RADIATION THERAPY AND CHEMOTHERAPY IN LOCALLY ADVANCED CANCER OF THE HEAD AND NECK Carlos A. Perez, M.D. Former Chairman/Professor Emeritus

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1 RADIATION THERAPY AND CHEMOTHERAPY IN LOCALLY ADVANCED CANCER OF THE HEAD AND NECK Carlos A. Perez, M.D. Former Chairman/Professor Emeritus Department of Radiation Oncology Mallinckrodt Institute of Radiology/ Siteman Cancer Center Washington University Medical Center St. Louis, MO

2 IRRADIACION Y QUIMIOTERAPIA EN CANCER DE CABEZA Y CUELLO LOCALMENTE AVANZADO Contenido de Presentacion Factores predictivos/ pronosticos Quimioterapia Neo-Adyuvante Preservacion de Laringe Quimioterapia + RT concomitante Tumores Irresecables Post-operatoria Agentes Biologicos Secuelas de Tratamiento Combinado

3 PROGNOSTIC FACTORS FOR CHEMORADIOTHERAPY IN H&N CANCER T and N stage- Primary tumor site Lymphovascular invasion, surgical margins, Nodal Extracapsular Tumor Extension Therapy factors Radiation Target volume Radiation dose/ fractionation Type of chemotherapy Number of courses given Dose Intensity of chemotherapy Performance status, hemoglobin level HPV +/ - Some predictive tumor markers Modified from Al-Sarraf M et al: Cancer Invest 13:41, 1995.

4 SURVIVAL IN PATIENTS WITH OROPHARYNGEAL CANCER TAX-324 HPV+ HPV Chaturvedi A K et al. JCO 29:4294, 2011 Posner et al, JCO 2011.

5 HPV / SMOKING AND OUTCOME WITH CT-RT IN OROPHARYNGEAL CANCER Gillison M L et al RTOG 0129, 323/ 433 patients, 2009

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7 MULTIDISCIPLINARY MANAGEMENT OF HEAD AND NECK CANCER Disease Stage Early stage Advanced (resectable) Advanced (nonresectable) Metastatic, recurrent or 60% of presentations Surgery and Radiotherapy Chemotherapy Investigational Curative Palliative

8 NEO-ADJUVANT CHEMOTHERAPY Potential Advantages Optimal drug delivery (higher doses) Reduction in tumor burden Early treatment of micrometastatic disease Improved treatment tolerance Potential Disadvantages Delay in potentially curative therapy Increased expense and duration of therapy Noncompliance with curative therapy Tumor cell accelerated repopulation Selection of chemo-radiation resistant tumor cells

9 CONCURRENT CHEMOTHERAPY Potential Advantages Added antitumor effect from two modalities Elimination of tumor cell accelerated repopulation Effect on locoregional disease and micrometastatic distant disease Decreased overall treatment time Potential Disadvantages Increased treatment morbidity Interruption of treatment due to toxicity, which may decrease tumor control

10 Taxanos en Quimioterapia de Inducción TAX-323 N- 358 Localmente avanzados (III-IVM0) Irresecables Randomización Por Sitio Tumoral Centro Seguimiento medio 32,5 meses P 100 mg/m2 F 1000 mg/m2 1-5 X 4 ciclos T 75 mg/m2 P 75 mg/m2 F 750 mg/m2 1-5 X 4 ciclos Convencional (70 Gy), Acelerada (70 Gy) o Hiperfraccionada (74Gy) Disección ganglionar cervical considerada antes o después de XRT Objetivo Primario: Sobrevida libre de Progresión NEJM 357:17, 2007 X R T

11 Taxanos en Quimioterapia de Inducción. n. TAX-323 FU: 51,1 m NEJM 357:17, 2007

12 Sequential Combined-Modality Therapy A Phase III Study: TAX 324 TPF vs. PF Followed by Chemoradiotherapy R A N D O M I Z E T P F P F EUA Carboplatin - AUC 1.5 Weekly Daily Radiotherapy Surgery TPF: Docetaxel 75 D1 + Cisplatin 100 D1 + 5-FU 1000 CI- D1-4 Q 3 weeksx3 PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks x 3 Posner et al, ASCO 2006.

13 Taxanos en Quimioterapia de Inducción TAX-324 Lancet Oncol 12:153, 2011

14 RECENT UPDATE NEOADJUVANT CT TRIALS ADVANCED HEAD & NECK CANCER

15 INDUCTION CHEMOTHERAPY AND CONCURRENT CT-RT IN LOCALLY ADVANCED HEAD & NECK CANCER Haddad R et al Lancet Oncol 14: 257. March 2013

16 RECENT UPDATE NEOADJUVANT CT TRIALS ADVANCED HEAD & NECK CANCER Loo SW, Geropantas K, Roques TW. DeCIDE and PARADIGM: nails in the coffin of induction chemotherapy in head and neck squamous cell carcinoma? Clin Transl Oncol. 2013;15: Haddad R, O'Neill A, Rabinowits G, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential CTRT) versus concurrent CTRT alone in locally advanced head and neck cancer (PARADIGM): a randomized phase 3 trial. Lancet Oncol Mar;14(3): Cohen EEW, Karrison T, Kocherginsky M, et al. DeCIDE: A phase III randomized trial of docetaxel (D), cisplatin (P), 5-fluorouracil (F) (TPF) induction chemotherapy (IC) in patients with N2/N3 locally advanced squamous cell carcinoma of the head and neck (SCCHN). J Clin Oncol ASCO Annual Meeting Proceedings (Post-Meeting Edition); 30(15, suppl.): abstr Faivre S, Albert S, Raymond E. Induction chemotherapy challenges for head and neck cancer. Lancet Oncol Mar;14(3): Epub 2013

17 CHEMORADIATION THERAPY IN ADVANCED HEAD AND NECK CANCER NEOADJUVANT CHEMOTHERAPY AND LARYNX PRESERVATION TRIALS

18 LARYNX PRESERVATION EORTC Randomized Trial Design Sequential arm (SEQ) 2 cycles CF* if PD, NC TL ± PORT if PR, CR 2 cycles CF* RT 70 Gy Alternating arm (ALT) 1 cycle CF** RT 20 Gy 1 cycle CF** RT 20 Gy 1 cycle CF** RT 20 Gy 1 cycle CF** (RT 60 Gy) * C: 100 mg/m 2 D1 + 5-FU: 5 1,000 mg/m 2 D1-5 ** C: 20 mg/m 2 D FU: mg/m 2 D1-5 Lefebvre et al. ASCO Abstract LBA6016.

19 RANDOMIZED EORTC TRIAL CARCINOMA OF THE LARYNX Lefebvre J L et al J Nat Cancer Inst 2009

20 RANDOMIZED EORTC TRIAL CARCINOMA OF THE LARYNX Lefebvre J L et al J Nat Cancer Inst 2009

21 Larynx Intergroup Study (RTOG ) XRT (70 Gy) D x, Staging XRT (70 Gy)/Cisplatin (excluding T 4 ) CisP-5FU x 3 XRT (70 Gy) ) (VA Larynx) Note: Primary Organ Preservation with surgical salvage accepted for all 3 study arms. Neck dissection included N2 and N3 disease. Forastiere, NEJM, 2003 Forastiere et al. ASCO Abstract 5517

22 Disease-Free Survival (RTOG 91-11) 11) 100 Failed / Total % Alive without Disease / / / / / / / / / // RT + Induction 120 / 173 RT + Concomitant 120 / 171 RT Alone 136 / 171 / / //// / / / //// / / / // // / ////// / / / // / // / / / ////// / //// / /// / / / / // /// / // / / / / // //// / // // / / // Years from Randomization Forastiere et al. ASCO Abstract 5517

23 Overall Survival (RTOG 91-11) 11) % Alive / / // / / / // / / / // // / Dead / Total RT + Induction 89 / 173 RT + Concomitant 106 / 171 RT Alone 96 / 171 / / / / / // /// / / / / // // / //// ////////// / /// /////// /////// / / // / / / // ///// // // / / // ///// / / / / // / /// ///// / // /// / / // 25 // Years from Randomization Forastiere et al. ASCO Abstract 5517

24 CHEMO-RT IN LARYNX PRESERVATION RANDOMIZED TRIAL, 3 VS 2 DRUGS French (Tour) study- Median follow up, 36 months 3 drugs: Docetaxel- 75 mg/ m2, day 1 CisPlatin- 75 mg/ m2, day 1 5FU- 750 mg/ m2, days continuous infusion 3 cycles, every 21 days 2 drugs: CisPlatin- 100 mg/ m2, day 1 5FU- 1 gm/ m2, days 1-5, 1 continuous infusion 3 cycles, every 21 days Concurrent Radiation Therapy Calais G et al J Nat Cancer Inst, March 24, 2009(electronic)

25 CHEMO-RT IN LARYNX PRESERVATION RANDOMIZED TRIAL, 3 VS 2 DRUGS 3 Drugs 2 Drugs P Value Number of Patients Larynx Preservation 70.3 % 57.5 % Normal Larynx Mobility 42.7 % 29.1 % 3 yr disease free survival 58 % 44 %.11 Overall Survival 60 % 60 %.57 Grade 4 Larynx Toxicity 6.2 % 13.6 % S.N.S. Calais G et al J Nat Cancer Inst, March 24, 2009 (electronic)

26 CHEMO-RADIATION IN LOCALLY ADVANCED H&N CANCER CONCURRENT CHEMOTHERAPY AND IRRADIATION (Unresectable tumors)

27 RANDOMIZED TRIAL: RT +/- CONCURRENT AND ADJUVANT CT IN CA. OF NASOPHARYNX Wee, J. et al. J Clin Oncol 23:6730, 2005

28 RANDOMIZED TRIAL: RT +/- CONCURRENT AND ADJUVANT CT IN CA. OF NASOPHARYNX Disease-free / Overall Survival Wee, J. et al. J Clin Oncol; 23:6730, 2005

29 GORTEC RT vs CTRT IN ADVANCED OROPHARYNX CANCER Denis F et al Int J Rad Oncol Bio Phys 55: 93, 2003

30 FRENCH RANDOMIZED TRIAL (RT+/- CT) Locoregional (LR) tumor control Denis, F. et al. J Clin Oncol; 22:

31 FRENCH RANDOMIZED TRIAL (RT+/- CT) Overall survival in advanced oropharyngeal cancer Denis, F. et al. J Clin Oncol; 22:69-76, 2004

32 LATE TOXICITY GORTEC RT vs CTRT IN ADVANCED OROPHARYNX CANCER Denis F et al Int J Rad Oncol Bio Phys 55: 93, 2003

33 RADIATION THERAPY +/- WKLY CISPLATIN IN UNRESECTABLE H&N CANCER Quon H et al Int J Rad Oncol Bio Phys 81: 719, 2011

34 RADIATION THERAPY +/- WKLY CISPLATIN IN UNRESECTABLE H&N CANCER Disease free Survival Overall Survival Quon H et al Int J Rad Oncol Bio Phys 81: 719, Nov 2011

35 CT / RT IN LOCALLY ADVANCED HEAD AND NECK CANCER POSTOPERATIVE CT/RT VERSUS RT

36 HEAD AND NECK CANCER POSTOPERATIVE CT/RT VERSUS RT EORTC TRIAL Patients randomized to: Radiation therapy alone: 66 Gy/ / 33 fractions or Chemotherapy plus radiation therapy: Same radiation therapy Cisplatin,, 100 mg/m 2 days 1, 22, 43 Bernier J, et al: IJROBP 51(suppl 1):1, 2001.

37 HEAD AND NECK CANCER POSTOPERATIVE CT/RT VERSUS RT EORTC TRIAL Progression-free survival. (Bernier J, et al: N Engl J Med 350: , 1952, 2004)

38 HEAD AND NECK CANCER POSTOPERATIVE CT/RT VERSUS RT EORTC TRIAL RT (n = 167) CT + RT (n = 167) p Value 5-Year disease-free survival 36% 47% Year overall survival 40% 53% Grade mucosal reaction* 21.3% 44.5% Grade CT acute toxicity* 1.9% 10.9% Note: No difference in late toxicity. Bernier J, et al: N Engl J Med 350: , 1952, *Bernier J, et al: IJROBP 51(suppl 1): 1,2001.

39 INTERGROUP PHASE III RTOG TRIAL SURGERY +/- RT IN HIGH RISK H&N CANCER Completely Resected High-Risk Pathology 459 patients S T R A T I F Y Age: <70 70 Risk: micro + margin 2 nodes or ECS RT: 60+/- 6 Gy/6 6.5 weeks, 2 Gy/fx Cisplatin: 100 mg/m 2 IV days 1, 22, & 43 R A N D O M I Z E RT alone RT/CT

40 POSTOPERATIVE CONCURRENT RADIATION THERAPY AND CHEMOTHERAPY FOR HIGH-RISK CARCINOMA OF THE HEAD AND NECK RT (n = 231) RT/CT (n = 228) p Value Grade 3 toxicity 39% 51% < Grade 4 toxicity 14% 25% 0.16 Fatal toxicity 0 2% Cooper JS, et al: N Engl J Med 350:1937, 2004.

41 ECOG 3311 P16+ Trial Low Risk OPSCC: Personalized Adjuvant Therapy Based on Pathologic Staging of Surgically Excised HPV+ Oropharynx Cancer Assess Eligibility: HPV (p16) + SCC oropharynx Stage III-IV: ct1-3, N1-2b (no T1N1) Baseline Functional/ QOL Assessment LOW RISK: T1-T2N0-N1 negative margins Transoral Resection (any approach) with neck dissection HIGH RISK: Positive Margins > 1 mm ECS or 4 metastatic LN R A N D O M I Z E Observation Radiation Therapy IMRT 50Gy/25 Fx INTERMEDIATE: Clear margins 1 mm ECS 2 3 metastatic LN PNI- LVI Radiation Therapy IMRT 60 Gy/30 Fx + Radiation Therapy IMRT 66 Gy/33 Fx + CDDP 40 mg/m 2 wkly Evaluate for 2-yr PFS Local-Regional Recurrence, Functional Outcomes/QOL

42 CHEMOIRRADIATION IN HEAD AND NECK CARCINOMA Meta-Analyses

43 CHEMOTHERAPY IN HEAD AND NECK CANCER META-ANALYSIS ANALYSIS (93 TRIALS, 17,346 PATIENTS) Pignon J-P et al Radiother & Oncol 92: 4, July 2009

44 CHEMOTHERAPY IN HEAD AND NECK CANCER META-ANALYSIS ANALYSIS (93 TRIALS, 17,346 PATIENTS) Pignon J-P et al Radiother & Oncol 92: 4, 2009

45 HEAD AND NECK CANCER Integration of Molecular Therapies into First-Line Regimens

46 PHASE III TRIAL RADIATION THERAPY +/_ CETUXIMAB SQUAMOUS CELL CARCINOMA OF HEAD AND NECK Stratify by Karnofsky score: vs Regional Nodes: Negative vs. Positive Tumor stage: AJCC T1-3 vs. T4 RT fractionation: Concomitant boost vs. Once daily vs. Twice daily R A N D O I M I Z E Arm 1 Radiation therapy Arm 2 Radiation therapy + Cetuximab, weekly Wk 1: 400 mg/m 2 IV no RT Wk 2-8: 250 mg/m 2 followed by RT Bonner J, et al. NEJM, 2006.

47 PHASE III TRIAL RADIATION THERAPY +/_ CETUXIMAB IN HEAD AND NECK CANCER- 5 YEAR SURVIVAL Lancet Oncol 11:21, 2010

48 CHEMOTHERAPY +/- CETUXIMAB IN HEAD AND NECK CANCER (Vermorken JB et al N. Engl J Med 359: 1116, Sept 2008) Randomized study- Arm 1-1 CisPlatin (100 mg/m2) or carboplatin,, day 1 5FU (1 gm/m2, 4 days) q 3 wks. for Arm 2-2 Same CT + cetuximab (400 mg/m2 initially, 250 mg/m2 per week for 6 cycles) 4 days) q 3 wks. for 6 cycles Arm 1 Arm 2 P value Median overall survival (mos.) Median progresssion-free survival (mos.) <0.001 Grade anemia 19% 13% Sepsis Grade 3 skin reactions 1 9 9% 0.02

49 New Targets and Therapies in HNC There are many new agents directed at important signaling pathways in HNC Survival, metabolism: EGFR, MET Cell death: PI3K, PTEN, MTOR Vascular support: Bevacizumab Differentiation? Biomarkers are potentially available for some agents, but aside from HPV as a prognostic marker, predictive markers are not ready for prime time Personalized cancer therapeutics are close to becoming a reality in HNC

50 CHEMORADIATION =/- ERLOTINIB IN LOCALLY ADVANCED HEAD AND NECK CANCER Martins R G et al. J Clin Oncol 2013;31:

51 CHEMORADIATION =/- ERLOTINIB IN LOCALLY ADVANCED HEAD AND NECK CANCER Martins R G et al. JCO 2013;31:

52 CHEMORADIATION =/- ERLOTINIB IN LOCALLY ADVANCED HEAD AND NECK CANCER Adverse Event Arm A: Chemoradiothera py(n = 96) Arm B: Erlotinib + Chemoradiotherapy (n = 95) P No. of Patients % No. of Patients % Rash Any grade Grade < Pain Any grade Grade 3 or Martins R G et al. J Clin Oncol 2013;31:

53 RTOG 0522 Phase III Trial for Stage III-IV IV HNSCC Schema Sample Size: 720 Stage III & IV* SCC of: Oropharynx Hypopharynx Larynx Stratify: Larynx ~ Others N0~N1,2a,2b~N2c-3 KPS ~ D vs IMRT *Exclude T1 any N or T2N1 R A N D O M I Z E Accelerated FX + CDDP: 100 mg/m 2, q3w X 2 Accelerated FX + CDDP: 100 mg/m 2, q3w X 2 C225: 400 mg/m 2 Pre-RT, then 250 mg/m 2 /wk x 7 One of Nine Protocols Covered Under the Medicare Anti-Cancer Drug National Coverage Decision.

54 Concurrent Chemoradiotherapy RTOG 0522: A Phase III Trial of Cisplatin CRT With or Without Cetuximab R A N D O M I Z E CisPl: 100 mg/m 2 XRT Cetuximab 400/250 mg CisPl: 100 mg/m 2 XRT Stratify: XRT as Standard or IMRT on DAHANCA Ang et al, 2011.

55 CHEMO-RADIATION IN OROPHARYNGEAL CANCER Feng FY et al J Clin Oncol 28:2732, June 1, 2010

56 RANDOMIZED COMPARISON CONCOMITANT BOOST RT ALONE VS CONCURRENT CHEMO-RT IN LOCALLYA ADV. OROPHARYNGEAL CANCER Rishi A et al Radiother & Oncol epubl June 2013

57 RANDOMIZED COMPARISON CONCOMITANT BOOST RT ALONE VS CONCURRENT CHEMO-RT IN LOCALLYA ADV. OROPHARYNGEAL CANCER Rishi A et al Radiother & Oncol epubl June 2013

58 RANDOMIZED COMPARISON CONCOMITANT BOOST RT ALONE VS CONCURRENT CHEMO-RT IN LOCALLYA ADV. OROPHARYNGEAL CANCER- Grade Toxicity Chemo RT (N=106) Conc Boost RT (N=110) P value Mucositis 40 (38%) 60 (55%) 0.02 Dermatitis 32 (31%) 87 (79%) 0.06 Dysphagia 44 (42%) 38 (34%) 0.04 Pain 13 (12% 13 (12%) 0.09 Xerostomia 20 (34%) 12 (18%) Dysphagia 4 (7%) 1 (4%) 0.04 Weight loss 18 (17%) 0 Fistula 0 2 (2%) Rishi A et al Radiother & Oncol epubl June 2013

59 CHEMOTHERAPY AND RADIATION THERAPY IN H&N CANCER: QUESTIONS What are the most reliable prognostic / predictive factors for benefit of combined chemo-radiation? What chemotherapy schema is best, when combined with RT? Are biological modifiers more effective and less toxic? Is hyperfractionated or accelerated radiation fractionation more effective than conventional fractionation? What are optimal schemas of chemotherapy and radiation therapy? Need additional trials on targeted therapies and EGFR inhibitors

60 CHEMO-RADIATION IN H & N CANCER Future Directions Better Patient Selection Altered Fractionation CRT vs. CF CRT RTOG 0129, NCI G Innovative Surgery, Reconstruction & Rehabilitation CO 2 Laser Surgery, Microvascular Reconstruction Better Chemotherapy & Adjuvant Biological Modifiers Taxanes, Cetuximab, Iressa Normal Tissue Radioprotectants Amifostine IMRT IMRT Chemotherapy

61 CHEMO-IRRADIATION IN HEAD AND NECK CANCER Conclusions: Minimal benefit with neoadjuvant chemotherapy Improved local regional tumor control and small benefit in overall survival with concurrent chemo-radiation therapy Increased toxicity with concurrent irradiation and chemotherapy Addition of cetuximab improves outcome, more toxicity Additional clinical trials necessary Amifostine may be helpful in reducing treatment toxicity according to some studies

62 MUCHAS GRACIAS POR VUESTRA ATENCION Y MUY BUENA SUERTE!

63 CHEMO RADIATION THERAPY IN LOCALLY ADVANCED H & N CANCER Treatment Toxicity

64 MUCOSITIS WITH IMRT AND CONCOMITANT CHEMOTHERAPY Sanguineti G et al Int J Rad Oncol Bio Phys 83: 235, May 2012

65 SEVERE TOXICITY AFTER CONCURRENT CT-RT IN HEAD AND NECK CANCER (RTOG (TRIALS) 230 patients in studies. 99 (43%) developed toxicity, 131 controls no toxicity Total Feeding tube > 2 yrs post- RT (12.6%) Grade 3+ late Pharyngeal dysfunction (27.3%) Laryngeal dysfunction (12.1%) Death (9.6%) Other (fistula, infection,etc) Any toxicity (43%) No severe late toxicity Machtay M et al J Clin Oncol 26: 3582, June 2008

66 SEVERE TOXICITY AFTER CONCURRENT CT-RT IN HEAD AND NECK CANCER (RTOG (TRIALS) Subgroup analyses based on patient/treatment characteristics Machtay, M. et al. J Clin Oncol; 26:

67 THYROID SIZE AFTER RT FOR LARYNGEAL CANCER Treated with Ext RT for larynx cancer Euthyroid Hypothyroid P Value N Average width change (mm) 4.1 (11%) 6.1 (20%).20 Also Receiving chemotherapy Yes No N Average width change (mm) 5.5 (16%) 3.9 (11.5%).26 Miller-Thomas MM et al Am J Neuroradiol Nov 27, 2008 (electronic)

68 CHEMO-IMRT DOSE TO PHARYNGEAL CONSTRICTORS AND DYSPHAGIA IN H & N CANCER Bhide S A et al Radiother & Oncol 93: 539, 2009

69 HEAD & NECK CANCER CT-RT LATE TOXICITY- DYSPHAGIA

70 HEAD & NECK CANCER CT-RT Permanent G-tubeG V60 < 60% V60 > 60% G-tube 12M

71 HEAD & NECK CANCER CT-RT Gastric Feeding Tube Bilateral Neck IMRT Temporary 48% (183/380) Unkn Primary Ipsilateral Neck IMRT None (0/15) Salivary Gland Ipsilateral Neck IMRT 12% (3/24) Permanent 20% (75/380) None (0/15) None (0/24) Chemotherapy 40% (153/380) 40% (6/15) 12% (3/24)

72 ELECTIVE GASTROSTOMY-TUBE TUBE IN HEAD & NECK CHEMO-RADIATION Weight Loss Chen AM et al Int J Rad Oncol Bio Phys 78: 1026, 2010

73 ELECTIVE GASTROSTOMY-TUBE TUBE IN HEAD & NECK CHEMO-RADIATION Permanent G-tube Esophageal Stricture G-tube- 30% No G-tube- 6% (p < 0.001) Chen AM et al Int J Rad Oncol Bio Phys 78: 1026, 2010

74 CHEMOIRRADIATION IN HEAD AND NECK CANCER Amifostine

75 PATHOPHYSIOLOGIC BASIS OF AMIFOSTINE RADIOPROTECTION

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77 PHASE III TRIAL OF RT ± AMIFOSTINE IN HEAD AND NECK CANCER

78 DOSE AT ONSET OF GRADE 2 XEROSTOMA MEDIAN RT DOSE

79 PATIENTS WITH NO SALIVA PRODUCTION AT ONE YEAR

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82 AMIFOSTINE IV or SC IN H & N CANCER GORTEC TRIAL Bardet E et al J Clin Oncol Jan 10, 2011: 119

83 AMIFOSTINE IV or SC IN H & N CANCER GORTEC TRIAL Bardet E et al J Clin Oncol Jan 10, 2011: 119