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Home , Alemtuzumab, Rituximab

Use of Monoclonal in Oncology Humera Khurshid, MD, and Natalie Sinclair, MD  Mo n o c l o n a l a n t i b o d i e s (MCA) can also deliver cytotoxic chemicals such Low Grade Non Hodgkins represent a significant addition to thera- as radioisotopes and toxins. The pharma- peutic options for a number of oncologic cologic characteristics are summarized. In a pivotal phase II trial, heavily pre- disorders. MCA are highly specific. They [Table 1] treated patients with relapsed low grade bind to and affect disease specific targets The Food and Drug Administration NHL were given single agent resulting in sparing of normal cells with (FDA) has approved several MCA for intravenously weekly for four weeks. Forty less side effects than traditional chemo- oncologic indications. eight percent of patients responded with therapy. This review focuses on MCA a median response of 12 months.1 After approved for clinical use. Rituximab retreatment the response rate was around MCA are produced by a single clone Rituximab was the first approved 40%.2 Rituximab was found to be effective of B cells and are mono specific. These MCA. This chimeric IgG molecule and safe when combined with standard antibodies can block essential cellular binds with high specificity to the CD20 first line . In the phase III receptors, directly induce , bind molecule on lymphoid cells of B lin- trial involving CD20 positive follicular to target cells, and recruit - eage. Rituximab is active against CD20 NHL patients the response rate was 81% dependant cellular or complement-de- positive Non Hodgkins in the combination group (Cyclophosph- pendent cytotoxicity mechanisms. They (NHL). amide, Vincristine and Prednisone (CVP)

Table 1. Target Mechanism Indication US FDA Adverse Reaction Approval Date

Rituximab (Rituxan) CD 20 ADCC, CDC, NHL 11/26/1997 Allergic Reactions Directly induces Maintenance 1/28/201 Tumor Lysis apoptosis in NHL Syndrome

Trastuzumab HER 2 Inhibition of HER2- Breast 9/25/1998 Cardiac (Herceptin) mediated tumor complications cell proliferation Allergic reactions and migration

Cetuximab (Erbitux) EGFR Inhibits EFGR Colon 2/12/2004 Allergic reactions mediated tumors Head and 3/1/2006 and skin rash cell invasion, neck cancer proliferation metastatis, Enhances Activity of some chemotherapuetic and radiotherapy

Penitumumab (Vectibix) EGFR Inhibits EFGR Colon 9/27/2006 Dermatologic mediated tumors toxicity cell invasion, proliferation metastatis,

Bevacizumab (Avastin) VEGF Inhibiton of VEGF Metastatic 10/11/2006 Proteinuria induced Non squamous Hypertension angiogenesis Thrombosis Colon 2/26/2004 Reduced wound Met Renal cell ca 7/31/2009 healing Recurrent Pulmonary gliomas 5/5/2009 Hemorrhage Met Breast 12/16/2010 in squamous histology

Alemtuzumab (Campath) CD 52 ADCC, CDC CLL 5/7/2001 Pancytopenia, Lymphopenia

325 Volume 94 No. 11 No v e m b e r 2011 with Rituximab) vs. 57 % in patients given Tr a s t u z u m a b zumab for 52 weeks, or weekly paclitaxel CVP alone [P = < 0.001]. Time to treat- Trastuzumab is a humanized mono- with concurrent trastuzumab followed ment failure was longer in the combination clonal antibody that targets HER2 also by trastuzumab alone for 40 weeks.16,17 group 27 vs. seven months [P = < 0.001]. known as C-erb-B2, a member of the Combined analysis demonstrated that ad- Benefit was not associated with any signifi- EGFR family. HER2 is over expressed in juvant trastuzumab paired with paclitaxel cant increase in toxicity.3 about 25-30% of breast cancer. Over ex- chemotherapy resulted in a greater than In January 2011 the US FDA ap- pression in early stage breast cancer is asso- 50 % reduction in recurrence risk, with proved Rituximab for maintenance therapy ciated with poor prognostic factor such as a four year disease free survival of 86% for previously untreated CD20 + high tumor grade,10 axillary lymph node vs. 73% and a 37% reduction in risk of NHL that achieved a response. This was involvement,11 increase mitotic rate,12 and death. The four year overall survival was based on the PRIMA study (Primary lack of estrogen and progesterone recep- 93% vs. 89%. This led to FDA approval Rituximab and Maintenance Phase III in- tor expression.13 It is also an independent and established adjuvant traztuzumab as tergroup trial). After achieving a response adverse prognostic factor.14 the standard of care.18 Similar results were to systemic chemotherapy, 1018 patients In a phase III trial patients with found in early analysis of a large multina- were randomized in a 1:1 manner to receive metastatic breast cancer (MBC) with tional trial, the Herceptin Adjuvant study either rituximab 375 mg/m2, intravenous- HER2 over expression, untreated patients (HERA trial).19 ly every eight weeks with a maximum of were randomized to receive standard Trastuzumab is associated with the 12 doses vs. observation. Progression free chemotherapy with and without Trastu- risk of cardiotoxicity manifested by an survival (PFS) was the primary endpoint zumab. Those who received Trastuzumab asymptomatic decline in the left ventricle and treatment. Rituximab increased PFS plus chemotherapy had a longer time to ejection fraction and less commonly by 46 % [P = < 0.001]. A higher percent disease progression, 7.4 months vs. 4.6 development of New York Heart Associa- of patients had a complete response at 2-4 months [P = < 0.001], a highly objective tion Class III or IV.20 The cardiac toxicity months with Rituximab maintenance [67 response rate, 50% vs. 32% [P = < 0.001], may be reversible in many patients and vs. 48 %].4 a longer median duration of response, 9.1 responds to standard treatments for heart vs. 6.1 months, [P = < 0.0001], longer failure. Anthracycline use and age greater High Grade Non-Hodgkins median survival, 25.1 months vs. 20.3 than 60 years are the strongest risk factors Lymphoma months [P = 0.046], and a 20 % lower risk for development of trastuzumab-related In a randomized phase III study of of death than patients who had received cardiac toxicity. , Doxorubicin, Vin- chemotherapy alone.15 cristine, and Prednisone (CHOP) che- Addition of trastuzumab to adjuvant Ce t u x i m a b motherapy with or without rituximab in chemotherapy significantly reduces the Epidermal Growth factor Recep- treatment naive patients, the rituximab likelihood of disease relapse and death tor (EGFR) also known as HER-1 is a arm showed a higher PFS, (53 vs. 35 % among women with HER2 positive early tyrosine kinase receptor and a member P = 0.0008) without increased toxicity.5,6 stage breast cancer. Two North American of the EFGR family. Over-expression is A phase III study, the MabThera Inter- cooperative group trials were designed seen in various epithelial tumors such as national Trial (or MInT trial), enrolled to evaluate the efficacy of adjuvant lung, breast, head and neck and colon. patients with high grade lymphoma, trastuzumab. In the National Surgical Over expression is associated with a poor aged 18-60 years and compared CHOP Adjuvant Breast and Bowel Project trial prognosis.21-23 plus rituximab with chemotherapy alone (NSABP B-31), 1736 patients with Her2 as first line treatment . The study was positive breast cancer received 4 cycles Metastatic Colorectal Cancer (CRC) closed early when interim analysis showed of doxorubicin and cyclophosphamide is a chimeric monoclonal a significantly longer time to treatment [AC] followed by four cycles of paclitaxel antibody that binds to EGFR, blocking failure in the combination group. After a 175mg/m2 every three weeks. They were its binding to its receptor thus preventing follow up of 34 months patients assigned randomly assigned to no further therapy receptor activation and downstream sig- to R-CHOP had significantly higher PFS, or weekly trastuzumab beginning with naling. Two monoclonal antibodies that (79% vs. 59%) and overall survival OS, the first course of paclitaxel. The North target EFGR are active for treatment of [93% vs. 84%].7 Central Cancer Treatment Group (NC- metastatic colorectal cancer, cetuximab CTG trial N9831) tested the value of and panitumamab. KRAS, the protein Small Lymphocytic Lymphoma and adding trastuzumab to sequential AC and product of the Ras oncogene, serves as Chronic Lymphocytic paclitaxel in concurrent vs. sequential tras- a mediator between extracellular ligand Rituximab is also active in Chronic tuzumab and paclitaxel. In this trial, 1615 binding and intracellular transduction Lymphocytic Leukemia (CLL).8 In a women with HER2 positive lymph node signals from EGFR to the nucleus. Ac- phase II study by the Cancer and Leuke- or high risk node negative breast cancer tivating KRAS mutations are detected mia Group B, plus Rituximab (greater than 1cm ER negative or greater in approximately 40% of metastatic based therapy in previously untreated than 2cm ER positive) received AC in one colorectal cancer, with good concordance patients gave a higher response rate and of the three different treatment strategies. between the primary and distant metasta- complete remission than chemotherapy Weekly paclitaxel for 12 weeks alone, sis.24 KRAS mutations are associated with alone.9 weekly paclitaxel followed by trastu- poor prognosis and overall resistance to 326 Medicine & Health/Rhode Island EGFR therapy. and Cetux- does not support the use of cetuximab in with FOLFOX (5-FU, Leucovorin, and imab are approved only for patients with combination with platinum and radiation Oxaliplatin) for first line treatment in wild type KRAS tumors. KRAS mutation therapy. Randomized trials are currently metastatic CRC35 is active analysis is commercially available. underway to evaluate this combination in first line metastatic CRC in combina- Cetuximab monotherapy was com- therapy. tion with oxaliplatin and irinotecan based pared to best supportive care in a random- regimens.36 ized trial of 572 heavily pretreated patients with Metastatic CRC.25 Median OS was Panitumumab is fully Non squamous non small cell lung significantly better with cetuximab (6.1 monoclonal cancer (NSCLC) vs. 4.6 months), and quality of life mea- The initial phase II study investigat- sures were also improved in the treatment antibodies specific ing a combination of paclitaxel and carbo- arm. In a subsequent analysis, the benefit for the extra cellular platin with or without bevacizumab raised of Cetuximab was restricted to patient safety concerns. Patients with squamous who lacked KRAS mutation (wild type domain of EGFR. cell histology had higher incidences of KRAS). Cetuximab has also been used fatal pulmonary hemorrhage (~30%). with chemotherapy with encouraging Cetuximab has shown benefit in Other risk factors were cavitary lesions, results.26 First line Cetuximab was evalu- patients with metastatic squamous cell hemoptysis, and brain metastases.37 ated in patients with previously untreated carcinoma of the head and neck with A pivotal phase III trial conducted metastatic CRC, 1198 were randomized combined cisplatin based chemothera- by Eastern Cooperative Oncology Group to 5-FU, leucovorin, and irinotecan py. 31 In a randomized phase III trial (ECOG 4599) included 878 previously (FOLFIRI) with or without Cetuximab.27 involving 442 patients with recurrent untreated NSCLC. They were random- Median PFS was modestly better in or metastatic head and neck squamous ized to carboplatin and paclitaxel given patients with combined therapy, 8.9 vs. cell carcinoma patients assigned to first every 21 days for six cycles vs. the same eight months, as was the overall response line platinum chemotherapy with or doublet combination with bevacizumab. rate (47% vs. 39%). However there was without cetuximab. The addition of Patients with squamous cell carcinoma, no significant difference in OS. In a pre- cetuximab to chemotherapy significantly hemoptysis, or history of brain metastases liminary report in patients with wild type prolonged the median PFS and OS (5.6 were excluded to minimize the risk of KRAS, response rates were significantly and 10.1 month vs. 3.3 and 7.4 months pulmonary or intracerebral hemorrhage. higher in those who received cetuximab respectively).32 Common side effects of Patients receiving chemotherapy plus be- in conjunction with chemotherapy.28 cetuximab include acneiform rash, hypo- vacizumab had a significant increase in the Cetuximab is indicated only for patients magnesemia, fever, and gastrointestinal objective response rate, (35% vs. 15%,) with wild type KRAS tumors. symptoms. with an overall survival of 12.3 months vs. Panitumumab is fully human mono- 10.3 month. One year and two years sur- clonal antibodies specific for the extra Be v a c i z u m a b vival were 51% vs. 44% and 53% vs. 50% cellular domain of EGFR. Panitumumab Bevacizumab is a humanized murine respectively.38 The bevacizumab contain- is approved in the US as a single agent monoclonal antibody that targets vascu- ing regimen was generally well tolerated. for KRAS wild type metastatic colorectal lar endothelial growth factor receptor In a second trial conducted in Europe, cancer after other drugs have failed.29 A (VEGF). VEGF is an important cell there was a benefit in terms of PFS how- specific mitogen that regulates vascular ever there was no significant difference in Head and neck cancer proliferation and permeability. It also OS between treatment arms.39 Cetuximab was compared concur- functions as anti apoptotic factor for rently with RT vs. RT alone in a mul- newly formed blood vessels. (33). The an- Metastatic Breast Cancer (MBC) tinational randomized study of patients tibody targets the process of angiogenesis Bevacizumab is FDA approved for with locally advanced head and neck and the acquisition of new blood vessels breast cancer that does not over express carcinoma.30 Compared to RT alone by the tumor. Her2. In the ECOG 2100 trial, 722 the addition of cetuximab significantly women with no prior treatment for MBC improved the duration of local control, Colorectal cancer were randomly assigned to bevacizumab (24 vs. 15 months), as well as PFS, (42% Addition of bevacizumab to a variety and paclitaxel or paclitaxel alone.40 Be- vs. 39%), and OS (55% vs. 45%). Im- of first line regimens used for metastatic vacizumab combined with paclitaxel portantly comparison of RT alone is no colorectal cancer improves outcome. In significantly increased the response rate longer the accepted standard for patients a randomized phase II trial previously 37% vs. 21%. and PFS (11.8 months with locally advanced head and neck untreated patients were assigned to bo- from 5.9 months). In a similar trial the cancer. As the toxicity profile of RT and lus irinotecan, fluorouracil (IFL) with combination of bevacizumab and doc- cetuximab is viewed to be more tolerable or without bevacizumab. Response rates etaxel was found to be more beneficial.41 compared to chemo-radiotherapy, some were higher with bevacizumab and it Pooled analysis from these trials show may consider it to be more of a substitute prolonged median survival by 4 months.34 improvement in PFS but no improve- for chemo-radiotherapy particularly in the Similar results were seen in a phase III ment in OS. treatment of elderly patients. Current data trials of bevacizumab in combination 327 Volume 94 No. 11 No v e m b e r 2011 Recurrent Malignant Gliomas (GBM) In a phase III trial, 297 previously 7. Pfreundschuh M, et al. CHOP-like chemo- Bevacizumab has demonstrated sig- untreated and symptomatic patients therapy plus rituximab versus CHOP-like chemotherapy alone in young patients with nificant clinical activity in phase II single with RAI stage I-IV CLL were randomly good-prognosis diffuse large-B-cell lymphoma: arm studies, both as single agent and when treated to or Chlorambu- a randomised controlled trial by the MabThera given with irinotecan to patients with cil.47 At follow up of 25 months patients International Trial (MInT) Group. Lancet Oncol. grade 3 and grade 4 malignant GBM. treated with alemtuzumab had a higher 2006;7(5):379-91. 8. Hainsworth JD, et al. Single-agent rituximab The most extensive experience with overall response rate 83% vs. 55% and as first-line and maintenance treatment for bevacizumab comes from a randomized PFS was 15 month vs. 12 months. On patients with chronic lymphocytic leukemia or non-comparative phase II trial in which subset analysis higher response rates were small lymphocytic lymphoma: a phase II trial 167 patients with recurrent GBM were of the Minnie Pearl Cancer Research Network. seen in high risk patients. The study was J Clin Oncol. 2003;21(9):1746-51. randomly assigned to bevacizumab either not powered to find an OS difference. 9. Byrd JC, et al. Randomized phase 2 study of as a single agent or in conjunction with iri- Alemtuzumab related toxicity in- fludarabine with concurrent versus sequential notecan.42 Treatment cycles where repeat- clude, lymphopenia, leukopenia, high treatment with rituximab in symptomatic, ed every two weeks. All patients received untreated patients with B-cell chronic lym- rate of febrile neutropenia as well as infu- phocytic leukemia: results from Cancer and prior chemotherapy with temozolomide. sion related , fever, dyspnea, Leukemia Group B 9712 (CALGB 9712). In this trial the objective response rate bronchospasm, rash, rarely pulmonary Blood. 2003;101(1):6-14. with bevacizumab alone or with combi- infiltrates, ARDS, and . 10. Berger MS, et al. Correlation of c-erbB-2 gene amplification and protein expression in human nation with irinotecan was 28% vs.38% breast carcinoma with nodal status and nuclear respectively and the six month PFS rates Co nc l u s i o n grading. Cancer Res. 1988;48(5):1238-43. and OS were 43% and 53%, 9.2 months Monoclonal antibodies have been 11. Slamon DJ, et al. Studies of the HER-2/neu and 8.7 months respectively. Treatment among the most important additions to proto-oncogene in human breast and ovarian cancer. Science. 1989;244(4905):707-12. with bevacizumab or bevacizumab plus the therapeutic portfolio of malignant 12. Borg A, et al. ERBB2 amplification in breast irinotecan was generally well tolerated disorders. In most circumstances the cancer with a high rate of proliferation. Onco- and toxicity was limited to that expected effect seems greatest when combined gene. 1991;6(1):137-43. with these agents.43 with cytotoxic agents. Several questions 13. Quenel N, et al. The prognostic value of c-erbB2 in primary breast carcinomas: a study on 942 cases. remain unanswered including the role of Breast Cancer Res Treat. 1995;35(3):283-91. Metastatic Renal Cell Carcinoma these agents both in mono and combined 14. Slamon DJ, et al. Use of chemotherapy plus a In a randomized phase II trial single therapy, duration of use, and the challenge monoclonal antibody against HER2 for meta- agent bevacizumab improved PFS in pa- static breast cancer that overexpresses HER2. N of limiting toxicity. Ongoing and future Engl J Med. 2001;344(11):783-92. tients with advanced renal cell cancer who clinical trials will help define the role of 15. Slamon DJ, et al. Human breast cancer: cor- progressed after .44 these agents in the . relation of relapse and survival with amplifi- Two phase III trials have had similar cation of the HER-2/neu oncogene. Science. results demonstrating improvement in 1987;235(4785):177-82. Re f e r e nc e s 16. Romond EH, et al. Trastuzumab plus adjuvant PFS with the use of bevacizumab plus 1. McLaughlin P, et al. Rituximab chimeric chemotherapy for operable HER2-positive breast alpha compared to Interferon anti-CD20 monoclonal antibody therapy for cancer. N Engl J Med. 2005;353(16):1673-84. relapsed : half of patients alpha alone. 45, 46 Both of these trials 17. Perez E. Updated results of the combined respond to a four-dose treatment program. J analysis of NCCTG N9831 and NSABP B-31 excluded patients with brain metastases Clin Oncol. 1998;16(8):2825-33. adjuvant chemotherapy with/without trastu- because of concern for intracranial hemor- 2. Davis TA, et al. Rituximab anti-CD20 mono- zumab in patients with HER2-positive breast rhage. The FDA approved avastin for use clonal antibody therapy in non-Hodgkin’s cancer. J Clin Oncol. 2008;25(18s). lymphoma: safety and efficacy of re-treatment. in combination with Interferon alpha for 18. Perez EA, et al. ACCO: ASCO core curriculum J Clin Oncol. 2000;18(17):3135-43. outline. J Clin Oncol. 2005;23(9):2049-77. the treatment of patients with metastatic 3. Marcus R, et al. An international Multi- 19. Smith I, et al. 2-year follow-up of trastuzumab renal cell carcinoma. Centre, Radomized, Open Label, Phase III after adjuvant chemotherapy in HER2-positive Trial Comparing Rituximab Added to CVP breast cancer: a randomised controlled trial. Avastin may have serious side effects Chemotherapy to CVP Chemotherapy Alone including bleeding, thromboses, hyper- Lancet. 2007;369(9555):29-36. in Untreated to Non-Hodgkins Lymphoma. 20. Ewer SM, Ewer MS, Cardiotoxicity profile of tension, and proteinuria, Blood. 2003;102(11):Abtract 87. trastuzumab. Drug Saf. 2008;31(6):459-67. 4. Salles G, et al. Rituximab maintenance 21. Salomon DS, et al. Epidermal growth factor- for 2 years in patients with high tumour related peptides and their receptors in hu- Al e m t u z u m a b burden responding to Alemtuzumab targets CD-52 and is man malignancies. Crit Rev Oncol Hematol. rituximab plus chemotherapy (PRIMA): a 1995;19(3):183-232. approved for the treatment of refractory phase 3, randomised controlled trial. Lancet. 22. Kim ES, Khuri FR, Herbst RS. Epidermal CLL, although it has not been compared 377(9759):42-51. growth factor receptor biology (IMC-C225). 5. Coiffier B, et al. CHOP chemotherapy plus Curr Opin Oncol. 2001;13(6):506-13. with Fludarabine based regimens. Both rituximab compared with CHOP alone in Alemtuzumab and Fludarabine based 23. Porebska I, Harlozinska A, Bojarowski T. Ex- elderly patients with diffuse large-B-cell lym- pression of the tyrosine kinase activity growth therapy have demonstrated superior re- phoma. N Engl J Med. 2002;346(4):235-42. factor receptors (EGFR, ERB B2, ERB B3) sponse rates compared to Chlorambucil 6. Coiffier B, Tilly H, Herbrecht R, GELA study in colorectal adenocarcinomas and adenomas. comparing CHOP and R-CHOP in elderly based therapy alone. Alemtuzumab alone Tumour Biol. 2000;21(2):105-15. patients with DLCL: 3 year median follow 24. Santini D, et al. High concordance of KRAS results in an overall response and complete up with an analysis according to co-morbid- status between primary colorectal tumors and response rates of approximately 83% and ity factors. J Clin Oncol. 2003;21:abtsract related metastatic sites: implications for clinical 24% respectively. 2395. practice. Oncologist. 2008;13(12):1270-5. 328 Medicine & Health/Rhode Island 25. Jonker DJ, et al. Cetuximab for the treat- 35. Hochster HS, et al. Safety and efficacy of oxali- 44. Yang JC, et al. A randomized trial of bevaci- ment of colorectal cancer. N Engl J Med. platin and fluoropyrimidine regimens with or zumab, an anti-vascular endothelial growth 2007;357(20):2040-8. without bevacizumab as first-line treatment of factor antibody, for metastatic renal cancer. N 26. Sobrero AF, et al. EPIC: phase III trial of metastatic colorectal cancer: results of the TREE Engl J Med. 2003;349(5):427-34. cetuximab plus irinotecan after fluoropy- Study. J Clin Oncol. 2008;26(21):3523-9. 45. Escudier B, et al. Phase III trial of bevaci- rimidine and oxaliplatin failure in patients 36. VanCutsem E. Safety and efficacy of first- zumab plus interferon alfa-2a in patients with with metastatic colorectal cancer. J Clin Oncol. line bevacizumab with FOLFOX, XELOX, metastatic renal cell carcinoma (AVOREN): 2008;26(14):2311-9. FOLFIRI and fluoropyrimidines in metastatic final analysis of overall survival. J Clin Oncol. 27. Van Cutsem E, et al. Cetuximab and chemother- colorectal cancer: the BEAT study. Annals of 28(13):2144-50. apy as initial treatment for metastatic colorectal Oncology. 2009:1882-5. 46. Rini BI, et al. Phase III trial of bevacizumab cancer. N Engl J Med. 2009;360(14):1408-17. 37. Johnson DH, et al. Randomized phase II trial plus interferon alfa versus interferon alfa 28. Van Cutsem E, et al. Safety and efficacy of comparing bevacizumab plus carboplatin and monotherapy in patients with metastatic renal first-line bevacizumab with FOLFOX, XELOX, paclitaxel with carboplatin and paclitaxel alone cell carcinoma: final results of CALGB 90206. FOLFIRI and fluoropyrimidines in metastatic in previously untreated locally advanced or J Clin Oncol. 28(13):2137-43. colorectal cancer: the BEAT study. Ann Oncol. metastatic non-small-cell lung cancer. J Clin 47. Hillmen P, et al. Alemtuzumab compared 2009;20(11):1842-7. Oncol. 2004;22(11):2184-91. with chlorambucil as first-line therapy for 29. Hecht JR, et al. Panitumumab monotherapy 38. Sandler A, et al. Paclitaxel-carboplatin alone chronic lymphocytic leukemia. J Clin Oncol. in patients with previously treated metastatic or with bevacizumab for non-small-cell lung 2007;25(35):5616-23. colorectal cancer. Cancer. 2007;110(5):980-8. cancer. N Engl J Med. 2006;355(24):2542-50. 30. Bonner JA, et al. Radiotherapy plus cetuximab 39. Reck M, et al. Overall survival with cisplatin- Disclosure of Financial Interest for squamous-cell carcinoma of the head and gemcitabine and bevacizumab or placebo as The authors and/or spouses/signifi- neck. N Engl J Med. 2006;354(6):567-78. first-line therapy for nonsquamous non-small- 31. Burtness B, et al. Phase III randomized trial of cell lung cancer: results from a randomised phase cant others have no financial interests to cisplatin plus placebo compared with cisplatin III trial (AVAiL). Ann Oncol. 21(9):1804-9. disclose. plus cetuximab in metastatic/recurrent head and 40. Miller K, et al. Paclitaxel plus bevacizumab neck cancer: an Eastern Cooperative Oncology versus paclitaxel alone for metastatic breast Group study. J Clin Oncol. 2005;23(34):8646- cancer. N Engl J Med. 2007;357(26):2666-76. Humera Khurshid, MD, is an Assis 54. 41. Miles DW, et al. Phase III study of bevaci- tant Professor of Medicine at the Warren 32. Vermorken, JB, et al. Platinum-based chemo- zumab plus docetaxel compared with placebo Alpert School of Medicine at Brown Uni- therapy plus cetuximab in head and neck cancer. plus docetaxel for the first-line treatment versity, and Oncologist at the Comprehensive N Engl J Med. 2008;359(11):1116-27. of human epidermal growth factor receptor 33. Rosen LS. Clinical experience with angiogenesis 2-negative metastatic breast cancer. J Clin Cancer Center at Rhode Island Hospital. signaling inhibitors: focus on vascular endothe- Oncol. 28(20):3239-47. Natalie Sinclaire, MD, is a Heam- lial growth factor (VEGF) blockers. Cancer 42. Friedman HS, et al. Bevacizumab alone and in tology and Oncology Fellow at the War- Control. 2002;9(2 Suppl):36-44. combination with irinotecan in recurrent glio- ren Alpert School of Medicine at Brown 34. Hurwitz H, et al. Bevacizumab plus iri- blastoma. J Clin Oncol. 2009;27(28):4733-40. notecan, fluorouracil, and leucovorin for 43. Cloughesy T, et al. Updated safety and survival University. metastatic colorectal cancer. N Engl J Med. of patients with relapsed glioblastoma treated 2004;350(23):2335-42. with bevacizumab in the BRAIN study. J Clin Co r r e s p o n d e nc e Oncol. 28(15s):Abstract. Humera Khurshid, MD e-mail: [email protected]

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