ARCON for T2-4 laryngeal cancer:  a phase III randomized trial              Hans Kaanders      Department of Radiation Onc...
ARCON      Accelerated Radiotherapy + CarbOgen + Nicotinamide          Tumor cell proliferation                     Chroni...
ARCON in a mouse mammary carcinoma Enhancement     2.1                                                                    ...
ARCON, phase II trial in H&N cancer          UMC Nijmegen          Oct. 1993 – Oct. 2000215 patients                      ...
ARCON phase II trial:             high local control rates in T3-4 tumorsLocal control (%)                                ...
Dutch multicenter randomized trial              ARCON vs Accelerated RT               in laryngeal carcinoma              ...
ARCON for T2-4 squamous cell carcinoma of the larynx                               Randomization  Accelerated Radiotherapy...
Patient characteristics (N = 345)                             Standard   Experimental                               arm   ...
Tumor site and T/N-stage (UICC 1997)                    Standard      Experimental                      arm             ar...
Acute toxicity: mucositisPatchy/confluent mucositis(%)                                                                 ARC...
Late toxicity                                     Standard   Experimental                                       arm       ...
ARCON for larynx carcinoma, local controlLocal control (%)        100         90         80         70         60         ...
ARCON for larynx carcinoma, regional controlRegional control (%)        100         90                                    ...
ARCON for larynx carcinoma, survivalSurvival (%)        100         90         80         70         60         ARCON     ...
Pimonidazole: an exogenous marker of hypoxiaHypoxic marker injection prior to biopsy                                      ...
ARCON improves regional control in hypoxic tumors              but not local control (N = 79)                   well oxyge...
ARCON vs Acc RT - Conclusions• High local-regional control rates with ARCON and Acc RT.• Equal levels of acute and late to...
What about hemoglobin?
Pre-treatment Hb is associated with poor prognosis                                      (larynx carcinomas)               ...
Randomized trial with EPO                           in H&N cancer patients with anemia               Locoregional         ...
Randomized trial with blood transfusions           in H&N cancer patients with anemia (DAHANCA 5)                         ...
ARCON for T2-4 squamous cell carcinoma of the larynx                           Randomization  Accelerated Radiotherapy    ...
Anemic patients have a worse outcome                Accelerated RT10080                                              20%60...
ARCON improves loco-regional control in anemic patients                 Accelerated RT                                   A...
and disease-free survival….                Accelerated RT                                   ARCON100                      ...
…but not overall survival.                Accelerated RT                                   ARCON100                       ...
Other prognostic clinical parameterslysis:         N-stage               WHO performance status                           ...
Other prognostic clinical parameterslysis:         N-stage               WHO performance status                           ...
Pimonidazole: an exogenous marker of hypoxiaHypoxic marker injection prior to biopsy                                      ...
No correlation between Hb and pimonidazole…      1                             Normal values                              ...
Effect of carbogen breathing                       air breathing                   carbogen breathing                     ...
“Reduced cord radius theory” (D. Hirst 1986)   Normal Hb                             air breathing         carbogen breath...
ARCON in anemic patients - Conclusions•   ARCON is the first treatment modality to demonstrate improved outcome    in anem...
ARCON in anemic patients - Conclusions•   ARCON is the first treatment modality to demonstrate improved outcome    in anem...
ARCON in anemic patients - Conclusions•   ARCON is the first treatment modality to demonstrate improved outcome    in anem...
ARCON in anemic patients - Conclusions•   ARCON is the first treatment modality to demonstrate improved outcome    in anem...
Translational studies….
High EGFR-expression correlates with           poor treatment outcomeAng KK et al. Cancer Res 2002;62:7350-7356
EGFR-expression in larynx carcinomano expression   intermediate     high
EGFR-expression: intensity vs fraction             Median EGFR fraction: 0.43                   (0.003 – 0.93)    180    1...
Accelerated radiotherapy can improve outcome              of high EGFR expressing tumorsBentzen SM et al. Journal of Clini...
Accelerated radiotherapy can improve outcome              of high EGFR expressing tumors                                  ...
ARCON can improve outcome  of low EGFR expressing tumors            100            75AR arm      50            25         ...
ARCON can improve LRC and DFS             of low EGFR expressing tumors100                                    100 75      ...
ARCON can improve LRC and DFS                of low EGFR expressing tumors   100                                          ...
ARCON can improve LRC and DSS                of low EGFR expressing tumors   100                                          ...
Acknowledgements• Nijmegen UMC St. Radboud                         • Groningen UMC  G. Janssens                           ...
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Hypoxia as a target for personalized medicine

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Lecture by Prof. Hans Kaanders in the context of the Course: "Tumour Hypoxia: From Biology to Therapy III". For the complete e-Course see http://www.myhaikuclass.com/MaastroClinic/metoxia

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  • Mercury
  • But overall, we found a good correlation between intensity and fraction EGFR. Biopsies with high overall expression also showed a mean high intensity. Therefore, patients were dichotomized in two groups based on low and high EGFR fractions and correlated with outcome. We did not found a correlation bewteen EGFR fraction and clinical parameters such as T&N stage and differentiation.
  • But overall, we found a good correlation between intensity and fraction EGFR. Biopsies with high overall expression also showed a mean high intensity. Therefore, patients were dichotomized in two groups based on low and high EGFR fractions and correlated with outcome. We did not found a correlation bewteen EGFR fraction and clinical parameters such as T&N stage and differentiation.
  • But overall, we found a good correlation between intensity and fraction EGFR. Biopsies with high overall expression also showed a mean high intensity. Therefore, patients were dichotomized in two groups based on low and high EGFR fractions and correlated with outcome. We did not found a correlation bewteen EGFR fraction and clinical parameters such as T&N stage and differentiation.
  • But overall, we found a good correlation between intensity and fraction EGFR. Biopsies with high overall expression also showed a mean high intensity. Therefore, patients were dichotomized in two groups based on low and high EGFR fractions and correlated with outcome. We did not found a correlation bewteen EGFR fraction and clinical parameters such as T&N stage and differentiation.
  • But overall, we found a good correlation between intensity and fraction EGFR. Biopsies with high overall expression also showed a mean high intensity. Therefore, patients were dichotomized in two groups based on low and high EGFR fractions and correlated with outcome. We did not found a correlation bewteen EGFR fraction and clinical parameters such as T&N stage and differentiation.
  • But overall, we found a good correlation between intensity and fraction EGFR. Biopsies with high overall expression also showed a mean high intensity. Therefore, patients were dichotomized in two groups based on low and high EGFR fractions and correlated with outcome. We did not found a correlation bewteen EGFR fraction and clinical parameters such as T&N stage and differentiation.
  • But overall, we found a good correlation between intensity and fraction EGFR. Biopsies with high overall expression also showed a mean high intensity. Therefore, patients were dichotomized in two groups based on low and high EGFR fractions and correlated with outcome. We did not found a correlation bewteen EGFR fraction and clinical parameters such as T&N stage and differentiation.
  • Mercury
  • But overall, we found a good correlation between intensity and fraction EGFR. Biopsies with high overall expression also showed a mean high intensity. Therefore, patients were dichotomized in two groups based on low and high EGFR fractions and correlated with outcome. We did not found a correlation bewteen EGFR fraction and clinical parameters such as T&N stage and differentiation.
  • The EGFR expression was limited to the cell membrane. We found a large variation of the EGFR fractions between the biopsies. Here you can see examples of tumorcells with no expression of EGFR, intermediate expression and high expression. Besides a variation in overall fractions, we also observed a variation in the intensity of the staining.
  • But overall, we found a good correlation between intensity and fraction EGFR. Biopsies with high overall expression also showed a mean high intensity. Therefore, patients were dichotomized in two groups based on low and high EGFR fractions and correlated with outcome. We did not found a correlation bewteen EGFR fraction and clinical parameters such as T&N stage and differentiation.
  • Hypoxia as a target for personalized medicine

    1. 1. ARCON for T2-4 laryngeal cancer: a phase III randomized trial Hans Kaanders Department of Radiation Oncology Radboud University Nijmegen Medical Centre The Netherlands
    2. 2. ARCON Accelerated Radiotherapy + CarbOgen + Nicotinamide Tumor cell proliferation Chronic hypoxia Acute hypoxia S D D S S D S S S DS S D S S S S S D S S D S D S S S S D S D S S S S D S S S S S D S DS D D S S S S SS S D S D S S D S S S DS S S S S S D S SS SD S D D D S S S S S D S S SD D S D S S D S SD D D S D S D S S S S S D D D S D D S D S S S S S SS D S D S D D S S SSS S D S D D S S S S S S S D D S S SS D D S D D S S S D S SS S S D S S D S D D SS S D S D S D S S SS D S SS S D D S D S D D D SSD S S S S D D S D Carbogen Nicotinamide 98% O2 + 2% CO2 Accelerated fractionation S D DS S D S S SS S D S S S S S D SD S D S D S S S S D S D S S S S D S S S S SS stem cellD differentiated cell
    3. 3. ARCON in a mouse mammary carcinoma Enhancement 2.1 ARCON ratio at the 2 TCD50 level conventional 1.9 accelerated carbogen - carbogen nicotinamide 1.8 relative to conventional 1.7 conventional radiotherapy 1.6 carbogen in air 1.5 1.4 1.3 accelerated 1.2 1.1 1Rojas 1996
    4. 4. ARCON, phase II trial in H&N cancer UMC Nijmegen Oct. 1993 – Oct. 2000215 patients larynx: 100Stage III-IV hypopharynx: 50 oropharynx: 52Median follow-up:68 months (37-127) oral cavity: 13
    5. 5. ARCON phase II trial: high local control rates in T3-4 tumorsLocal control (%) 44 patients oropharynx larynx 79 patients hypopharynx oral cavity 21 patients 12 patients Time (months)
    6. 6. Dutch multicenter randomized trial ARCON vs Accelerated RT in laryngeal carcinoma Secondary endpoints: • larynx preservationPrimary objective: • regional control• To improve local tumor control • toxicity • quality of life • disease-free survival • overall survivalTranslational side study: Is the hypoxic status of the tumor predictive for outcome?
    7. 7. ARCON for T2-4 squamous cell carcinoma of the larynx Randomization Accelerated Radiotherapy Accelerated Radiotherapy + carbogen and nicotinamide Fractionation schedule: primary metastatic nodes Acc. RT 68 Gy 68 Gy ARCON 64 Gy* 68 Gy *Aim: improve tumor control with equal toxicity between arms!
    8. 8. Patient characteristics (N = 345) Standard Experimental arm armTotal 174 171Female 39 30Male 135 141Mean age (SD) 61 (9.1) 62 (9.9)WHO performance status 0 140 137 1 34 33
    9. 9. Tumor site and T/N-stage (UICC 1997) Standard Experimental arm armGlottic 74 74Supraglottic 100 97T2 (advanced) 67 55T3 80 95T4 27 21N0 117 115N1 20 23N2 37 33N3 - -
    10. 10. Acute toxicity: mucositisPatchy/confluent mucositis(%) ARCON Acc. RT Weeks after start of treatment
    11. 11. Late toxicity Standard Experimental arm armSevere subcutaneous fibrosis 12 16Mucosal ulceration 14 11Nasogastric tube feeding 11 11(> 6 m after randomisation)Chondritis 17 22Cartilage necrosis 15 12 tracheostomy 4 5 laryngectomy 0 0
    12. 12. ARCON for larynx carcinoma, local controlLocal control (%) 100 90 80 70 60 ARCON Acc. RT 50 0 12 24 36 48 60 Time (months)
    13. 13. ARCON for larynx carcinoma, regional controlRegional control (%) 100 90 p = 0.04 80 70 60 ARCON Acc. RT 50 0 12 24 36 48 60 Time (months)
    14. 14. ARCON for larynx carcinoma, survivalSurvival (%) 100 90 80 70 60 ARCON Acc. RT 50 0 12 24 36 48 60 Time (months)
    15. 15. Pimonidazole: an exogenous marker of hypoxiaHypoxic marker injection prior to biopsy well oxygenated tumor Immunohistochemical staining Pimonidazole hypoxic tumor Blood vessels
    16. 16. ARCON improves regional control in hypoxic tumors but not local control (N = 79) well oxygenated hypoxic 92% 93% 91% 80%localcontrol well oxygenated hypoxic 96% 100% 92%regional 55%control
    17. 17. ARCON vs Acc RT - Conclusions• High local-regional control rates with ARCON and Acc RT.• Equal levels of acute and late toxicity.• No improvement of local tumor control rate (4 Gy lower dose in ARCON arm).• Significant improvement of regional control rate (therapeutic gain).• Oxygenation status of the primary tumor is predictive for outcome. ARCON is only effective in hypoxic tumors.
    18. 18. What about hemoglobin?
    19. 19. Pre-treatment Hb is associated with poor prognosis (larynx carcinomas) high Hb low Hb p = 0.007Haugen et al., Clin Cancer Res 2004
    20. 20. Randomized trial with EPO in H&N cancer patients with anemia Locoregional tumor control (%) 100 80 p = 0.04 60 placebo 40 20 Epoetin β 0 0 12 24 36 48 60 72 Time after treatment (months)Henke et al, Lancet 2003
    21. 21. Randomized trial with blood transfusions in H&N cancer patients with anemia (DAHANCA 5) 100 Locoregionaltumor control (%) 75 p = 0.04 50 25 0 0 12 24 36 48 60 Time after treatment (months)Hoff et al, Radiother. Oncol. 2011
    22. 22. ARCON for T2-4 squamous cell carcinoma of the larynx Randomization Accelerated Radiotherapy Accelerated Radiotherapy + carbogen and nicotinamide Fractionation schedule: primary metastatic nodes Acc. RT 68 Gy 68 Gy ARCON 64 Gy* 68 Gy
    23. 23. Anemic patients have a worse outcome Accelerated RT10080 20%604020 normal Hb p < 0.01 low Hb 0 0 12 24 36 48 60 months
    24. 24. ARCON improves loco-regional control in anemic patients Accelerated RT ARCON 100 100 80 80 20% 60 60 40 40 20 normal Hb 20 normal Hb p < 0.01 low Hb low Hb 0 0 0 12 24 36 48 60 0 12 24 36 48 60 months months
    25. 25. and disease-free survival…. Accelerated RT ARCON100 10080 8060 24% 6040 4020 normal Hb 20 normal Hb p < 0.01 low Hb low Hb 0 0 0 12 24 36 48 60 0 12 24 36 48 60 months months
    26. 26. …but not overall survival. Accelerated RT ARCON100 100 80 80 60 60 40 40 20 normal Hb 20 normal Hb p < 0.01 low Hb p = 0.03 low Hb 0 0 0 12 24 36 48 60 0 12 24 36 48 60 months months
    27. 27. Other prognostic clinical parameterslysis: N-stage WHO performance status Locoregional Disease-free Overall control survival survival Multivariate analysis (p-value) AR ARCON AR ARCON AR ARCON N-stage: N0 vs. N+ < .01 .11 < .01 .02 < .01 .14 Hemoglobin: low vs. normal < .01 .91 < .01 .21 .06 .02 WHO perf.: 0 vs. 1 .54 .72 .99 .67 < .01 .15
    28. 28. Other prognostic clinical parameterslysis: N-stage WHO performance status Locoregional Disease-free Overall control survival survival Multivariate analysis (p-value) AR ARCON AR ARCON AR ARCON N-stage: N0 vs. N+ < .01 .11 < .01 .02 < .01 .14 Hemoglobin: low vs. normal < .01 .91 < .01 .21 .06 .02 WHO perf.: 0 vs. 1 .54 .72 .99 .67 < .01 .15
    29. 29. Pimonidazole: an exogenous marker of hypoxiaHypoxic marker injection prior to biopsy well oxygenated tumor Immunohistochemical staining Pimonidazole hypoxic tumor Blood vessels
    30. 30. No correlation between Hb and pimonidazole… 1 Normal values M: 8.5 – 11.0 F: 7.5 – 10.0 0.1 0.01 0.0001 6 7 8 9 10 11 12 HB (mmol/ml)
    31. 31. Effect of carbogen breathing air breathing carbogen breathing HF=16,3% HF=5,3% hypoxia vessels hypoxia vesselsLjungkvist et al., Int J Radiat Oncol Biol Phys 2000
    32. 32. “Reduced cord radius theory” (D. Hirst 1986) Normal Hb air breathing carbogen breathing Anemic blood transfusion or erythropoietin Anemic air breathing carbogen breathingHirst, Int J Radiat Oncol Biol Phys 1986
    33. 33. ARCON in anemic patients - Conclusions• ARCON is the first treatment modality to demonstrate improved outcome in anemic patients.
    34. 34. ARCON in anemic patients - Conclusions• ARCON is the first treatment modality to demonstrate improved outcome in anemic patients.• But…, patients with low Hb do not have more hypoxic tumors.
    35. 35. ARCON in anemic patients - Conclusions• ARCON is the first treatment modality to demonstrate improved outcome in anemic patients.• But…, patients with low Hb do not have more hypoxic tumors.• Suggested mechanism: - shorter O2 diffusion distances in tumors of anemic patients. - no compensatory increase of tumor cord thickness with ARCON.
    36. 36. ARCON in anemic patients - Conclusions• ARCON is the first treatment modality to demonstrate improved outcome in anemic patients.• But…, patients with low Hb do not have more hypoxic tumors.• Suggested mechanism: - shorter O2 diffusion distances in tumors of anemic patients. - no compensatory increase of tumor cord thickness with ARCON.• Other potential mechanisms: - increased plasma flow with low hematocrit (increased effect of carbogen, glycolytic switch). - different effect of ARCON on red blood cell 2,3-DPG and subsequent O2 unloading in anemic patients. - carboxyhemoglobin deblocking by carbogen in smokers.
    37. 37. Translational studies….
    38. 38. High EGFR-expression correlates with poor treatment outcomeAng KK et al. Cancer Res 2002;62:7350-7356
    39. 39. EGFR-expression in larynx carcinomano expression intermediate high
    40. 40. EGFR-expression: intensity vs fraction Median EGFR fraction: 0.43 (0.003 – 0.93) 180 160 140 120 100 80 60 40 0.0 0.2 0.4 0.6 0.8 1.0 EGFR fraction
    41. 41. Accelerated radiotherapy can improve outcome of high EGFR expressing tumorsBentzen SM et al. Journal of Clinical Oncology 2005
    42. 42. Accelerated radiotherapy can improve outcome of high EGFR expressing tumors Accelerated arm of larynx study 100 75 50 25 EGFR low EGFR high 0 0 12 24 36 48 60 monthsBentzen SM et al. Journal of Clinical Oncology 2005
    43. 43. ARCON can improve outcome of low EGFR expressing tumors 100 75AR arm 50 25 EGFR low EGFR high 0 0 12 24 36 48 60 months 100 75ARCON arm 50 25 EGFR low p = 0.02 EGFR high 0 0 12 24 36 48 60 months
    44. 44. ARCON can improve LRC and DFS of low EGFR expressing tumors100 100 75 75 50 50 25 25 EGFR low EGFR low p = 0.02 EGFR high p = 0.05 EGFR high 0 0 0 12 24 36 48 60 0 12 24 36 48 60 months months
    45. 45. ARCON can improve LRC and DFS of low EGFR expressing tumors 100 100 75 75 50 50 25 25 EGFR low EGFR low p = 0.02 EGFR high p = 0.05 EGFR high 0 0 0 12 24 36 48 60 0 12 24 36 48 60 months monthsIndependent prognostic factor in MV analysis (age, sex, T, N, subsite, grade, Hb, EGFR)HR 2.43 (1.01 – 5.87), p = 0.05.
    46. 46. ARCON can improve LRC and DSS of low EGFR expressing tumors 100 100 75 75 50 50 25 25 EGFR low EGFR low p = 0.02 EGFR high p = 0.05 EGFR high 0 0 0 12 24 36 48 60 0 12 24 36 48 60 months monthsIndependent prognostic factor in MV analysis (age, sex, T, N, subsite, grade, Hb, EGFR)HR 2.43 (1.01 – 5.87), p = 0.05.Why are high expressing EGFR tumors resistant to ARCON?•better defense mechanisms after “O2-shock” and simultaneous radiotherapy?•induction of HIF-1 pathway by EGFR through hypoxia-independent mechanisms?•more rapid activation of DNA-repair processes?
    47. 47. Acknowledgements• Nijmegen UMC St. Radboud • Groningen UMC G. Janssens H. Bijl S. Rademakers • Maastro Clinic I. Hoogsteen P. van den Ende P. Span J. Bussink • Leiden UMC• Utrecht UMC A. Chin Ch. Terhaard • London Mt Vernon• Amsterdam VUMC M. Saunders P. Doornaert R. De Bree Financial support: Dutch Cooperative Head and Neck Oncology Group

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