Your SlideShare is downloading. ×
0
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×
Saving this for later? Get the SlideShare app to save on your phone or tablet. Read anywhere, anytime – even offline.
Text the download link to your phone
Standard text messaging rates apply

LLA 2011 - J.M. Connors - Problems of the design and interpretation of phase II and III trials

408

Published on

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
408
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
0
Comments
0
Likes
0
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide
  • Kaplan-Meier analysis of the probability of the failure-free survival, progression-free survival, relapse-free survival, and overall survival according to intention to treat. ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; BEA, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone; CEC, cyclophosphamide, vincristine, procarbazine, prednisone, epidoxirubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine.
  • Transcript

    • 1. Challenges in Interpreting Phase II and III Clinical Trial Data Joseph M Connors, MD British Columbia Cancer Agency University of British Columbia June 2011 Ascona
    • 2. Disclosures: Joseph M Connors, MD My presentation may include discussion of off-label use of alemtuzumab bendamustine bortezomib brentuximab vedotin cisplatin cytarabine denileukin diftitox etoposide gemcitabine lenalidomide 131 I-tositumomab rituximab thalidomide 90 Y-ibritumomab June 2011 Research Support including clinical trials NCIC Canada, SWOG, Amgen, Bayer Healthcare, Cephalon, Genentech, Johnson & Johnson, Roche Canada (Hoffmann-La Roche), Lilly, Merck, Seattle Genetics Employee None Paid Consultant None Stockholder None Speakers’ Bureau None Paid Advisory Board - Pharma None Advisory Board/Committee - Foundation ASH, ASCO, Lymphoma Foundation Canada, Lymphoma Research Foundation (US), NCIC Canada Board member None
    • 3. <ul><li>Generalizability </li></ul><ul><ul><li>The problem of the shifting denominator </li></ul></ul><ul><li>Treatment intensity </li></ul><ul><ul><li>Reduced dose does NOT equal reduced treatment </li></ul></ul><ul><ul><li>The fallacy of not viewing whole treatment strategy </li></ul></ul><ul><li>Stage migration </li></ul><ul><ul><li>The magic of the Will Rogers phenomenon </li></ul></ul>Challenges in Interpreting Phase II and III Clinical Trials
    • 4. <ul><li>Generalizability </li></ul><ul><ul><li>The problem of the shifting denominator </li></ul></ul>Challenges in Interpreting Phase II and III Clinical Trials Generalizability
    • 5. <ul><li>Question </li></ul><ul><ul><li>What is the CR rate with optimal chemotherapy for AML? </li></ul></ul><ul><ul><ul><li>25% </li></ul></ul></ul><ul><ul><ul><li>35% </li></ul></ul></ul><ul><ul><ul><li>45% </li></ul></ul></ul><ul><ul><ul><li>55% </li></ul></ul></ul><ul><ul><ul><li>65% </li></ul></ul></ul><ul><ul><ul><li>75% </li></ul></ul></ul><ul><ul><ul><li>85% </li></ul></ul></ul>Challenges in Interpreting Phase II and III Clinical Trials Generalizability
    • 6. <ul><li>The Toronto Leukemia Study </li></ul><ul><ul><li>272 consecutive patients with acute myeloid leukemia </li></ul></ul><ul><ul><li>14 Toronto hospitals </li></ul></ul><ul><ul><li>Overall response rate CR 44% </li></ul></ul><ul><ul><li>1 st 130 (DA) patients => CR 34% </li></ul></ul><ul><ul><li>2 nd 142 (DAT) patients => CR 52% </li></ul></ul>Challenges in Interpreting Phase II and III Clinical Trials Generalizability <ul><ul><li>With a ~50% increase in CR rate outcome must have improved! </li></ul></ul>18%
    • 7. <ul><li>The Toronto Leukemia Study CR rate % </li></ul><ul><ul><li>272 consecutive patients 44 </li></ul></ul><ul><ul><ul><li>43 pts not given chemotherapy </li></ul></ul></ul><ul><ul><ul><ul><li>> 70 years of age 15 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>prior MDS 11 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>prior chemo or concurrent CA 7 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>WBC > 100 2 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>other 10 </li></ul></ul></ul></ul><ul><ul><li>229 given chemotherapy 52 </li></ul></ul>Challenges in Interpreting Phase II and III Clinical Trials Generalizability
    • 8. <ul><li>The Toronto Leukemia Study CR rate % </li></ul><ul><ul><li>272 consecutive patients 44 </li></ul></ul><ul><ul><li>229 given chemotherapy 52 </li></ul></ul><ul><ul><ul><li>31 pts < 1 full cycle of chemotherapy </li></ul></ul></ul><ul><ul><li>198 received > 1 cycle 60 </li></ul></ul>Challenges in Interpreting Phase II and III Clinical Trials Generalizability
    • 9. <ul><li>The Toronto Leukemia Study CR rate % </li></ul><ul><ul><li>272 consecutive patients 44 </li></ul></ul><ul><ul><li>229 given chemotherapy 52 </li></ul></ul><ul><ul><li>198 received > 1 cycle 60 </li></ul></ul><ul><ul><ul><li>58 pts age > 70 </li></ul></ul></ul><ul><ul><li>140 pts age < 70 76 </li></ul></ul>Challenges in Interpreting Phase II and III Clinical Trials Generalizability
    • 10. <ul><li>The Toronto Leukemia Study CR rate % </li></ul><ul><ul><li>272 consecutive patients 44 </li></ul></ul><ul><ul><li>229 given chemotherapy 52 </li></ul></ul><ul><ul><li>198 received > 1 cycle 60 </li></ul></ul><ul><ul><li>140 pts age < 70 76 </li></ul></ul><ul><ul><ul><li>11 pts had prior MDS </li></ul></ul></ul><ul><ul><li>129 pts without prior MDS 81 </li></ul></ul>Challenges in Interpreting Phase II and III Clinical Trials Generalizability
    • 11. <ul><li>The Toronto Leukemia Study CR rate % </li></ul><ul><ul><li>272 consecutive patients 44 </li></ul></ul><ul><ul><li>229 given chemotherapy 52 </li></ul></ul><ul><ul><li>198 received > 1 cycle 60 </li></ul></ul><ul><ul><li>140 pts age < 70 76 </li></ul></ul><ul><ul><li>129 pts without prior MDS 81 </li></ul></ul><ul><ul><ul><li>7 pts had prior chemoTx </li></ul></ul></ul><ul><ul><li>122 pts with no prior chemoTx 85 </li></ul></ul>Challenges in Interpreting Phase II and III Clinical Trials Generalizability
    • 12. <ul><li>The Toronto Leukemia Study CR rate % </li></ul><ul><ul><li>272 consecutive patients 44 </li></ul></ul><ul><ul><li>229 given chemotherapy 52 </li></ul></ul><ul><ul><li>198 received > 1 cycle 60 </li></ul></ul><ul><ul><li>140 pts age < 70 76 </li></ul></ul><ul><ul><li>129 pts without prior MDS 81 </li></ul></ul><ul><ul><li>122 pts with no prior chemoTx 85 </li></ul></ul><ul><ul><li>1 st 130 34 </li></ul></ul><ul><ul><li>2 nd 142 52 </li></ul></ul>Challenges in Interpreting Phase II and III Clinical Trials Generalizability <ul><ul><li>Med surv (mos) 1 st 130 (DA) 2 nd 142 (DAT) </li></ul></ul><ul><ul><li>All pts 3.2 5.7 </li></ul></ul><ul><ul><li>All CRs 16.2 17.6 </li></ul></ul><ul><ul><li>129 no MDS 13.4 </li></ul></ul><ul><ul><li>122 no prior chemo 15.7 </li></ul></ul><ul><ul><li>P = not significant for any comparison </li></ul></ul><ul><ul><li>Med surv (mos) </li></ul></ul><ul><ul><li> 5 </li></ul></ul><ul><ul><li> 8 </li></ul></ul><ul><ul><li> 10.7 </li></ul></ul><ul><ul><li> 12.7 </li></ul></ul><ul><ul><li> 13.4 </li></ul></ul><ul><ul><li> 15.7 </li></ul></ul><ul><ul><li>10.7 15.7 p<0.003 </li></ul></ul>
    • 13. <ul><li>Treatment intensity </li></ul><ul><ul><li>Reduced dose does NOT equal reduced treatment </li></ul></ul><ul><ul><li>The fallacy of not viewing whole treatment strategy </li></ul></ul>Challenges in Interpreting Phase II and III Clinical Trials Treatment Intensity
    • 14. <ul><li>Question </li></ul><ul><ul><li>Which group of advanced stage Hodgkin lymphoma patients will have a better outcome? </li></ul></ul><ul><ul><ul><li>Pts who receive < 80 % of the planned dose of chemoTx </li></ul></ul></ul><ul><ul><ul><li>Pts who receive > 90 % of the planned dose of chemoTx </li></ul></ul></ul>Challenges in Interpreting Phase II and III Clinical Trials Dose Intensity
    • 15. <ul><li>German Hodgkin Study Group HD6 & HD9 </li></ul><ul><li>Test Tx group CVPP/ABVD n = 266 </li></ul><ul><li>Validation Tx group #1 CVPP/ABVD n = 181 </li></ul><ul><li>Validation Tx group #2 CVPP/ABVIMEP n = 250 </li></ul>Challenges in Interpreting Phase II and III Clinical Trials Treatment Intensity <ul><li>2 sets of pts defined by Tx toxicity </li></ul><ul><li>Low toxicity average WHO toxicity grade < 2.1 </li></ul><ul><li>High toxicity average WHO toxicity grade > 2.1 </li></ul>
    • 16. Challenges in Interpreting Phase II and III Clinical Trials Treatment Intensity <ul><li>Dose intensity of delivered chemoTx and outcome by toxicity group </li></ul><ul><li> Dose </li></ul><ul><li> intensity </li></ul><ul><li>Low toxicity 90 % </li></ul><ul><li>High toxicity 78 % </li></ul><ul><li>p 0.0001 </li></ul><ul><li>Which group will have the best outcome? </li></ul><ul><li>5-y FFTF </li></ul><ul><li>47 % </li></ul><ul><li>68 % </li></ul><ul><li>Relative risk low : high 2.0 </li></ul><ul><li>p 0.0001 </li></ul>
    • 17. Challenges in Interpreting Phase II and III Clinical Trials Treatment Intensity
    • 18. <ul><li>Question </li></ul><ul><ul><li>Why did less intense treatment produce a better outcome? </li></ul></ul>Challenges in Interpreting Phase II and III Clinical Trials Dose Intensity <ul><li>Answer </li></ul><ul><ul><li>Cancer cells do not care what you give the patient </li></ul></ul><ul><ul><li>They care what amount/concentration of drug reaches them & how long they are exposed to it </li></ul></ul><ul><ul><li>The cells of patients with more neutropenia are exposed to more drug </li></ul></ul><ul><ul><ul><ul><li>Higher concentration </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Longer exposure time </li></ul></ul></ul></ul>
    • 19. <ul><li>Question </li></ul><ul><ul><li>Which group of advanced stage Hodgkin lymphoma patients will have a better outcome? </li></ul></ul><ul><ul><ul><li>Pts who receive < 80 % of the planned dose of chemoTx </li></ul></ul></ul><ul><ul><ul><li>Pts who receive > 90 % of the planned dose of chemoTx </li></ul></ul></ul><ul><ul><ul><li>The correct answer depends on why the dose was reduced </li></ul></ul></ul><ul><ul><ul><li>Biological effect (toxicity) => lower dose is better </li></ul></ul></ul><ul><ul><ul><li>Arbitrary (age ?, comorbidity ?) => higher dose is better </li></ul></ul></ul>Challenges in Interpreting Phase II and III Clinical Trials Dose Intensity
    • 20. B Bleomycin E Etoposide A Adriamycin C Cyclophos O Vincristine P Procarbazine P Prednisone Std mg/m 2 10 100 25 650 1,4 100 40 Challenges in Interpreting Phase II and III Clinical Trials Dose Intensity Escalated mg/m 2 10 200 35 1250 1,4 100 40 G-CSF sc 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 22 restart
    • 21. HD9 Trial Design( 1992-97 ) (1281 patients recruited) CS IIB-IIIA with risk factors CS IV Arm A 4x COPP+ABVD  RT Arm B 8x BEACOPP standard  RT Arm C 8x BEACOPP escalated  RT+G-CSF RT to initial bulk and residual tumor
    • 22. Engert, A. et al. J Clin Oncol; 27:4548-4554 2009 Kaplan-Meier analysis of the probability of (A) freedom from treatment failure
    • 23. Kaplan-Meier analysis of the probability of (B) overall survival in each treatment arm Engert, A. et al. J Clin Oncol; 27:4548-4554 2009
    • 24. Engert, JCO 2009; 27:4548 Kaplan-Meier analysis of the probability of (A) freedom from treatment failure COPP/ABVD arm closed early > 15 y ago
    • 25. ABVD for Advanced Stage Hodgkin Lymphoma ~ 90 % 5-y OS % Year of publication First author 73 1992 Canellos 78 1998 Hasenclever 82 2003 Duggan 83 2003 Diehl 86 2008 Gianni 84 2009 Federico 90 2009 Hoskin 91 2009 Moccia 88 2010 Gordon
    • 26. SV after relapse (months) Probability Survival after relapse Arm C 10 / 22 (5%) Arm B 19 / 42 (8%) Arm A 11 / 37 (15%) GHSG 2001 HD9 A vs. B : p=0.033 A vs. C : p=0.105 B vs. C : p=0.893 BEACOPP esc. BEACOPP bas. COPP/ABVD 100 80 60 40 20 0 1,0 ,8 ,6 ,4 ,2 0,0
    • 27. Cure esc BEACOPP Potential Strategies to Cure Advanced Stage Hodgkin Lymphoma ABVD High dose chemotherapy + autologous stem cell transplant Progression Endpoints = PFS RFS EFS TTP Endpoints = OS FF2F Progression Cure
    • 28. Potential Strategies to Cure Advanced Stage Hodgkin Lymphoma Study Regimen 5-y PFS (%) P 5-y OS (%) P Reference GHSG HD9 eBEACOPP 87 0.001 91 0.02 Diehl, 2003 COPP/ABVD 69 83 GISL HD2000 eBEACOPP 81 0.038 92 NS Federico, 2009 ABVD 68 84 GSM-HD eBEACOPP 85 0.004 89 0.39 Gianni, 2008 ABVD 73 86
    • 29. Kaplan-Meier analysis of the probability of the progression-free survival and overall survival according to intention to treat. Federico M et al. JCO 2009;27:805-811 ©2009 by American Society of Clinical Oncology Endpoint = PFS Endpoint = OS
    • 30. <ul><li>Treatment intensity </li></ul><ul><ul><li>Reduced dose does NOT equal reduced treatment </li></ul></ul><ul><ul><ul><li>Remember </li></ul></ul></ul><ul><ul><ul><ul><li>The dose that matters is the one that reaches the cancer cells </li></ul></ul></ul></ul><ul><ul><li>The fallacy of not viewing whole treatment strategy </li></ul></ul><ul><ul><ul><li>Remember </li></ul></ul></ul><ul><ul><ul><ul><li>Overall survival is the goal, not primary treatment efficacy </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Increasing intensity brings improved effectiveness at the price of increased toxicity </li></ul></ul></ul></ul><ul><ul><ul><ul><li>We need better, not stronger, treatments </li></ul></ul></ul></ul>Challenges in Interpreting Phase II and III Clinical Trials Treatment Intensity
    • 31. <ul><li>Stage migration </li></ul><ul><ul><li>The magic of the Will Rogers phenomenon </li></ul></ul>Challenges in Interpreting Phase II and III Clinical Trials Stage Migration & Lead Time Bias
    • 32. <ul><li>Stage migration </li></ul><ul><ul><li>The magic of the Will Rogers phenomenon </li></ul></ul><ul><li>During the 1930s worldwide depression </li></ul><ul><ul><li>Poverty stricken farmers in Oklahoma moved by the 1000s to California </li></ul></ul><ul><ul><li>Will Rogers, an American commentator noted </li></ul></ul><ul><ul><li>“ When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states.” </li></ul></ul>Challenges in Interpreting Phase II and III Clinical Trials Stage Migration & Lead Time Bias
    • 33. <ul><li>Yale Unversity lung cancer study </li></ul><ul><li>Era 1 1953-1964 n = 1266 </li></ul><ul><li>Era 2 1977 n = 131 </li></ul><ul><li>Overall 6-month survival </li></ul><ul><li>Era 1 1953-1964 44 % </li></ul><ul><li>Era 2 1977 55 % </li></ul>Challenges in Interpreting Phase II and III Clinical Trials Stage Migration & Lead Time Bias Treatment must have become more effective
    • 34. Challenges in Interpreting Phase II and III Clinical Trials Stage Migration & Lead Time Bias
    • 35. Lead time bias Challenges in Interpreting Phase II and III Clinical Trials Stage Migration & Lead Time Bias
    • 36. Correction for lead time bias Challenges in Interpreting Phase II and III Clinical Trials Stage Migration & Lead Time Bias
    • 37. Impact of new tests on the 131 Era 2 (1977) patients Challenges in Interpreting Phase II and III Clinical Trials Stage Migration & Lead Time Bias
    • 38. Challenges in Interpreting Phase II and III Clinical Trials Stage Migration & Lead Time Bias
    • 39. Challenges in Interpreting Phase II and III Clinical Trials Stage Migration & Lead Time Bias x
    • 40. Correction for lead time bias Challenges in Interpreting Phase II and III Clinical Trials Stage Migration & Lead Time Bias
    • 41. Hodgkin lymphoma Treatment by Stage <ul><li>Limited stage </li></ul><ul><ul><ul><ul><li>Ann Arbor stage I or II </li></ul></ul></ul></ul><ul><ul><ul><ul><li>No B symptoms </li></ul></ul></ul></ul><ul><ul><ul><ul><li>No bulky tumor </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Maximum tumor diameter < 10 cm </li></ul></ul></ul></ul><ul><ul><ul><ul><li>[Mediastinal mass ratio < 1/3 (obsolete)] </li></ul></ul></ul></ul><ul><li>Advanced stage </li></ul><ul><ul><ul><ul><li>Ann Arbor stage III or IV or </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Presence of B symptoms or </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Bulky disease at any site </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>> 10 cm mass </li></ul></ul></ul></ul></ul>
    • 42. Hodgkin Lymphoma Staging <ul><li>Required staging tests </li></ul><ul><li>Hematopathology review </li></ul><ul><li>History </li></ul><ul><li>Physical examination </li></ul><ul><li>Chest radiograph </li></ul><ul><li>CBC, creatinine, bilirubin, alkaline phosphatase, SPE (alb) </li></ul><ul><li>CT scan of neck, thorax, abdomen and pelvis </li></ul><ul><li>Bone marrow aspiration and biopsy </li></ul><ul><ul><ul><li>Only if B Sx or blood cell cytopenia </li></ul></ul></ul>
    • 43. Lymphoma: FDG/PET/CT <ul><li>50 yo woman </li></ul><ul><ul><li>L axillary node ~3 cm </li></ul></ul><ul><ul><li>PEx otherwise normal </li></ul></ul><ul><li>CBC, LFTs, LDH, creatinine normal </li></ul><ul><li>CT scans </li></ul><ul><ul><li>L axillary node ~3 cm, otherwise normal </li></ul></ul><ul><li>Path </li></ul><ul><ul><li>L axillary node mixed cellularity Hodgkin lymphoma </li></ul></ul><ul><li>Stage IA </li></ul><ul><li>Prognosis excellent, PFS > 90% </li></ul>
    • 44.  
    • 45. Lymphoma: FDG/PET/CT <ul><li>50 yo woman </li></ul><ul><ul><li>L axillary node ~3 cm </li></ul></ul><ul><ul><li>PEx otherwise normal </li></ul></ul><ul><li>CBC, LFTs, LDH, creatinine normal </li></ul><ul><li>CT scans </li></ul><ul><ul><li>L axillary node ~3 cm, otherwise normal </li></ul></ul><ul><li>Path </li></ul><ul><ul><li>L axillary node mixed cellularity Hodgkin lymphoma </li></ul></ul><ul><li>PET scan </li></ul><ul><ul><li>L axillary, R neck, L inguinal nodes positive </li></ul></ul><ul><li>Stage IIIA </li></ul><ul><li>Prognosis still excellent but now, at this institution </li></ul><ul><ul><li>Stage IA patients will do better </li></ul></ul><ul><ul><li>Stage IIIA patients will do better </li></ul></ul>
    • 46. <ul><li>Stage migration </li></ul><ul><ul><li>The magic of the Will Rogers phenomenon </li></ul></ul><ul><li>Introduction of better diagnostic/staging tests </li></ul><ul><li>Always </li></ul><ul><ul><li>Improves outcome of limited stage </li></ul></ul><ul><ul><li>Improves outcome of advanced stage </li></ul></ul><ul><li>Seldom </li></ul><ul><ul><li>Improves outcome of all patients </li></ul></ul>Challenges in Interpreting Phase II and III Clinical Trials Stage Migration & Lead Time Bias
    • 47. <ul><li>Generalizability </li></ul><ul><ul><li>The problem of the shifting denominator </li></ul></ul><ul><li>Treatment intensity </li></ul><ul><ul><li>Reduced dose does NOT equal reduced treatment </li></ul></ul><ul><ul><li>The fallacy of not viewing whole treatment strategy </li></ul></ul><ul><li>Stage migration </li></ul><ul><ul><li>The magic of the Will Rogers phenomenon </li></ul></ul>Challenges in Interpreting Phase II and III Clinical Trials
    • 48. Hodgkin Lymphoma Limited Stage <ul><li>Definition </li></ul><ul><ul><ul><ul><li>Ann Arbor stage I or II </li></ul></ul></ul></ul><ul><ul><ul><ul><li>No B symptoms </li></ul></ul></ul></ul><ul><ul><ul><ul><li>No bulky tumor </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Max tumor diameter < 10 cm (Mediastinal mass ratio < 1/3) </li></ul></ul></ul></ul>
    • 49. Hodgkin Lymphoma Limited Stage <ul><li>Treatment guided by functional imaging </li></ul><ul><li>f-up = 3-66 months; med 33; 82% > 18 (longest time to relapse) </li></ul><ul><li> </li></ul><ul><li>CS IA, IIA, </li></ul><ul><li>low bulk </li></ul>ABVD x 2 PET PET neg PET pos ABVD x 2 IFRT n = 117 117 117 96 (82 %) 21 (18 %) 95 22 Relapse 4 2 Deaths Hodg 0 0 (BMT) (3) (2) Feb 2011
    • 50. Feb 2011
    • 51. Feb 2011
    • 52.  
    • 53. Demographics and Baseline Characteristics N=102 Age* 31 yr (15  77) Gender 48 M / 54 F ECOG status 0 42 (41%) 1 60 (59%) Refractory to frontline therapy 72 (71%) Refractory to most recent treatment 43 (42%) Prior chemotherapy regimens* 3.5 (1  13) Prior radiation 67 (66%) Prior ASCT 102 (100%) Time from ASCT to first post transplant relapse* 6.7 mo (0  131) * Median (range)
    • 54. Maximum Tumor Reduction per IRF <ul><li>* 4 patients were not included in the analysis </li></ul><ul><ul><li>3 patients had no measurable lesions per IRF </li></ul></ul><ul><ul><li>1 patient had no postbaseline scans </li></ul></ul>Individual Patients (n=98)* Tumor Size (% Change from Baseline) 94% (96 of 102) of patients achieved tumor reduction 100
    • 55. Response Results N=102 IRF Investigator Overall response rate (95% CI) 75% (65, 83) 72% (62, 80) Complete remission 34% 33% Partial remission 40% 38% Stable disease 22% 27% Progressive disease 3% 0% Not evaluable 1% 1%

    ×