sense, as a great deal of time 369: 2469-2471. will be taken up by this topic, at the Journal of Clinical Oncology4, 5, and in helping to 2.Porter ME, Teisberg EO. Redefining Health the expense of time expended in Care. Boston: Harvard Business School Press, cancer care and research. Some of produce the recent NCI-ASCO 2006. position paper on making trials the current and emerging chaos 3.Raghavan D: Costs of cancer care: is clearly a problem of politics, more accessible to the community Rhetoric, value, and steps forward. Semin. with both sides of the houses of and especially to under-served Oncol., 2013, 40: 659-661. government, both federal and state, populations, published in Journal 4.Schnipper LE, Smith TJ, Raghavan D et 6 failing to execute complete and of Oncology Practice. In addition, al: American Society of Clinical Oncology fiscally justified plans for healthcare our Chair of Solid Tumor Oncology identifies five key opportunities to improve care and reduce costs: the top five list for oncology. coverage and reimbursement. The and Investigational Therapeutics, J. Clin. Oncol., 2012, 30: 1715-1724. schism between federal and state Ed Kim, MD, has recently produced a provocative manuscript on 5.Schnipper LE, Lyman GH, Blayney DW et policies is particularly problematic in al: American Society of Clinical Oncology 1 treatment selection and value in North Carolina. That said, it’s time top five list in oncology. J. Clin. Oncol., 2013, for our nation to focus on costs and the management of lung cancer, 31: 4362-4370. in yet another high-tier journal.7 quality of cancer care, leading to 6.Denicoff AM, McCaskill-Stevens W, Grubbs SS increased value for both patients Not to be outdone, the leaders of et al: The National Cancer Institute-American and the community. I appreciate the our Department of Hematologic Society of Clinical Oncology cancer trial accrual view of Professor Michael Porter, Oncology, Blood Disorders and symposium: summary and recommendations. J. from Harvard School of Business, Bone Marrow Transplantation, Ed Oncol. Pract., 2013, 9: 267-276. who defines “value” as “outcome Copelan, MD, and Belinda Avalos, 7.Kim ES, Neubauer M, Cohn A, et al: divided by cost,” linking two very MD, have summarized their data on Docetaxel or pemetrexed with or without important parameters.2 a new, more cost-effective approach cetuximab in recurrent or progressive non- small-cell lung cancer after platinum-based The whole basis of developing to bone marrow transplantation in 8 therapy: a phase 3, open-label, randomised Levine Cancer Institute has been 1,230 cases in Blood . trial. Lancet Oncol, 2013,14:1326-1336. If you asked any within our team, to improve value – as outlined in 8.Copelan EA, Hamilton BK, Avalos B my recent editorial in “Seminars our focus remains quality and et al: Better leukemia-free and overall in Oncology”3, our approach has consistency, as supported by our survival in AML in first remission following been to use electronically driven recent score of the top 1 percent in cyclophosphamide in combination with pathways to rationalize and refine the Press Ganey survey. However, it busulfan compared with TBI. Blood, 2013, care, focusing on using the most is increasingly clear that our nation 122: 3863-3870. effective anti-cancer agents, and simply cannot afford the current choosing less toxic options when the costs of healthcare, and we all need Sincerely, efficacies of different approaches to focus on the provision of value are the same. Where approaches in addition to volume. We need to are equivalent in anti-cancer efficacy look at the reported advances and and toxicity, our intent is to move ensure that they are real, and of true We welcome your feedback at [email protected] to a cost-based algorithm. We also clinical relevance, and not merely and look forward to bringing you more news are improving value by developing the products of a statistical exercise in the future!

2 I UPDATES IN CANCER FOR CLINICIANS A PUBLICATION OF CAROLINAS HEALTHCARE SYSTEM

The SELECT Lung Cancer Study: What did we learn about cetuximab and chemotherapy in second line treatment?

antibody targeting EGFR, is Though these results were FDA approved for the treatment disappointing, definitive of head and neck cancer and information will be gained colorectal cancer. Kras has been from a current intergroup identified as a marker of resistance study, Southwest Oncology against cetuximab in patients with Group (SWOG) S0819, testing colon cancer; however, no markers cetuximab with chemotherapy have been identified in head and and bevacizumab. This is currently Edward S. Kim, MD Chair of the Department of Solid Tumor neck cancer. the largest front-line metastatic Oncology and Investigational Therapeutics In lung cancer, cetuximab has lung cancer study open to accrual been studied extensively. The (currently more than 1,000 patients FLEX study, a frontline advanced on study) and was based on Targeted therapies have non-small cell lung cancer (NSCLC) SWOG S0536, a single-arm, phase become incorporated into our trial combined with chemotherapy, II study with promising efficacy daily practice and management showed a statistically significant using carboplatin, paclitaxel, of patients with lung cancer. The improvement in overall survival bevacizumab, and cetuximab discoveries of epidermal growth (OS), however, this translated into (OS: 15 months, RR: 56 percent).4 factor receptor (EGFR) mutations only a five week difference.1 The Biomarker analyses are a co- and anaplastic lymphoma drug was not approved based primary endpoint with overall kinase (ALK) translocations on this information. Numerous survival. have transformed survival in biomarkers had been investigated The need for additional approximately 20 percent of lung to identify those patients that may treatments for lung cancer patients cancer patients. The number benefit from cetuximab treatment is paramount. However, the risk of available compounds which including Kras, EGFR (expression, versus benefit of embarking on target these pathways continues FISH), and others. A subset of large phase III efforts needs to be to grow and currently includes patients from the FLEX study based on solid, encouraging prior gefitinib, erlotinib, and afatinib showed that H-score predicted evidence. This leads to several for patients with EGFR mutation- an improved overall survival of 12 questions: What parameters would positive lung cancer. Crizotinib months (95 percent CI: 10.2-15.2 best be used in order to test (approved), LDK378 (currently months) compared to 9.6 months hypotheses in the current age of under investigation) and others are (95 percent CI: 7.6-10.6 months).2 targeted therapy? Should a valid not far away for patients with ALK We observed initial activity with biomarker always be incorporated? positive lung cancer. Other targets a single arm study of docetaxel Our hope is that a population of of interest include MET, Kras, T790 and cetuximab in previously biomarker-enriched lung cancer (EGFR), FGFR, anti-CTLA-4, anti- treated lung cancer patients.3 patients who benefit from the PD-1 and BRAF. There are multiple Efficacy was encouraging with a S0819 regimen will be identified. ongoing studies evaluating agents response rate (RR) of 20 percent Until we have this answer, higher against these targets. (95 percent CI: 10.4-33.0 percent) levels of early phase data need to Bevacizumab is an example and thus the SELECT study was be generated in order to produce of a targeted agent that has developed. This randomized clinically meaningful endpoints in demonstrated improved study enrolled more than 900 subsequent randomized studies efficacy in combination with patients with previously treated and, for now, cetuximab appears chemotherapy, but does not NSCLC. Chemotherapy with to have a little role in non-small have a specific measured target. pemetrexed or docetaxel with or cell lung cancer. Whether bevacizumab works without cetuximab was utilized. REFERENCES: synergistically with chemotherapy Unfortunately, no significant 1. Pirker R, Pereira JR, Szczesna A, or if there is a specific unknown improvements in efficacy were von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Yu CT, Ganul V, biomarker is still unclear. Other observed. We also tested H-score Roh JK, Bajetta E, O’Byrne K, de Marinis VEGF targeted agents have not in this population and also did not F, Eberhardt WE, Goddemeier T, Emiq M, been able to demonstrate similar observe a benefit in those patients efficacy. Cetuximab, a monoclonal testing positive. CONTINUED ON PAGE 5

CarolinasHealthCare.org/UpdatesInCancerV4 I 3 Incorporating Palliative Care into Clinical Pathways

Cancer Society, and was based at common distressing conditions on multiple randomized trials encountered by individuals with that reflect the benefit of early cancer, including treatment-related palliative care for improving side effects. When symptoms patients’ quality of life, patient increase to a more challenging and family satisfaction, decreased level of management, the caregiver morbidity and decreased pathways also provide guidance Niki Koesel, NP (left) healthcare service utilization. on when referral to a palliative Hospice and Palliative Medicine Temel et al. demonstrated medicine specialist should prolonged survival in the setting be considered. The symptom Connie Edelen, MD (right) Hospice and Palliative Medicine of metastatic non-small cell lung management pathways were cancer (NSCLC) when palliative created based on the medical care is integrated at the time of evidence across the oncology and diagnosis.2 palliative medicine literature and Levine Cancer Institute supports are reviewed on a monthly basis full integration of palliative care at Levine Cancer Institute disease- into standard oncology care specific section meetings. The through development of its full- symptom management pathways time outpatient clinic devoted to will evolve as new research is developed.3 Jessica Masterson, MD (left) interdisciplinary palliative care. Medical Oncology Additionally, palliative medicine At this year’s American Academy has been incorporated into of Hospice & Palliative Medicine’s Raghava Reddy Induru, MD (right) multiple evidence-based tumor- Annual Assembly, more than Medical Oncology specific Levine Cancer Institute 2,400 medical providers convened clinical pathways. Screening for to review the advancing role palliative medicine referrals are of palliative medicine within In 2012, ASCO released a recommended within Levine healthcare, across all care provisional clinical opinion stating Cancer Institute’s clinical pathways settings. Many studies and topics that concurrent palliative care at the time of advanced disease presented centered around the should be considered early in the in conjunction with ongoing role of palliative medicine for course of advanced or metastatic disease specific treatments. patients with cancer. Specifically, cancer and/or in the setting Symptom management pathways topics including evidence-based of a high symptom burden.1 were developed (locally) to symptom management for This statement follows other guide oncology clinicians in symptoms associated with cancer organizational recommendations providing primary palliative care or its treatment, caregiver distress by the NCCN, Commission on in order to optimize symptom and support, survivorship needs, Cancer, Institute of Medicine, management along their patients’ clinical trials and prognostication European Society of Medical treatment course. These symptom were highlighted throughout the Oncology and the American management pathways are aimed assembly. However, the release CONTINUED ON PAGE 5 Progress in Hematologic Cell Transplantation continued from page 1

free survival and overall survival are all better with IV busulfan and cyclophosphamide than with TBI and cyclophosphamide. Additionally, the safety of this regimen is similar to that of reduced-intensity regimens that have less anti-leukemia activity. Busulfan in combination with TBI is the new standard preparative regimen for allogeneic transplantation in patients with acute myeloid leukemia. The hematopoietic cell transplant team has incorporated these findings into its treatment protocols for the transplant program at Carolinas Medical Center, Charlotte, NC, with the new 16 bed unit opening January 22, 2014. The new unit provides positive pressure filtered air flow and other state-of-the-art protective environmental measures for patients with hematologic malignancies.

REFERENCES: 1. Copelan EA, Hamilton BK, Avalos B, et al: Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI. Blood, 2013, 122: 3863-3870.

4 I UPDATES IN CANCER FOR CLINICIANS A PUBLICATION OF CAROLINAS HEALTHCARE SYSTEM

Palliative Medicine The SELECT Lung Cancer Study: What continued from page 4 did we learn about cetuximab and of the 3rd edition of the “Clinical chemotherapy in second line treatment? Practice Guidelines for Quality continued from page 3 Palliative Care” published by the National Consensus Project for Quality Palliative Care and Gatzemeir U; FLEX Study Team. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomized phase III trial. Lancet 2009 May authored by specialty pioneers 2; 373(9674):1525-31. Drs. Betty Ferrell and Diane Meier 2. Pirker R, Pereira JR, von Pawel J, Krzakowski M, Ramlau R, Park K, de Marinis F, Eberhardt may have been the highlight WE, Paz-Ares L, Storkel S, Schumacher KM, von Heydebreck A, Celik I, O’Byrne KJ. EGFR for many palliative medicine expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients teams.4 These guidelines serve as with advanced non- small-cell lung cancer: analysis of data form the phase 3 FLEX study. principles for practicing the most Lancet Oncol. 2012 Jan; 13(1):33-42. effective and beneficial palliative 3. Kim ES, Mauer AM, William WN jr, Tran HT, Liu D, Lee JJ, Windt P, Hong WK, Vokes EE, medicine. Special emphasis Herbst RS. A Phase 2 study of cetuximab in combination with docetaxel in chemotherapy- refractory/resistant patients with advanced nonsmall cell lung cancer. Cancer. 2009 Apr is made on the necessity of 15;115(8): 1713-22. interdisciplinary team members to 4. Kim ES, Moon J, Herbst RS, Redman MW, Dakhil SR, Velasco MR Jr, Hirsch FR, Mack PC, provide evidence-based symptom Kelly K, Heymach JV, Gandara DR. Phase II trial of Carboplatin, Paclitaxel, Cetuximab, and management and holistic care Bevacizumab followed by Cetuximab and Bevacizumab in advanced nonsquamous non- that includes social, spiritual small-cell lung cancer: SWOG S0536. J Thorac Oncol. 2013 Nov 1 [Epub]. and ethical components. As the state of the science for palliative medicine continues to grow, it is imperative that teams across the country develop and grow their own interdisciplinary programs in conjunction with these guidelines, both of which are especially crucial for providing good patient care within cancer institutes.

REFERENCES: 1. Smith TJ, Temin S, Alesi ER, et al. American Society of Clinical Oncology Provisional Clinical Opinion: The Integration of Palliative Care Into Standard Oncology Care. J Clinical Oncol. March 10, 2012 2012;30(8): 880-887. 2. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. Aug 19 2010;363(8):733-742. 3. Reduction of cancer-related fatigue with dexamethasone: A double-blind, randomized, placebo-controlled trial in patients with advanced cancer. Frisbee- Hume S, Palmer JL, Delgado-Guay LEVINE CANCER INSTITUTE MO, Bull J, Phan AT, Tannir NM, Litton JK, Reddy A, Hui D, Dalal S, Massie L, Research and Administrative Headquarters, Reddy SK, Bruera E. J Clin Oncol. 2013 located in Charlotte, NC Sep 1;31(25):3076-82. doi: 10.1200/ JCO.2012.44.4661. Epub 2013 Jul 29. 4. National Consensus Project for Quality LEARN MORE ABOUT LEVINE CANCER INSTITUTE Palliative Care. (2013). Clinical Practice CarolinasHealthCare.org/UpdatesInCancerV4 Guidelines for Quality Palliative Care, Third Edition. Pittsburg, PA. http://www.nationalconsensusproject.org

CarolinasHealthCare.org/UpdatesInCancerV4 I 5 Stereotactic Radiation Approaches for Primary and Oligometastatic Malignancies best established for patients with used to manage brain metastases, inoperable early-stage lung cancer, where it has proven worth as first where prospective trials have line therapy, as postoperative demonstrated local control rates therapy, and in combination that rival surgical results. The most with whole-brain radiation. mature data comes from Radiation Growing evidence also shows that Therapy Oncology Group (RTOG) radiosurgery to the resection cavity John Heinzerling, MD (left) 0236, a phase II study of SBRT after resection of limited-brain Radiation Oncology for patients with medically- metastases may be as effective inoperable stage I-II non-small as adjuvant whole-brain radiation Roshan Prabhu, MD, MS (right) cell lung cancer (NSCLC), which therapy (the current standard). To Radiation Oncology achieved an impressive two year that end, we also offer radiosurgery local control rate of 93.7 percent.1 to an operable lesion either prior Another recently completed phase to planned surgical resection or II trial (RTOG 0618) evaluated after surgery to the resection bed SBRT as an alternative to surgery as an alternative to whole brain in patients with operable early radiation therapy. Our institutional stage NSCLC. At ASCO 2013, experience with pre-operative SRS encouraging early results were for cranial metastases is unique; our presented, with a two year overall early results are promising, and will Ben Moeller, MD survival rate of 84.4 percent.2 be published in the near future. Radiation Oncology Inspired in part by success in We have within Levine Cancer treating primary lung cancers, Institute an experienced stereotactic When applied to therapeutic SBRT has also been recently used program for treatment of primary radiation, the term stereotactic in the oligometastatic setting, and metastatic tumors. In addition, refers to an extremely precise where survival times are often there are many opportunities that method of immobilization, imaging significantly longer than for the Levine Cancer Institute model and targeting of a malignancy in patients with frankly metastatic provides for further developing order to maximize dose to the disease. As in the definitive this modality in a clinical research tumor while minimizing dose setting, SBRT appears to be an setting, and we are actively working to surrounding normal tissues. effective and well-tolerated local towards this goal. First used to treat targets in the therapy for patients with limited brain, using fixed head frames, metastatic disease within the REFERENCES: lung. Local control rates for lung 1. Timmerman, R., et al., Sterotactic body the advent and integration of radiation therapy for inoperable early advanced imaging modalities and metastases treated with SBRT stage lung cancer. JAMA, 2010. 303(11): p. immobilization techniques in the have been reported as high as 1070-6. 3 treatment room have allowed this 94.7 percent. In the liver, as well, 2. Timmerman, R., et al., RTOG 0618: technology to be transported to SBRT is an attractive option for Stereotactic body radiation therapy (SBRT) those not medically fit for hepatic to treat operable early-stage lung cancer the extracranial setting, where it is patients. J Clin Oncol, 2013. (suppl; typically called stereotactic body metastasectomy; early studies abstract 7523). radiotherapy (SBRT). Here, we have demonstrated local control 4 3. Tree, A., et al. Sterotactic body offer a brief review of recent data rates of 92 percent. radiotherapy for oligometastases. Lancet and current trends in the field of Intracranial stereotactic Oncol, 2013. 14(1): p. 28-37. stereotactic radiotherapy. radiotherapy, termed stereotactic 4. Rusthoven K., et al. Multi-institutional The role for SBRT is currently radiosurgery (SRS), has long been phase I/II trial of stereotactic body radiation therapy for liver metastases. J Clin Oncol, 2009. 27(10): p. 1572-8.

LEARN MORE ABOUT LEVINE CANCER INSTITUTE CarolinasHealthCare.org/UpdatesInCancerV4 UPDATES IN CANCER FOR CLINICIANS

FALL 2013

Quality of Life Improvements in Sarcoma Therapy

drugs used for sarcoma therapy, used doxorubicin liposomes in doxorubicin and ifosfamide, can both osteosarcoma and Ewing’s be given with increased safety and sarcoma patients. fewer side effects. After Europe, There is a new option to reduce the Middle East and Africa banned mucositis: glutamine-disaccharide use of dexrazoxane because of controlled (swish/swallow for potential concern about increase 10 seconds). Dr. Anderson has Peter Anderson, MD, PhD (left) in MDS in Europe, the Children’s published one pilot study, and Medical Oncology Oncology group did an analysis two randomized placebo clinical of more than 1,000 osteosarcoma trials, and designed a successful Jeffrey Kneisl, MD (right) patients treated in four studies. one in breast cancer patients, Surgical Oncology Lisa Kopp, MD, reported too. An improved glutamine the results at the American disaccharide formulation Society of Clinical Oncology: (orange- or grape-flavored), development of MDS was very now commercially available rare in this population and (healiosproducts.com), has there were no increased events trehalose in addition to sucrose to when comparing osteosarcoma promote the entry (roughly 1,000 patients who had received times greater) of the glutamine dexrazoxane before doxorubicin nutrient into mucosal cells. Joshua Patt, MD (left) versus doxorubicin alone. Pazopanib, an oral drug for Surgical Oncology Therefore, to reduce incidence recurrent soft tissue sarcomas is Michael Livingston, MD (right) of long-term cardiotoxicity, now commercially available. The Medical Oncology the use of dexrazoxane is mechanism of action is VEGF not contraindicated. It is Dr. inhibition. This drug is generally Anderson’s opinion that benefit well tolerated at 800 mg per day. Levine Cancer Institute’s (less mucositis in the short term A common side effect is a salt multidisciplinary sarcoma team and less cardiotoxicity in the long and peppering or whitening of evaluates patients for current term) outweighs any potential risk. the hair. Fatigue can usually be treatment options and novel For patients who have received managed by taking the drug at research studies. However, a major more than 350 mg/m2 or have a bedtime. Diarrhea and GI side consideration is the patient’s more than 10 pecent decrease effects, when they occur, are quality of life. The two major in EF, Dr. Anderson has safely managed with loperamide.

CONTINUED ON PAGE 7

LEARN MORE ABOUT LEVINE CANCER INSTITUTE AND Personalized Message from Novel Approaches Upper GI OUR CLINICAL TRIALS: Leukemia Care in the President for Bone Metastasis Malignancies CarolinasHealthCare.org/updatesincancerV3 the Carolinas Message from the Comprehensive Cancer Center) • David Johnson, MD, (chair of medicine, and Sarah Baxter, PhD, (David UT Southwestern and a former ASCO president), a member, but unable to President of Levine Murdoch Research Institute) attend this review provide laboratory leadership • Mark Legnini, PhD, (former leader Cancer Institute in the Hematology Oncology of health policy and planning at Translational Labs. Jimmy Brookings Institute, now a consultant) Hwang, MD, has joined us from • Debasish Roychowdhury, MD, (chief Georgetown University, where medical officer, Sanofi Aventis) he was director of the Fellowship • Michael Steinberg, MD, (chair, Program, to develop a Hematology Radiation Oncology at UCLA and and Oncology Fellowship, and health consultant for many years to the to help lead in advanced upper Rand Corporation) gastro-intestinal cancers and phase • David Winchester, MD, (surgical Derek Raghavan, MD, PhD oncologist and medical director, President, Levine Cancer Institute I trials. Jai Patel, Pharm. D., has American College of Surgeons joined us from UNC Chapel Hill, to Cancer Programs) provide pharmacologic support for Their preliminary report indicates our early phase trials program. Leila We’ve been busy at Levine strong endorsement for our direction Hadzikadic Gusic, MD, and Meg Cancer Institute, focusing on and aims, and the extraordinary Forster, MD, surgical oncologists, growth and review of progress. progress over the past two years, from University of Pittsburgh Carolinas HealthCare System was with the addition of more than 80 Cancer Institute and the Moffitt granted nursing Magnet status, and faculty to Levine Cancer Institute. Cancer Center, respectively will be our team was delighted to be able As part of our quest for helping develop our programs in to support our nursing leadership excellence, we also underwent a breast cancer and upper gastro- in the review process. Oncology formal review of our Medical Physics intestinal cancer. Roshan Prabhu, nursing, and the certifications program in Radiation Oncology, MD, has joined the Levine Cancer and responsibilities that go with completed last month by Tim Institute /SERO collaboration, this crucial discipline, are a huge Fox, MD, (chief of Physics, Emory coming from the very strong part of Levine Cancer Institute’s University) and Ping Xia, MD, (chief radiation oncology program at values, and it was exciting to the of Medical Physics, Cleveland Clinic Emory University. extramural validation. We were Taussig Cancer Center). Their report The Levine Cancer Institute delighted that the Commission is eagerly awaited. External Advisory Board completed on Cancer reviewed seven of our We seem to be on track to our first formal review in late July. programs and accorded us highest develop a really unique resource for This true blue ribbon panel includes: honors, with eight out of eight this region, providing better care commendations. • Donald “Skip” Trump, MD, President and research for our patients, with of Roswell Park Cancer Institute (chair) We continue to recruit actively. a focus on innovation and support. Jon Gerber, MD, and Mike • John DiPersio, MD, (chief, This edition will tell you more. Grunwald, MD, have joined us Hematologic Oncology and deputy from Johns Hopkins Cancer director, Washington University Sincerely, Comprehensive Cancer Center) Center to expand the leukemia program, and Saad Usmani, MD, • Norm Hubbard, PhD, (senior administrator, Seattle Cancer Care from Bart Barlogie’s program at Alliance) the University of Arkansas, now We welcome your feedback at • Fadlo Khuri, MD, (chief of Medical [email protected] leads the myeloma program. Oncology, Emory University/Winship and look forward to bringing you more news Larry Druhan, PhD (Ohio State Cancer Institute in the future!

Independent News on Advances in Hematology/Oncology Independent News on Advances in Hematology/Oncology Independent News on Advances in Hematology/Oncology

clINIcAlONcOlOgy.cOM • September 2013 • Vol. 8, No. 9 ClINICAlONCOlOgy.COM • July 2013 • Vol. 8, No. 7 cLINIcALONLO cO gy.cOM • June 2013 • Vol. 8, No. 6

IMAGES in ONCOLOGy INSIDE IMAGES in ONCOLOGY INSIDE A Glimpse of INSIDE IMAgES in ONCOLOgy Chemo for Scrambling To Deal SOLID TUMORS CURRENT PRACTICE Next-Generation SOLID TuMORS Smoldering Sequencing Dose-dense regimen Supreme Court rules on ASCO Coverage With Sequestration refines testicular cancer MM? Not Yet! gene patenting case ...... 3 Study suggests broader Standard- vs. high-dose therapy...... 15 screening for high-risk women Community practices brace for How I Manage... radiation for advanced he report by Maria- Axilla radiotherapy called MGUS and Smoldering Chicago—Next-generation compre- non-small cell 28% cut to office drug payments TVictoria Mateos, new breast cancer Multiple Myeloma: hensive genomics screening in black lung cancer ...... 12 MD, PhD, of the Uni- Orlando, Fla.–Community oncologists are scrambling to deal with a standard...... 21 versity Hospital of Sal- Robert Kyle, MD ...... 10 women with breast cancer is provid- massive funding cut that leaves cancer specialists at a financial loss every amanca in Spain, in the ing an early look at how these tests ‘On the Spot’ debate: time they administer expensive oncology drugs to Medicare patients in CURRENT PRACTICE Aug. 1, 2013, issue of The The Tumor Board: Conrad are likely to be applied widely in rou- Controversies in breast tine care. Rather than testing only for a community clinic. New England Journal of Simpfendorfer, MD ...... 24 cancer management ...... 26 Steven Vogl, MD LEVINE CANCER INSTITUTE “There is no good way to deal with this cut,” said Ted Okon, the execu- Maurie Markman, MD: Medicine (NEJM) is both BRCA1 and BRCA2 genes, the BROCA The essential patient assay used in a recent study looked for tive director of the Community Oncology Alliance (COA), an organization very important and very, very difficult Expert Forum: perspective...... 9 1 mutations in 18 genes associated with that represents community cancer centers and their patients. “We’re see- to read quickly. The question under Controversies in breast HEMATOLOgIC DISEASE ing a variety of reactions on the part of practices but I think most are still study is fashionable: At what point do increased breast cancer risk and found Few oncologists cancer management ...... 26 in disbelief that this is really happening. Oncologists are a bit like deer in physicians decide that a condition in at least one inherited mutation in 22% How I Manage ... monitor lab headlights with these cuts.” asymptomatic patients is life-threaten- “Untitled (Aerial Perspective),” a carcinomatous invasion of bone. of the women examined. “ Walking,” squamous carcinoma cells go for a stroll. Primary mediastinal Many practices are turning away a portion of their Medicare patients. quality...... 20 SOLID TUMORS “Modern genomics approaches ing and deserves treatment as a cancer? For more information see page 8. For more information see page 2. large B-cell lymphoma: see SEQUENCING, page 8 Others are redirecting all Medicare patients to hospitals. Meanwhile, some see VOGL, NY, page 10  Quality cancer care:  John Sweetenham, MD ...... 10 are sticking to their usual practices, taking in all of their patients and hop- ASCO Coverage No longer just ing that a solution comes before their practices become untenable. Bevacizumab for advanced about survival...... 20 Counterfeit Chemo FEATURED IN ASCO Coverage “While we are affected, we haven’t turned down any patients and we ASCO 2013 cervical cancer ...... 4 Drug Shortage Fosters Imaging to detect haven’t shut down any clinics,” said Lucio Gordan, MD, a medical oncologist Clinical Conundrums ...... 22 The second in a two-part special at a Florida Cancer Specialists Clinic in Gainesville. relapses in patients Sorafenib for refractory report on drug fraud in the U.S. Variety of Coping Strategies see SEQUESTRATION, page 25 with diffuse large B-cell  Affordable Care Act Impact: It’s All in thyroid cancer ...... 14 here are several ways in which fake lymphoma ...... 13 and counterfeit drugs can get into Chicago—The cancer drug shortage is forc- by the numbers HEMATOLOGIC DISEASE T the Details ... and There Are No Details the hands of physicians and patients. ing oncologists to cobble together a mix of by the Counterfeit Chemo The Internet is probably the easiest coping strategies, some of which are rais- Financial Distress Improving hematopoietic numbers CuRRENT PRACTICE way to access fakes because there is ing costs, according to results of a survey A special two-part report on drug fraud in the U.S. Chicago—With several key provisions of ...... In a survey of 164 cancer stem cell transplant 11 little to no oversight. Consumers may of board-certified U.S. oncologists. Eighty- Physicians’ Adaptations Readers Respond: the Affordable Care Act (ACA) set to take Overall Effects of the ACA on Physicians’ Incomes illard Ray Lamb, MD, a physician and part owner of the McLeod patients, as a result of cost: purchase drugs on the Internet for the three percent of oncologists have been con- To Drug Shortages Letters to the Editor ...... 9 effect on Jan. 1, it is still difficult to pre- Minimizing Hodgkin CLINICAL ONCOLOGY Cancer and Blood Center in Johnson City, Tenn., received a fax in Increased revenue convenience, to avoid potential embar- fronted with drug shortages that affected M 45% | Medication dict exactly how it will affect the treat- lymphoma radiation 79% Switch regimens » September 2007 from Quality Specialty Products (QSP). The message indi- non-adherence ment of cancer, a panel of policy experts • More covered patients due to insurance mandate and Medicaid growth rassment (as with Viagra) or to get what treatment decisions, according to the sur- Maurie Markman, MD: treatment ...... 12 77% Substitute drug partway cated that QSP, a business in Winnipeg, Canada, could provide physicians due to cost • More covered preventative services such as mammography screenings seems to be a good deal on costly drugs. vey. In 37% of cases, oncologists felt com- told oncologists at the 2013 annual meet- through therapy Interpreting quality-of-life with substantial discounts on a list of expensive prescription drugs, includ- However, if it seems too good to pelled to engage in a rationing process, Did not fill a ing of the American Society of Clinical Decreased revenue studies ...... 14 ing chemotherapy medications bevacizumab (Avastin, Genentech/Roche) 27% | be true, it probably is, said Chris selecting among patients to whom they 43% Delay treatment prescription Oncology (ASCO). • Penalties for failing to comply with quality reporting programs and rituximab (Rituxan, Biogen Idec/Genentech). For example, QSP was The 900-page act, colloquially known as COMING Vansteenkiste, the project manager of offered a remaining quantity of a drug. 37% Choose among patients Clinical Conundrums ...... 29 Partially filled a • Fee-for-service replaced by bundled payments and medical home selling a 400-mg vial of Avastin for less than $2,000, whereas an FDA- 25% | Obamacare, is dauntingly complex, yet very the Intellectual Property Crime Team “The vast majority of oncologists in this 29% Omit doses prescription and shared savings programs at Europol. A study conducted by the country are facing wrenching decisions approved vial of the same drug costs about $2,400. little deals specifically with cancer care. NExT MONTH 20% Reduce doses Dr. Lamb, along with physicians and part owners Charles Famoyin, Took less “There are really very few oncology- European Alliance for Access to Safe about how to allocate lifesaving drugs when EDuCATIONAL REVIEW 22% | 17% Refer patients to another MD, and William Kincaid, MD, and business manager Michael Combs, medication than specific components,” said William C. Penley, MD, a medical In describing the scope of the ACA, Dr. Penley said it is easier Special ASCO Medications (EAASM) found, after there aren’t enough to go around,” Keerthi prescribed practice Lung cancer, close-up. agreed Mr. Combs should order cancer drugs from QSP. Soon after, oncologist at Tennessee Oncology in Nashville, who has served to follow the themes of the legislation than the specifics, many of analyzing a range of medications pur- Gogineni, MD, of Abramson Cancer Cen- Pathogenesis of a coverage issue chased from online pharmacies, that ter at the University of Pennsylvania in Source: J Clin Oncol..2013;(suppl:abstr.CRA6510). patients at McLeod Cancer started receiving chemotherapy treatments Source: Journal of Clinical Practice... Image courtesy of Science Photo Library on ASCO’s Government Relations Committee and the board of which are likely to be modified, even if the specific regulations Hereditary Predisposition doi:.10.1200/JOP.2013.000971 see COUNTERFEIT, page 6 see SHORTAGES, page 8 from the QSP supply. the Association of Community Cancer Centers. see AFFORDABLE CARE, page 19   To Breast Cancer ...... 16  see COUNTERFEIT, page 23  REVIEWS & COMMENTARIES REVIEWS & COMMENTARIES REVIEWS & COMMENTARIES Expert Insights From Levine Cancer Institute Expert Insights From Levine Cancer Institute Expert Insights From Levine Cancer Institute Osteosarcoma Dose-Dense Chemo-N0 Study Similar Genetic Anagrelide Cytarabine Improves Survival Differs Regimen Does Not Confirms Utility Alterations Effective for Essential Combination Therapy by Gender Improve R-CHOP of uPA/PAI-1 Found in Primary Thrombocythemia for Mantle Cell and Age ...... 16 for DLBCL ...... 18 Biomarker ...... 17 and Metastatic ...... 17 Lymphoma ...... 21 Peter Saad Z. NSCLC ...... 18 Anderson, MD Usmani, MD Wendy Brick, MD Edward Kim, MD Edward Copelan, MD Belinda Avalos, MD

2 I UPDATES IN CANCER FOR CLINICIANS A PUBLICATION OF CAROLINAS HEALTHCARE SYSTEM

State of the Art in Myeloma Management

The management of multiple strategy. Clinicians and cancer myeloma (MM) has seen a drastic researchers now recognize that change over the last 15 years, with such prognostication needs to the median survival for an average include the host factors (age, MM patient improving from more co-morbidities and performance than 2 years to 7 to 10 years. MM status), disease burden (ISS and/ represents a malignant clonal or DSS) and disease biology. Saad Zafar Usmani, MD, FACP expansion of transformed plasma MM researchers recognize Medical Oncology cells. These cells eventually that our ability to assess the undergo clonal evolution and depth of response, by way of heterogeneity, which is believed following serum M proteins and/ to be the basis of drug-resistance or bone marrow examinations, with sequencing therapy. This is inadequate. Inclusion of novel makes MM a complex, multi-hit imaging (PET/CT) and specialized malignancy with a prognosis and lab tests (DNA PCR and/or flow outcome that is extremely variable, cytometry) to assess minimal even in the era of novel agents. residual disease are being The initial prognostic models included to assess better depth were developed based on of response in clinical trials. We clinical observations and routine also recognize that we need to laboratory findings. The most find a better answer for high-risk commonly used systems are myeloma patients and develop International Staging System new drug classes that can improve (ISS) and Durie-Salmon Staging their outcomes. (DSS), which includes data on the Levine Cancer Institute’s Plasma presence of bone lytic lesions, Cell Disorders program has calcium, creatinine, albumin, opened its doors to patients at b-2 microglobulin, hemoglobin its administrative and research concentration and serum levels of headquarters in Charlotte, monoclonal proteins. Both these NC. The program brings these models provide an estimation advances in management to the of burden of disease and also MM patients being cared for in capture host factors/morbidity, but Carolinas HealthCare System. do not account for the biologic We intend to achieve this goal heterogeneity of MM. Several by establishing uniform practice techniques using comprehensive guidelines which help the evaluation of bone marrow oncologists across the Institute’s samples (metaphase cytogenetics, vast network of satellite sites in fluorescent in situ hybridization treating MM patients and have and gene expression profiling) readily available access to expert have helped us identify the opinion. The program also brings biologic bad actors in MM. value to Carolinas HealthCare The eventual goal of System communities by offering prognostication for any human clinical trials with novel treatments disease is to provide for for both newly diagnosed and risk-adaptive therapeutic previously treated MM patients.

CarolinasHealthCare.org/updatesincancerV3 I 3 Novel Approaches for Bone Metastasis

SBRT has shown long-term local suppression without demonstrated control of more than 90 percent, efficacy for endpoints beyond including favorable outcomes pain control have limited the for radioresistant histologies. broad implementation of Common fractionation schemes these agents. In May, the FDA include 6 to 30 Gy in 1 to 5 approved Radium 223 Dichloride, fractions. Multiple institutional the first alpha particle emitting Hadley Sharp, MD (left) studies suggest an SBRT approach radiopharmaceutical, for use in Radiation Oncology is more effective than conventional patients with castrate-resistant doses in all but the most metastatic prostate cancer (CRPC), Derek McHaffie, MD (right) radiation-sensitive histologies with symptomatic bone disease Radiation Oncology (lymphoma, myeloma, germ cell and no visceral metastases, based tumors). Limitations of these upon the results of the phase III Bone metastases are a common studies include heterogeneity in ALYSYMPCA trial [4]. This study source of morbidity in patients patient characteristics, reported randomized 921 CRPC patients, with metastatic cancer. Disease endpoints, and fractionation who were otherwise receiving the involving the spine is of particular schemes, making it difficult to highest standard of care in a 2 to interest due to the risk of unify into concise treatment 1 fashion to Radium 223 versus developing metastatic epidural recommendations. RTOG 0631, placebo . The study showed spinal cord compression (MESCC). recently opened at Levine Cancer improvements in the trial’s primary In addition, pain and structural Institute has initiated the phase end point of survival (14.9 months instability can greatly compromise III portion of the trial comparing vs. 11.3 months; P<0.001) and patient performance status. The SBRT to high dose conventional time to skeletal-related events management of spinal metastases radiation for spinal metastases (15.6 months vs. 9.8 months; presents a unique challenge, with a primary endpoint of pain P<0.001). Furthermore, no requiring a multidisciplinary control. Other areas of active clinically meaningful differences in approach. When evaluating investigation include defining the the rate of grade 3 or 4 toxicities role of SBRT for inoperable spinal were observed between arms. metastatic involvement of the cord compressive lesions and Radium 223 is incorporated spine, one must consider current residual disease post-operatively. into hydroxyapatite formation, neurologic function, radiation Optimizing fractionation schemes preferentially at sites of increased sensitivity, mechanical stability and to balance local control, pain bone turnover. Once deposited, systemic disease characteristics response, and the risk of it undergoes a series of alpha [1]. Surgical resection followed neurologic sequelae or post- particle (two protons and two by fractionated radiation is the treatment vertebral body fracture neutrons) emissions with a half-life standard of care for MESCC. will be important moving forward of 11.6 days. An alpha particle However, the management of [2]. At Levine Cancer Institute, we has 7,300 times the mass of a beta the non-compressive tumors, are participating in cooperative particle, transferring much higher inoperable patients, previously group studies and establishing energy to the surrounding tissue irradiated lesions, or radioresistant multidisciplinary approaches to and resulting in more potent anti- histologies (sarcoma, renal cell spinal tumors. tumor effects via non-repairable carcinoma or melanoma) require In patients with multifocal double-stranded DNA breaks. a more variable approach. In all symptomatic bone metastasis, As a result of their size, they also these settings, the proximity of systemic Radiopharmaceuticals manifest increasing stopping power tumor to the spinal cord makes can be an effective pain control and shorter effective ranges at delivering a tumor ablative dose strategy. Agents such as the target site compared to beta while sparing adjacent neural Strontium89 and Samarium153- particles. For Radium 223 decay, tissues, a unique challenge. EDTMP, which decay through the range is measured at less than Using stereotactic techniques beta emission, have been 100 μm, minimizing bone marrow and prior knowledge of the shown to result in high rates suppression. By comparison, radiation tolerance of the spinal of objective pain response [3]. therapeutic beta-emitters have a cord, experience with spinal Concerns regarding bone marrow range of 2.5-7 mm. Based upon

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4 I UPDATES IN CANCER FOR CLINICIANS A PUBLICATION OF CAROLINAS HEALTHCARE SYSTEM

Update in HPV-Related Head and Neck Cancers

The incidence of oropharyngeal anesthesia with direct laryngoscopy (tonsil and base of tongue) and biopsy is critical for diagnostic squamous cell carcinoma purposes as well as evaluating the (OPSCC) is rapidly increasing and extent of disease for treatment is directly associated with the planning. Early stage disease limited rising rates of human papilloma to the primary site may be amenable virus (HPV) infection. Fortunately, to surgical resection, resulting in the Michael Haake, MD (left) these patients with HPV-related possibility of treatment de-escalation. Radiation Oncology OPSCC are generally younger Salvage surgery is also critical in and have significantly improved those patients whose OPSCC is Zvonimir Milas, MD (left) survival rates in comparison to Surgical Oncology refractory to primary treatment or those with smoking- and alcohol- is recurrent after treatment. Finally, induced carcinoma. surveillance of treated patients The goals of cure and quality requires both radiographic imaging of life are of equal and critical as well as examination with office- importance. To achieve these based laryngoscopy. goals, it takes a comprehensive Radiation techniques, such as team approach. Surgery, Intensity Modulated Radiation chemotherapy and radiation Therapy (IMRT) allows true “dose therapy all serve vital roles in the painting” of the area at risk, as Ed Kim, MD treatment of OPSCC. Evaluation determined on the CT/PET. The Chair of the Department of Solid Tumor and treatment by oral medicine, planning software allows for Oncology and Investigational Therapeutics speech therapy, and physical setting dose constraints on normal therapy are very important to tissue to minimize long term minimize post-treatment sequela. symptoms such as dry mouth, soft Thus, a multidisciplinary evaluation tissue fibrosis and scarring. by medical oncology, radiation Chemotherapeutic approaches oncology, and head and neck have included utilizing sequential surgical oncology is necessary induction chemotherapy at the to chart the ideal treatment plan same time as radiation, which has which is individualized for each increased the control of cancers and patient and compliant with the standards of care. the overall cure rate. Novel targeted Surgical intervention for OPSCC agents, such as cetuximab and has changed over the years. others, combined with radiation may Historically, oropharyngeal cancer hold even more promise with less was managed with open surgery toxicity. As noted above, people and then followed by radiation with HPV-related cancers of the therapy for advanced primary oropharynx have a better prognosis. tumors or nodal disease. However, Research is ongoing at Levine there was much morbidity incurred Cancer Institute and elsewhere to despite the good outcomes. determine if such patients can have Currently, many investigators de-escalation of their chemotherapy and centers have moved towards and radiotherapy and still get the organ preservation treatment. same results. The currently accepted standard Multimodality care of patients with of care for most cases of OPSCC OPSCC is critical for both curative utilizes radiation therapy, with purposes and functional outcomes. or without chemotherapy, as the Current treatment outside of the primary treatment modality. research trial setting should still The surgical arm of treatment focus on standard therapy with often has a diagnostic, therapeutic, multidisciplinary discussion prior to and surveillance role. An exam under treatment initiation.

CarolinasHealthCare.org/updatesincancerV3 I 5 Upper GI Malignancies improved survival, primarily by especially severe diarrhea and stabilizing disease, and was rash (7). Lapatinib may not have tolerable, about as anticipated performed as expected because with anti-VEGF monoclonal the greater toxicities that occurred antibodies (6). Additional data in combination with chemotherapy from a parallel study of paclitaxel may have resulted in lower dose with or without ramucirumab is intensity. Our future approaches Jimmy Hwang, MD expected. will focus on innovative therapies Medical Oncology Hecht presented a that add both clinical relevance to phase III study evaluating statistical significance. Progress in the treatment of lapatinib in HER-2 amplified Optimism about the metastatic gastroesophageal metastatic gastroesophageal potential of targeted therapy adenocarcinomas at the ASCO cancers has been slow. In patients in gastroesophageal cancer with HER-2 overexpressing/ amplified disease, the ToGA study proved the addition Chemotherapy/Lapatinib Chemotherapy Comment of trastuzumab to cisplatin/ Median Survival 12.2 months 10.5 months HR=0.91 (P=0.35) fluoropyrimidine therapy Median PFS 6.0 months 5.4 months HR 0.82 (P=0.10) improved survival (1). Since Objective Response 53% 40% then, other molecularly-targeted therapies, including bevacizumab, TABLE 2: Capecitabine/Oxaliplatin with or without Lapatinib as First-Line Therapy in cetuximab, panitumumab, Metastatic Gastroesophageal Cancer (from Hecht et al, 7) and everolimus failed to show significant survival benefits in large randomized trials (2-5). 2013 has annual meeting (Table 2). Patients continues. Further exploration produced mixed results. were randomized to oxaliplatin of HER-2 targeting therapies At the Gastrointestinal Cancer and capecitabine (850 mg/m2 persists with pertuzumab (with Symposium, Fuchs reported a BID D#1-14) every three weeks trastuzumab), and ado-trastuzmab- phase III study in the second-line with either lapatinib 1250 mg emtansine (T-DM1), in the setting comparing ramucirumab daily, or placebo. Adding lapatinib initial and second line settings (IMC 1121), a fully human to chemotherapy increased respectively, based on their monoclonal antibody targeting overall survival somewhat, efficacy in breast cancer. VEGF Receptor 2, to placebo but not significantly. However, Immunotherapy, especially (Table 1). Ramicirumab significantly lapatinib also increased toxicity, the PD-1 pathway, is an area of investigation in many malignancies, which may Ramucirumab Placebo Comment overexpress the ligands PDL-1 Median Survival 5.2 months 3.8 months HR 0.776 (P=0.0473) or PDL-2, thereby suppressing 1-year Overall Survival 18% 11% immune surveillance. Inhibiting interactions between PD-1 and its Median PFS 2.1 months 1.3 months HR=0.483 (P<0.0001) ligands, currently with antibodies, 12 week PFS 40% 16% may help eradicate malignancy. Objective Response Rate 3.4% 2.6% Data from patients with gastric Disease Control Rate 49% 23% P<0.0001 cancer suggests that targeting the

TABLE 1: Ramucirumab as Second-line therapy in Metastatic Gastroesophageal Cancer PD-1 pathway is beneficial (8). (From Fuchs et al, 6) Another promising target is c-Met, a tyrosine kinase receptor activated by its ligand HGF

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6 I UPDATES IN CANCER FOR CLINICIANS A PUBLICATION OF CAROLINAS HEALTHCARE SYSTEM

FLIMS Quality of Life Upper GI Malignancies Workshop Recap Improvements in continued from page 6 Sarcoma Therapy (hepatocyte growth factor). continued from page 1 About half of patients with gastroesophageal cancers Ifosfamide+ mesna is a express c-Met, making this is an commonly used regimen for attractive target (9). Onartuzumab treatment of bone and soft tissue (MetMAb), a monoclonal sarcomas. Dr. Anderson recently antibody targeting c-Met, is being Kathryn F. Mileham, MD published stability results so evaluated in randomized studies in Medical Oncology pharmacies have information combination with oxaliplatin/5FU for prolonged seven- or 14-day (FOLFOX). Tivantinib (ARQ197), a infusions. The excellent stability tyrosine kinase inhibitor of c-Met, Kathryn R. Mileham, MD, of ifosfamide+ mesna at 20 mg/ is also being evaluated with Medical Oncologist at Levine mL for seven and 14 days allows FOLFOX. Cancer Institute, part of Carolinas portable pumps and outpatient Hopefully, we are entering an HealthCare System, was selected to treatment. Use at Levine Children’s era in gastroesophageal cancer attend the 15th annual Methods in Hospital and Levine Cancer where treatment decisions will Clinical Cancer Research Meeting in Institute will involve rental/ be determined by the patient’s Flims, Switzerland. Dr. Mileham was consignment of reliable pumps by and their tumor’s molecular one of five delegates from North InfuSystem. Oncology pharmacy characteristics. America selected to attend this will provide the mesna + ifosfamide prestigious international workshop, in a 200-1000 mg bag to be carried REFERENCES: which focuses on the development in a backpack, handbag or other 1. Bang Y-J, et al. Lancet 2010; 376: 687- 697. of protocols and translational bag. This should offer an easy and research studies. Dr. Mileham’s study 2. Ohtsu A, et al. J Clin Oncol 2011; 29: reliable means to give ifosfamide/ 3968-3976 proposal centered on targeting mesna to patients on an outpatient 3. Lor dick F, et al. Lancet Oncology 2013; specific biomarker pathways in early basis. The Infusystem is also useful 14: 490-499 stage lung cancer patients. 4. W addell T, et al. Lancet Oncology 2013; for overnight mesna infusions after 14: 481-489. cyclophosphamide. Using this set 5. V an Cutsem E, et al. J Clin Oncol 30; up, both Levine Children’s Hospital 2012 (suppl 4; LBA3). and Levine Cancer Institute can 6. Fuchs CS, et al. J Clin Oncol 30; 2012 Novel Approaches (suppl 34; abstract LBA5) facilitate more outpatient-friendly 7. Hecht JR, et al. J Clin Oncol 31, 2013 for Bone Metastasis sarcoma therapy. (supl; abstract LBA 4001). continued from page 4 Finally, there is a new targeted 8. Saito H, et alJ Surg Oncol 2013; 107: alpha-emitting radiopharmaceutical 517-522. 9. Blumenschein GR, Jr, et al. J Clin Oncol for bone metastases, radium-223. the benefits and favorable side 2012; 30: 3287-3296. This drug (Xifigo) is FDA approved effect profile observed in this trial, for prostate cancer, but should also expanded and evolving indications become a useful adjunct in the will likely be forthcoming. treatment of osteosarcoma. The REFERENCES: advantage of alpha emitters is low 1.Laufer, I., et al., The NOMS framework: marrow toxicity and less likelihood approach to the treatment of spinal of resistance, since the high energy metastatic tumors. Oncologist, 2013. 18(6): p. 744-51. charged alpha particles cause 2.Sahgal, A., et al., Probabilities of difficult-to-repair double strand radiation myelopathy specific to breaks in cancer cells. Thus, axial stereotactic body radiation therapy to or metastatic cases may have new guide safe practice. Int J Radiat Oncol Biol Phys, 2013. 85(2): p. 341-7. and better means to facilitate 3.Finlay, I.G., M.D. Mason, and M. Shelley, control, with or without surgery or Radioisotopes for the palliation of external beam radiotherapy. Since metastatic bone cancer: a systematic the radiopharmaceutical acts like review. Lancet Oncol, 2005. 6(6): p. 392-400. calcium and is incorporated into 4.Parker, C., et al., Alpha emitter new bone, the screening test is radium-223 and survival in metastatic a routine bone scan to identify prostate cancer. N Engl J Med, 2013. osteoblastic lesions amenable to 369(3): p. 213-23. this new alpha radiotherapy.

CarolinasHealthCare.org/updatesincancerV3 I 7 Personalized Leukemia Care in the Carolinas

Current risk assessment is primarily remission, based on existing based upon cytogenetic and clinical parameters) are likely to molecular characteristics. These relapse.1 Such assays potentially features help identify poor risk offer another manner in which patients who might benefit from leukemia care can be personalized. consolidation with allogeneic BMT Patients with persistent LSCs (thus, and provide promising targets for at high risk of eventual relapse) Michael Grunwald, MD (left) both current and future therapies. can be assigned to more intensive Medical Oncology Despite this progress, most AML therapy such as BMT or to a patients who achieve complete clinical trial. Jonathon Gerber, MD (right) Levine Cancer Institute will soon Medical Oncology remission are not ultimately cured. Existing risk factors are be offering clinical trials with novel not able to prognosticate well for targeted agents for hematologic individual patients, particularly malignancies. We will have the Levine Cancer Institute is those in the favorable and ability - also via a clinical protocol - removing obstacles to the care of intermediate risk groups. The to assess for the presence of LSCs oncology patients by delivering leukemia stem cell (LSC) model after treatment. This assay will cancer care closer to home. This has gained acceptance as a allow us to determine which novel summer witnessed the inception potential explanation as to why agents are active against the LSCs of the leukemia program within remission often does not translate and, thus, have curative potential. the Department of Hematologic to cure. Standard chemotherapy is This ability to personalize therapies Oncology and Blood Disorders. typically effective at wiping out the and administer them locally The leukemia program provides differentiated bulk of the leukemia, whenever feasible will ensure that cutting edge care for patients with but emerging data suggests that Levine Cancer Institute delivers acute and chronic leukemias, as the LSCs are more resistant. The the best care possible for patients well as myelodysplastic syndrome few surviving LSCs may be too few with leukemia. and the myeloproliferative in number to detect by clinically neoplasms. With the planned REFERENCES available means. In such cases, the 1. J. M. Gerber et al., Blood 119, 3571 opening of the blood and marrow patient appears to be in complete (2012). transplant (BMT) unit in early remission. However, any remaining 2014 and the introduction of new LSCs ultimately regenerate the clinical studies, Levine Cancer leukemia, with resultant clinical Institute will offer optimal and relapse. As such, only those comprehensive care to leukemia patients in whom the LSCs are fully patients throughout the Carolinas. eradicated would be predicted to Personalization has increasingly attain cure. become a goal of leukemia A recently developed flow treatment. Indeed, the early cytometry-based assay is proving recognition that AML is a promising in detecting LSCs and heterogeneous disease prompted predicting which AML patients efforts to risk-stratify patients. (who are otherwise in complete

LEARN MORE ABOUT LEVINE CANCER INSTITUTE AND OUR CLINICAL TRIALS: CarolinasHealthCare.org/updatesincancerV3 UPDATES IN CANCER FOR CLINICIANS

MARCH 2013

Current Updates in Immunotherapy

B7H1/B7DC ? B7H1/B7DC PD-1 - B7-1/b7-2 CD28 B7-CD28 B7-1/B7-2 CTLA-4 - SIGNAL 2 family B7RP-1 ICOS B7H3 ? - B7H4/X BTLA DENDRITIC - Asim Amin, MD, PhD MHC/pep TCR CELL OR SIGNAL 1 T CELL Medical Oncology 4-1BBL 4-1BB TUMOR CELL CD27L CD27 OX40L OX40 SIGNAL 2 Immunotherapy with Interleukin 2 TNFR/ligand LIGHT LIGHT-R family has been the mainstay for treatment 4-1BB 4-1BBL of advanced malignant melanoma and CD40 CD40L

renal cell cancer and has shown to Figure 1 induce durable responses in a select population of patients (1, 2). Advances in understanding of immune checkpoints cells (APCs) constituting signal 1. This is with the B7 family of molecules on the and key cell processes have allowed followed by modulation of the immune APC and displaces CD28 (stimulatory for development of new immune response by several other interactions signal) leading to inhibition of the T cell. modulatory approaches (CTLA-4/PD-1 between the APC and the T cell – signal Blocking of the CTLA-4 molecule (the inhibition) and targeted therapy (BRAF/ 2 (fig. 1) (3). Initially, interaction of an brakes for the immune system) results in MEK inhibition, VEGF/mTOR inhibition) immune-stimulatory molecule CD-28 uninhibited activity of the T cell that has for both disease processes that are expressed on the T cell with B7 family of been shown to translate into clinically applicable to most of the population. molecules on the APC results in activation relevant anti-tumor activity. Generation of anti-tumor immune of the T cell (fig. 2). Subsequent down- Ipilimumab, an IgG1 antibody directed response by T lymphocytes is a complex regulation of the T cell activation ensues against the CTLA-4 molecule has process that requires primary antigen with expression of an inhibitory molecule shown objective response as well as presentation in the context of self-HLA CTLA-4 (cytotoxic T lymphocyte antigen survival advantage in several phase II, molecules by the antigen presenting 4) on the activated T cell (red) that interacts as well as two phase III, trials in patients

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Stay Connected for Clinical Updates and Download The Cancer Letter, Updates from Options for Featuring Levine Cancer Institute: Creating Excellence in Message from Society of Metastatic Updates from GI Care and Biomarker the President Neuro-Oncology Castrate Resistant ASCO 2013 www.carolinashealthcare.org/updates-in-cancer Driven Research 2013 Prostate Cancer Message from the President of Levine Cancer Institute

In this issue, we have included updates I hope you find this interesting – please from the recent ASCO GI and GU feel free to contact me with any topics meetings, featuring new data that may you’d like to see covered in future issues. influence your patterns of practice. In Visit www.levinecancerinstitute.org/ addition, we thought that the associated updates-in-cancer to sign up to receive features on neuro-oncology and the updates from Levine Cancer Institute or emerging roles of immunotherapy might download your free copy of The Cancer Derek Raghavan, MD, PhD be useful to you. Letter, with coverage written about the President We were very gratified to see the recent Institute.* coverage of our new research and Dear Colleagues, administrative headquarters along with Sincerely, I’m pleased to present the second issue our academic and clinical programs in of Updates in Cancer for Clinicians for your two back-to-back issues of The Cancer review. Levine Cancer Institute is creating Letter, and I thought you might be and distributing these publications as a interested to read an independent view service to our collaborating clinicians. The of our work. Paul Goldberg, a highly intent is to provide useful information to keep respected medical journalist known for you abreast of the latest developments in his tough coverage of cancer centers, We welcome your feedback at oncology while featuring our new programs spent a couple of days looking at Levine [email protected] offered at Carolinas HealthCare System’s Cancer Institute, and seems to have and look forward to bringing you more Levine Cancer Institute. been impressed with what he saw! news in the future!

Levine Cancer Institute featured in a two-part series by The Cancer Letter.

Vol. 39 No. 1 Jan. 4, 2013

© Copyright 2013 The Cancer Letter Inc. All rights reserved. Price $405 Per Year. To subscribe, call 800-513-7042 or visit www.cancerletter.com. Vol. 39 No. 2 Jan. 11, 2013

PO Box 9905 Washington DC 20016 Telephone 202-362-1809 © Copyright 2013 The Cancer Letter Inc. The Raghavan Experiment The Raghavan ExperimentPO Box 9905 Washington DC 20016 Telephone 202-362-1809 All rights reserved. Price $405 Per Year. An Irrational System: To subscribe, call 800-513-7042 or visit www.cancerletter.com. With $500 Million to Draw On, An Iconoclast An Outside Analysis of The Raghavan Experiment American HealthcareBlazing the Pathways: Informatics Platform Invents Rational Care for a Gigantic System . . . Page 3 This is the first story in a two-part series exploring an attempt by Provides Foundation for "Center Without Walls" one regional heath care organization to devise a better system for delivery This is the second article in a two-part series exploring an attempt of cancer care to 14,000 new patients a year. The Question of Cost By Paul Goldberg by. .one . Page regional 5 heath care organization to devise a better system for delivery of cancer care. The first article appeared in CHARLOTTE, N.C.—The job offer presented to Derek Raghavan late The Cancer Letter. The Raghavan Experiment An audio recording of a conversationthe with Jan. Raghavan 4 issue of in 2010 had the look of a dare. A Convergenceis available of on The Cancer Letter website. Building a "Nationally A vast health system in North and South Carolina was asking him to Academic And Prominent Cancer Center" Community Practice create a better way to practice oncology. . . . Page 7 By Paul Goldberg . . . Page 2 Raghavan, a medical oncologist who came to the U.S. from Australia CHARLOTTE, N.C.—The Carolinas Health System was looking for the next big therapeutic area to develop. in 1991, sees this country’s healthcare system with clarity of an outsider. Creating Research “We started as every other health system in the country started—and His public persona here is shaped largely by years of service on the FDA In Brief that was by embracing cardiovascular services,” said Paul Franz, an Infrastructure Oncologic Drugs Advisory Committee, where he established himself as the Menendez and Allison of the massive organization. “It’s common knowledge that cardiovascular . . . Page 3 sort of guy you don’t want to match wits with. Move fromservices USC are the best market share opportunity, and also happens executiveto be the The job offer had the feel of Raghavan’s own precisely aimed, lethal, To Cedars-Sinaimost profitable service line.” Edward Kim Creates Australian-accented remarks. . . . Page 11 It boiled down to this: Oncology made sense. Pathways for LCI In 2007, when the system first focused on cancer, its hospitals were So Derek, you have, on numerous occasions, trashed the way America . . . Page 5 FDA Newstreating about 10,000 new patients a year, a considerable number. (Now, it’s treats cancer. You have cast ridicule and moral indignation at the cooperative treating about 14,000.) groups, pharmaceutical companies, the NCI. Premarket Approval Pathways in Action Now, create a system that meets your own exacting specifications, old AwardedThe to competitionBreast was weak. There were excellent cancer centers along (Continued to page 2) the system’s boundaries, but not in its core area around Charlotte. “There . . . Page 6 mate. Cancerwas no Tissue one who was performing at anywhere close to a national prominence Assessment Tool On NCI Designation level,” said Franz,. . . Page executive 12 vice president of the Physician Services Group. Fiscal Cliff Patients usually saw general oncologists at local practices. If those And Strategic Plans Sequestration Delayed for Two Months patients had more complicated diseases and the money to travel, they left . . . Page 9 to get care elsewhere. The opportunity to fill the vacuum was even more While Congress DebatesBy Conor Hale Debt and Budgets obvious because changes in reimbursement were weakening physician- Early Detection owned, office-based practices—potentially making doctors more willing to Through a series of hurried negotiations and late-night bills, lawmakers American Cancer Society join hospitals. Hospitals, on the other hand, remained robust, in part because Publishes CT Screening in Washington narrowly avoided the worst punishments of the fiscal cliff—but they can charge higher rates. *Permission to distribute has been granted from The Cancer Letter. set up another crisis by postponing the automatic federal(Continued budget to cuts page until 10) Guidelines for Lung Cancer March 1. . . . Page 10 In Brief (Continued to page 5) Capitol Hill Goodfellow Moves to Ohio State University Report to the Nation I UPDATES IN CANCER FOR CLINICIANS 2 Pres. Obama SignsBy Matthew Recalcitrant Bin Han Ong Cancer Bill PAUL GOODFELLOW Annual Report Shows gynecologic oncology research at Thewill Ohiolead aState new University research team Comprehensive devoted to Decreasing Overall President Barack Obama signed a bill Jan. 2 requiring(Continued NCI toto pagedevelop 10) Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Cancer Death Rates scientific frameworks for “recalcitrant” cancers. Research Institute. . . . Page 10

(Continued to page 11) A PUBLICATION OF CAROLINAS HEALTHCARE SYSTEM

Creating Clinical Excellence in Patient Care and Biomarker Driven Research

NON-SMALL CELL LUNG CANCER Non-Small Cell Lung Cancer

Clinical Trial

Pathway 1 (Carboplatin/premetrexed/bevacizumab*) Preferred

Pathway 2 (Carboplatin/paclitaxel/bevacizumab*) • Non- Observation or • Maintenance Squamous Pathway 3 (Platinum/pemetrexed) cell carcinoma

Edward S. Kim, MD (left) Acceptable Pathway 4 (Carboplatin/paclitaxel) Tumor Pathway 5 (Carboplatin/gemcitabine) Chair of the Department of Solid Tumor response Pathway 6 (Carboplatin/docetaxel) evaluation Oncology and Investigational Therapeutics First-line chemotherapy Blood (4 cycles) Collection Protocol Pathway 7 (Carboplatin/nab-paclitaxel) •Progression PhD (right) (subsequent Carol Farhangfar, Pathway 8 (Carboplatin/gemcitabine) chemotherapy) Assistant Vice President of Tissue Procurement Preferred Squamous cell and Research carcinoma Pathway 9 (Carboplatin/docetaxel) Acceptable Pathway 10 (Carboplatin/paclitaxel) The challenge of uniting a system with Note: Clinical * Bevacizumab use preferred if patient eligible: multiple hospitals and clinics across a Non-squamous trial Age < or equal to 70 years large geographic distribution can be participation No history of gross hemoptysis encouraged Stable or treated brain metastasis daunting. As more options for treatment of cancer patients become approved, the struggle for community medical oncologists becomes more daunting. We have embarked on several to be informed of the latest treatment support clinical and translational initiatives to create a system that pathways. There will also be access research with a suite of molecular delivers similar clinical care and at the to standardized chemotherapy orders, platforms supported by a centralized same time, raises awareness for the informed consents, drug toxicity forms, biospecimen repository. Ultimately, clinical trial opportunities. chemotherapy teaching sheets, etc. In we plan to make molecular testing Treatment guidelines were created order to facilitate awareness of clinical platforms available where appropriate through working groups utilizing many trials, this clinical pathway tool will for all cancer patients. The platforms sources, but most importantly their own display the open clinical trials in “real- will include molecular analysis tools practice patterns. Once a consensus time” fashion. such as mutation analysis, copy number, was reached, the guidelines were Our vision at LCI is to create a network rearrangements, and others needed formalized and placed online. The that is consistent in clinical care, for our research programs. We will working groups became the tumor proactive in accrual to clinical trials, work closely with our colleagues in the sections and meet monthly. Guideline and broad specimen collection for Cannon Research Center, Molecular updates are considered each month molecular analysis. Both new standard Pathology, our research laboratories and depending on the amount of new data treatment regimens and clinical trials many others to establish best practices. being reported. are becoming more integrated with A systematic collection of residual tissue As the pressures mount on seeing molecular analysis. For example, that can be utilized for retrospective more patients and in a timely manner, one of the best known examples is studies combined with specific statistics have shown that national treatment of patients with BRaf V600E collections to support clinical trials, in accrual rates to clinical trials have been mutant melanoma with vemurafenib particular investigator-initiated studies, poor. This has been based on many with new discoveries quickly be added will be developed. Clinical annotation reasons including limited eligibility, poor to the molecular testing and targeted of the specimens collected is crucial to variety, time to enrollment, etc. treatment repertoire. support this effort. We plan, as a team, The clinical pathway tool will be We envision adding this type of to lead the way integrating advanced implemented this year for all affiliated transformative approach for patient genomic and molecular testing into our clinicians within our Levine Cancer care and translational research at clinical treatment pathways for cancer Institute system. This electronic internet- Levine Cancer Institute and Carolinas patients in the community. based system will allow practitioners Healthcare System. Our goal is to

www.carolinashealthcare.org/updates-in-cancer I 3 The Levine Cancer Institute Charter Hospital System: Carolinas Medical Center-NorthEast

North Carolina greater access to world- and addressing those issues through renowned cancer specialists, treatment transportation, home healthcare, options and clinical trials when and community education and other means. where they’re needed most. Levine And because of the breadth and depth Cancer Institute is changing the course of Carolinas HealthCare System, the of cancer care by removing the barriers Institute is also able to conduct more that separate patients from world-class research and collaborate with more Garry Schwartz, MD (left) research, breakthrough treatments and cancer specialists. Drs. Steffens and Medical Oncology quality cancer care. Schwartz represent oncology specialists Work is well under way to develop who collaborate closely with the Institute Thomas Steffens,MD (right) even more survivorship and outreach participating in pathway development Medical Oncology programs in the counties surrounding and clinical research. CMC-NorthEast. Levine Cancer Institute The relationship between Levine Cancer offers a full spectrum of services to Institute, CMC-NorthEast and the other As part of Levine Cancer Institute support patients before, during and after member institutions located throughout and Carolinas HealthCare System’s treatment, to improve long-term care and the Carolinas brings increased access charter membership, Carolinas Medical patients’ quality of life. The Institute and to cancer specialists, research and Center-NorthEast, located in Concord, CMC-NorthEast are piloting programs innovative programs and services to N.C., provides patients in Cabarrus, to understand the accessibility issues patients closer to where they live. Rowan and surrounding counties in cancer patients in rural areas face

CMC-NorthEast Stanly Regional Medical Center

CMC-Lincoln CMC-University

CHANGING THE COURSE OF CANCER CARE

CMC-Union

4 I UPDATES IN CANCER FOR CLINICIANS A PUBLICATION OF CAROLINAS HEALTHCARE SYSTEM

Advances in Gliobastoma Updates from Society of Neuro-Oncology 2013

Should bevacizumab be given in dilemma have been initiated by RTOG newly diagnosed glioblastoma? Can (RTOG 0825) and Roche (AVAglio). we improve the median overall survival AVAglio is a large, randomized, double- as reported by Stupp to be 14.6 blind, placebo-controlled, phase III trial months? Opinions differ and much has evaluating the addition of bevacizumab been offered anecdotally on the topic. to the current standard of care for newly Evidence has been sparse on the topic, diagnosed glioblastoma. Patients had and no randomized trials have been Ashley Sumrall, MD (left) acceptable KPS scores and were all Neuro-Oncology, Medical Oncology completed. Safety of administering ages. Approximately 90 percent of bevacizumab in the newly diagnosed the sample consisted of patients who Dan Haggstrom, MD (right) setting was deemed acceptable based had maximal tumor resection. In total, Medical Oncology on data from several small pilot studies. more than 900 patients were enrolled at A nonrandomized, phase II study more than 140 centers worldwide. At from Duke followed 75 patients with the recent Society of Neuro-Oncology newly-diagnosed glioblastoma who Annual Meeting in Washington, DC, received concurrent chemoradiotherapy preliminary results from AVAglio and bevacizumab. Median overall were released to much anticipation. survival (as measured from time of Investigators reported a 36 percent enrollment) was 21.2 months and risk reduction in progression of disease median progression-free survival or death. Median PFS of 10.6 months topped 14 months (95 percent CI: 12- from time of enrollment was observed MD (left) Stuart Burri, 16). Another nonrandomized study (compared to 6.2 months in the control Radiation Oncology from UCLA followed 70 patients with arm). Investigators reported significant glioblastoma. They received similar improvements in standardized quality- Anthony Crimaldi, MD (right) Radiation Oncology therapy with bevacizumab. Median of-life assessments between the arms. overall survival (as measured from Also, average steroid requirements date of diagnosis) was 19.6 months were lower in the experimental arm. and median progression-free survival There is no doubt that the overall was just shy of 14 months (95 percent survival data from this study will be CI: 11-16). These data appear similar, anxiously awaited. The RTOG 0825 but the different definitions of survival data will hopefully mature soon, and will are significant. Attempts to solve the likely enrich this ongoing discussion.

Anthony Asher, MD, FAANS, FACS (left) Neurological Surgery

Morgan Stuart, MD (right) Neurological Surgery

www.carolinashealthcare.org/updates-in-cancer I 5 Current Updates in Immunotherapy

CONTINUED FROM PAGE 1

ANTI PD 1 PD-L1/B7H1 PD-L2/B7DC

APC TCR PD 1

B7 CD 28 T T APC PD 1 PD-L1/B7H1 CTLA 4 IPILIMUMAB TUMOR ANTI PD 1

Figure 2 Figure 3

with advanced melanoma (4, 5). The 1) is yet another inhibitory checkpoint advanced melanoma whose disease treatment is generally tolerated well, expressed on the surface of T cells that has progressed after treatment with but may result in toxicity peculiar to the can interact with its ligands PDL-1 and CTLA-4 inhibition. mechanism of action (uninhibited T cell PDL-2. Interaction with either results In the context of immunotherapy, yet activation) in the form of auto-immune in suppression of the T cell (fig. 3). another approach has been to harness breakthrough events (dermititis, colitis, Interestingly, PDL-1 may be expressed the activity of APCs for more effective endocrinopathy, hepatitis) that if not not only on APCs but some tumor presentation of tumor antigen to the T recognized and managed appropriately cells thereby providing a potential cells. A study using autologous tumor can result in significant morbidity and protective mechanism directly to the mRNA from the kidney tumor harvested even death. tumors against immune anti-tumor at the time of nephrectomy for priming Identification of mutant BRAF (a mechanisms. Blocking of the PD-1 of autologous APCs in combination with component of the MAP kinase signaling molecule with an anti-PD-1 antibody sunitinib showed improvement in overall pathway) in almost 50 percent of results in preventing the T cell to be survival for intermediate and poor risk cutaneous melanomas has led to switched off and thereby exert anti- patients compared to historical controls the development and approval of tumor effect. In the phase I setting PD-1 treated with sunitinib alone (8). We are vemurafinib, a BRAF inhibitor (BRAFi) inhibition has exhibited responses in now embarking on a phase III study having shown survival advantage in a the range of (20-30 percent) in various to confirm addition of immunotherapy phase III study (6). Responses observed tumor types including, melanoma, renal adds durability to responses observed with BRAFi are rapid and substantial cell carcinoma and non-small cell lung with VEGF inhibition alone. however generally not durable. cancer (7). REFERENCES: 1. Atkins M.B. et al. J Clin Oncol. 1999;17:2105 We are currently in the process of We are currently studying the 2. Fyfe G et al. J Clin Oncol. 1995;13:688 3. Topalian et al. J Clin Oncol. 2011;29:4828 studying the combination of BRAFi combination of VEGF tyrosine kinase 4. Hodi S et al. (10.1056/NEJMoa1003466) published on June 5, 2010, updated on June 14, 2010, at NEJM.org. followed by immune modulation with inhibition in combination with anti-PD-1 5. Robert C et al. (10.1056/NEJMoa1104621) published on June 5, 2011, at NEJM.org. CTLA-4 inhibition and the role of vertical therapy for patients with advanced 6. Chapman et al. N Engl J Med 2011;364:2507 7. Topalian S et al. N Engl J Med. 2011;366:2443 blockade with BRAF and MEK inhibition. renal cell carcinoma and the role of anti- 8. Amin A et al. ASCO GU Symposium 2013. Abstract #357 PD-1 (programmed cell death protein PD-1 monotherapy for patients with

6 I UPDATES IN CANCER FOR CLINICIANS A PUBLICATION OF CAROLINAS HEALTHCARE SYSTEM

Expanding Options for Patients with Metastatic Castrate Resistant Prostate Cancer

Improved understanding and arm (8.3 vs. 16.5 months, p <0.001). pharmacologic targeting of the These results led to an expanded FDA androgen pathway has recently approved indication to include men benefited patients with advanced previously untreated with docetaxel, prostate cancer following regulatory providing an effective new treatment approval of abiraterone and option for patients prior to or in lieu of enzalutamide in this population. chemotherapy. Earle Burgess, MD (left) Abiraterone acetate, a potent inhibitor Enzalutamide, a high affinity androgen Medical Oncology of CYP17, impairs adrenal androgen receptor antagonist, has also recently synthesis leading to greater reduction demonstrated an impressive 4.8 MD (right) Steve Riggs, of systemic testosterone levels than month overall survival benefit in men Urologic Oncology achieved with medical or surgical with advanced, castrate-resistant castration alone. The importance prostate cancer after prior docetaxel of targeting extragonadal androgen (3). Like abiraterone, enzalutamide synthesis was underscored by the is anticipated to demonstrate activity results of the COU-AA-301 trial(1). in the pre-chemotherapy setting, In this randomized phase III trial, though until results of the PREVAIL trial patients with metastatic, castrate (NCT01212991) are available, routine resistant prostate cancer, previously use should be reserved for patients treated with docetaxel, received previously treated with docetaxel. John Mahoney, MD (left) either abiraterone or placebo with Although the activity of these new Medical Oncology prednisone. The trial was unblinded agents highlights the critical role following preplanned interim analysis androgen signaling continues to play Kris Gaston, MD (right) showing a 3.9 month overall survival in driving prostate cancer progression Urologic Oncology benefit in the abiraterone arm, following castration, pharmacologic providing the basis for FDA approval targeting of other molecular pathways of abiraterone after chemotherapy. is also showing promise. c-MET Often patients with castrate resistant is an oncogenic receptor tyrosine disease are not ideal candidates for kinase that is inhibited by the small docetaxel-based therapy due to age molecular cabozantinib. A randomized or medical comorbidities; therefore, phase II trial of cabozantinib in men the findings of the companion COU- with advanced prostate cancer was AA-302 trial are of particular interest halted early on the basis of significant to practioners (2). In this study, men radiographic and clinical benefit with chemonaive metastatic, castrate- observed in the cabozantinib arm (4). resistant prostate cancer also received The results of ongoing phase III trials either abiraterone or placebo with of cabozantinib in advanced prostate prednisone. With a median follow up cancer are eagerly anticipated. duration of 22.2 months, abiraterone REFERENCES: 1. de Bono et al. NEJM Vol 364 2011, p.1995 plus prednisone reduced the risk of 2. Ryan et al. NEJM Vol 368 2013, p. 138 3. Scher et al. NEJM Vol 367 2012, p.1187 death or radiographic progression by 4. Smith et al. JCO Epub 2012 Nov 19 47 percent compared to the placebo

www.carolinashealthcare.org/updates-in-cancer I 7 Updates from GI ASCO 2013

At the 2013 GI ASCO, Daniel von Hoff Another intriguing study was the and colleagues presented the results SCALOP trial, which studied the of MPACT, a large randomized trial approach of induction chemotherapy evaluating the combination of nab- with gemcitabine plus capecitabine, paclitaxel plus gemcitabine versus followed by concomitant radiation with gemcitabine alone in patients with either gemcitabine or capecitabine. metastatic adenocarcinoma of the The combination of gemcitabine plus Jean Chai, MD (left) pancreas. The experimental arm gave radiation was associated with increased Medical Oncology Nab-paclitaxel at 125 mg per meter fatigue and hematologic toxicity, while squared and gemcitabine at 1000 mg achieving inferior 9-month progression Reza Nazemzadeh, MD (right) per meter squared on days 1, 8 and 15 free survival (gemcitabine 51.4 percent Medical Oncology every 28 days. The control arm used vs capecitabine 62.9 percent) and gemcitabine dosed at 1000 mg per overall survival (gemcitabine 13.4 meter squared weekly for 7 weeks then months vs capecitabine 15.2 months). on days 1, 8, and 15, every 4 weeks. 861 In gastric and GEJ cancers, two patients received treatment between the interesting studies were presented. The two arms. The experimental arm had an COUGAR-02 trial confirmed a survival overall survival of 8.5 months compared benefit with second line chemotherapy to 6.7 months with single agent compared to best supportive care in gemcitabine. While this improvement a very nice randomized trial from the Stuart Salmon, MD (left) was modest, the one-year survival was UK. This trial studied second line Medical Oncology 35 percent in the experimental arm docetaxel in patients with gastric, which was significantly greater than the esophageal, and GEJ cancer. Overall Josh Hill, MD (right) control arm at 22 percent. There was survival with docetaxel was 5.2 months Surgical Oncology a two-year survival rate of 9 percent vs 3.6 months with active supportive in the experimental arm, but only 4 care, thus validating the utility of percent with single agent gemcitabine. chemotherapy in these patients While many investigators have Response rates are also increased at A novel targeted agent, Ramucirumab, spent years looking at combination 22 percent with nab-paclitaxel plus a fully human IgG1 monoclonal chemotherapy in the hopes of improved gemcitabine versus 7 percent with antibody targeting VEGF-receptor 2, survival for metastatic pancreatic cancer, gemcitabine alone was found to be active in gastric and the results have been disappointing. In Nab-paclitaxel plus gemcitabine appears GEJ cancer. Ramucirumab increased fact, single agent gemcitabine is still to be an active and more tolerable overall survival in the second line recognized as a standard treatment alternative for metastatic pancreas cancer. setting compared to placebo in a option, especially in the patients who have Reflecting the typical patient population randomized, double-blind, placebo poorer performance status. A promising in community practice, a large number controlled phase III trial. Patients treated recent advance has been an aggressive of patients with a Karnofsky performance with ramucirumab had a median combination of fluorouracil, leucovorin, status of 70 percent or greater (ECOG 0-2) OS of 5.2 months vs 3.8 months for irinotecan and oxaliplatin (FOLFIRINOX) were included and 42 percent of patients placebo. Disease control rate was 49 showing a 3.6 month survival advantage were 65 years or older. In contrast, the percent for ramucirumab compared and a response rate of more than 30 trial investigating FOLFIRINOX was to 23 percent. This will certainly lead percent. However, this has proven to be comprised of a younger cohort with to further study of Ramucirumab in a difficult regimen in clinical practice. better performance status, and yet there other settings and in combination appeared to be greater toxicity. with chemotherapy.

Stay Connected for Clinical Updates and Download The Cancer Letter, Featuring Levine Cancer Institute: www.carolinashealthcare.org/updates-in-cancer A PUBLICATION OF CAROLINAS HEALTHCARE SYSTEM UPDATES IN CANCER FOR CLINICIANS

JANUARY 2013

Updates from ASH 2012: Gene Encoding and Sequencing to Personalize Therapy

effector cells to the B cell-specific CD19 Dr. Ley summarized his own work antigen. CAR proteins expressed on T and that of others, including several cells were composed of an antibody that presentations at the meeting, using could bind to a specific target (here the whole genome sequencing to study CD19 antigen found on B cell leukemias) clonal evolution in large numbers of fused to a transmembrane domain patients with AML. By sequencing followed by one or more cytoplasmic several hundred primary tumor and Edward Copelan, MD (right) signaling domains to generate relapse genomes, Ley and colleagues Chair of the Department of Hematologic Oncology proliferative and antitumor activity. A T have provided an unprecedented view and Blood Disorders cell engineered with this design could of the development and evolution of specifically recognize a leukemia cell, AML. A series of non-transforming Belinda Avalos, MD (left) kill it, disengage and kill another—then mutations appear to accumulate with Vice Chair of the Department of Hematologic age in pre-leukemic stem cells. A Oncology and Blood Disorders divide and make more engineered T cells so that one cell could kill more dominant mutation cluster consisting Two important themes of the 2012 than 1,000 leukemia cells following of genes recurrently mutated in AML ASH meeting emerged from special injection, meriting it the moniker “serial leads to leukemic transformation by a lectures given by Carl June, MD, from killer.” In addition to achieving sustained founding clone. Extensive mutational the University of Pennsylvania and complete remissions in four of nine analysis can be used to discriminate recipient of the Ernest Beutler Award, evaluable patients with refractory CLL, intermediate risk AML patients into and Tim Ley, MD, from Washington complete remission was also obtained clinically relevant groups with distinct University and E. Donnall Thomas in a child with ALL who experienced life- prognoses and to delineate patients Award recipient. Dr. June presented threatening cytokine storm associated who would and would not benefit striking results using tumor-specific with tumor lysis that was successfully from intensified chemotherapy and/ cellular immunotherapy in two lymphoid treated with TNF and IL-6 antagonists. or transplantation. Relapse of AML malignancies, CLL and ALL. June and Along with accrual of larger numbers of results either from a founding clone colleagues introduced genes encoding patients with B-Cell malignancies, new which gains mutations that confer a artificial receptors called chimeric protocols are currently being developed survival advantage or from a subclone antigen receptors (CARs) into patients’ to extend the groundbreaking work of of the founding clone, detectable at autologous T cells in vitro in order to cancer-specific T cells to pancreatic, diagnosis, which survives initial therapy, redirect the specificity of these immune prostate and breast cancer. gains new mutations and expands at

CONTINUED ON PAGE 6

Stay Connected for Clinical Updates and Download The Cancer Letter, featuring Levine Cancer Institute: New Treatment Options Development of www.carolinashealthcare.org/updates-in-cancer Message from for Lung Cancer Highlights from Targeted Translational the President Patients with EGFR SABC 2012 Chemotherapy in Science Mutations Ovarian Cancer Message from the President of Levine Cancer Institute

of Texas MD Anderson Comprehensive Cancer Center, Edward S. Kim, MD, will serve as chair of the Department of Solid Tumor Oncology. Edward A. Copelan, MD, FACP, from Cleveland Clinic’s Taussig Cancer Institute will serve as chair of the Department of Derek Raghavan, MD, PhD, President Hematologic Oncology and Blood Disorders. We have recruited more Carolinas HealthCare System’s than 50 faculty from the Carolinas and Levine Cancer Institute Research and Levine Cancer Institute is built on the across the USA. Administrative Headquarters. concept of cancer care without walls, Updates in Cancer for Clinicians will spanning throughout the system’s inform you on exiting news from Levine network of affiliated hospitals and Cancer Institute. providers in the Carolinas. The Institute is working to define the future of cancer We welcome your feedback at care – where innovations in research, [email protected] clinical trials, patient support and and look forward to bringing you more treatment are brought closer to home news in the future! for patients. We continue to build an elite cancer program, with the recruitment of A view of the infusion floor at internationally renowned experts to lead Levine Cancer Institute. the clinical teams. From the University

Translational Science Pharmacogenic Approaches to Personalize Cancer Therapy

A key event in the development of inhibiting its activity, the therapeutic AML is the disruption of the myeloid efficacy of ATRA could be potentiated. differentiation program and aberrant Specifically, the combination of ATRA self-renewal of leukemic stem cell. and topoisomerase II inhibitors, such as Differentiation therapy with the retinoic ICRF-193 or dexrazoxane (a clinically acid analog, all-trans retinoic acid active topoisomerase II inhibitor), (ATRA) has been successful in treating led to enhanced differentiation and Ram Ganapathi, PhD (left) acute promyelocytic leukemia, a preferential activation of the cell death Chair of Cancer Pharmacology cytogenetically distinct subtype of AML pathway, as compared to differentiation characterized by the PML-RARα gene coupled growth arrest induced by Marukh Ganapathi, PhD (right) translocation. However, ATRA has ATRA alone. Based on this preclinical Senior Scientist shown little promise in differentiation finding, we were able to formulate a therapy of other subtypes of AML. To clinical hypothesis that the combination Complexities in the genetic landscape develop strategies that would improve of ATRA with the clinically relevant of tumors significantly impact the differentiation therapy for other forms topoisomerase II catalytic inhibitor, design of optimal strategies for effective of AML, including relapsed/refractory dexrazoxane, leads to improved treatment of cancer. The goal of Cancer disease, we studied the role of a key response in AML patients. We are Pharmacology/Translational Research nuclear enzyme, topoisomerase II, in now poised to test this hypothesis in at Levine Cancer Institute is to support ATRA-induced differentiation of AML and develop novel paradigms for cancer cells. Using different AML cell lines and care. As such, our ongoing translational AML blast cells from relapsed/refractory CONTINUED ON PAGE 7 research has focused on the areas of patients, we were able to demonstrate acute myeloid leukemia (AML), renal cell that by targeting topoisomerase II, carcinoma and ovarian cancer. either by deleting the enzyme or

2 I UPDATES IN CANCER FOR CLINICIANS A PUBLICATION OF CAROLINAS HEALTHCARE SYSTEM

Novel Treatments for Lung Cancer Patients With EGFR Mutations

of 13.6 versus 6.9 months (HR, 0.47; molecular profiling is necessary in order p<0.0001). (2) Additionally, objective to provide the best available therapy. response rate, disease control, cancer- This requires sufficient tissue sampling related symptoms and quality of life for precise pathologic diagnosis. While were also improved with afatinib. The patients with unknown driver mutations most frequent adverse events were are still treated with chemotherapy, diarrhea and rash, although no patients those with EGFR mutations or ALK Edward S. Kim, MD (left) discontinued afatinib for rash. LUX- rearrangements have expanding options Chair of the Department of Solid Tumor Lung 3 is the first randomized study to for targeted personalized treatment. Oncology and Investigational Therapeutics demonstrate benefit of an oral targeted REFERENCES therapy versus chemotherapy in a 1. http://seer.cancer.gov/statfacts/html/lungb.html Kathryn Mileham, MD (right) molecularly selected population. Based 2. Yang JC, Schuler MH, Yamamoto N, et al. LUX-Lung 3: Medical Oncology on these results, afatinib is currently A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with available through an open label advanced adenocarcinoma of the lung harboring EGFR-activating Lung cancer remains the leading expanded access program at a starting mutations. J Clin Oncol 2012;30(suppl): LBA7500. cause of cancer-related deaths in the dose of 40 mg/daily. United States, (1) and non-small cell While management of lung cancer lung cancer (NSCLC) accounts for more is in rapid evolution the standard of than 85 percent of the cases. With most “chemotherapy for all” no longer exists. patients presenting with advanced National guidelines concur that disease, there is an urgency to maximize treatment efficacy while minimizing drug toxicity. Through a deeper EXTRACELLULAR understanding of the biology driving DOMAIN NSCLC, novel treatment paradigms EGFR HER2 HER2 are based on disease biomarkers with EGFR HER2 EGFR A HER2 corresponding targeted therapy. This HER4 HER3 has been best achieved with advanced EGFR

HER2 treatment options for the two-thirds HER3

HER4 of adenocarcinoma patients in whom EGFR driver mutations are identified. Somatic mutations in the tyrosine B kinase domain of the epidermal growth factor receptor (EGFR) are found in 15-

20 percent of lung adenocarcinomas. KINASE INTRACELLULAR TYROSINE Afatinib is an oral small-molecule DOMAIN EGFR-tyrosine kinase inhibitor that binds irreversibly to EGFR and NU HER2. Recent compelling data from CLE US the LUX-Lung 3 trial have been reported. In this randomized phase III PROLIFERATION study, patients with EGFR-mutated, PROGRESSION DIFFERENTIATION advanced lung adenocarcinomas were treated frontline with afatinib versus pemetrexed-cisplatin. The A: The epidermal growth factor family of B: Afatnib is an oral, small-molecule, EGFR- extracellular protein ligands includes cell surface tyrosine kinase inhibitor that irreversibly binds to study enrolled 345 patients and met receptors EGFR (ErB-1), HER2 (ErB-2), HER3 (ErB- the ErbB family homo- and heterodimers inhibiting 3), and HER4 (ErB-4). When EGFR is dimerized, signal transduction. its primary endpoint demonstrating intrinisic intracellular tyrosine kinase activity significantly prolonged progression is stimulated by autophosphorylation causing downstream activation and signaling leading to DNA free survival (PFS) in patients treated synthesis and cell proliferation. with afatinib (11.1 vs 6.9 months; HR, Mutations in EGFR are clustered near the tyrosine 0.58; p=0.0004). In preplanned analysis, kinase domain possibly providing stabilization and additive gain. Therapeutic approaches targeting those patients with common mutations EGFR tyrosin kinase halt this signaling cascade. (Del19 or L858R) had a median PFS

www.carolinashealthcare.org/updates-in-cancer I 3 Levine Cancer Institute: Built on the Strength of a Network

At Levine Cancer Institute we’ve developed a sophisticated The Institute’s research and administrative headquarters academic and clinical cancer institute without walls, located in Charlotte, NC, opened in October 2012. While the spanning Carolinas HealthCare System (CHS) and providing Institute functions as a series of integrated cancer programs state-of-the-art treatment and research programs are closer distributing high-quality cancer care system-wide, this to where our patients live. building serves as its center for communication, research and administration. It houses the technology infrastructure to seamlessly connect physicians and care teams and share best practices and programs. The building features nine cancer clinics, infusion therapy, palliative care, as well as cutting-edge teleconferencing technology that allows physicians to collaborate long-distance, further breaking down geographic barriers and improving care across CHS. With six floors and more than 171,000 square feet of space, the building includes an extensive clinical trials operation with a special Phase I therapeutic unit designed to evaluate new treatment options, and multidisciplinary clinics to treat complex and rare cancers. “The opening of the building is symbolic of the entire Levine Cancer Institute network being fully functioning, for the advancement of patient care across the Carolinas,” said Dr. Derek Raghavan. “The new resources and technology this space affords will enable us to be better connected to our partner institutions across the Carolinas to share knowledge, standard protocols and research, while offering patients in Charlotte a state-of-the-art CHANGING THE COURSE OF CANCER CARE place to receive their cancer care.”

Integration of Roper St. Francis Cancer Care Into Our Network

provided by Roper St. Francis Cancer is a national model that shows how we Care physicians, who help more than are investing in our community and the 1,700 newly diagnosed cancer patients lives of patients by removing barriers each year. Top tumor sites include that separate them from access to breast, prostate, lung and colorectal breakthrough research and treatments.” cancers. Roper St. Francis Cancer “ The providers and patients of Roper Care is the market leader by volume for St. Francis Healthcare are excited Steve Akman, MD, breast, prostate and colorectal cancers*. about our partnership with Levine Medical Director, Roper St. Francis Cancer Care The relationship between Levine Cancer Institute,” said Steven Akman Cancer Institute, Roper St. Francis MD, Medical Director of Roper St. In 2012, Carolinas HealthCare System’s Cancer Care and other member Francis Cancer Care. “This partnership Levine Cancer Institute announced institutions brings increased access facilitates rapid access to advanced its charter member institutions, to cancer specialists, research and cancer therapies and technologies in our including Roper St. Francis Cancer innovative programs and services to Charleston community that heretofore Care, as part of the system’s new patients closer to where they live. had only been available to institutions cancer care network. “We take cancer care very seriously. of the size and scale of Levine Cancer Roper St. Francis Cancer Center Through our elite network of affiliated Institute.” was established in 2010 through a hospitals and physicians across partnership between Roper St. Francis *Based upon 2010 data provided by the Commission on Cancer the Carolinas, we are able to bring of the American College of Surgeons Healthcare and Charleston Hematology patients the best cancer care in a Oncology Associates. The 76,000 more convenient way,” said Derek square-foot outpatient cancer center Raghavan, MD, PhD, and President of is home base for many of the services the Institute. “Levine Cancer Institute

4 I UPDATES IN CANCER FOR CLINICIANS A PUBLICATION OF CAROLINAS HEALTHCARE SYSTEM

Highlights from SABC 2012

percent for controls (absolute risk compared to 62 percent of the black reduction 3.7 percent). Breast cancer women (p<0.001). Further analysis mortality during these same years noted differences between 7 and 15 was 12.2 percent versus 15 percent, percent for every year from 2002 to for an absolute mortality reduction of 2007. With adjusted analysis, black 2.8 percent. The greatest additional women were 33 percent less likely benefit was seen in the second decade to undergo SLNB than white women Wendy Brick, MD (left) after diagnosis, as there was almost (relative risk=0.74, 95 percent CI 0.67- Medical Oncology no difference in death and recurrence 0.81, p<0.001). between the two groups during the five Black women in the U.S. have a 41 Richard White, MD, FACS (right) years of extra tamoxifen. The difference percent higher breast cancer death Surgical Oncology came in later years, consistent with rate than white women despite a lower the understanding that tamoxifen incidence. 45 percent of black women has an effect that lasts long after are diagnosed with regional or distant women stop taking it. Breast cancer disease versus 35 percent of white mortality during the second decade women [MMWR 2012]. Van Ravesteyn after diagnosis was decreased almost [2011] proposed a model suggesting 30 percent in women who continued that differences in screening use tamoxifen for 10 years. explained 8 percent and differences in These results are relevant for any adjuvant therapy explained 19 percent woman currently taking tamoxifen and of these disparities. Methods to address Steven Limentani, MD (left) may be even more so for premenopausal disparities are being tested throughout Medical Oncology women, who have little risk of tamoxifen the U.S. and are critical to changing the causing uterine cancer or venous course of cancer care. MD, FAC Teresa Flippo-Morton, (right) thrombotic events. Women and their REFERENCE: Surgical Oncology doctors should consider this evidence Black DM, San Antonio abstract 2012 when deciding how long to continue Axillary Node Dissection May The ATLAS Trial: tamoxifen or any other endocrine therapy. Not Be Needed For Everyone Treatment Implications Evaluation of the long-term side ACOSOG Z-1071 studied the use of While current treatment guidelines effects of longer term tamoxifen sentinel node biopsy in a group of women recommend that women with estrogen will require lengthier follow up and with breast cancer who had previously receptor positive breast cancer receive meta-analysis of all relevant trials for been considered contraindicated for anti-estrogen therapy for five years, final assessment. this procedure; biopsy-proven node the recently published results of the REFERENCE: positive women. This multicenter trial Adjuvant Tamoxifen: Longer Against The Lancet, 2012 DOI: 10.1016/S0140-6736(12)61963-1 enrolled 756 women with node positive Shorter (ATLAS) results suggest that 10 breast cancer. years of adjuvant treatment should be Racial and Staging Disparities All patients received neoadjuvant considered for some women. Racial disparities in the care of chemotherapy prior to surgery. All The international trial recruited women with breast cancer have women had re-evaluation of the axilla patients from 1996-2005 and enrolled become the norm rather than the with ultrasound and then surgery patients were randomized to stop exception (MMWR 2012, Lund 2008, with a sentinel lymph node procedure tamoxifen at five years (control) van Ravesteyn 2011). Investigators (encouraging both blue dye and or continue for a total of 10 years. from MD Anderson Cancer Center radionucleotide for mapping), followed Allocation to continue tamoxifen for used SEER Medicare data to assess by complete axillary node dissection. 10 years versus stopping at five years the utilization of the relatively new reduced breast cancer recurrence (617 technology of axillary sentinel lymph CONTINUED ON PAGE 6 recurrences in 3,428 women allocated node biopsy (SLNB) in the staging of to continue versus 711 in 3,418 controls women with breast cancer. The use of p=0.002) and breast cancer mortality SLNB was compared in white women (311 deaths with recurrence in women versus the use in black women. allocated to continue versus 397 in 5.7 percent of 31,274 women controls p=0.01). Risk of recurrence retrieved from the database were black during years 5-14 was 21.4 percent while 89 percent were white. 74 percent for continuing tamoxifen versus 25.1 of the white women underwent SLNB,

www.carolinashealthcare.org/updates-in-cancer I 5 Highlights from SABC 2012

CONTINUED FROM PAGE 5 treated in the neoadjuvant setting TDM-1, Docetaxel and revealed eight of nine (88 percent) Results demonstrated that 40 percent Pertuzumab in Breast Cancer treated with the doublet and three of of patients with positive sentinel lymph Patients five (60 percent) treated with the triplet node prechemotherapy had a complete T-DM1 is a drug in which Trastuzumab regimen achieved a pathologic complete pathologic response in the axilla. The has been covalently linked to a novel response in the breast and lymph nodes. false negative rate of the procedure was chemotherapeutic emtansine, also More data will be available once all 12.6 percent, though the SLN procedure known as DM1. Pertuzumab, in contrast, patients have undergone the surgical was able to correctly identify nodal interferes with her2- her3 dimerization, portion of their treatment. Although the status in 91 percent of patients. Further a novel action different from the numbers are small, the rate of pathologic evaluation of the data is needed before mechanism action of Trastuzumab. complete response is encouraging. Data this can routinely change practice, but it This phase I dose escalation study will be utilized as the basis for a phase III does give hope that a subset of women was performed beginning with stage IV randomized trial that will compare these with node positive disease in the axilla disease patients, but also those with combinations to the current standard may, in the future, be able to omit an stage II and stage III breast cancer treated of care for women with breast cancer automatic axillary node dissection. in the neoadjuvant setting followed by an treated in the neoadjuvant setting. expansion cohort. Sites for this study REFERENCE: REFERENCE: Martin Miguel; “Interim Results From a Phase 1b/2a Study 1. Boughey Judy C, Suman Vera J, Mittendorf Elizabeth A, et. al; included Levine Cancer Institute, Baylor of Trastuzumab Emtansine and Docetaxel, With and Without “The role of sentinel lymph node surgery in patients presenting Pertuzumab, in Patients With HER2-Positive Locally Advanced with node positive breast cancer (T0-T4, N1-2) who receive College of Medicine and multiple sites in or Metastatic Breast Cancer”, presented at San Antonio Breast neoadjuvant chemotherapy results from the ACOSOG Z1071 Cancer Symposium, Dec. 5, 2012, San Antonio, Texas. trial”, Abstract presented at: 35th San Antonio Breast Cancer Europe. Symposium: abstract S2-1. Presented Dec 5, 2012, San Antonio, Genetically engineered adoptive cell therapy Texas. The study demonstrated that doublet 2. Johnson K, “ In Node-Positive Breast Cancer, Sentinel Biopsy via CAR-expressing T-cells Could Avert ALND”, Medscape, Dec 6, 2012. and triplet combinations were well tolerated. Early analysis of patients

Updates from ASH 2012: Gene Encoding and Sequencing to Personalize Therapy

CONTINUED FROM FRONT PAGE Malignant Malignant B-Cell relapse. A comparison of relapse versus but offers clinicians B-Cellbetter tools for risk primary tumor mutations demonstrated assessment and selection of existing CD19 increased numbers of transversions at initial therapy and CD19 new weapons, relapse, likely resulting from cytotoxic including “serial killer” cells, for the chemotherapy. melee.

In addition, Francesco Lo-Coco, MD, REFERENCES: from the University of Rome Tor Vergata, 1. Lo-Coco Francesco, et. all; 54th American Society of Hematology Annual Meeting, Atlanta, GA, 2012 Abstract 6. Chimeric 2. Adamia Sophia, et. all; 54th American Society of Hematology Antigen presented interesting results from a Annual Meeting, Atlanta, GA, 2012 Abstract 652. Receptor 3. Fisher A, Daniel C, et. all; 54th American Society of Hematology phase III, randomized, prospective trial Annual Meeting, Atlanta, GA, 2012 Abstract 706. (CAR) from the Italian GIMEMA group and 4. Porter David L, et. all; 54th American Society of Hematology Annual Meeting, Atlanta, GA, 2012 Abstract 717. German SAL and AMLSG groups at the 5. Kalos Michael, et. all; 54th American Society of Hematology Annual Meeting, Atlanta, GA, 2012 Abstract 756. Plenary Session. Data demonstrated 6. Ley Timothy J; 54th American Society of Hematology Annual Meeting, Atlanta, GA, 2012, E. Donnal Thomas Lecture: The AML a two-year, non-inferior EFS in adult Genome. 7. Blazar BR, June CH; 54th American Society of Hematology patients with newly diagnosed non- Annual Meeting, Atlanta, GA, 2012, Ernest Beutler Lecture: T-Cell CAR-Expressing Infusions: A New Tool for Transfusion Medicine That Has Come of T-Cell high-risk APL (WBC ≤10x109/L) treated Age. with a chemotherapy-free regimen of

ATRA and arsenic trioxide compared to CD19

standard ATRA + Idarubicin. Single chain of linked variable heavy Together, these presentations + light regions of anti-CD19 mAb demonstrate that the leukemic genome Transmembrane domain in an individual patient is a “moving Co-stimulatory domain target”, whose cure requires eradication Signaling domain Figure 1: Genetically Engineered Adoptive of the founding clone and its subclones, Cell Therapy Via Car-Expressing T-Cells. TCR-derived CD3ζ chain

6 I UPDATES IN CANCER FOR CLINICIANS A PUBLICATION OF CAROLINAS HEALTHCARE SYSTEM

Translational Science Pharmacogenic Approaches to Personalize Cancer Therapy

CONTINUED FROM PAGE 5 preclinical mouse models that mimic suggest that specific single nucleotide Using high throughput sequencing relapsed/refractory AML. This study will polymorphisms (SNPs) in the VEGF strategies, we sought to identify genes serve as a platform in the development gene and the combination of VEGF that are deregulated in ovarian cancer of a clinical protocol for treating AML. and VEGF-receptor may be useful as and contribute to failure of adjuvant In the past few years, treatment of markers to define treatment associated treatment or disease recurrence renal cell cancer has included the toxicity and overall survival, respectively. following an initial complete response. discovery and approval of drugs that Ovarian cancer is a major cause Our preliminary studies have identified target angiogenesis related pathways. of mortality among gynecologic a subset of genes that can distinguish However, the rapid entry of these malignancies in the United States and tumors that respond well to therapy drugs in clinical practice has not Western Europe. The standard of care and those that potentially lead to kept pace with our understanding for patients with advanced disease early relapse or recurrence. Following of treatment associated toxicity and includes surgical cytoreduction of validation of these genes in a larger mechanisms governing response to tumor burden followed by adjuvant patient cohort, we plan to carry out optimize therapy. We have embarked chemotherapy with a platinum-based prospective clinical trials using the gene on a pharmacogenomic approach of regimen that in most cases includes a signature to predict treatment failure or screening for DNA polymorphisms in taxane. Although response rate with recurrent disease. Results from these gene(s) associated with angiogenesis this approach is high (>70 percent), studies could allow us to offer alternate related pathways that can be exploited resistance to primary therapy and therapeutic strategies to patients with to maximize efficacy and reduce toxicity subsequent recurrence (relapse) is resistant or recurrent disease. of targeted therapy for kidney cancer. substantial. A further complication REFERENCE: Studies analyzing polymorphisms in is the limited success of second line Genome Med. 2011 Dec 30;3(12):79; Cancer 118: 1946-1954, vascular endothelial growth factor therapy in patients failing primary 2012. (VEGF) and VEGF-receptor (VEGFR) therapy or those with recurrent disease.

Figure 1: Preclinical Studies in AML Evaluating Response of Patient Blast Cells to the Combination of ATRA and ICRF-193.

Figure 2: Association of VEGF and VEGFR2 SNPs with Toxicity (P = .01) and Overall Survival (P = .03) in Renal Cell Carcinoma Patients Treated with Sunitinib.

www.carolinashealthcare.org/updates-in-cancer I 7 Targeted Folate Receptor Therapy for Ovarian Cancer The PRECEDENT Study

targeted cancer therapy.[6] Further, FR had the best clinical response [8] and expression appears to be a negative this hypothesis was supported by results prognostic factor in ovarian cancer from the PRECEDENT trial. In this group, patients and may allow targeting of the hazard ratio for disease progression cells that are resistance to conventional was 0.381 (p=0.013) resulting in a median chemotherapy.[4, 5] PFS increase from 1.5 to 5.5 months. The therapeutic agent vintafolide This is the first randomized trial to show is a folate-chemotherapy conjugate a significant benefit to combination Wendel Naumann, MD, FACOG, FACS, (left) designed to deliver desacetylvinblastine chemotherapy in platinum resistant Gynecologic Oncologist monohydrazide (DAVLBH) directly to ovarian cancer.[7] FR-expressing cells while minimizing Based on the success of the James Symanowski, PhD (right) exposure of vintafolide to non- randomized phase II trial, the PROCEED Biostatistician FR-expressing cells.[6] Normally, trial has been launched as an international DAVLBH is so toxic that it cannot be phase III approval trial for vintafolide Epithelial ovarian cancer is the second used systemically. However, it can in women with FR-positive ovarian most common gynecologic malignancy be conjugated with folate in such a cancer by etrafolatide scan. The trial in the United States.[1] The combination way that the drug is only active when will be conducted in approximately 600 of aggressive surgery, platinum- taken up into the cell and the linkage participants, with a primary objective to based chemotherapy, intraperitoneal is broken by the lower intracellular compare PFS between the study arms in chemotherapy and the development pH. Toxicity from this agent is minimal FR-positive participants. of new drugs has resulted in a median due to nonspecific hepatic breakdown survival of approximately five years in REFERENCE: resulting in constipation. 1. Siegel R., D. Naishadham and A. Jemal, Cancer statistics, 2012. women with advanced ovarian cancer. We conducted the first randomized, CA: a cancer journal for clinicians, 2012.62(1): p. 10-29. [2] When patients become resistant to 2. Armstrong D.K., et al., Intraperitoneal cisplatin and paclitaxel in open label, international phase II ovarian cancer. The New England Journal of Medicine, 2006.354(1): platinum, response rates are less than p. 34-43. clinical trial with this compound in the 3. Naumann R.W. and R.L. Coleman, Management strategies for 20 percent and overall survival (OS) is recurrent platinum-resistant ovarian cancer. Drugs, 2011.71(11): p. PRECEDENT trial comparing vintafolide 1397-412. less than one year [3]. The development 4. Low P.S. and A.C. Antony, Folate receptor-targeted drugs for in combination with pegylated liposomal cancer and inflammatory diseases. Advanced drug delivery reviews, of new drugs is needed, but until 2004.56(8): p. 1055-8. doxorubicin (PLD) versus PLD alone, in 5. Kalli K.R., et al., Folate receptor alpha as a tumor target in recently, no clinical trial has generated epithelial ovarian cancer. Gynecologic oncology, 2008.108(3): p. women with platinum-resistant recurrent 619-26. any advantage over single agent therapy. 6. Reddy J.A., et al., Preclinical evaluation of EC145, a folate-vinca ovarian cancer.[7] The primary objective alkaloid conjugate. Cancer research, 2007.67(9): p. 4434-42. Folate is a vitamin required for DNA 7. Naumann R.W., et al., PRECEDENT: A randomized phase II trial was to compare the PFS population comparing EC145 and pegylated liposomal doxorubicin (PLD) in replication and cell division. Folate of patients with measurable disease, combination, versus PLD alone, in subjects with platinum-resistant receptor (FR) is strongly expressed ovarian cancer. J Clin Oncol, 2011.15_suppl(29): p. 5045. and results were statistically significant 8. Symanowski J., et al., Use of 99m-Tc-EC20 (a folate-targeted in many cancers, including over 80 imaging agent) to predict response to therapy with EC145 (HR=0.626; p=0.031). Previous studies (folate-targeted therapy) in advance ovarian cancer. J Clin Oncol, percent of epithelial ovarian cancers 2010.28(15_suppl): p. 5034. suggested patients in whom all lesions but not in normal tissues, making FR expressed the folate receptor by scan an excellent molecular candidate for

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