ECCLU 2011 - A. Bex - Kidney cancer - Adjuvant and neo-adjuvant treatment
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ECCLU 2011 - A. Bex - Kidney cancer - Adjuvant and neo-adjuvant treatment
- 1. Adjuvant and neoadjuvant treatment of renal cell carcinoma Axel Bex, MD, PhD The Netherlands Cancer Institute 12 May 2011, Lugano, Switzerland
- 5. Ongoing Phase III Adjuvant Studies for RCC UISS = UCLA integrated staging system. US NIH, 2009, 2010a, 2010b, 2011a, 2011b. Trial N Patient Characteristics Treatment Arms Study Duration Primary End Point S-TRAC: Sunitinib Trial in Adjuvant Renal Cancer Treatment 600 High-risk patients according to UISS Sunitinib Placebo 1 yr DFS ASSURE: Adjuvant Sorafenib or Sunitinib for Unfavorable RCC 1,923 Non-metastatic RCC; disease stage II–IV Sunitinib Sorafenib Placebo 1 yr (9 treatment cycles) DFS SORCE: Sorafenib in Patients with Resected Primary RCC at High/Intermediate Risk of Relapse 1,656 Patients with high- and intermediate-risk resected RCC Sorafenib Sorafenib/ Placebo Placebo 3 yrs DFS EVEREST: Everolimus for Renal Cancer Ensuing Surgical Therapy 1,218 Pathological stage intermediate or very high-risk patients with full or partial nephrectomy Everolimus Placebo 9 treatment cycles RFS PROTECT: Pazopanib as an Adjuvant Treatment for Localized RCC 1,500 Patients with moderately high or high risk of relapse with nephrectomy of localized or locally advanced RCC Pazopanib Placebo 1 yr DFS
- 7. Downsizing ? True advance or just a good idea ?
- 10. Volume versus longest diameter Larger tumors have often less percentage reduction of longest diameter than smaller tumors (median 6-12 % versus 20-25 %), but the volume reduction is equivalent if not more than in smaller tumors
- 13. Multiple Case Reports of Effective Downsizing of CVT Prior to sunitinib After 2 cycles of sunitinib Downsizing after 2 courses of sunitinib 50 mg 4 wks on and 2 wks off CVT = caval vein thrombus. Harshman et al, 2009; Karakiewicz et al, 2008; Kroeger et al, 2010.
- 14. Succesful case reports are the raisins in the porridge
- 16. Difference in response to TKI in the primary tumour and metastatic sites Median reduction of longest diameter of primary tumours 12 % with a PR rate of 6 % according to RECIST PR rate at metastatic sites 27 % No histological proven CR after surgery ! Combined analysis of two phase II trials Powles et al. Ann Oncol 2011
- 21. CN: IMT Planned CN: Targeted Therapy Metastatic Burden Metastatic Burden Symptomatic Primary Limited Extensive Limited Extensive Good Risk Yes No Poor Risk Yes No Appropriate Appropriate Uncertain Uncertain Uncertain Inappropriate RAND Appropriateness Panel on CN RAND = Research and Development; IMT = immunotherapy. Halbert et al, 2006.
- 23. Outcome of Patients With mRCC Treated With Targeted Therapy Without CN Prior to sunitinib After 2 cycles of sunitinib LDH = lactate dehydrogenase; ULN = upper limit of normal; ECOG = Eastern Cooperative Oncology Group; PS = performance status; N2 = retroperitoneal lymph node metastasis; LLN = lower limit of normal. Richey et al, 2010. 10.4 30.3 5.5 Prognostic Factors LDH > ULN Calcium ≥ 10 mmol/L EGOG PS ≥ 2 N2 disease Platelets > ULN Lymphocytes < LLN Bone metastases ≥ 2 Smoker
- 26. Benefit Reported in a Largely Nephrectomised Patient Population (n = 339 vs. n = 36) N Death/nRisk Sunitinib 375 44/326 38/283 48/229 42/180 14/61 4/2 IFN- α 375 61/295 46/242 52/187 25/149 15/53 1/1 Total Deaths Sunitinib 190 IFN- 200 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 OS Probability (%) Time (mos) 0 3 6 9 12 15 18 21 24 27 30 33 36 Sunitinib (n = 375) Median = 26.4 mos (95% CI: 23.0–32.9) IFN- α (n = 375) Median = 21.8 mos (95% CI: 17.9–26.9) HR = 0.821 (95% CI: 0.673–1.001) p = .051 (log rank) HR = hazard ratio; CI = confidence interval. Motzer et al, 2009. OS: Final Analysis (ITT Population)
- 31. MSKCC Risk Factors Prim ary Metastatic Disease = At Least Intermediate Risk Motzer et al, 2002. Intermediate risk 62% Median survival 13.8 mos 1-yr survival 58% 3-yr survival 17%
- 34. A Combined Analysis of 66 Patients With Clear Cell mRCC Treated With Presurgical Sunitinib in 2 Independent Phase II Trials Powles et al, European Urology in press. Median OS > 13% 10.4 mos vs. 27 mos ≤ 13% ( p = .001)
- 36. Metastasectomy After Targeted Therapy in Patients With Advanced RCC (n = 22) Prior to sunitinib After 2 cycles of sunitinib Retrospective analysis of consolidative metastasectomy (CR after surgery) No. cycles 1–10 Recurrence n = 11 after median of 42 wks No recurrence n = 11 after median of 43 wks Alive n = 21 at median FUP of 109 wks Postoperative treatment n = 9 (1–5 cycles) FUP = follow-up. Karam et al, 2011.
- 38. Overview of Targeted Therapy Pre-Surgical Phase II Trials in RCC NR = no response. Jonasch et al, 2009, 2010; Cowey et al, 2010; Powles et al, 2011 . Trial Bevacizumab Sorafenib Sunitinib Sunitinib Sunitinib Author Jonasch Cowey Powles Powles Jonasch No. Patients 50 30 19 33 30 No. Nephrectomies 42 30 16 21 17 Days off prior to surgery 28 2–21 1 14 1 Median time of surgery (mins) 168 185 180 195 NR Median estimated blood loss 400 (0–7,000) 950 (200–3,000) 650 (80–3,000) 750 (90–4,700) NR Duration in hospital (days) 5 (1–70) 7.5 (5–13) 8 (7–17) 7 (4–36) NR Restart therapy (days) 28 28–42 28 21 28 Complications Clavien-Dindo Grade I 9 (21%) 1 (3.3%) 3 (18%) 2 (9.5%) 1 (5.8%) Grade II 0 0 0 0 0 Grade III 2 (4.7%) 0 0 1 0 Grade IV 0 1 0 2 0 Grade V 2 0 0 1 0
- 39. Halftime of Targeted Agents and Stages of Wound Healing Clark, 1996; Enoch et al, 2004. Agent Halftime Sorafenib 25–48 hrs Sunitinib Active metabolite of sunitinib 40–60 hrs 80–110 hrs Bevacizumab 22 (11–50) days
- 41. Patients with localized disease potentially curable by surgery should not be put at risk by neoadjuvant therapy until….. … we have more effective drugs … .with less toxicity … ..more evidence on safety, efficacy and predictive factors from presurgical trials in mRCC patients who need systemic treatment
Notes de l'éditeur
- T3 N0 or NX, M0, Fuhrman’s grade ≥2, ECOG ≥1 or T4 N0 or NX, M0, any Fuhrman grade, and any ECOG PS or any T, N1-2, M0, any Fuhrman’s grade, and any ECOG PS
- Also comment on: 1. danger of progression, 2. little decrease with medication we have, 3. until now only downsizing, but we would need downstaging for good concepts. Look up definition of neoadjuvant therapy.
- Fig. Sections demonstrating liver invasion of patient no. 4 at baseline ( a) and after 10 months sunitinib treatment ( b). Cytoreductive surgery was reconsidered and the primary tumour removed with resection of adjacent liver tissue
- Left Figure: Waterfall plot showing primary tumor maximum overall response to treatment with targeted agents. Bold lines indicate partial response and progressive disease, as defined by Response Evaluation Criteria Solid Tumors. Right Fig. – Primary tumor response to a targeted agent according to the amount of response. Most patients show minimal response or tumor stability during treatment.
- Also comment on: 1. danger of progression, 2. little decrease with medication we have, 3. until now only downsizing, but we would need downstaging for good concepts. Look up definition of neoadjuvant therapy.
- Also comment on: 1. danger of progression, 2. little decrease with medication we have, 3. until now only downsizing, but we would need downstaging for good concepts. Look up definition of neoadjuvant therapy.
- Left image: Fig: Pretreatment computed tomography scan demonstrates the left-sided primary tumor with a necrotic center and a massive renal vein and inferior vena cava thrombus with cephalad extension into the right atrium. Right image: A magnetic resonance image demonstrates the residual thrombus after two cycles of sunitinib. The thrombus consists of a solid component (dark filling defect at the ostium of the renal vein) and of a thin stalk that emanates from the proximal part of the renal vein.
- Also comment on: 1. danger of progression, 2. little decrease with medication we have, 3. until now only downsizing, but we would need downstaging for good concepts. Look up definition of neoadjuvant therapy.
- Figure: CT scans of the first patient at baseline (A) and after (B) one cycle of sunitinib. A1 and B1: The primary tumour has decreased in size. A 2–3 and B 2–3: The caval vein thrombosis has increased in size (A2 and B2) and extends from infrahepatic (A2) towards the right atrium (B3). Note the absence of the thrombus in the right atrium before treatment (A3).
- Also comment on: 1. danger of progression, 2. little decrease with medication we have, 3. until now only downsizing, but we would need downstaging for good concepts. Look up definition of neoadjuvant therapy.
- Kaplan–Meier survival curves of patients with metastatic renal cell carcinoma and primary tumor in place treated with targeted therapy based on the presence zero to one, two to three, or four or more poor prognostic factors.
- Kaplan-Meier estimates of overall survival. IFN-, interferon alfa. In the sunitinib-treated group, median OS was extended to 26.4 months, compared with 21.8 months in the IFN-α-treated group This is the first time that OS of more than 2 years has been achieved with targeted agents in the first-line setting in mRCC. Although the difference missed statistical significance, this development remains highly clinically relevant
- Survival stratified according to risk group (N 437); 26 patients who were missing one or more of the five risk factors were excluded. indicates last follow-up.
- Also comment on: 1. danger of progression, 2. little decrease with medication we have, 3. until now only downsizing, but we would need downstaging for good concepts. Look up definition of neoadjuvant therapy.