David GalvinUrology Trainee Teaching Session

22nd March 2004

Metastatic Renal Cell Cancer and Immunotherapy

“ mRCC “

•30% of patients will present with metastatic disease

•Of the remaining 70%, 40% will develop metastases eventually

•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

•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 19962 Montie JE et al. J Urol 1997

• 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%

Cytoreductive Nephrectomy

(CRN)

•Retrospective Reviews

•No control group

•Not randomised

•Not standardised treatment of follow-up

•Single centre

•Need multi-centre randomised clinical trial

Critique

•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

•Histologically confirmed metastatic RCC

•Resectable primary tumour

•Good performance status

•No prior chemo/immuno or radiation Tx.

Criteria

bilirubin < x3 normalcreatinine < 265uM/lno prior malignancy

•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)

•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

Treatment Schedule

•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 Interferon23 serious

complications

Results: SWOGControls Surgery

Partial Response

1 (1.1%) 3 (3.3%)

Complete Response

1 (1.1%) 0

Overall Survival

8.1 months11.1 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

Results: SWOGMedian Survival

(mo)One year Survival

No Surgery Surgery No Surgery Surgery

Measureable Disease 7.8 10.3 34% 46%

No Measureable

Disease11.2 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%

Results: EORTC85 patients randomised

42 Surgery43

No Surgery

3 excluded1 not eligible2 no Tx.

13 excluded1 not eligible

4 not fit8 no Tx.

29 completed treatment

40 completed treatment

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

Rate12% 19%

•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

Purpose of CRN

1.Delay time to progression and Increase survival time

2.Increase response rate to Immunotherapy

•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

•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 ?

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%

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

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

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

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

Rini BI. J Clin Oncol. 2000

Stadler WM. J Urol. 2003

Ravaud A et al. : Br J Cancer. 2003

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

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 wereLower stageIncreased disease-free survivalIncreased overall survival

•Recommend Nephrectomy for incidental RCC with an excellent outcome