Milestones in Oncology: Events that Changed the Course of Cancer Therapy and Implications for the Future
,, .. Milestones in Oncology: Events that Changed the Course of Cancer Therapy and Implications for the Future
Target Audience Continuing Pharmaceutical Education The target audience for this complimentary activity is medical 1.25 contact hours (.125 CEUs) of credit for oncologists, hematologists, oncology nurses, and pharmacists. pharmacists. Approval of this course for pharmacists is under a cosponsorship agreement between The American School of Oncology and Medical Education Program Overview Collaborative, Inc. MEC is accredited by the Accreditation This is an exciting and thought-provoking overview of a few of Council for Pharmacy Education as a provider of continuing the milestones in the development of cancer therapy as we know pharmacy education. ACPE # 815-999-07-039-H01. The it today. Several knowledgeable scientists and practitioners program is designed for all pharmacists. who are considered foremost international experts describe the evolution of oncology as a specialty and advancements made in the cure of, as well as management of, a multitude of cancers. Continuing Nursing Education Included in the monograph are discussions on the development Medical Education Collaborative, Inc. is accredited as a provider of curative therapy for Hodgkin disease, testicular cancer, of continuing nursing education by the American Nurses as well as advancements in the treatment of chronic myeloid Credentialing Center’s Commission on Accreditation. leukemia, non-small cell lung cancer, head and neck cancer, and breast cancer. Timelines are presented to indicate the amazing RNs, LPNs, LVNs, and NPs can receive up to 1.25 contact hours evolution of clinical trials and the discoveries of a number of for participation in this program. This program is cosponsored antineoplastic and targeted agents through the last several with Medical Education Collaborative, Inc. and The American decades. School of Oncology. Provider approved by the California Board of Registered Nursing, Provider Number CEP 12990, for 1.50 contact hours. Educational Objectives To receive credit, participants must score at least 70% on After completing the monograph, the participant will be able to: the post-test and submit it along with the credit application 1. Identify important discoveries in the history of cancer therapy. and evaluation form to the address or fax number indicated. 2. Differentiate between historical and current clinical trial Statements of credit will be mailed 6 to 8 weeks after data pertinent to testicular cancer, Hodgkin disease, chronic completion of the activity. myeloid leukemia (CML), breast cancer, non-small cell lung For questions about the accreditation of this program, please cancer (NSCLC), and cancer of the head and neck. contact MEC at 303.420.3252 or [email protected]. 3. Cite historical milestones in the development of successful therapy for CML, Hodgkin disease, breast cancer, and lung cancer. Disclaimer Medical information is ever-changing, transformed frequently Accreditation by new research and clinical experience. Although MEC makes every effort to present accurate information, no warranty, expressed or implied, is offered. Furthermore, the user should use his/her own judgment, knowledge, experience, and Jointly sponsored by The American School of Oncology™ diagnostic decision-making before applying any information, and Medical Education Collaborative, Inc. whether provided by MEC, other users, or third parties, to any Release date: April 2007 Expiration date: April 2008 professional or personal use. The information contained and displayed within this enduring material is provided solely for educational and discussion purposes. Continuing Medical Education This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of The American School of Oncology and Medical Education Collaborative, Inc (MEC). MEC is accredited by the ACCME to provide continuing medical education for physicians. MEC designates this educational activity for a maximum of 1.25 AMA PRA Category 1 Credits™. Participants should claim only credit that is commensurate with the extent of their participation in the activity. Dear Colleague:
In Febrary 2007, The American School of Oncology™ presented a panel discussion in conjunction with the 13th Annual Meeting of the Network for Oncology Communication and Research (NOCR) titled “Milestones of Oncology - Events that Changed the Course of Cancer Therapy and Implications for the Future.”
It is my pleasure to present this monograph to you featuring a review of important events that shaped the face of today’s oncologic therapy and foreshadow what cancer therapy will look like in the future. Dr Howard Burris chaired a distinguished group of thought leaders who presented, in round-robin fashion, oncologic milestones, their consequences, and their potential. The brief, but intense lectures were presented by Drs George Canellos, Craig Nichols, Clifford Hudis, Roy Herbst, and Brian Druker.
The American School of Oncology™ hopes that this monograph reporting the result of the panel discussion is both educational and entertaining. We hope that you will fi nd it useful in the management of your patients.
Sincerely,
Jim Epstein, MD Medical Director The American School of Oncology™
Support Support for Milestones in Oncology – “Events that Changed the Course of Cancer Therapy and Implications for the Future” has been provided by educational grants from Abbott Laboratories; Bristol-Myers Squibb Company; Genentech BioOncology; MGI PHARMA, INC.; Ortho Biotech Products, L.P.; Pfi zer Inc; and sanofi -aventis, U.S.
Milestones in Oncology: Events that Changed the Course of Cancer Therapy and Implications for the Future
Faculty Faculty Disclosure George P. Canellos, MD Medical Education Collaborative, Inc. (MEC) is committed to the provision Discussant of CME that is balanced, objective, and evidence based. MEC adheres to William Rosenberg Professor of Medicine Accreditation Council for Continuing Medical Education (ACCME) Essentials and Standards. Accordingly, all parties involved in content development have Harvard Medical School disclosed any real or apparent confl icts of interest relating to the topics of this Senior Physician educational activity and the disclosure summary follows. MEC has established Dana Farber Cancer Institute mechanisms to resolve confl icts of interest should they arise. Participants in Boston, Massachusetts MEC CME Brian J. Druker, MD programs are afforded the opportunity to provide feedback on the quality Discussant of individual programs. JELD-WEN Chair of Leukemia Research • George P. Canellos, MD – Dr Canellos is a member of the advisory board for Oregon Health & Science University Bristol-Myers Squibb. He is a stockholder for Abbott Laboratories; Amgen; Cancer Institute GlaxoSmithKline; Proctor & Gamble and Wyeth Pharmaceuticals, Inc. Portland, Oregon • Tad B. Coles, DVM – To the best of his knowledge, Dr Coles has no confl ict of interest to disclose relating to the topics of this educational activity. Roy Herbst, MD, PhD Discussant • Trudy Grenon Stoddert, ELS – To the best of her knowledge, Ms Stoddert Attending Physician has no confl ict of interest to disclose relating to the topics of this educational activity. Professor of Medicine The University of Texas • Craig R. Nichols, MD – Dr Nichols is a member of the speaker bureau M. D. Anderson Cancer Center for Biogen Idec Inc. He receives other fi nancial support from Amgen and Houston, Texas Genentech BioOncology. • Roy Herbst, MD, PhD – Dr Herbst is a consultant for Bristol-Myers Squibb; Clifford A. Hudis, MD Eli Lilly and Company; and sanofi -aventis, U.S. He is a member of the Discussant speaker bureau for Eli Lilly and Company and Genentech BioOncology. He Chief, Breast Cancer Medicine Service receives grant/research support from Amgen; AstraZeneca Pharmaceuticals Associate Attending Physician LP; Bristol-Myers Squibb; Genentech BioOncology; and sanofi -aventis, U.S. Memorial Sloan-Kettering Cancer Center He is on the advisory board for Amgen; AstraZeneca Pharmaceuticals LP; New York, New York and Genentech BioOncology. Craig R. Nichols, MD • Clifford A. Hudis, MD – Dr Hudis is a consultant for Amgen; Bristol-Myers Discussant Squibb; GlaxoSmithKline; MERCK & CO., Inc.; Novartis Pharmaceuticals Professor of Medicine Corporation; Pfi zer Inc; Roche Pharmaceuticals Inc. and sanofi -aventis, U.S. He is a member of the speaker bureau for AstraZeneca Pharmaceuticals LP Associate Director of Clinical Cancer Research and Genentech BioOncology. He is a stockholder for Genomic Health Inc. OHSU Cancer Institute Oregon Health & Science University • Brain J. Druker, MD – Dr Druker is a consultant for EMD Serono, Inc. He receives other fi nancial support from Bristol-Myers Squibb and Novartis Portland, Oregon Pharmaceuticals Corporation. Tad B. Coles, DVM • All American School of Oncology staff members who are in a position to Medical Writer control the content of this activity have no fi nancial relationships with any Overland Park, Kansas commercial interests that are relevant to this activity. Trudy Grenon Stoddert, ELS • The employees of Medical Education Collaborative, Inc. have no fi nancial Medical Editor relationships to disclose. Alpharetta, Georgia This activity includes presentations in which faculty may discuss off-label and/or investigational use of pharmaceuticals or instruments not yet FDA- approved. Participants should note that the use of products outside currently FDA-approved labeling should be considered experimental and are advised to consult current prescribing information for FDA-approved indications.
4 Milestones in Oncology: Events that Changed the Course of Cancer Therapy and Implications for the Future
Table of Contents
Development of Combination Chemotherapy Regimens for Hodgkin Disease George Canellos, MD...... 6
Curative Therapy for Advanced Nonseminoumatous Germ Cell Tumors Craig R. Nichols, MD ...... 9
Changing the Paradigm in Breast Cancer: Postoperative Adjuvant Chemotherapy Clifford A. Hudis, MD ...... 11
Discovery of The Epidermal Growth Factor Receptor And Its Therapeutic Implications Roy Herbst, MD, PhD ...... 18
Evolution of Targeted Therapy Over Chronic Myeloid Leukemia Brian Druker, MD...... 22
Continuing Education Registration ...... 27
Program Post-Test ...... 28
Program Evaluation ...... 29
Educational Outcomes Measurement...... 29
5 Milestones in Oncology: Events that Changed the Course of Cancer Therapy and Implications for the Future
Development of Combination vincristine; M, methotrexate; P, prednisone. MOPP – M, nitrogen mustard; O, vincristine; P, procarbazine; P, prednisone. Adapted Chemotherapy Regimens for with permission from DeVita VT. The consequences of the chemotherapy of Hodgkin’s disease: the 10th David A. Karnofsky Hodgkin Disease Memorial Lecture. Cancer. 1981;47:1-13. Copyright © 1981 John George Canellos, MD Wiley & Sons, Inc.
A short while later, in 1964, the MOPP regimen (nitrogen Hodgkin lymphoma was not the fi rst cancer discovered, mustard, vincristine, procarbazine, and prednisone) was but it was the fi rst in which treatments were investigated developed after procarbazine became available. This that were ultimately successful. Prior to the development program entailed 2 weeks of therapy and 2 weeks of of combination chemotherapy, Hodgkin disease had a rest for 6 cycles. From 1964 through 1975 the complete poor prognosis for long-term survival although a number remission rate was very high, ranging from 76% to 100% of potent single agents were being used. Complete depending on the stage of disease when treatment was remission from this form of malignant lymphoma ranged started. This was very encouraging, but at the time there from less than 5% with prednisone or carmustine therapy was disagreement among hematologists. Many thought to 27% with vinblastine. Using the precedent that was that MOPP was too much chemotherapy and would be being set in the treatment of childhood lymphoblastic associated with toxicity. leukemia, single agents were sequentially combined with encouraging results. Some of the more important researchers pursuing these ideas at that time were The unique features of MOPP are that each drug is useful, Tom Frei (Emil Frei, III), J. Freireich (Emil J. Freireich), full doses are used, cyclical administration gives the bone Vincent DeVita, and John Moxley, III. The fi rst combination marrow a chance to recover, a fi xed sliding dose scale treatment regimen for lymphoma came about in and schedule modifi cations could be used as needed, 1963 when MOMP (cyclophosphamide, vincristine, and the duration of therapy is quite long. The next drug methotrexate, and prednisone) therapy was introduced.1 we studied was carmustine or BCNU and, basically, we Treatment with MOMP produced a response rate of 50% to found that after complete remission with MOPP either 60%, which was quite exciting. intermittent MOPP or intermittent carmustine could be helpful, but that maintenance therapy after remission was not necessary.2 Remission was judged by the amount of decrease in lymph node size, but the bottom line was really measured by patient follow up.
One of the major problems with MOPP is the negative effect it has on reproductive tissues. Sperm counts drop precipitously in male patients and after only one or two cycles they are considered sterile. We called them “Sertoli only” because that’s all that was left. With the germinal epithelium absent, there were increased levels of follicle-stimulating hormonr (FSH) in these patients. In women, amenorrhea is very common with MOPP therapy, especially in women over 25 years of age.
Figure 1. Schematic representation of infl ux of new drugs effective against Hodgkin disease into clinical use over time.1 MOMP – M, mustard like drug (cyclophosphamide); O,
6 Another disadvantage of the MOPP regimen is an increase in the incidence leukemia-related complications, which peaks 6 years after the start of treatment.3
Table 1. Hodgkin disease: risk of second malignancy by type of treatment.1 TNI indicates total nodal irradiation; EF, extended fi eld radiation; RRX MOPP, group of patients treated with MOPP after relapse from radiotherapy; MOPP RRX, the reverse sequence. Reprinted with permission from Devita Figure 2. Risk function for the development of a leukemia- 3 VT. The consequences of the chemotherapy of Hodgkin’s related event in all patients regardless of type of treatment. disease: the 10th David A. Karnofsky Memorial Lecture. Cancer. The natural log transformation of the risk equation an the 1981;47:1-13. Copyright © 1981 John Wiley & Sons, Inc. two-sided P value for the nonlinear term are shown. Reprinted with permission from Blayney DW, Longo DL, Young RC, et al. Decreasing risk of leukemia with prolonged follow-up after The British developed MVPP (nitrogen mustard, chemotherapy and radiotherapy for Hodgkin’s disease. N Engl vinblastine, procarbazine, prednisone), a minor J Med. 1987;316:710-714. Copyright © 1987 Massachusetts modifi cation of MOPP, with no therapy from day 14 to day Medical Society. All rights reserved. 44, at which point the cycle recurs. An improved MOPP modifi cation, ChlVPP has oral chlorambucil substituted Almost all of the patients suffering with post-MOPP for intravenous nitrogen mustard. There have been leukemia were found to have alkylating-agent–induced many clinical trials comparing these chemotherapeutic cytogenic abnormalities in chromosomes 5, 7, or both.4 regimens and there is little difference in effi cacy. Investigation into the therapy that preceded post-MOPP Certainly ChlVPP is much more tolerable because the leukemia revealed that patients who failed radiotherapy combination avoids the use of nitrogen mustard. and were subsequently treated with the MOPP regimen were 18 times more likely to develop secondary Subsequently, the era of nonalkylating agent malignancy (mostly leukemia) than expected.1 chemotherapy, pioneered by the Milan group with the ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) regimen,5 was found to be void of the reproductive and leukemic side effects of MOPP. After Tom Frei became chairman of the Cancer and Leukemia Group B (CALGB) in 1982, I was asked to design a comparative trial. The trial was designed for patients with stage III and IV disease with a crossover built in between MOPP and ABVD, but without radiotherapy. The results, published in the New England Journal of
7 Milestones in Oncology: Events that Changed the Course of Cancer Therapy and Implications for the Future
Medicine, indicated that MOPP was inferior.6 But the References fact that we were at the National Cancer Institute (NCI) 1. DeVita VT. The consequences of the chemotherapy of probably infl uenced the results because the patients Hodgkin’s disease: the 10th David A. Karnofsky Memorial were younger and the toxicity protocol at NCI resulted Lecture. Cancer. 1981;47:1-13. in modifi cation of the nitrogen mustard dose, which, I 2. Young RC, Canellos GP, Chabner BA, Schein PS, Schein think, compromised the MOPP results. I have actually PS, DeVita VT. Maintenance chemotherapy for advanced just fi nished the 20-year follow up report and the overall Hodgkin’s disease in remission. Lancet. 1973;1:1339-1343. survival is about the same between the two groups. 3. Blayney DW, Longo DL, Young RC, et al. Decreasing risk of leukemia with prolonged follow-up after chemotherapy and radiotherapy for Hodgkin’s disease. N Engl J Med. This trial introduced ABVD as a regimen that could 1987;316:710-714. be given to patients with low risk disease. 6 Initially, 4. Canellos GP, Arseneau JC, DeVita VT, Whang-Peng J, the reason ABVD was developed was to try to improve Johnson RE. Second malignancies complicating Hodgkin’s effi cacy over that of MOPP, but when the effi cacy turned disease in remission. Lancet. 1975;1(7913):947-949. out to be essentially the same, then the safety issue, 5. Bonadonna G, Zucali R, Monfardini S, De Lena M, Uslenghi the lack of sterilization and secondary malignancy side C. Combination chemotherapy of Hodgkin’s disease effects, became a major issue. Today we realize that with with adriamycin, bleomycin, vinblastine, and imadazole ABVD there will be less myelotoxicity, less sterilization, carboxamide versus MOPP. Cancer. 1975;36:252-259. and minimal leukemogenesis compared with MOPP or 6. Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy MOPP hybrids. Still, 35% of the patients in stage III/IV of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP will relapse. Since 1990 there has been a veritable alternating with ABVD. N Engl J Med. 1992;327:1478-1484. alphabet soup of regimens touted, and that research is ongoing and beyond the scope of this discussion.
The MOPP experience provided the impetus for two important events. First, we showed that adult malignancy could be chemotherapeutically treated into complete remission. Second, this fact was instrumental in the approval by the American Board of Internal Medicine of medical oncology as a bona fi de subspecialty. Those developments paved the way for further development of medical oncology and the use of combination chemotherapy for other cancers.
8 Curative Therapy for Advanced 2 years of therapy in an attempt to achieve total cell kill, as was the tradition at that time, keeping in step Nonseminoumatous Germ Cell Tumors with the maintenance chemotherapy regimen used in childhood acute lymphoblastic leukemia.5 The results Craig R. Nichols, MD were dramatic with 70% (33/47) CR with chemotherapy alone. Five additional patients obtained CR after surgical Barnett Rosenburg was not a physician, but was a excision of residual, much shrunken, tumor. Side effects biologist at Michigan State. He has had an enormous included nausea, vomiting, and myelosuppression- durable contribution to oncology as he was the fi rst induced infections.4 person to consider that cisplatin might be an important agent in the management of malignancies. We are Further studies performed at Indiana University from quite fortunate that Dr Rosenburg was blessed with a 1976 to 1978 revealed that the vinblastine dose could serendipitous turn of events and a persistent personality. be reduced (from 0.4 mg/kg to 0.3 mg/kg) without He was studying the effect of electromagnetic fi elds on decreasing effi cacy.6 More signifi cantly, studies cell division in 1965. He noticed that Escherichia coli cells performed from 1978 to 1981 challenged one of the exposed to electrical current generated with a platinum 1 basic tenets of oncology, that maintenance therapy cathode elongated, but did not divide. The effect was was necessary to prevent relapse. The results of the reproducible and reversible. The use of other cathode randomized trial using induction chemotherapy with metals did not cause the effect, prompting Rosenburg to 4 cycles of PVB with or without 2 years of vinblastine hypothesize that elemental platinum was coming off of 7 2 maintenance revealed no difference. Both groups the electrode and disrupting cell division mechanisms. had a relapse rate of 5%, as reported in the New He subsequently identifi ed cisplatin and even suggested England Journal of Medicine, thus 4 courses of PVB that it should be studied as an antineoplastic agent. (0.3 mg/kg) without maintenance became standard Remarkably, this is how the drug we use today originated. therapeutic protocol. The next step, again investigated by randomized clinical trials, was the study of etoposide Subsequently, phase I studies were performed.3 In as a substitute for vinblastine.8 The results of the trial today’s regulatory environment I doubt it would have revealed cisplatin + etoposide + bleomycin (BEP) was been developed as an oncolytic because this drug was equivalent to PVB or slightly more effi cacious with extraordinarily toxic causing nausea, vomiting, renal diminished neuromuscular toxicity. Therefore, 4 cycles of failure, and neurotoxicity. In yet another instance of BEP became the new standard of care. serendipity, there were a few young men with germ cell tumors that happened to be in the trial, and some of Then we began to look at these patients differently. We them went into complete remission. realized there was a large group of patients who had low volume disease and low markers, and these patients With that background, my friend and mentor, Dr were almost invariably (>90%) cured (“good-prognosis” Larry Einhorn at Indiana University began including group). There was a smaller group of patients with large cisplatin as a component of combination chemotherapy volume disease, mediastinal germ cell tumors, and high with vinblastine and bleomycin (VB), which were markers for which the cure rate was only about 50% being used with marginal success. The VB regimen (“poor-prognosis” group). We started investigating these resulted in 10% to 20% complete remission (CR) for patients differently, asking if we could cure the low-risk patients with metastatic testicular cancer. Einhorn patients with lesser toxicity. On the other hand, rather and Dr John Donahue used the cisplatin + vinblastine than manage toxicity in the high-risk patients, we sought + bleomycin (PVB) regimen in a study of 47 patients to fi nd out if additional doses or increased therapies with disseminated testicular cancer.4 The regimen could increase the cure rate. So at that point, trials used the 3-drug combination for remission induction focusing on either good-prognosis or poor-prognosis followed by vinblastine for maintenance for a total of groups came about. 9,10
9 Trials in the good-prognosis group revealed that 3 cycles 3. Higby DJ, Wallace HJ Jr, Albert DJ, Holland JF. of BEP had the same effi cacy as 4 cycles.9 We also found Diaminodichloroplatinum: a phase I study showing that dropping bleomycin from the regimen was not responses in testicular and other tumors. Cancer. acceptable even if 4 cycles of therapy were instituted, 1974;33:1219-1215. and that substituting carboplatin for cisplatin was not 4. Einhorn LH, Donohue J. Cis-diamminedichloroplatinum, effective.10 Thus, 3 cycles of BEP remains the standard vinblastine, and bleomycin combination chemotherapy for good-prognosis patients with disseminated germ cell in disseminated testicular cancer. Ann Intern Med. 1977;87:293-298. tumors with 90% cure after 9 weeks of therapy. 5. Einhorn LH. Curing metastatic testicular cancer. Proc Natl Acad Sci U S A. 2002;99:4592-4595. Trials in the poor-prognosis group investigated doubling 6. Einhorn LH, Williams SD. Chemotherapy in disseminated the cisplatin dose11,12 and substituting ifosfamide for testicular cancer. West J Med. 1979;131:1-3. 13 bleomycin and revealed increased toxicity without 7. Einhorn, L. H., S. D. Williams, et al. The role of maintenance additional therapeutic benefi t. A recently published trial therapy in disseminated testicular cancer. N Engl J Med. compared 4 cycles of BEP with 2 cycles of BEP plus 2 1981;305:727-731. very high dose cycles requiring stem cell transplant, but 8. Williams SD, Birch R, Einhorn LH, Irwin L, Greco FA, we were unable to improve the benefi t in the high-risk Loehrer PJ. Treatment of disseminated germ-cell tumors subset group.14 with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med.1987;316:1435-1440. So this short review highlights how, via successful use of 9. Culine S, Theodore C, Terrier-Lacombe MJ, Droz JP. Are 3 cycles of bleomycin, etoposide and cisplatin or 4 cycles randomized clinical trials, we got the effective therapies of etoposide and cisplatin equivalent optimal regimens that we have available today. At the present time we for patients with good risk metastatic germ cell tumors have no burning therapeutic questions to answer, no of the testis? The need for a randomized trial. J Urol. new drugs or concepts for the untreated patient, no new 1997;157:855-858; discussion 858-859. ideas to test via clinical trials. If you are old enough to 10. Bokemeyer C, Kohrmann O, Tischler J, et al. A randomized remember, you can take a stroll with me down Memory trial of cisplatin, etoposide and bleomycin (PEB) versus Lane, and recall that prior to effective chemotherapy carboplatin, etoposide and bleomycin (CEB) for patients we had to do radical surgeries for patients with stage with ‘good-risk’ metastatic non-seminomatous germ cell III disease, and we had to do radical radiation therapy tumors. Ann Oncol. 1996;7:1015-1021. for patients with seminoma. Now we have a good 11. Ozols RF, Ihde DC, Linehan WM, Jacob J, Ostchega Y, chemotherapy safety net and can offer very nontoxic Young RC. A randomized trial of standard chemotherapy approaches to those with early Stage I disease, such v a high-dose chemotherapy regimen in the treatment of as surveillance in both clinical stage I seminoma and poor prognosis nonseminomatous germ-cell tumors. J Clin nonseminoma, along with limited radiation therapies, Oncol. 1988;6:1031-1040. and limited surgeries, It has been an incredible era 12. Nichols CR, Williams SD, Loehrer PJ, et al. Randomized to live through and we have giants in oncology like study of cisplatin dose intensity in poor-risk germ cell Larry Einhorn and Barnett Rosenberg to thank for the tumors: a Southeastern Cancer Study Group and Southwest chemotherapeutics we have available today. Oncology Group protocol. J Clin Oncol. 1991;9:1163-1172. 13. Einhorn LH. VP 16 plus ifosfamide plus cisplatin as salvage therapy in refractory testicular cancer. Cancer Chemother References Pharmacol. 1986;18 Suppl 2:S45-S50. 1. Rosenberg B, Vancamp L, Krigas T. Inhibition of cell division 14. Einhorn LH, Brames MJ, Juliar B, Williams SD. Phase II in Escherichia coli by electrolysis products from a platinum study of paclitaxel plus gemcitabine salvage chemotherapy electrode. Nature. 1965;205:698-699. for germ cell tumors after progression following high- 2. Rosenberg B, Renshaw E, Vancamp L, Hartwick J, Drobnik dose chemotherapy with tandem transplant. J Clin Oncol. J. Platinum-induced fi lamentous growth in Escherichia coli. 2007;25:513-516. J Bacteriol. 1967;93:716-721.
10 Changing the Paradigm in Breast yourself with such a low number of subjects. Another common problem with clinical trials of that era was Cancer: Postoperative Adjuvant selecting suboptimal chemotherapeutic agents to test. Chemotherapy Clifford A. Hudis, MD Next, let’s look at the development of adjuvant combination chemotherapy. Now there were many inventors of the cyclophosphamide + methotrexate + It is a pleasure to talk about this topic that stretches over fl uorouracil (CMF) regimen, but the Milan group study of several decades and has infl uenced the lives of several CMF versus no treatment in node-positive breast cancer million people, if not more. Since this program is about patients was a true landmark with more than 2 decades chemotherapy, adjuvant hormone therapy, although very of follow-up.2 The treatment in this trial was 12 cycles of important, will be discussed peripherally, if at all. CMF consisting of oral cyclophosphamide (100 mg/m2) from day 1 through day 14 and intravenous methotrexate (40 mg/m2) and fl uorouracil (600 mg/m2)on days 1 and 8, First, I am going to focus on the establishment of followed by 2 weeks rest, and then the cycle recurred. standard chemotherapeutic regimens. I will also cover There was statistically signifi cant improvement in both the so called “taxane wars”, which have consumed a disease-free status and overall survival that is worth good bit of the last decade, and discuss why biology emphasizing. Also they showed that 6 months of CMF matters. Finally, I’ll talk about the new (not old) targeted was equivalent to 12 months, which helped put a realistic agents, the monoclonal antibodies that will, of course, time limit on the duration of chemotherapy. infl uence our approach in the future.
There were some pretty dramatic changes in the 1980s. An early randomized adjuvant chemotherapy trial that In 1985 Richard Peto organized the fi rst true meta- served as a real launch pad was the National Surgical analysis, not just pooled analysis of published data. In Adjuvant Breast and Bowel Project (NSABP) Protocol 1 contrast, Peto required that the raw data be brought to B-05 study. This study was characteristic of the brave Oxford. He was looking for evidence of small differences thinking at the time in that it: 1) pitted chemotherapy in treatments that would be important from a public with a single agent, L-phenylalanine mustard (L-PAM), health standpoint. It was easy, at that time, to fi nd trials against placebo; and 2) did so using postoperative, NED with confl icting results and Peto said that the data (no evidence of disease), patients. Some may remember from these trials could be put together, if the design that at the time this idea of subjecting apparently healthy was similar enough, and that better estimates could patients to a toxic therapy was an anathema. They be made about the real benefi t, or lack thereof, than by randomized a very modest number of patients, just looking at just the individual trial results. Just because 380, yet the results (10 years later) demonstrated of random chance the smaller individual trials were a signifi cant improvement in both disease-free status prone to overstating or understating the true impact of and overall survival, which improved by 8% and therapy. The resultant paper, published in 1988, provided 5%, respectively. meta-analysis of 28 tamoxifen trials (16,513 women) and 40 chemotherapy trials (13,442 women), which revealed, Although this trial was very successful in supporting the among other things, that tamoxifen was effective developing concept that postoperative chemotherapy only in women aged over 50 years, that combination could be useful, it also points out an all-or-nothing trial- chemotherapy was more effective than single-agent design fl aw typical of that era. With these small numbers chemotherapy, and that there was no survival advantage you might have a home run with results, like this trial to be gained by administration of chemotherapy for 8 to had. Conversely, you might miss effects that could be 24 months versus 4 to 6 months.3 very important from a public health standpoint, but that fell below the high statistical-signifi cance bar you set for
11 Milestones in Oncology: Events that Changed the Course of Cancer Therapy and Implications for the Future
Also in the late 1980s, 4 clinical trials (3 chemotherapy, 1 tamoxifen) evaluating adjuvant therapy in node- negative breast cancer were reported to the National Cancer Institute (NCI).4-7 Up until that time, adjuvant chemotherapy was routinely recommended for node- positive, ER-negative breast cancer, based on the consensus conference from the NIH. In 1990, the NIH Consensus Development Panel stated we should consider adjuvant therapy for patients with node- negative tumors greater than 1 cm in maximal diameter.8
Adjuvant chemotherapy regimens have been largely developed along empirical lines. Some of the more popular ones are listed in Table 1. Of the many variations of the CMF regimen, it is unclear that any one version offers an advantage over another. It is clear, though, Table 1. Widely used adjuvant chemotherapy regimens. that oral CMF provides better effi cacy than intravenous Courtesy of Clifford A. Hudis, MD. CMF for patients with stage IV disease. Consider this; for AC, which is the universal favorite in North America, there has never been a study that demonstrated it was Theoretically, there should be an improvement in better than CMF. It seems the whole world is convinced effi cacy if the time between treatments is shortened that AC is better, but there is no randomized clinical when dose size is maintained as a constant. This theory, trial in support of that conviction. There are also some that more frequent, or dense, dosing is superior, makes popular sequential regimens, but again, these are based sense because using dose dense therapy: 1) decreases on practical experience and have no scientifi c evidence, the time for tumor regrowth, 2) allows for treatment which is kind of embarrassing in this era. These drugs with a smaller volume, and 3) results in a greater come along and we pile them onto an existing regimen overall cell-kill as indicated in Figure 1. This theory or replace one drug with another. Some of the adjuvant was inadvertently tested when Bonadonna and the rest therapies have been based on mathematical models of the Milan group set out to test the Goldie-Coleman Richard Simon and Larry Norton worked on at NCI hypothesis by comparing sequential doxorubicin (DOX) decades ago.9 One of the issues they addressed is and CMF with alternating DOX and CMF.12 As indicated that tumors grow at a diminishing rate, relying on a in Figure 2, the 10-year relapse-free survival rate for Gompertzian growth pattern. In other words, as the the alternating group was 28% versus 42 % for the tumor gets larger its rate of growth decreases. Also, if sequential (increased dose density) group. you accept the log-kill model of Skipper and Schabel10,11 then it makes sense that therapy applied later, on a fractional cell-kill basis, is not going to get as close to a cure as the same therapy applied earlier, such as in the adjuvant setting.
12 for doses of cyclophosphamide above 600 mg/m2. So although dose escalation was not promising, the dose density results led to modern chemotherapy trials, which are often sequential in design. When paclitaxel came along, we grafted it onto an existing design in the CALGB where a low, intermediate, or high dose DOX was being tested. In another example, the taxane data in stage IV disease became available while we were running an anthracycline dose escalation trial and so we grafted paclitaxel onto that trial.
Additionally, although CALGB 9344 DOX dose escalation didn’t help, sequentially adding paclitaxel did.13 The advantage of sequentially adding paclitaxel was echoed in NSABP B-28.16 One other point about the Henderson 13 Figure 1. Increased reduction in tumor size with dense dosing. study is that it was unusually large. They had over 3,000 Courtesy of Clifford A. Hudis, MD. patients and this was a direct lesson of Peto’s Oxford overview analysis mentioned earlier,3 that it takes big randomized trials to fi nd small, but clinically important differences.
There are many ways to give taxane. The Breast Cancer International Research Group Study 001 (BCIRG 001)17 provided a head to head comparison between TAC (docetaxel + doxorubicin + cyclophosphamide) and FAC (fl uorouracil + doxorubicin + cyclophosphamide). Docetaxel was given at 75 mg/m2 to the TAC group, 5- fl uorouracil was given at 500 mg/m2 to the FAC group and both groups were given DOX at 50 mg/m2 and cyclophosphamide at 500 mg/m2. This study established that the chemotherapy cycle with docetaxel was superior to that with fl uorouracil.
Figure 2. Sequential or alternating treatment: 10-year disease- This brings us to an interesting, but negative, factorial free survival.12 design study that, although not yet published, was reported by the Eastern Cooperative Oncology Group DOX indicates doxorubicin; CMF, cyclophosphamide, methotrexate, fl uorouracil. (ECOG) last year at the San Antonio Breast Cancer Symposium.18 Joe Sparano was the principal investigator Courtesy of Clifford A. Hudis, MD. of this trial (ECOG 1199) of AC plus a taxane, paclitaxel versus docetaxel, (paclitaxel 175 mg/m2 q 3 wk x 4 or 80 2 2 Although simple human nature led us to think that mg/m weekly x 12; docetaxel 100 mg/m q 3 wk x 4 or 2 higher doses and longer treatment regimens would 35 mg/m weekly x 12), and as written and analyzed, it is result in higher survival rates, beyond a certain point negative. People talk about subsets and ER-positives and dose escalation did not do so. As an example, DOX negatives, and so forth, but you have to live with the way dose escalation above 60 mg/m2 in CALGB 9344 yielded you design your study. If your goal was to demonstrate nothing.13 Similar NSABP fi ndings14,15 were demonstrated that there is a difference between the taxanes, then
13 Milestones in Oncology: Events that Changed the Course of Cancer Therapy and Implications for the Future
this study did not do it. It also did not demonstrate a women. However, here is the critical caveat: we did no difference for schedule, so that is worth highlighting centralized ER testing and in our fi rst study we did not as well. even know the ER status of all the patients. Additionally, keep in mind that ER-positive status is open to discussion, because regardless of 5% stain or 95% stain, In contrast, CALGB 9741 was a cleanly designed study both are classifi ed as positive and lumped together. that provided us with some good information that can 19 Nevertheless, that was the hypothesis generating point be applied clinically. What made this study clean? that we pursued, and what we found was that ER- Every woman on the study got four doses of 3 drugs of positive women displayed about half the benefi t from the same exact dose. There was no variability. The only chemotherapy as that found in ER-negative women, in thing that mattered was whether they got concurrent AC terms of recurrence and death. The theory we proposed or sequential AC and whether they got q 3 wk therapy to explain this phenomenon involves the natural history or q 2 wk. As you know, the q 2 wk arm has remained of breast cancer and the fact that ER-negative breast superior to q 3 wk after six and a half years of follow- cancer has an earlier relapse peak. There may also be up. Furthermore, sequential chemotherapy was as a biological basis to explain the differential benefi t that effective as concurrent chemotherapy. Most clinicians ER-positive and ER-negative women get prefer concurrent therapy, in order to shorten the from chemotherapy. treatment duration. So, the results of this study not only demonstrate that dose densities are an important approach to establish chemotherapeutics, but also that The next step in determining who will benefi t from you have some fl exibility in terms of how you administer chemotherapy involves gene testing. There is a 21 multi- the drugs. gene quantitative PCR assay to determine the recurrence score (RS) for a patient.25 The genes they test for are shown in Figure 3.25-28 They are able to identify low-risk The modern era of chemotherapeutics is clearly or high-risk patients in terms of prognosis and they were colored by biologics. When I reviewed the 4 pivotal also able, based on NSABP B-20, to predict who benefi ts adjuvant therapy trials testing the monoclonal antibody, from chemotherapy. This undermines the argument that trastuzumab, for effi cacy in HER2-positive breast cancer 20-23 ER status is all determining in terms of chemotherapy patients, I found that regardless of what regimen benefi t because what this test indicates is that subsets trastuzumab was added to, the risk of recurrence was of patients with ER-positive breast cancer benefi t. So you lowered by 50%. This raises the question of whether have to be a little cautious about the “one size fi ts all” the chemotherapy backbone, over which we have interpretation. At the same time, Dan Hayes did this in labored so much, matters anymore. It may well be that CALGB 9344 last year looking at HER2 status and it turns once you give trastuzumab, you are leveling a playing out regardless of ER status, the HER2-positive women fi eld, and it does not matter if you do or do not give the benefi ted from paclitaxel.29 So, again, you have to be very anthracycline, if you do or do not give the taxane, and so careful and not jump to unfounded conclusions. forth. All this is yet to be worked out and is important from a toxicity point of view, but these trials clearly show that the trastuzumab is making an essential difference.
The effect of ER status on chemotherapeutic prognosis came into question during review of the results gathered in CALGB studies 8541, 9344 (Intergroup 0148), and 9741 (Intergroup C9741).24 Don Berry got into several unplanned retrospective subset analyses and the data suggested that ER status was an important predictor of chemotherapy benefi t. He noted that benefi t from taxane and dose density was greater in ER-negative
14 All that said, what this is really allowing us to do, in the lowest risk cohort of patients, is identify maybe those who should or should not get chemotherapy and tailor therapy more precisely. This is process is being investigated by Joe Sparano as demonstrated by the protocol of the TAILORRx study of ER-positive breast cancer patients. In this study the lowest-risk, low-RS patients are treated with hormone therapy only; high risk, high-RS patients are treated with hormone therapy and chemotherapy. The middle of the road patients are randomized and some get hormone therapy only and others get both hormone therapy and chemotherapy. This study is set up to answer the question, “Is it safe to drop chemotherapy in patients with an intermediate score?”
Figure 3. Panel of 21 Genes and the Recurrence-Score Algorithm.25 It is important to point out that breast cancer death rates The recurrence score on a scale from 0 to 100 is derived from the reference- normalized expression measurements in four have been falling. There are obviously many reasons steps. First, expression for each gene is normalized relative to the for this including improved mammography and tumor expression of the fi ve reference genes (ACTB [the gene encoding detection at earlier stages, improved chemotherapy, β-actin], GAPDH, GUS, RPLPO, and TFRC). Reference-normalized improved surgical techniques, and, of course, hormone expression measurements range from 0 to 15, with a 1-unit therapy. Although this talk focused on chemotherapy, increase refl ecting approximately a doubling of RNA. Genes are systemic tamoxifen use, around the world, may be grouped on the basis of function, correlated expression, or both. responsible for more lives saved than almost any Second, the GRB7, ER, proliferation, and invasion group scores other intervention. That said, tailoring chemotherapy are calculated from individual gene-expression measurements, to the individual helps. Canadian provincial studies of as follows: GRB7 group score = 0.9 x GRB7 + 0.1 x HER2 (if the result is less than 8, then the GRB7 group score is considered implementation of guideline-based use of chemotherapy 8); ER group score = (0.8 x ER + 1.2 x PGR + BCL2 + SCUBE2) ÷ 4; indicate an association with falling mortality over time. proliferation group score = (Survivin + KI67 + MYBL2 + CCNB1 [the So what we are doing is having a very real effect. We gene encoding cyclin B1] + STK15) ÷ 5 (if the result is less than 6.5, anticipate that this effect will continue to increase then the proliferation group score is considered 6.5); and invasion over time. group score = (CTSL2 [the gene encoding cathepsin L2] + MMP11 [the gene encoding stromolysin 3]) ÷ 2. The unscaled recurrence score (RSU) is calculated with the use of coeffi cients that are References predefi ned on the basis of regression analysis of gene expression 1. Fisher B, Fisher ER, Redmond C. Ten-year results from and recurrence in the three training studies 26-28: RS = +0.47 x GRB7 U the National Surgical Adjuvant Breast and Bowel Project group score −0.34 x ER group score +1.04 x proliferation group (NSABP) clinical trial evaluating the use of L-phenylalanine score +0.10 x invasion group score +0.05 x CD68 −0.08 x GSTM1 mustard (L-PAM) in the management of primary breast −0.07 x BAG1. A plus sign indicates that increased expression is cancer. J Clin Oncol. 1986;4:929-941. associated with an increased risk of recurrence, and a minus sign indicates that increased expression is associated with a decreased 2. Bonadonna G, Valagussa P, Moliterni A, Zambetti M, risk of recurrence. Fourth, the recurrence score (RS) is rescaled Brambilla C. Adjuvant cyclophosphamide, methotrexate, from the unscaled recurrence score, as follows: RS = 0 if RS <0; RS and fl uorouracil in node-positive breast cancer: the results U of 20 years of follow-up. N Engl J Med. 1995;332:901-906. = 20 x (RSU−6.7) if 0 < RSU <100; and RS = 100 if RSU>100. Reprinted with permission from Paik S, Shak S, Tang G, et al. A multigene 3. Early Breast Cancer Trialists’ Collaborative Group. Effects assay to predict recurrence of tamoxifen-treated, node-negative of adjuvant tamoxifen and cytotoxic therapy on mortality in breast cancer. N Engl J Med. 2004;351:2817-2826. Copyright © 2004 early breast cancer. An overview of 61 randomized trials Massachusetts Medical Society. All rights reserved. among 285,896 women. N Engl J Med. 1988;319:1681-1692.
15 Milestones in Oncology: Events that Changed the Course of Cancer Therapy and Implications for the Future
4. Fisher B, Redmond C, Dimitrov NV, et al. A randomized 16. Manounas EP, Bryant J, Lembersky B, et al. Paclitaxel clinical trial evaluating sequential methotrexate and after doxorubicin plus cyclophosphamide as adjuvant fl uorouracil in the treatment of patients with node-negative chemotherapy for node-positive breast cancer: results from breast cancer who have estrogen-receptor-negative NSABP B-28. J Clin Oncol. 2005;23:3686-3696. tumors. N Engl J Med. 1988;320:473-478. 17. Martin M, Pienkowski T, Mackey J, et al; Breast Cancer 5. The Ludwig Breast Cancer Study Group. Prolonged disease- International Research Group 001 Investigators. Adjuvant free survival after one course of perioperative adjuvant docetaxel for node-positive breast cancer. N Engl J Med. chemotherapy for node-negative breast cancer. N Engl J 2005;352:2302-2313. Med. 1988;320:491-496. 18. Sparano JA, Wang M, Martino S, et al. Phase III study of 6. Mansour EG, Gray R, Shatila AH, et al. Effi cacy of adjuvant doxorubicin-cyclophosphamide followed by paclitaxel chemotherapy in high-risk node-negative breast cancer. An or docetaxel given every 3 weeks or weekly in patients intergroup study. N Engl J Med. 1988;320:485-490. with axillary node-positive of high-risk node-negative 7. Fisher B, Costantino K, Redmond C, et al. A randomized breast cancer: results of North American Breast clinical trial evaluating tamoxifen in the treatment of Cancer Intergroup Trial E1199. Breast Cancer Res Treat. patients with node-negative breast cancer who have 2005;94(suppl1). Abstract 48. estrogen-receptor-positive tumors. N Engl J Med. 19. Citron ML, Berry DA, Cirrincione C, et al. Randomized 1988;320:479-484. trial of dose-dense versus conventionally scheduled and 8. Treatment of Early-Stage Breast Cancer. NIH Consens sequential versus concurrent combination chemotherapy Statement 1990 Jun 18-21;8(6)1-19. as postoperative adjuvant treatment of node-positive primary breast cancer: fi rst report of Intergroup Trial 9. Norton L, Simon R. Tumor size, sensitivity to therapy, C9741/Cancer and Leukemia Group B Trial 9741. J Clin and design of treatment schedules. Cancer Treat Rep. Oncol. 2003;21:1431-1439. 1977;61:1307-1317. 20. Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al. 10. Skipper HE, Schnabel FM Jr, Wilcox WX: Experimental Trastuzumab after adjuvant chemotherapy in HER2-positive evaluation of potential anti-cancer agents XIII: on the breast cancer. N Engl J Med. 2005;353:1659-1672. criteria and kinetics associated with “curability” of experimental leukemia. Cancer Chemother Rep. 1964;35:1. 21. Romond EH, Perez EA, Bryant J et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast 11. Skipper HE. Kinetics of mammary tumor cell growth and cancer. N Engl J Med. 2005;353:1673-1684. implications for therapy. Cancer. 1971;28:1479-1499. 22. Slamon D, Eiermann W, Robert N et al. Phase 12. Bonadonna G, Zambetti M, Valagussa P. Sequential or III randomized trial comparing doxorubicin and alternating doxorubicin and CMF regimens in breast cancer cyclophosphamide followed by docetaxel (AC T) with with more than three positive nodes. Ten-year results. doxorubicin and cyclophosphamide followed by docetaxel JAMA. 1995;273:542-547. and trastuzumab (AC TH) with docetaxel, carboplatin 13. Henderson IC, Berry DA, Demetri GD, et al. Improved and trastuzumab (TCH) in HER2 positive early breast outcomes from adding sequential Paclitaxel but not from cancer patients: BCIRG 006 study. Breast Cancer Res Treat escalating Doxorubicin dose in an adjuvant chemotherapy 2005;94(suppl 1):S5. regimen for patients with node-positive primary breast 23. Joensuu H, Kellokumpu-Lehtinen P-L, Bono P et al. Adjuvant cancer. J Clin Oncol. 2003;21:976-983. docetaxel or vinorelbine with or without trastuzumab for 14. Fisher B, Anderson S, Wickerham DL, et al. Increased breast cancer. N Engl J Med. 2006;354:809-820. intensifi cation and total dose of cyclophosphamide in a 24. Berry DA, Cirrincione C, Henderson IC, et al. Estrogen- doxorubicin-cyclophosphamide regimen for the treatment receptor status and outcomes of modern chemotherapy of primary breast cancer: fi ndings from National Surgical for patients with node-positive breast cancer. JAMA. Adjuvant Breast and Bowel Project B-22. J Clin Oncol. 2006;295:1658-1667. 1997;15:1858-1869. 25. Paik S, Shak S, Tang G, et al. A multigene assay to predict 15. Fisher B, Anderson S, DeCillis A, et al. Further evaluation recurrence of tamoxifen-treated, node-negative breast of intensifi ed and increased total dose of cyclophosphamide cancer. N Engl J Med. 2004;351:2817-2826. for the treatment of primary breast cancer: fi ndings from National Surgical Adjuvant Breast and Bowel Project B-25. 26. Esteban J, Baker J, Cronin M, et al. Tumor gene expression J Clin Oncol. 1999;17:3374-3388. and prognosis in breast cancer: multi-gene RT-PCR assay of paraffi n-embedded tissue. Proc Am Soc Clin Oncol. 2003;22:850. Abstract 3416.
16 27. Cobleigh MA, Bitterman P, Baker J, et al. Tumor gene expression predicts distant disease-free survival (DDFS) in breast cancer patients with 10 or more positive nodes: high throughout RT-PCR assay of paraffi n-embedded tumor tissues. Proc Am Soc Clin Oncol. 2003;22:850. Abstract 3415. 28. Paik S, Shak S, Tang G, et al. Multi-gene RT-PCR assay for predicting recurrence in node negative breast cancer patients—NSABP studies B-20 and B-14. Breast Cancer Res Treat. 2003;82:S10. Abstract 16. 29. Hayes DF, Thor A, Dressler L, et al. HER2 predicts benefi t from adjuvant paclitaxel after AC in node-positive breast cancer: CALGB 9344. J Clin Oncol. 2006;24(18S pt 1). Abstract 510.
17 Milestones in Oncology: Events that Changed the Course of Cancer Therapy and Implications for the Future
Discovery Of The Epidermal Growth proposed that EGFR could be a chemotherapeutic -target and in the late 1970s and 1980s he was involved in many Factor Receptor And Its Therapeutic preclinical studies in which his lab developed monoclonal Implications antibodies (mAbs 225 and 528) against the receptor. Mendelsohn, Baselga, and others were heavily involved in Roy Herbst, MD, PhD early clinical studies showing that the antibody, cetuximab, was active and useful. (See fi gure 1] The focus of this discussion will be on the epidermal growth factor receptor (EGFR) and its therapeutic implications, especially in head and neck malignancy. EGFR is one of the In the 1990s the tyrosine kinase inhibitors (TKIs) were HER receptors and is also known as HER-1 or Erb-B1. The investigated and the fi rst agent that went to trial was OSI- principal ligand for this receptor is either epidermal growth 774, known today as erlotinib. At about this time a drug factor (EGF) or tissue growth factor alpha (TGFα) and there called gefi tinib really took the lung cancer world by storm. are a number of important signal transaction pathways that Clinical trials demonstrated that patients with lung cancer are activated by this ligand.1 This receptor has an external that had been refractory to the taxanes and platinum were transmembrane, an internal domain, and is present in all responding to those single agent TKIs. The results led to cells. Although it tends to be more important in certain very quick approval in Japan, where studies demonstrated epithelial tumors, many tumors are subject to regulation by an amazingly good response in a large group of patients. this pathway. “Which ones?” is the most important question Although the results were not as good in the United States, to ask. I’ll return to this topic at the end of this talk, but the it was approved here based on phase II data. That brings big questions in this fi eld now are, “What is the target?” us to 2004, where cetuximab was being studied in head, and, “Who are the patients most likely to benefi t from neck, lung, and colorectal cancer, and gefi tinib was being inhibition of this receptor?” studied in a multitude of tumor types, while erlotinib was just emerging. First though, for a historical overview of EGFR, we can turn to a schema Jose Baselga and I put together for a review We were involved with some of those early phase I studies of gefi tinib (Figure 1). Stanley Cohen won the Noble Prize of gefi tinib in patients with non-small cell lung cancer in the 1960s for discovering EGFR while working with (NSCLC) and other solid tumors in 2000.3 There were mice corneas at Vanderbilt University. John Mendelsohn actually 2 phase I studies being done, one in Europe and
Timeline | The discovery and development of gefitinib EGFR-TK mutations Figure 1. The discovery and Japan is the first country to Gefitinib receives accelerated discovered; they might Gefitinib has a benign safety profile because it is used at 2 its optimal biological dose, unlike chemotherapy, which approve gefitinib for use in approval for third-line use in patients identify patients that go development of gefi tinib. is used at its maximum tolerated dose patients with inoperable or with advanced NSCLC who had on to have marked recurrent NSCLC failed standard chemotherapies responses to gefitinib Adapted from Herbst RS, Isolation of murine epidermal First anti-EGFR Discovery of new class of Fukuoka M, Baselga J. growth factor (EGF) by monoclonal EGFR tyrosine-kinase inhibitors Gefitinib demonstrates Gefitinib is the Food and Drug Understanding more Cohen heralds era of antibodies (TKIs) by Zeneca leads to favourable tolerability in first EGFR-TKI to Administration approves about the molecular Gefi tinib–a novel targeted targeted cancer treatment (mAbs) identification of gefitinib Phase I clinical trials reach the clinic the first EGFR-TKI mechanism of gefitinib approach to treating cancer. Nat Rev Cancer. 2004;4:956- 965. Copyright © 2004 Nature 1960s 1980s 1983 1990s 1994 1997 1998 2000 2002 2003 2004 Publishing Group. All rights reserved.
EGFR proposed as First clinical trial of anti- First clinical trials Phase II trials demonstrate Gefitinib investigated in Clinical experience with anticancer target by EGFR mAbs confirms of gefitinib confirm clinically meaningful activity of combination with EGFR-TKIs grows Mendelsohn mode of action mode of action gefitinib 250 mg/day in non- chemotherapy in NSCLC small-cell lung cancer (NSCLC) Gefitinib is now approved in >30 2004 and beyond: Phase III trials demonstrate no added countries for use in pretreated building knowledge benefit of adding gefitinib to standard NSCLC; more than 190,000 patients to optimize the use first-line chemotherapy in NSCLC have been treated worldwide of gefitinib in cancer
18 one in the US with continuous oral daily dosing. What we US. Trials of this drug versus chemotherapy are ongoing found was that about 10% of highly symptomatic patients and data will probably be available in about a year. The who had failed to respond to numerous chemotherapies main side effect of erlotinib is skin rash; in fact, if we are had an amazing response, and another 30% of the not seeing this effect we start to wonder if the patient will patients had stable disease. There were some mild respond or if they are even getting the right drug. We look adverse effects, skin rash, and diarrhea. However, there at this as a form of pharmacokinetic marker. Erlotinib was no myelosuppression or alopecia and very little is also approved in combination with gemcitabine for neurotoxicity. Patients with certain characteristics (non- pancreatic cancer6 and studies are underway for its use in smokers, women, people of Asian descent) and people with patients with a variety of other tumor types. bronchioalveolar carcinoma, had a better response. This drug was a targeted therapy and clinical data suggested that it worked better in patients with certain characteristics, Proper patient selection is very important. Figure 2 is an not yet molecular characteristics, but other clinical example of what can happen when a 50-year-old woman characteristics. Yet this is where there was a disconnect who never smoked is treated with erlotinib as fi rst-line in critical thinking because the patients were not selected therapy for NSCLC. She had some brain disease and based on EGFR expression. Granted, there were some had just had radiation and we did not want to give her valid concerns expressed about how to stain for EGF with chemotherapy. She had a dramatic response. A few years immunohistochemistry and about obtaining and preserving ago we learned that certain patients with specifi c genetic the tissue. But what happened was that tissue was obtained changes had tumors growing, in large part, due to an up- in some, but not all of the studies. Drug development regulation of the EGFR and that these patients also respond then went forward into phase II studies without suffi cient very well to small molecule EGFR inhibitors. This patient selection of patients, a process that critically fl awed the had a 99% response and went back to work, but about a pharmaceutical development of this agent. year later developed a secondary mutation and she was unresponsive to treatment. These secondary mutations are being described more now, but we still don’t have a good The agent went through a phase III study with the Iressa way to treat patients with these mutations. Survival in Lung Evaluation (ISEL) study.4 It was performed outside the US since gefi tinib was already approved here. The gefi tinib treatment was not associated with a signifi cant improvement when used as a second- or third-line treatment in about 1700 patients with refractory NSCLC. About 800 of those patients had adenocarcinoma, but even with those patients, where the drug does work a little bit better, the results did not reach statistical signifi cance. The study did show evidence of benefi t among non-smokers and Asians, but at this time the drug is, for all practical purposes, off the market in the US and rumor has it that it will become harder and harder to get it, even for National Cancer Institute (NCI) studies.
Frances Shepherd and her group studied another tyrosine kinase EGFR inhibitor, erlotinib, for NCI of Canada.5 This was studied as a second- or third-line therapy for patients with NSCLC and achieved statistical signifi cance for the Figure 2. Never smoking 50-year-old woman treated with single primary endpoint of survival, improving median survival agent erlotinib as fi rst-line therapy for NSCLC (Deletion in Exon by 2 months and 1-year survival by about 45%. This drug 19). Courtesy of Roy Herbst, MD, PhD. is used frequently since it is the only approved second- or third-line alternative to chemotherapy available in the
19 Milestones in Oncology: Events that Changed the Course of Cancer Therapy and Implications for the Future
As we learn more about molecular studies we are recognizing the importance of EGFR screening in lung cancer and in the other tumor types, as well.7-9 We need to look at mutations, gene amplifi cation, and at EGFR protein levels as predictors of response. Also, we need to determine the best way to obtain fresh, uniform biopsies for testing. EGFR inhibitors were developed without a target and we are fi nding the target as we move forward. There must have been 20,000 or 30,000 patients treated with these agents before a full effort was undertaken to try to obtain tissue. Part of the reason that we didn’t focus on developing a target was because of the diffi culty inherent in getting tissue from refractory lung cancer. Regardless, the whole fi eld has changed, and this is our main focus now.
Table 1. Comparison of EGFR inhibitors. Combining EGFR inhibitors with antiangiogenic drugs is a TGF indicates transforming growth factor. way to target a tumor in multiple ways. One study of this *Gefi tinib, erlotinib. approach combines erlotinib, which inhibits tumor cell †Cetuximab, ABX-EGF. growth and blocks synthesis of angiogenic proteins by tumor cells, with bevacizumab, which inhibits endothelial Courtsey of Roy Herbst, MD, PhD. cells from responding to angiogenic protein.10 A similar study, which was recently reported in Prague at the Early trials with cetuximab (IMC-225) combined with European Organisation for Research and Treatment of cisplatinum to treat patients with head and neck tumors Cancer (EORTC), had compelling results. The phase II, and NSCLC that were refractory to platinum treatment 120-patient trial of erlotinib/bevacizumab combination showed some success.13-15 These early strategies were therapy as a second-line treatment for lung cancer had a developed in head and neck cancer trials (which preceded 57% 1-year survival versus 31% with chemotherapy.11 those done in colon cancer) and investigated if the mAbs plus platinum would have activity in patients refractory to platinum. It was a diffi cult study because the patients In the future multi-targeted molecules such as ZD6474, were quite ill after platinum therapy and there was some which has both anti-EGFR and anti-VEGF activity, will single agent activity of cetuximab, as well. Dr Robert and be investigated further.12 One concern with ZD6474 is an others in Alabama combined cetuximab with radiation imbalance in the IC50 (50% inhibitory concentration) for and noted an effect,16 which led to a large phase III study each activity, which could be a problem. led by Dr Bonner.17 Patients with locally advanced head and neck cancer were treated with radiation or radiation Two other drugs to consider are the monoclonal plus cetuximab and the results were extraordinary, with antibodies (mAbs) panitumumab and matuzumab. overall survival and median duration of locoregional Panitumumab is approved by the FDA for use in control about double with combined therapy. Cetuximab metastatic colorectal cancer. Three phase II clinical and panitumumab are FDA approved for colon cancer and trials are currently underway to investigate the use of studies are underway in other solid tumors as well. matuzumab in colorectal, gastric, and non-small cell lung cancers. See Table 1 for a comparison of the An interesting story about how we got started at looking mechanism of action for EGFR TK inhibitors and mAbs. into using cetuximab and panitumumab for colon cancer emphasizes the importance of paying attention to the experiences of the front-line practitioner. At one of the
20 early investigative meetings for head and neck cancer, 8. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations a fellow physician from Florida asked if he could have in the epidermal growth factor receptor underlying ten minutes. He brought up some x-rays and said, “This responsiveness of non-small-cell lung cancer to gefi tinib. N is a woman who has refractory colorectal cancer. I gave Engl J Med. 2004;350:2129-2139. her irinotecan (CPT-11). She failed that so I combined it 9. Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor with cetuximab on a compassionate IND (investigational receptor gene and protein and gefi tinib sensitivity in non- new drug) [program].” She had some activity from that small-cell lung cancer. J Natl Cancer Inst. 2005;97: 643-655. treatment and, based on that, studies were started with 10. Herbst RS, Johnson DH, Mininberg E, et al. Phase I/II trial cetuximab plus CPT-11, and of course the rest is history. evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase The future of this fi eld is in molecular markers. We inhibitor erlotinib for patients with recurrent non-small-cell have agents that target EGFR and we know it is a potent lung cancer. J Clin Oncol. 2005;23:2544-2555. and safe target. The goal for all tumor types will be to 11. Herbst R, O’Neill V, Fehrenbacher L, et al. A phase II, determine the best patients to treat with the best therapy multicenter, randomized clinical trial to evaluate the effi cacy and use the agents early and in the right combinations. and safety of bevacizumab (Avastin®) in combination with Ultimately we need to personalize the therapy to the either chemotherapy (docetaxel or pemetrexed) or erlotinib hydrochloride (Tarceva®) compared with chemotherapy individual patient. alone for non-small-cell lung cancer. Presented at the 18th EORTC - NCI - AACR Symposium on “Molecular Targets and References Cancer Therapeutics”; November 7-10, 2006; Prague, Czech Republic. Abstract 53. 1. Herbst RS, Bunn PA Jr. Targeting the epidermal growth factor receptor in non-small cell lung cancer. Clin Cancer 12. Wedge SR, Ogilvie DJ, Dukes M, et al. ZD6474 inhibits Res. 2003;9(16 Pt 1):5813-5824. vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res. 2. Herbst RS, Fukuoka M, Baselga J. Gefi tinib–a novel targeted 2002;62:4645-4655. approach to treating cancer. Nat Rev Cancer. 2004;4:956-965. 13. Shin DM, Donato NJ, Perez-Soler R, et al. Epidermal growth 3. Herbst RS, Maddox AM, Rothenburg ML, et al. Selective oral factor receptor-targeted therapy with C225 and cisplatin epidermal growth factor receptor tyrosine kinase inhibitor in patients with head and neck cancer. Clin Cancer Res. ZD1839 is generally well-tolerated and has activity in non- 2001;7:1204-1213. small-cell lung cancer and other solid tumors: results of a phase I trial. J Clin Oncol. 2002;20:3815-3825. 14. Baselga J, Pfi ster D, Cooper MR. Phase I studies of anti- epidermal growth factor receptor chimeric antibody C225 4. Thatcher N, Chang A, Parikh P, et al. Gefi tinib plus alone and in combination with cisplatin. J Clin Oncol. best supportive care in previously treated patients with 2000;18:904-914. refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre 15. Herbst RS, Arquette M, Shin DM, et al. Phase II multicenter study (Iressa Survival Evaluation in Lung Cancer). Lancet. study of the epidermal growth factor receptor antibody 2005;366:1527-1537. cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol. 5. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al; National 2005;23:5578-5587. Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 16. Robert F, Ezekiel MP, Spencer SA, et al. Phase I study of 2005;353:123-132. anti–epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced ® 6. Tarceva (erlotinib) tablets [prescribing information]. South head and neck cancer. J Clin Oncol. 2001;19:3234-3243. San Francisco, Calif: Genentech, Inc; and Melville, NY: OSI Pharmaceuticals; 2005. 17. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and 7. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al. Epidermal neck. N Engl J Med. 2006;354:567-578. growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol. 2003;21:3798-3807.
21 Milestones in Oncology: Events that Changed the Course of Cancer Therapy and Implications for the Future
Evolution of Targeted Therapy Over Chronic imatinib emerged as the primary compound for clinical development.5 Preclinical studies clarifi ed the activity of Myeloid Leukemia the compound against cells containing and expressing Brian Druker, MD BCR-ABL and demonstrated an acceptable animal toxicology profi le.
The important thing I want to discuss is the triumph Clinical studies started in June 1998 with a phase I of science over disease. As you know, the cause of dose-escalation study of patients with chronic CML who chronic myeloid leukemia (CML) in over 90 % of patients had failed to respond to interferon alfa (INF- ) therapy.6 is the presence of a constitutively active BCR-ABL α Nearly all of the patients (53/54) receiving doses over tyrosine kinase, which is the result of translocation 300 mg had a complete hematologic response, 53% had of chromosomes 9 and 22 of the Philadelphia (Ph) cytogenic responses, and 13% had a complete cytogenic chromosome. Imatinib (formerly ST1571) inhibits BCR- response. Phase II CML studies followed, which looked ABL tyrosine kinase and is highly effi cacious in treating at imatinib as a single agent in patients refractory to patients with CML. In addition, we have some promising INF- therapy and accelerated phase and myeloid blast new ABL inhibitors that are more potent and show α crisis patients. signifi cant activity in imatinib-resistant patients and may improve outcomes even further. That is the triumph. Although developed with an original target of PDGF-R, imatinib also inhibited c-kit tyrosine kinase. Since But I would like to go back and review how we got here c-kit activating mutations are associated with many and a good place to pick up the thread of this story, a gastrointestinal stromal tumors (GIST), we studied the story that is woven into the fabric of successful oncologic ability of imatinib to inhibit c-kit kinase activity in cells therapeutics, is when Nowell and Hungerford discovered and found the results promising.7 A clinical study of the Ph chromosome in 1960.1 That breakthrough imatinib use in patients with advanced unresectable or was followed in 1973 by Janet Rowley’s discovery metastatic GIST confi rmed that inhibition of the c-kit that reciprocal translocation of the long arms of pathway was promising indeed, with more than half chromosomes 9 and 22 resulted in the Ph chromosome.2 of the patients demonstrating a sustained objective This led to the discovery in the 1980s that the ABL response to therapy.8 tyrosine kinase locus translocated to the BCR locus creating the fusion gene protein, BCR-ABL.3 Before imatinib became available, INF-α plus cytarabine was considered the standard therapy for CML.9,10 A In the late 1980s, despite the fact that there was a lot of large phase III, prospective, open-label, multicenter, skepticism, a team of scientists led by Nicholas Lydon randomized, controlled trial was conducted in an and Ales Matter at Novartis (then Ciba Geigy) started outpatient setting and compared imatinib and INF- performing high-throughput screens searching for α plus cytarabine therapy of chronic-phase CML patients.11 kinase inhibiting compounds.4 They followed this time- The results indicated imatinib was superior as a fi rst- consuming approach in the face of arguments that line therapy in newly diagnosed chronic-phase CML. A kinase inhibitors would never work, would be toxic, and, 5-year follow-up of that study confi rmed that imatinib for CML, would never make enough money to justify therapy induced durable responses in a high proportion development. Analysis of the relationship between of patients.12 structure and activity was essential to the development of a series of compounds that were optimized to inhibit a variety of specifi c targets. A lead compound was Table 1 is a review of the imatinib timeline. identifi ed with activity against platelet-derived growth factor receptor (PDGF-R) and ABL tyrosine kinase, but it had low potency and specifi city, so a series of related compounds were synthesized. Out of this process,
22 From these timelines you can see that the process of moving through trials and getting FDA approval is improving. So how do we repeat and improve upon the success we have had with CML therapy?
We must not forget that this processs started with the identifi cation of a target, ABL tyrosine kinase inhibition. So we must fi rst identify a molecular pathogenic target that is active early in the disease process. Then we must fi nd or formulate a specifi c agent to inhibit that target. Treatment with molecularly targeted agents should be given as early in the course of disease as possible. Patient selection for clinical trials is also extremely important. In CML studies, patients with BCR-ABL were identifi ed by the presence of the Ph chromosome. Table 1. Imatinib timeline Remarkable results can be attained when an agent targeting a specifi c abnormality that is easily identifi able OHSU indicates Oregon Health and Science University; CML, chronic myeloid leukemia; GIST, gastrointestinal stromal is given early in the disease process. Looking for other tumors; FDA, US Food and Drug Administration. Courtesy of diseases with similar molecular processes and looking Brian Druker, MD. for other molecular processes that a drug inhibits will increase the utility of a drug that has been selected for clinical development. The challenge is to access the Table 2 is a review of the dasatinib timeline, one of the vast amount of structural data in the fi eld so that series newer ABL inhibitors: of molecules can be found or developed for selectivity against the specifi cally intended targets. To address this problem we will need to use a team approach with specialists in structural biology, computational chemistry, structurally directed medicinal chemistry, array screening assays, and molecular and cellular biology, to use genome-based methods to identify and evaluate more candidate agents and targets.5
To improve the drug development process we must remember to take full advantage of industry/academic collaborations. Defi ning the disease by molecular subtype is essential as we move into an era where more and more small market diseases are being addressed. As we match the right patient to the right drug we can expect clinical trials to get smaller, smarter, and quicker. But the FDA will need to develop a new paradigm for cancer drug approvals, including Table 2. Dasatinib timeline. post-marketing surveillance. Regulations for drug CML indicates chronic myeloid leukemia; FDA, US Food and reimbursement will also need to change so that bringing Drug Administration. Courtesy of Brian Druker, MD. chemotherapeutic oncology drugs to market remains profi table. If these suggestions are heeded, then drug prices will fall along with drug development costs.
23 Milestones in Oncology: Events that Changed the Course of Cancer Therapy and Implications for the Future
Dasatinib, an even more potent drug than imatinib, made 5. Druker BJ, Lydon NB. Lessons learned from the it through clinical trials in less than 3 years, tapped FDA development of an abl tyrosine kinase inhibitor for chronic approval, and made it through the FDA in 6 weeks from myelogenous leukemia. J Clin Invest. 2000;105(1):3-7. the time it was submitted to its approval. The point here 6. Druker BJ, Talpaz M, Resta DJ, et al. Effi cacy and safety of a is that if you understand the disease and you understand specifi c inhibitor of the BCR-ABL tyrosine kinase in chronic your target, then you can have very rapid, very successful myeloid leukemia. N Engl J Med. 2001;344:1031-1037. drug discovery and delivery. The future is targeted 7. Heinrich MC, Griffi th DJ, Druker BJ, Wait CL, Ott KA, Zigler therapy, understanding what we are doing, why we are AJ. Inhibition of c-kit receptor tyrosine kinase activity doing it, who the patients are, and who would benefi t by STI 571, a selective tyrosine kinase inhibitor. Blood. from the therapy. We are just beginning to see the dawn 2000;96:925-932. of that era and my hope is that within the next 5, 10, 20 8. Demetri GD, von Mehren M, Blanke CD, et al. Effi cacy and years, that era will be entirely upon us and we will see safety of imatinib mesylate in advanced gastrointestinal survival rates for other cancers improve, much like what stromal tumors. N Engl J Med. 2002;347:472-480. we have seen for CML with survival rates going from less 9. Guilhot F, Chastang C, Michallet M, et al. Interferon alfa-2b than 50% to 95% or more. combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Chronic Myeloid Leukemia Study Group. N Engl J Med. 1997;337:223-229. References 10. Baccarani M, Rosti G, de Vivo A, et al; Italian Cooperative 1. Nowell PC, Hungerford DA. A minute chromosome in Study Group on Myeloid Leukemia. A randomized study human granulocytic leukemia. Science. 1960;132:1497- of interferon-alpha versus interferon-alpha and low-dose 1501. arabinosyl cytosine in chronic myeloid leukemia. Blood. 2002;99:1527-1535. 2. Rowley JD. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identifi ed 11. O’Brien SG, Guilhot F, Larson RA, et al; IRIS Investigators. by quinacrine fl uorescence and Giemsa staining. Nature. Imatinib compared with interferon and low-dose cytarabine 1973;243:290-293. for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994-1004. 3. Heisterkamp N, Stam K, Groffen J, de Klein A, Grosveld G. Structural organization of the bcr gene and its role in the 12. Druker BJ, Guilhot F, O’Brien SG, et al; IRIS Investigators. Ph’ translocation. Nature. 1985;315:758-761. Five-year follow-up of patients receiving imatinib for chronic 4. Druker BJ. STI571 (Gleevec) as a paradigm for cancer myeloid leukemia. N Engl J Med. 2006;355:2408-2417. therapy. Trends Mol Med. 2002;8(4 Suppl):S14-18.
Abbreviations NIH: National Institute of Health ER: estrogen receptor NOCR: Network for Oncology Communication AC: doxorubicin + cyclophosphamide Erb-B1: EGFR and Research BCIRG: Breast Cancer International Research NSABP: National Surgical Adjuvant Breast and Group FAC: fl uorouracil + doxorubicin + cyclophosphamide Bowel Project CAF/FAC: cyclophosphamide + doxorubicin + NSABP: National Surgical Adjuvant Breast and fl uorouracil FEC/CEF: fl uorouracil + epirubicin + cyclophosphamide Bowel Project CALGB: Cancer and Leukemia Broup B HER1 receptor: EGFR NSCLC: non-small cell lung cancer CMF: cyclophosphamide + methotrexate + PCR: polymerase chain reaction fl uorouracil HER2 receptor: a member of the EGFR family that is notable for its role in the pathogenesis of RS: recurrence score DOX: doxorubicin breast cancer and as a target of treatment TAC: docetaxel + doxorubicin + ECOG: Eastern Cooperative Oncology Group ISEL: Iressa Study in Lung Cancer cyclophosphamide EGF: epidermal growth factor L-PAM: L-phenylalanine mustard TGFα: tissue growth factor alpha EGFR: epidermal growth factor receptor NCI: National Cancer Institute TK: tyrosine kinase EORTC: European Organisation for Research NED: no evidence of disease VEGF: vascular endothelial growth factor and Treatment of Cancer
24 Notes:
25 Milestones in Oncology: Events that Changed the Course of Cancer Therapy and Implications for the Future
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27 Milestones in Oncology: Events that Changed the Course of Cancer Therapy and Implications for the Future
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1. After 20 years of follow-up, what are the results of the clinical trial comparing MOPP and ABVD in the treatment of Hodgkin Disease? a. MOPP was proven to be more effective b. ABVD was proven to be more effective c. Overall survival is the same in both groups
2. A recently published trial comparing 4 cycles of BEP with 2 cycles of BEP + 2 high-dose cycles + stem cell transplant, showed improved benefi t with the transplant regimen in metastatic germ-cell tumors. a. T b. F
3. ______may be an indicator of effi cacy in patients receiving EGFR inhibitor therapy. a. Skin rash b. Nausea c. Myelotoxicity
4. Which of the following is true? a. There has never been a study demonstrating improved effi cacy of AC over CMF. b. Dose escalation increases effi cacy in anthracycline therapy of breast cancer.
5. Stanley Cohen was credited with the discovery of epidermal growth factor in: a. the 1980s b. the 1990s c. the 1960s d. the 1800s
6. ______is the only approved second- or third-line alternative to chemotherapy in NSCLC patients available in the US. a. Gefi tinib b. Erlotinib c. Bevacizumab d. Sunitinib
7. A phase II study recently reported at the EORTC in Prague indicated that the combination of the following two targeted agents had compelling results compared with chemotherapy in lung cancer treatment: a. erlotinib, bevacizumab b. sorafenib, pertuzumab c. gefi tinib, erlotinib
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29 Milestones in Oncology: Events that Changed the Course of Cancer Therapy and Implications for the Future
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30 Published by: The American School of Oncology, 4325 Alexander Drive, Alpharetta, GA 30022 This publication is designed to provide accurate and authoritative information about the subject matter covered. The information contained herein is based on sources believed to be accurate and reliable. We have exercised reasonable care to ensure the accuracy of the information. However, no representation or warranty is made as to such accuracy. Readers should check primary sources where appropriate and use traditional research techniques to make sure that the information has not been affected or changed by recent developments. © 2007, The American School of Oncology
Milestones in Oncology: Events that Changed the Course of Cancer Therapy and Implications for the Future