הוראה בנושאי טיפול תרופתי בסרטן

1. הוראה בנושאי טיפול תרופתי בסרטן נושאים כלליים: מטרות הטיפול, הערכת תגובה אובייקטיבית וסובייקטיבית , הערכת רעילות, מחקר קליני, קינטיקה של הגידול, קביעת מינון ותדירות הטיפול ערך: פרופ’ נ. חיים , מאי 2003, עודכן אפריל 2006 כתובת לשאלות והערות: n_haim@rambam.health.gov.il

2. Goals & Response evaluation • Goals • Objective & subjective response evaluation

3. מטרות הטיפול הכימותרפי • טיפול להשגת ריפוי מלא (curative ) • טיפול פליאטיבי (palliative ) • טיפול משלים (adjuvant ) וטיפול neoadjuvant (או induction chemotherapy )

4. מדדים אובייקטיביים להערכת תגובה לטיפול • בדיקה גופנית: מדידת גודל בלוטות, גושים , כבד וכו’ • בדיקות הדמיה:CT , אולטרסאונד, MRI , מיפויים • סמני גידול (tumor markers ): CEA, CA-125, BETA-HCG, ALPHA-FETO PROTEIN • הערכת תגובה ע”י ביופסיה חוזרת

5. הגדרת התגובה האובייקטיבית לטיפול • תגובה (הפוגה) מלאה - complete response • תגובה (הפוגה) חלקית- partial response • התייצבות המחלה- stable disease • התקדמות המחלה- tumor progression

6. Objective evaluation of response to chemotherapy • WHO Miller AB et al. Reporting results of cancer treatment. Cancer 47: 207-14, 1981 • RECIST (response evaluation criteria in solid tumors) Therasse P et al. New guidelines to evaluatethe response to treatment in solid tumors. J Natl Cancer Inst 92: 205-16, 2000

7. WHO criteria for evaluation of response Miller AB et al. Reporting results of cancer treatment. Cancer 47: 207-14,1981 measurability of disease: measurable, bidimensional measurable, unidimensional nonmeasurable, evaluable

8. RECIST (response evaluation criteria in solid tumors) guidelines (collaboration between EORTC, NCI & NCI of Canada-RECIST working group) measurability of disease: • Measurable lesion: 20 mm or more with conventional techniques or 10 mm or more with spiral CT. • Nonmeasurable lesion: all smaller lesions and truly nonmeasurable (e.g. bone lesions, leptomeningeal disease, effusions, etc). • The term “evaluable” in reference to measurability will not be used.

9. WHO definition of partial response for bidimentional lesion(s) Miller AB et al. Reporting results of :cancer treatment. Cancer 47: 207-14, 1981 single lesion: greater than or equal to 50% decrease in tumor area (multiplication of longest diameter by the greatest perpendicular diameter)., multiple lesions: a 50% or more decrease in the sum of the products of the multiple lesions (there can be no appearance of new lesions or progression of any lesion.)

10. Response evaluation: WHO vs. RECIST (new response evaluation criteria in solid tumors)criteria PR: WHO: 50% decrease in sum of products; confirmed at 4 wks RECIST: 30% decrease in sums of longest diameters; confirmed at 4 wks PD: WHO: 25% increase in sum of products RECIST: 20% increase in sums of longest diameters

11. Evaluation of response to imatinib mesylate (glivec) in GIST • Bleeding during treatment with glivec may cause an increase in the size of measurable lesions. Thus, standard response evaluation criteria, such as those recommended by the WHO or RECIST may be inappropriate to evaluate early treatment effects. This can be done by 18-FDG-PET (functional evaluation) or by MRI (extent of tumor necrosis) (Reichardt P et al. J Clin Pathol 57: 215-7, 2004). • The optimal criteria for tumor response remain to be delinieated…..should also include reduction in tumor density (Hounsfield Units) on tomography, and metabolic activity (FDG)….Stable disease and even increase in tumor size may be associated with pathologic response and survival benefit..(Blay JY et al. Ann Oncol 16: 566-78, 2005, consensus meeting).

12. RECIST and response evaluation to modern targeted therapies “The RECIST criteria for response (and its predecessors) were designed primarily for cytotoxic drugs and are not applicable to all new agents”. For example, these criteria do not consider durable modest regressions, or prolonged disease stability as activity, which we now know is effect of several agents such as gefitinib, erlotinib, and bevacizumab”. Ratain MJ. Phase II studies of modern drugs directed against new targets. If you are fazed, too, then resist RECIST. J Clin Oncol 22: 4442-5, 2004 (editorial)

13. הערכה סוביקטיבית של מצב החולה • מצב תפקודי ( Performance Status ): (ECOG-ZUBROD/WHO) • דרגה 0- אין שום הגבלה, דרגה 1- מוגבל בפעילות פיזית קשה, דרגה 2 - מוגבל בעבודה ובפעולות יומיומית שגרתיות, אך נמצא מחוץ למיטה ברוב הזמן, דרגה 3- רוב הזמן במיטה, דרגה 4-מרותק למיטה • שאלון איכות חיים (Quality of Life) • clinical benefit

14. Therapeutic index & Toxicity evaluation

15. Therapeutic index Therapeutic index is the relation between the desired and undesired effects of therapy.

16. CTCAE (Common Terminology Criteria for Adverse Events) • http://ctep.cancer.gov …..CTCAE (formerly known as CTC) v2.0 and v3.0 (v3.0 – publish date: December 12, 2003)

17. Clinical trials

18. סוגי מחקר קליני • Definition & goals of phase I, II, & III • DLT, MTD, recommended phase II dose (RPTD) • Initial dose & dose escalation in phase I • Alpha & beta errors (in phase II)

19. סוגי מחקר קליני • Phase I : שלב ראשון לאחר המחקרים הפרה-קליניים. מטרתו בעיקר לקבוע את המנה המרבית הנסבלת maximal tolerated dose)=MTD( של תרופה חדשה או טיפול חדשני. • Phase II : מטרתו לבדוק את הפעילות של התרופה או של הטיפול במחלה מסוימת. • Phase III : מטרתו להשוות את התרופה החדשה (או את הטיפול החדש) לתרופה או לטיפול המקובלים. המחקר הוא prospective randomized trial .

20. Phase I trial • מינון התחלתי: one -tenth of the mouse equivalent LD10 • מינון ברמה מסוימת ניתן בד”כ לקבוצות של 3 חולים. מעלים את המינון בקבוצה הבאה לפי סולם Fibonacci ( כלומר: 100%, 65%, 50%, 40%, ואח”כ 33%). • עולים במינון עד שמגיעים ל- MTD (בד”כ המנה שגורמת ל- DLTב-2/3 או ב- 2 או 3 מתוך 6 חולים).המינון ברמה הנמוכה יותר מ- MTD הוא ה-RPTD.

21. Phase II trial design Alpha & beta errors: Alpha error is a measure of the probability of accepting an inactive drug (false-positive). Beta error- a measure of the probability of rejecting an active drug (false-negative) sample size in phase II: assuming that 20% is a true response rate:the study will be terminated if no response is seen after 14 cases (beta=0.05). (if 1 responds-add 45 pts for beta=0.05)

22. Phase IV Trials Designed for postmarketing surveillance of approved drugs (the final validation before commercialization and routine use).

23. מושגים שונים במחקרים קליניים • Randomization, • stratification, • single-blinded, double -blinded, • crossover design, • power, • intention -to- treat analysis, • subgroup analysis • confidence intervals, • meta-analysis

24. Parameters (end-points) in cancerchemotherapy • Objective response rate (and type of response, i.e. CR or PR) • Duration of response • Time to tumor progression (or time to treatment failure) • Survival • Quality of life • Cost

25. Relative and absolute risk reduction Example: 10-year survival without treatment = 92% 10-year survival with treatment = 96% Relative reduction of 10-year mortality =50% Absolute reduction of 10-year mortality =4%

26. Evidence Based Medicine

27. Levels of Evidence and Grade for Recommendations • Level I: Evidence is obtained from meta-analysis of multiple , well-designed, controlled studies. Randomized trials have to be with low false-positive and false negative errors (high power). • Levels II:…at least one well-designed experimental study or low-power randomized, controlled clinical trial. • Level III:…well designed, quasi experimental studies such as non-randomized , controlled single –group, pre-post cohort, time or matched case-control series. • Level IV:…well designed non-experimental studies… • Level V:…case reports and clinical examples. American Society of Clinical Oncology. J Clin Oncol 14: 671-9, 1996

28. Grade of Recommendation: A-D….

29. Biological models • Skipper & Gompertzian models • Goldie and Coldman model • Norton-Simon hypothesis

30. Skipper laws • Doubling time of proliferating cancer cells is constant, forming a straight line on a semi logarithmic plot. • Cell kill by drugs follows first-order kinetics (log cell kill), which means that a given drug concentration applied for a defined time period will kill a constant fraction of the total cell population (e.g., 2-log kill=99% of tumor cells). (Skipper laws are derived from murine (L1210) experiments and only apply to cells in the proliferating compartment).

31. Gompertzian growth curve The growth fraction of the tumor is not constant but decreases exponentially. Growth curve is sigmoid (and not linear-as in Skippers` model) in a semi-logarithmic plot: at first, cells number increases slowly because of the small number of cells,... then-rapidly..., reaching a maximum rate at approx. one-third of max. tumor size…then slower (due to anoxia…exit of cells to G0…). (unlike the Gompertzian model, Skipper`s laws apply only to the proliferating fraction)

32. Goldie and Coldman model • הסבר עקרונות. מהי הדרך העדיפה לתת כימותרפיה על פי מודל זה? • תשובה בשקופית הבאה

33. Goldie and Coldman model A mathematical model that applies to the development of resistance to anticancer drugs by cancer cells without prior exposure to these drugs: • spontaneous mutations to resistance occur at a predictable frequency.Therefore, probability of mutations increases with tumor size. • When non-homogeneous tumor cells are subjected to selective drugs, sensitive tumor cells will be destroyed while subpopulations of resistant cells will survive. • Paradoxically, sensitive normal tissues never develop resistance. • The model predicts that the maximal chance for cure occurs when all available effective drugs are given simultaneously.

34. Norton-Simon hypothesis • The growth curves that best fit these data had a sigmoid (Gompertzian) shape. The growth rate decreases as the tumor grows. • The proportion of cells killed per chemotherapy dose increases as the tumor shrinks since more cells are mitotic. • But regrowth between the cycles is faster at lower tumor burdens. • Simulations of chemotherapy effects predicted that the simple manipulation of compressing the conventional schedule of drug administration (dose-dense therapy) would achieve greater efficacy by minimizing the regrowth of tumor cells between treatment cycles (Piccart-Gebhart MJ, Mathematics and oncology: a mach for life? J Clin Oncol 21: 1425-8, 2003 (editorial)

35. Dose-intensity & Dose density

36. Dose-intensity & Dose-density • הסבר • compare 90 mg/m2 every 3 weeks, vs. 30 mg/m2/week with regard to dose intensity & dose-density. • תשובות בשקופיות הבאות

37. Dose-intensity & Dose-density • Dose-intensity: מנת התרופה ליחידת זמן:(מינון /שטח גוף/ יחידת זמן) • Dose-density (Dose-dense chemotherapy): מתן מנות מוגברות במרווחים קצרים ככל האפשר contd

38. Dose-intensity & Dose-density For the same dose intensity of 90 mg/m2 every 3 weeks, 30 mg/m2/week gives a greater dose density than the 3-weekly administration.

39. Tolerability of dose-dense chemotherapy with GCSF-breast cancer Citron ML et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer:….CALGB. J Clin Oncol 21: 1431-39, 2003 • AC (doxorubicin 60 mg/m2 & cyclophosphamide 600 mg/m2) and Paclitaxel (175 mg/m2) • Regular regimen (q 3 weeks) was compared to dose-dense regimen (q 2 weeks +GCSF support). • Treatment was well tolerated. Severe neutropenia was less frequent in patients who received the dose-dense regimens.

40. Tolerability (and possible superiority) of dose-dense chemotherapy with GCSF-non Hodgkin`s lymphoma • Regular CHOP (given every 3 weeks) was compared to 2 weekly (=dose intense=CHOP-14) CHOP with GCSF support on days 4-13. • Treatment with 2 weekly CHOP can be safely administered with a comparable toxicity profile. • Dose-dense therapy was associated with better survival. Pfreundschuh M et al. Blood 104: 626-33, 2004 (young pts with good prognosis) Pfreundschuh M et al. Blood 104: 634-41, 2004 (elderly pts)

41. Superiority of dose-dense therapy in breast cancer Citron ML et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer:….CALGB. J Clin Oncol 21: 1431-39, 2003 Dose-dense chemotherapy improved disease free survival and overall survival.

42. Metronomic therapy

43. Metronomic therapy Experimental treatment with delivery of non-toxic, low-dose chronic therapy that has a target not only in the tumor but also in other compartments, mainly the vasculature (i.e. anti-angiogenic therapy) (Rozados VR et al. Ann Oncol 16: 1543-50, 2004; cyclophosphamide in rat lymphoma and sarcoma).

44. Body surface area for determining the dose of cytotoxic drugs

45. Body-surface area • “data that supported the introduction of BSA- based dose-calculation in the late 1950s (sulfadiazine, acetylsalicylic acid…renally excreted drugs) were reviewed…..the routine use of BSA for dose calculation should be reevaluated”. Gurney H. J Clin Oncol 14:2590-611, 1996 (Review)

46. Body-surface area & calculation of chemotherpy dose • Gurney HP. J Clin Oncol 16: 2299, 1998 (Epirubicin) “These results led us to question the use of BSA for epirubicin dose calculation”. • Mathijssen RHJ et al. J Clin Oncol 20: 81, 2001 (Irinotecan) “BSA is not a predictor of CPT-11 clearance or SN-38 pharmacokinetics “ • de Jongh FE et al. J Clin Oncol 19: 3733, 2001 (Cisplatin) “…no rationale for continuing BSA-based dosing of cisplatin was found….” Abdah-Bortnyak R, Tsalic M, Haim N. Med Oncol 20: 363-8, 2003 (evaluation of the safety of dosing obese patients according to actual body weight) “…this policy is relatively safe”.