• Like
Renal cell cancer
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

Published

 

  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Be the first to comment
    Be the first to like this
No Downloads

Views

Total Views
219
On SlideShare
0
From Embeds
0
Number of Embeds
2

Actions

Shares
Downloads
17
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

Transcript

  • 1. David GalvinUrology Trainee Teaching Session22nd March 2004Metastatic Renal CellCancer andImmunotherapy
  • 2. “ mRCC “• 30% of patients will present with metastaticdisease• Of the remaining 70%, 40% will developmetastases eventually
  • 3. • Classically, RCC is resistant to both chemo-and radiotherapy (~5% response rate)• Palliative role for nephrectomy in metastaticdisease• Spontaneous regression of metastatic lesionsfollowing nephectomy (0.7%)• Immunotherapy as a therapeutic option witha response rate of 12 to 39%Surgery in IncurableDisease
  • 4. • Nephrectomy is thought to:• reduce tumour burden• remove the source of new metastases• potential increase the respone toimmunotherapy (32% v 5% 1)• improve quality of life/relief of symptoms• does not increase survival alone 2Nephrectomy in mRCC1Joffe JK et al. Br J Urol 19962Montie JE et al. J Urol 1997
  • 5. • Cytoreductive surgery prior to IL-2 based therapy inpatients with metastatic renal cell cancer.Walther MM et al. Urology 1993;42(3): 250-7• 93 patients with mRCC underwent CRN (1985-90)• 40% did not receive Immunotherapy due to diseaseprogression. Poor performance status.• 60% (56) continued to Immunotherpay• 27% (15) response rate (4CR, 11 PR)CytoreductiveNephrectomy (CRN)
  • 6. • Cytoreductive surgery in the management of metastaticrenal cell carcinoma: the UCLA experienceFranklin JR et al. Semin Urol Oncol 1996; 14(4): 230-6• 195 patients over 11 years with mRCC whounderwent radical nephrectomy• 38% did not proceed to Immunotherapy• 62% completed IL-2 therapyCytoreductiveNephrectomy (CRN)
  • 7. • Retrospective Reviews• No control group• Not randomised• Not standardised treatment of follow-up• Single centre• Need multi-centre randomised clinical trialCritique
  • 8. • Synchronous European and American basedclinical trial initiated in 1989• Aim was to clarify the role of nephrectomyin metastatic renal cell cancer• Criteria identical in both studies• 1991 to 1998SWOG and EORTCSWOG 8949, EORTC 30947
  • 9. • Histologically confirmed metastatic RCC• Resectable primary tumour• Good performance status• No prior chemo/immuno or radiation Tx.Criteriabilirubin < x3 normalcreatinine < 265uM/lno prior malignancy
  • 10. • Patients stratified depending on;• performance status (SWOG/WHO)• presence of lung metastases• presence of a measureable metastasesRandomisationIn both studies, both groups were identical except that those with a poorperformance status were over-represented in the non-surgical arm.(In SWOG, 58% v 45%, p=0.04)
  • 11. • Surgical Group• Immediate radical nephrectomy < 4/52• Interferon therapy commenced < 4/52• Non-surgical Group• Immediate Interferon alpha2b• Follow up at 8, 12, 16, 20, 24, 36 and 52weeksTreatment Schedule
  • 12. • Both Groups• Interferon alpha 2b• Induction Therapy: 1.25 million IU/m2• Escalated to 5 million IU/m2• Then 5 million IU/m2 every M W F• Dose adjustment with toxic effects• Stopped with disease progressionTreatment Schedule
  • 13. • 246 (2 x 123)patients in 80institutions• 98 patients had anephrectomy• Interferon given atday 19 post-op• 2 declined Tx.• 83 controlsResults: SWOG5 (3/2) ineligible dueto histology17 were unfit forsurgery1 death due toInterferon23 seriouscomplications
  • 14. Results: SWOGControls SurgeryPartial Response 1 (1.1%) 3 (3.3%)CompleteResponse1 (1.1%) 0Overall Survival 8.1 months 11.1 months *1 year survival 36% 49%37% of all patients had inadequate data for assessment and were deemed non respondersProportional hazards regression model suggested that the difference was NOT due todifferences in performance status* = p<0.05
  • 15. Results: SWOGMedian Survival (mo) One year SurvivalNo Surgery Surgery No Surgery SurgeryMeasureableDisease 7.8 10.3 34% 46%No MeasureableDisease 11.2 16.4 43% 63%Good PerformanceStatus11.7 17.4 49% 63%Poor PerformanceStatus4.8 6.9 28% 32%Lung MetsOnly 10.3 14.3 41% 58%Other Mets 6.3 10.2 34% 45%
  • 16. Results: EORTC85 patientsrandomised42 Surgery43No Surgery3 excluded1 not eligible2 no Tx.13 excluded1 not eligible4 not fit8 no Tx.29 completedtreatment40 completedtreatment
  • 17. Results: EORTCControls SurgeryPartial Response 4 (10%) 3(7%)CompleteResponse1 (2%) 5 (12%)Time toprogression3 months 5 monthsOverall ResponseRate12% 19%
  • 18. • Response to Immunotherapy did not differbetween the 2 groups• Time to disease progression and overallsurvival consistently better in Surgery group• Recommend tumour nephrectomy prior toimmunotherapy as standard treatment forthose with operable disease and a goodperformance statusConclusions
  • 19. Purpose of CRN1. Delay time to progression and Increasesurvival time2. Increase response rate to Immunotherapy
  • 20. • Excellent clinical study, well designed withhigh accurement rate• Complete data unavailable on one third ofpatients in SWOG study• Large variation in response rate betweenSWOG and EORTC remains unexplained• Surgery is impossible to standardiseCritique
  • 21. • Han KR et al. Urology Feb 2003• 297 of 424 patients reviewed• 144 multiple mets, 120 mets to lung only,33 mets to bone only• Compared overall survival and responseto treatment between the 3 groupsDoes Site or Numberof Metastases matter ?
  • 22. MedianSurvivalNephrectomyplus InterferonResponse toInterferonMultipleMets11months13months14%BoneOnly27months31months20%LungOnly27months31months44%
  • 23. Prognostic Features• Performance Status ^• Previous Nephrectomy ^• No nephrectomy has poor prognosis• Delayed Mets. >21 months• Site of metastases (Lung > Bone)• Low Hb *• High Serum Calcium *• High LDH > 1.5 * Motzer RJ et al. J Clin Oncol 2004^ Motzer RJ et al. J Clin Oncol 1999
  • 24. Prognostic Features• Negrier S, NEJM. RiskStratification.• ESR > 7 2• LDH > 280 2• Hb < 10 1• + Granulocytes 1• Bone/Nonpulm 1Score Risk0 Low1-3 Intermediate> 4 High
  • 25. Histological variants• Heidlberg Classification, 1997. Consensus Conference• 5 year survival (overall) according to subtype• Conventional (80%) 70% 5 year• Papillary (15%) 87% 5 year• Type 1 (MUC 1+) better prognosis• Type 2 (MUC 2+) worse prognosis• Chromophobe (5%) 87% 5 year survival• Collecting Duct (1%) <25% 5 yearAmin MB. Am J Surg Pathol. 2002 Mar. Mayo Clinic 2003Leroy X. Mod Pathol. 2002 Nov
  • 26. 2. Surgery for Metastases• Only 1.6 - 3.2 % of patients have a primarytumour and a solitary met.• Improved prognosis if metastasis developsafter nephrectomy• 23 to 35% long term survival• Best sites are lung, adrenal gland and brain
  • 27. Surgery for SolitaryMetastases• MD Anderson. Slaton JW et al.• 5 year survival• Lung mets. 56%• Locoregional 49%• Skin 38%
  • 28. Surgery for PulmonaryMetastases• Meimarakis G et al.Ann Thor Surg 2002• 105 patients between 1980-2000• 54% 3 year survival• 33% 10 year survival• Good Prognosis: Mets < 4cm and completeresection
  • 29. 3. Surgery for Palliation• Palliative Nephrectomy in;• Severe haemorrhage• Severe pain• Paraneoplastic syndromes• Compression of adjacent viscera• Although Embolisation may also besuccesful
  • 30. 4. Palliative Embolisation• May be curative in localised disease in non-surgicalcanidates• Embolisation of symptomatic disease in mRCC• Occlusion of main renal artery, accessory vessels andtumour feeding vessels• Use of ethanol, coils or coated biospheres• ‘post-embolisation’ syndrome• May be combined with Immunotherapy• ? Role for Cytoreductive Embolisation
  • 31. 5. Immunotherapy• Presence of MDR-1 confers resistance toChemotherapeutic agents (9%)• Adjuvant radiotherapy confers no advantage• Immunotherapy• Interferon• Interleukin-2
  • 32. Interferon-α 2b• Cytokine with antiviral, immunomodulatoryand antiproliferative activity• 13.7% response rate as a monotherapy in1306 patients• Complete response rate is 1.8%• Toxic: hypotension, decreased performancestatus, mucositis, fever, dyspnoea andVT
  • 33. Interleukin-2• T-cell growth factor, discovered 1976• Overall 15.4% response rate as amonotherapy agent in 1714 patients• Toxicity is dose-dependent• Can cause capillary leak syndrome and renalcompromise (prerenal azotemia)
  • 34. Capillary Leak Syndrome• Increased capillary permeability• Fluid retention and Interstitial oedema• Decresaed peripheral vascular resistance• Hypotension, tachycardia and oligouria
  • 35. Combined IL-2, IFN- α• 1411 patients (phase 1 and 2 trials) withcombined treatment• 20.6% overall response rate, with a 4.4%complete response rate• Synergistic anti-tumour activity• Regardless of method of administration• Confirmed by Negrier in phase 3 trial
  • 36. Addition of 5 FU• Response rates increased to 33%, with 11% completeresponders (Kirchner et al. 1998)• No additional benefit (Negrier et al. 1997)• 5.7% response (40% stable) in patients who had failedstandard Immunotherapoy• Addition of Gemcitabine• Increased progression-free survival from 8 to 28 months !• 17% response rate• Significant toxicity• Modest improvement in survival ratesRini BI. J Clin Oncol. 2000Stadler WM. J Urol. 2003Ravaud A et al. : Br J Cancer. 2003
  • 37. 6. Future Therapies• Anti-VEGF (bivacizumab - Avastin)• Significant decrease in time toprogression with no increase insurvival• Anti-TNF α (infliximab)• Blocks Il-6 and TNF activity in mRCCYang, NEJM 2003
  • 38. Thalidomide• Anti-angiogenic and Immunomodulatory• Inhibits Il-6,TNF and other cytokines• Causes drowsiness, neuropathy,thrombogenic and GI disturbance• May increase time to progression• Revimid (cc-5013)
  • 39. Future Therapies• Gemcitabine / Docetaxel• Inhaled IL-2 for Lung metastases• Antibody to cG250 (radioimmunotherapy)• Vaccines• Stem Cell transplantation
  • 40. •DISCUSSION
  • 41. Incidental RCC: Irish Experience• A comparison of symptomatic (85%) andincidentally (15%) detected RCC• Retrospective review of 189 patients• Incidental tumours wereLower stageIncreased disease-free survivalIncreased overall survival• Recommend Nephrectomy for incidentalRCC with an excellent outcome