nephrectomy - kidnye amputation - UNNECESSARY!!!

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Metastatic Renal Cell Cancer and Immunotherapy

David Galvin

Urology Trainee Teaching Session
22nd March 2004
mRCC


30% of patients will present with metastatic disease

Of the remaining 70%, 40% will develop metastases eventually
Surgery in Incurable Disease
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%


Nephrectomy in mRCC
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
Cytoreductive Nephrectomy (CRN)
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)

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
Response rate of 18%
Critique
Retrospective Reviews
No control group
Not randomised
Not standardised treatment of follow-up
Single centre
Need multi-centre randomised clinical trial
SWOG and EORTC
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
Criteria
Histologically confirmed metastatic RCC
Resectable primary tumour
Good performance status
No prior chemo/immuno or radiation Tx.
Randomisation
Patients stratified depending on;
performance status (SWOG/WHO)
presence of lung metastases
presence of a measureable metastases
Treatment Schedule
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
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
Results: SWOG
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
Results: SWOG

Results: EORTC
Results: EORTC

Conclusions
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
Purpose of CRN
Delay time to progression and Increase survival time
Increase response rate to Immunotherapy


Critique

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


Does Site or Number of Metastases matter ?
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

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
Prognostic Features
Negrier S, NEJM. Risk Stratification.
ESR > 7 2
LDH > 280 2
Hb < 10 1
+ Granulocytes 1
Bone/Nonpulm 1
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
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
Surgery for Solitary Metastases
MD Anderson. Slaton JW et al.
5 year survival
Lung mets. 56%
Locoregional 49%
Skin 38%
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
3. Surgery for Palliation
Palliative Nephrectomy in;
Severe haemorrhage
Severe pain
Paraneoplastic syndromes
Compression of adjacent viscera
Although Embolisation may also be succesful
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
5. Immunotherapy
Presence of MDR-1 confers resistance to Chemotherapeutic agents (9%)
Adjuvant radiotherapy confers no advantage
Immunotherapy
Interferon
Interleukin-2
Interferon-? 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 and VT
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)
Capillary Leak Syndrome
Increased capillary permeability
Fluid retention and Interstitial oedema
Decresaed peripheral vascular resistance
Hypotension, tachycardia and oligouria
Combined IL-2, IFN- ?
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
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
6. Future Therapies
Anti-VEGF (bivacizumab - Avastin)
Significant decrease in time to progression with no increase in survival

Anti-TNF a (infliximab)
Blocks Il-6 and TNF activity in mRCC
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)
Future Therapies
Gemcitabine / Docetaxel
Inhaled IL-2 for Lung metastases
Antibody to cG250 (radioimmunotherapy)
Vaccines
Stem Cell transplantation


DISCUSSION
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