1. David Galvin
Urology Trainee Teaching Session
22nd March 2004
Metastatic Renal Cell
Cancer and
Immunotherapy

2. “ mRCC “
• 30% of patients will present with metastatic
disease
• Of the remaining 70%, 40% will develop
metastases eventually

3. • Classically, RCC is resistant to both chemo-
and radiotherapy (~5% response rate)
• Palliative role for nephrectomy in metastatic
disease
• Spontaneous regression of metastatic lesions
following nephectomy (0.7%)
• Immunotherapy as a therapeutic option with
a response rate of 12 to 39%
Surgery in Incurable
Disease

4. • Nephrectomy is thought to:
• reduce tumour burden
• remove the source of new metastases
• potential increase the respone to
immunotherapy (32% v 5% 1
)
• improve quality of life/relief of symptoms
• does not increase survival alone 2
Nephrectomy in mRCC
1
Joffe JK et al. Br J Urol 1996
2
Montie JE et al. J Urol 1997

5. • Cytoreductive surgery prior to IL-2 based therapy in
patients 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 disease
progression. Poor performance status.
• 60% (56) continued to Immunotherpay
• 27% (15) response rate (4CR, 11 PR)
Cytoreductive
Nephrectomy (CRN)

6. • Cytoreductive surgery in the management of metastatic
renal cell carcinoma: the UCLA experience
Franklin JR et al. Semin Urol Oncol 1996; 14(4): 230-
6
• 195 patients over 11 years with mRCC who
underwent radical nephrectomy
• 38% did not proceed to Immunotherapy
• 62% completed IL-2 therapy
Cytoreductive
Nephrectomy (CRN)

7. • Retrospective Reviews
• No control group
• Not randomised
• Not standardised treatment of follow-up
• Single centre
• Need multi-centre randomised clinical trial
Critique

8. • Synchronous European and American based
clinical trial initiated in 1989
• Aim was to clarify the role of nephrectomy
in metastatic renal cell cancer
• Criteria identical in both studies
• 1991 to 1998
SWOG and EORTC
SWOG 8949, EORTC 30947

9. • Histologically confirmed metastatic RCC
• Resectable primary tumour
• Good performance status
• No prior chemo/immuno or radiation Tx.
Criteria
bilirubin < x3 normal
creatinine < 265uM/l
no prior malignancy

10. • Patients stratified depending on;
• performance status (SWOG/WHO)
• presence of lung metastases
• presence of a measureable metastases
Randomisation
In both studies, both groups were identical except that those with a poor
performance 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 52
weeks
Treatment 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 progression
Treatment Schedule

13. • 246 (2 x 123)
patients in 80
institutions
• 98 patients had a
nephrectomy
• Interferon given at
day 19 post-op
• 2 declined Tx.
• 83 controls
Results: SWOG
5 (3/2) ineligible due
to histology
17 were unfit for
surgery
1 death due to
Interferon
23 serious
complications

14. Results: SWOG
Controls Surgery
Partial Response 1 (1.1%) 3 (3.3%)
Complete
Response
1 (1.1%) 0
Overall 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 responders
Proportional hazards regression model suggested that the difference was NOT due to
differences in performance status
* = p<0.05

15. Results: SWOG
Median Survival (mo) One year Survival
No Surgery Surgery No Surgery Surgery
Measureable
Disease 7.8 10.3 34% 46%
No Measureable
Disease 11.2 16.4 43% 63%
Good Performance
Status
11.7 17.4 49% 63%
Poor Performance
Status
4.8 6.9 28% 32%
Lung Mets
Only 10.3 14.3 41% 58%
Other Mets 6.3 10.2 34% 45%

17. Results: EORTC
85 patients
randomised
42 Surgery
43
No Surgery
3 excluded
1 not eligible
2 no Tx.
13 excluded
1 not eligible
4 not fit
8 no Tx.
29 completed
treatment
40 completed
treatment

18. Results: EORTC
Controls Surgery
Partial Response 4 (10%) 3(7%)
Complete
Response
1 (2%) 5 (12%)
Time to
progression
3 months 5 months
Overall Response
Rate
12% 19%

20. • Response to Immunotherapy did not differ
between the 2 groups
• Time to disease progression and overall
survival consistently better in Surgery group
• Recommend tumour nephrectomy prior to
immunotherapy as standard treatment for
those with operable disease and a good
performance status
Conclusions

21. Purpose of CRN
1. Delay time to progression and Increase
survival time
2. Increase response rate to Immunotherapy

22. • Excellent clinical study, well designed with
high accurement rate
• Complete data unavailable on one third of
patients in SWOG study
• Large variation in response rate between
SWOG and EORTC remains unexplained
• Surgery is impossible to standardise
Critique

23. • 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 response
to treatment between the 3 groups
Does Site or Number
of Metastases matter ?

24. Median
Survival
Nephrectomy
plus Interferon
Response to
Interferon
Multiple
Mets
11
months
13
months
14%
Bone
Only
27
months
31
months
20%
Lung
Only
27
months
31
months
44%

25. 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

26. Prognostic Features
• Negrier S, NEJM. Risk
Stratification.
• ESR > 7 2
• LDH > 280 2
• Hb < 10 1
• + Granulocytes 1
• Bone/Nonpulm 1
Score Risk
0 Low
1-3 Intermediate
> 4 High

27. 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 year
Amin MB. Am J Surg Pathol. 2002 Mar. Mayo Clinic 2003
Leroy X. Mod Pathol. 2002 Nov

28. 2. Surgery for Metastases
• Only 1.6 - 3.2 % of patients have a primary
tumour and a solitary met.
• Improved prognosis if metastasis develops
after nephrectomy
• 23 to 35% long term survival
• Best sites are lung, adrenal gland and brain

29. Surgery for Solitary
Metastases
• MD Anderson. Slaton JW et al.
• 5 year survival
• Lung mets. 56%
• Locoregional 49%
• Skin 38%

30. Surgery for Pulmonary
Metastases
• 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 complete
resection

31. 3. Surgery for Palliation
• Palliative Nephrectomy in;
• Severe haemorrhage
• Severe pain
• Paraneoplastic syndromes
• Compression of adjacent viscera
• Although Embolisation may also be
succesful

32. 4. Palliative Embolisation
• May be curative in localised disease in non-surgical
canidates
• Embolisation of symptomatic disease in mRCC
• Occlusion of main renal artery, accessory vessels and
tumour feeding vessels
• Use of ethanol, coils or coated biospheres
• ‘post-embolisation’ syndrome
• May be combined with Immunotherapy
• ? Role for Cytoreductive Embolisation

33. 5. Immunotherapy
• Presence of MDR-1 confers resistance to
Chemotherapeutic agents (9%)
• Adjuvant radiotherapy confers no advantage
• Immunotherapy
• Interferon
• Interleukin-2

34. Interferon-α 2b
• Cytokine with antiviral, immunomodulatory
and antiproliferative activity
• 13.7% response rate as a monotherapy in
1306 patients
• Complete response rate is 1.8%
• Toxic: hypotension, decreased performance
status, mucositis, fever, dyspnoea andVT

35. Interleukin-2
• T-cell growth factor, discovered 1976
• Overall 15.4% response rate as a
monotherapy agent in 1714 patients
• Toxicity is dose-dependent
• Can cause capillary leak syndrome and renal
compromise (prerenal azotemia)

36. Capillary Leak Syndrome
• Increased capillary permeability
• Fluid retention and Interstitial oedema
• Decresaed peripheral vascular resistance
• Hypotension, tachycardia and oligouria

37. Combined IL-2, IFN- α
• 1411 patients (phase 1 and 2 trials) with
combined 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

38. Addition of 5 FU
• Response rates increased to 33%, with 11% complete
responders (Kirchner et al. 1998)
• No additional benefit (Negrier et al. 1997)
• 5.7% response (40% stable) in patients who had failed
standard Immunotherapoy
• Addition of Gemcitabine
• Increased progression-free survival from 8 to 28 months !
• 17% response rate
• Significant toxicity
• Modest improvement in survival rates
Rini BI. J Clin Oncol. 2000
Stadler WM. J Urol. 2003
Ravaud A et al. : Br J Cancer. 2003

39. 6. Future Therapies
• Anti-VEGF (bivacizumab - Avastin)
• Significant decrease in time to
progression with no increase in
survival
• Anti-TNF α (infliximab)
• Blocks Il-6 and TNF activity in mRCC
Yang, NEJM 2003

40. 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)

41. Future Therapies
• Gemcitabine / Docetaxel
• Inhaled IL-2 for Lung metastases
• Antibody to cG250 (radioimmunotherapy)
• Vaccines
• Stem Cell transplantation

42. •DISCUSSION

43. Incidental RCC: Irish Experience
• A comparison of symptomatic (85%) and
incidentally (15%) detected RCC
• Retrospective review of 189 patients
• Incidental tumours were
Lower stage
Increased disease-free survival
Increased overall survival
• Recommend Nephrectomy for incidental
RCC with an excellent outcome