ECCLU 2011 - A. Bex - Kidney cancer - Adjuvant and neo-adjuvant treatment

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  • 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.
  • ECCLU 2011 - A. Bex - Kidney cancer - Adjuvant and neo-adjuvant treatment

    1. 1. Adjuvant and neoadjuvant treatment of renal cell carcinoma Axel Bex, MD, PhD The Netherlands Cancer Institute 12 May 2011, Lugano, Switzerland
    2. 2. Adjuvant and neoadjuvant treatment of renal cell carcinoma: Overview <ul><li>Locally advanced and possibly locally confined disease </li></ul><ul><li>Metastatic disease </li></ul><ul><li>Safety of targeted therapy </li></ul>RCC = renal cell carcinoma.
    3. 3. Localized Disease <ul><li>Is there an adjuvant treatment following nephrectomy to improve DFS and outcome in high-risk disease? </li></ul><ul><li>What about neoadjuvant therapy to improve outcome? </li></ul><ul><li>Neoadjuvant therapy to downsize and facilitate surgery? </li></ul><ul><li>Caval thrombus: Primary resection or neoadjuvant therapy? </li></ul>DFS = disease-free survival.
    4. 4. Autologous Therapeutic Vaccine Vs. Observation Alone for Patients at High Risk of Recurrence After Nephrectomy <ul><li>Clinical events committee-based RFS (A) and OS (B) in patients (ITT population) </li></ul>RFS = recurrence-free survival; OS = overall survival; ITT = intent-to-treat. Wood et al, 2008. <ul><li>No difference in RFS </li></ul><ul><li>A possible improvement in RFS in patients with early stage disease who received vitespen will require further validation </li></ul>
    5. 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
    6. 6. <ul><li>What should neoadjuvant targeted therapy for localized RCC achieve ? </li></ul><ul><li>Downsizing </li></ul><ul><li>- locally confined renal masses for nephron sparing surgery that would otherwise be candidates for nephrectomy </li></ul><ul><li>- locally advanced renal tumours to allow complete surgical resection </li></ul><ul><li>Downstaging </li></ul><ul><li>- reduce extent of locoregional disease and micrometastasis before surgical resection </li></ul><ul><li>Improve outcome parameters </li></ul><ul><li>- prolong disease-free and overall survival in renal tumours with high-risk of recurrence </li></ul>
    7. 7. Downsizing ? True advance or just a good idea ?
    8. 8. Neoadjuvant Sunitinib for Surgically Complex Advanced RCC of Doubtful Resectability: Downsizing to Reconsider Cytoreductive Surgery <ul><li>Cytoreductive surgery in only 3 of 10 pati ents </li></ul><ul><li>Sunitinib 50 mg/d for 4 wks on and 2 wks off until 48 hrs prior to surgery </li></ul>Bex et al, 2009.
    9. 9. Primary Tumor Response to Targeted Agents in 168 Patients With mRCC Prior to sunitinib After 2 cycles of sunitinib <ul><li>Primary tumor maximum overall response to treatment with targeted agents </li></ul><ul><li>Primary tumor response to a targeted agent according to the amount of response </li></ul>mRCC = metastatic RCC. Abel et al, 2011.
    10. 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
    11. 11. Prospective Trial of 3 Mos Preoperative Sunitinib at 37.5 mg/d <ul><li>N = 20; cT1b-cT3b, any N/M category </li></ul><ul><li>Sunitinib 90 days; discontinued day before surgery (n = 15) </li></ul><ul><li>Non-metastatic neoadjuvant 67% (16/20) </li></ul><ul><li>Reduced tumor size 85% (17/20) </li></ul><ul><li>Mean change in diameter -11.8% (-27% to 11%) </li></ul><ul><li>Partial nephrectomy 40% (5.3 [4.4–7.2] cm) </li></ul>Hellenthal et al, 2010.
    12. 12. Does downsizing really improve resectability ? <ul><li>do we need to reduce small locally confined lesions by another centimeter or 2 that are resectable by NSS anyway ? </li></ul><ul><li>does downsizing of large locally advanced tumors by 6-12 % ease surgery ? </li></ul><ul><li>there is no universally accepted definition of unresectability </li></ul><ul><li>the decision of unresectability is often based on imaging </li></ul>
    13. 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. 14. Succesful case reports are the raisins in the porridge
    15. 15. Progression of CVT Within 4 Wks TKI in a RCC Patient <ul><li>Planned surgery was aborted due to reduced performance to WHO 3 </li></ul>TKI = tyrosine kinase inhibitor; WHO = World Health Organization. Bex et al, 2010.
    16. 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
    17. 17. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis <ul><li>1.) Intravenous tumor inoculation with 231/LM2-4 LUC+ cells in SCID mice. Sunitinib 7 days pre- or 7 days postinoculation versus vehicle: </li></ul><ul><ul><li>Median survival significantly decreased in treated groups (p < 0.001) </li></ul></ul><ul><li>2.) Xenografted tumor resection followed by 7 days sunitinib versus vehicle: </li></ul><ul><li>Increase in spontaneous metastasis and decrease in survival (p < 0.001) </li></ul>Ebos et al., Cancer Cell 15:232-239, 2009
    18. 18. There are clinical observations of new and early progression after TKI in human mRCC <ul><li>25 % of presurgically treated mRCC patients had PD in the 4 weeks treatment break after surgery (though 71 % stabilized after reintroduced treatment) </li></ul><ul><li>Powles et al.,Ann Oncol 2011 </li></ul><ul><li>mRCC patients treated with targeted therapy were significantly more likely to progress with new metastases in previously uninvolved anatomic sites while achieving control at existing sites of disease. </li></ul><ul><li>Plimack et al.,Cancer 1859-66, 2009 </li></ul><ul><li>Trigger for evasive resistance </li></ul><ul><li>No control of micrometastatic disease </li></ul>
    19. 19. Who will benefit from neoadjuvant therapy ? <ul><li>Apart from subtype we lack predictive biomarkers </li></ul><ul><li>Why subject patients with localized RCC who are principally curable by surgery to a toxic therapy of which we cannot predict efficacy in the individual patient and delay definite treatment ? </li></ul>
    20. 20. Metastatic Disease ‘presurgical therapy’ <ul><li>Advantages in primary metastatic disease </li></ul><ul><ul><li>There is a need for systemic therapy </li></ul></ul><ul><ul><li>Presurgical therapy may help to identify those who may not benefit from cytoreductive nephrectomy </li></ul></ul><ul><li>Metastases </li></ul><ul><ul><li>What is the role of metastasectomy after targeted therapy? </li></ul></ul>
    21. 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.
    22. 22. Best Survival in RCC Patients on Temsirolimus Without Prior Nephrectomy <ul><li>No nephrectomy: Median OS = 11.5 mos and 6.2 mos in the temsirolimus and IFN groups, respectively </li></ul><ul><li>Nephrectomy: Median OS = 10.4 mos and 7.8 mos in the temsirolimus and IFN groups, respectively </li></ul>Subgroup Analysis of Patients With a Poor MSKCC Risk Group MSKCC = Memorial Sloan-Kettering Cancer Center. Logan et al, 2008. No Nephrectomy Nephrectomy
    23. 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
    24. 24. Use of Systemic Treatment After CN in the Community Setting <ul><li>Multi-Institutional Retrospective Analysis of 141 Patients After CN </li></ul><ul><li>Systemic Therapy 70% (98/141) </li></ul><ul><li>No Systemic Therapy 31% (43/141) </li></ul><ul><li>– Rapid PD 30% (13/43) </li></ul><ul><li>– Decision for surveillance 21% (9/43) </li></ul><ul><li>– Patient refusal 23% (10/43) </li></ul><ul><li>– Perioperative death 19% (8/43) </li></ul><ul><li>– Unknown reasons 7% (3/43) </li></ul>Kutikov et al, 2010.
    25. 25. CARMENA Phase III Study of Sunitinib Only Vs. Nephrectomy Followed by Sunitinib <ul><li>Primary objective : Is sunitinib alone non-inferior to nephrectomy plus sunitinib in terms of OS? </li></ul>Nephrectomy Sunitinib 50 mg/day (schedule 4/2) Sunitinib 50 mg/day (schedule 4/2) RANDOM I ZA T I ON N = 576 Metastatic clear cell RCC Biswas et al, 2009; US NIH, 2010c.
    26. 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)
    27. 27. CN in mRCC Patients Treated With VEGF-Targeted Therapy ( n = 314 patients; n = 201 with CN vs. n = 113 without CN) Prior to sunitinib After 2 cycles of sunitinib <ul><li>Kaplan-Meier curve of OS from initiation of VEGF targeted therapy by CN, and KPS 80 or > (A) or KPS < 80 (B) </li></ul>VEGF = vascular endothelial growth factor; KPS = Karnofsky performance status. Choueiri et al, 2011.
    28. 28. Analysis of OS of Sunitinib Vs. IFN- α <ul><li>The final analysis of the trial showed sunitinib provided OS > 2 yrs (median: 26.4 mos) </li></ul><ul><li>PFS according to MSKCC risk stratification (sunitinib vs. IFN- α ; mos) </li></ul><ul><ul><li>Favorable: 14.9 vs. 8.4 </li></ul></ul><ul><ul><li>Intermediate: 10.7 vs. 3.8 </li></ul></ul><ul><ul><li>Poor: 3.9 vs. 1.2 </li></ul></ul><ul><li>For patients with intermediate risk, a median time of almost 16 mos between progression and death </li></ul><ul><li>What does that imply for a primary tumor if left in situ? </li></ul>PFS = progression-free survival. Motzer et al , 2007, 2009.
    29. 29. Progression of Primary Tumor During Treatment With TKI <ul><li>Retrospective study (n = 19) to downsize primary tumor </li></ul><ul><ul><li>Local primary tumor progression (RECIST); n = 9 (47%) </li></ul></ul><ul><li>Presurgical phase II trial (n = 22) </li></ul><ul><ul><li>n = 2; local progression with SD and PR at metastatic sites </li></ul></ul>Prior to Sunitinib After 2 Cycles of Sunitinib SD = stable disease; PR = partial response. Thomas, Rini, Lane, et al, 2009; Powles et al, 2011.
    30. 30. Prolonged Complete Responses After Withdrawal of TKIs <ul><li>N = 36; after previous nephrectomy, of which 20 with a combination of metastasectomy and targeted agents </li></ul><ul><ul><li>Median time off treatment: 7 (1–31) mos </li></ul></ul><ul><li>N = 65; of whom 26 with surgery </li></ul><ul><ul><li>15 patients CR (65%) after median time off treatment: 322 days </li></ul></ul><ul><ul><li>Benefit potential time off drug </li></ul></ul>Albiges et al, 2010; Heng et al, 2007; Johannsen et al, 2010.
    31. 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%
    32. 32. MDACC Surgical Risk Factors for CN in Patients With mRCC <ul><li>Kaplan-Meier analysis of OS for patients with mRCC who underwent CN based on the number of preoperative risk factors (≤ 3 vs. ≥ 4; p < .001). The solid line represents patients with mRCC who underwent medical therapy alone (reference line). </li></ul>MDACC = The University of Texas M. D. Anderson Cancer Center; CTCAE = Common Terminology Criteria for Adverse Events; LN = lymph node. Culp et al, 2010. <ul><ul><li>Serum albumin CTCAE v.4.0 grade 2 or worse </li></ul></ul><ul><ul><li>Serum LDH > 1.5 x UNL </li></ul></ul><ul><ul><li>Liver metastases </li></ul></ul><ul><ul><li>Symptoms at presentation due to metastases </li></ul></ul><ul><ul><li>Retroperitoneal LN involvement </li></ul></ul><ul><ul><li>Supra-diaphragmatic LN involvement </li></ul></ul><ul><ul><li>Clinical stage T3/T4 </li></ul></ul>
    33. 33. SURTIME, a EORTC-GU 30073 Phase III Study Investigating the Sequence of Nephrectomy and Sunitinib <ul><li>Primary end point: PFS </li></ul><ul><li>Secondary end points: OS, association with prognostic gene and protein expression profiles </li></ul>Nephrectomy Sunitinib 50 mg/day (schedule 4/2) Nephrectomy Sunitinib 50 mg/day (schedule 4/2) Patients with synchronous mRCC and primary tumor in situ RANDOM I Z AT I ON N = 458 Biswas et al, 2009; US NIH, 2010d.
    34. 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)
    35. 35. <ul><li>Neoadjuvant 5 Cycles Sunitinib PR </li></ul>Treatment With Sunitinib Enabled Complete Resection of Massive Lymphadenopathy Not Previously Amenable to Excision in Patients With RCC Patard et al, 2009. Tumor Unresectable at Initial Surgery Second Look Surgery Following Sunitinib Therapy: Retroperitoneum View After LN Dissection
    36. 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.
    37. 37. Safety of Targeted Therapy in Combination With Surgery <ul><li>When to stop targeted therapy prior to surgery? </li></ul><ul><li>Are there intra-/perioperative complications associated or attributable to targeted therapy? </li></ul><ul><li>When to begin or restart after surgery? </li></ul>
    38. 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. 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
    40. 40. Conclusions: Locally Advanced Disease <ul><li>There is no evidence supporting the use of adjuvant therapy for patients with high risk of recurrence after nephrectomy. Multiple phase III trials are ongoing. </li></ul><ul><li>There are no phase III trials investigating neoadjuvant therapy for high-risk disease </li></ul><ul><li>The effect of neoadjuvant therapy to downsize tumors, metastases, and CVT is limited with the available targeted agents </li></ul><ul><li>Neoadjuvant targeted therapy to downsize lesions and facilitate surgery is investigational. Patients with irresectable disease may receive targeted therapy after which surgery may be reconsidered in individual cases. </li></ul>
    41. 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

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