Renal Cell Carcinoma · Renal Cell Carcinoma STAGE 5 yr overall survival Stage I – T1N0 80-95% Stage II – T2N0 80% Stage III – T3N0 or N+ 60% Stage IV – T4 or M1 10-30% (improved

Renal Cell Carcinoma

A) PUBLIC HEALTH EPIDEMIOLOGY

• Incidence: 9th most common cancer worldwide, 11th most common in Canada, incidence 12.9/100,000 in Canada in 2015, highest incidence in developing countries, most common in 6th- 8th decade of life, M > F

• Mortality: 5 year overall survival 71% (all stages) RISK FACTORS

• Environmental/Chemical/Infections: • Established: Smoking, phenacetin containing analgesics, hypertension, obesity • Possible: Diabetes Mellitus, trichloroethylene, renal cystic disease, renal transplant, end-stage renal disease

patients on dialysis, physical activity Genetic:

• Clear cell (ccRCC) o Loss of mutation of Von Hippo Lindau gene (VHL) – 58% of ccRCC

§ VHL gene on chromosome 3p regulates hypoxia induced pathway (HIF) and targets it for degradation. In ccRCC, its dysfunctional and HIF accumulates leading to activate of survival genes that mediate glucose transport, proliferation and angiogenesis (VEGF).

o mutations in PBRM1 (40%), BAP1 (15%), SETD2 (15%) which part of the chromatin remodeling-histone methylation pathway. Like VHL also located on the chromosome 3p. BAP1 associated with shorter survival.

o Succinate Dehydrogenase Familial Renal Ca (clear cell and chromophobe) with mutated succinate dehydrogenase D

o Tuberous Sclerosis Complex with mutated TSC1/2 • Papillary cell

o Type 1 - MET gain on pro-oncogene o Type 2 - Hereditary Leiomyomatosis RCC. Associated with CDKN2A silencing, SETD2

mutations, TFE3 fusions, and increased expression of the NRF2–antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) assoc. with poor survival and mutation of the gene encoding fumarate hydratase (FH) (NEJM 2016)

• Chromophobe RCC o loss of chromosomes 1,26,10,13, 17 and 21, mutations in PTEN, Birt-Hogg-Dube syndrome

(caused by germline mutation in folliculin gene – FLCN) • Renal medullary

o associated with hemoglobinopathies, most commonly sickle cell trait, loss of expression of the chromatin regulatory gene SNF5/INI-1.

Most RCC of both types express PD-L1 PREVENTION & SCREENING

• Prevention: Nil • Screening: Only for high-risk individuals – i.e. VHL syndrome, tuberous sclerosis, strong family history,

previous kidney irradiation, young patients with end-stage renal disease on dialysis x >3-5 years. Screen with yearly U/S Abdo/ CT Abdo/ MRI

B) PRESENTATION & DIAGNOSIS SYMPTOMS & SIGNS

• Common Symptoms: Flank pain, abdominal pain, hematuria, asymptomatic • Common Signs: abdominal/ flank mass, paraneoplastic syndromes – anemia, hypertension, hepatic

dysfunction, fever and night sweats, hypercalcemia, cachexia, thrombocytosis • Not so common: AA amyloidosis, polycythemia, polymyalgia rheumatica


INVESTIGATIONS • Laboratory: (e.g. important bloodwork, tumour markers): CBC, lytes, urea, creatinine, calcium • Diagnostic Imaging and staging: renal ultrasound, CT Abdo, MRI (if CT non-diagnostic), CT Chest, CT

Head, Bone scan (if bone pain or elevated ALP) • Diagnostic Procedures: percutaneous biopsy, partial/ full nephrectomy • Management of Solitary Renal Mass (Management of Small Renal Masses: American Society of Clinical

Oncology Clinical Practice Guideline Feb 2017) o Renal tumor biopsy should be obtained if it would change managment o Standard partial nephrectomy for all patients whom intervention is indicated. Radical if partial not

possible o Percutaneous thermal ablation can be considered if can achieve complete ablation and biopsy should

be obtained • Patients with radiographic T3+ or node involvement should have lymph node staging done

PATHOLOGY & MOLECULAR BIOLOGY Common Histology:

• Clear cell RCC aka ccRCC (75%) – VHL • Non Clear Cell RCC (nccRCC)

o Papillary cell RCC – Type I (5%) – cMET, Type 2 (10%) – FH, cMYC o Chromophobe RCC (5%) and Oncocytoma (5%) - both BHD o Rare: collecting duct, renal medullary, urothelial o Other types – see 2013 Classification (Srigley, JR et al. Am J Surg Pathol 2013)

• Common Metastatic Sites: lung, bone, brain, liver, adrenals

o All patients with non-clear cell, except chromophobe do poorly once they develop mets • Relevant Molecular Biology: Lots of stuff here. Unclear what you are expected to know. Not generally

agreed on biomarkers to guide the choice of therapy

Kidney cancer TNM staging AJCC UICC 2017 Primary tumor (T)

T category T criteria

T1 Tumor ≤7 cm in greatest dimension, limited to the kidney

T1a Tumor ≤4 cm in greatest dimension, limited to the kidney

T1b Tumor >4 cm but ≤7 cm in greatest dimension, limited to the kidney

T2 Tumor >7 cm in greatest dimension, limited to the kidney

T2a Tumor >7 cm but ≤10 cm in greatest dimension, limited to the kidney

T2b Tumor >10 cm, limited to the kidney

T3 Tumor extends into major veins or perinephric tissues, but not into the ipsilateral adrenal gland and not beyond Gerota's fascia

T3a Tumor extends into the renal vein or its segmental branches, or invades the pelvicalyceal system, or invades perirenal and/or renal sinus fat but not beyond Gerota's fascia

T3b Tumor extends into the vena cava below the diaphragm

T3c Tumor extends into the vena cava above the diaphragm or invades the wall of the vena cava

T4 Tumor invades beyond Gerota's fascia (including contiguous extension into the ipsilateral adrenal gland)

Regional lymph nodes (N)

N1 Metastasis in regional lymph node(s)

Distant metastasis (M)

M1 Distant metastasis


STAGE 5 yr overall survival Stage I – T1N0 80-95% Stage II – T2N0 80% Stage III – T3N0 or N+ 60% Stage IV – T4 or M1 10-30% (improved with recent targeted therapies) Prognostic Factors in Stage IV: MSKCC RF – older, published in 1999. Most trials stratified based on these factors. Uses LDH, HgB, serum Ca, time <1 year of disease free, KPS <=80%. Validated from a time of treated with only interferon and immunotherapy as treatments. A more recent paper (with Canadian investigators) looked at prognostic factors in the modern era of patients treated with VEGF inhibitors (JCO 2009). It validated some factors of MSKCC (HgB, Ca2+, time to targeted treatment, KPS <80), but added thrombocytosis, neutrophila and lost LDH. The result was: International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) Prognostic Factors

1. Anaemia 2. Thrombocytosis 3. Neutrophilia 4. Hypercalcemia 5. Karnofsky performance status <80, 6. < 1 year from diagnosis to first-line targeted therapy

• favorable risk (no risk factors, median OS 43 months) • intermediate risk (one to two risk factors, median OS of 22 months) • poor risk (three or more risk factors, median 8 months)

• Has been externally validated in patient treated with VEGF inhibitors - median OSs at 44 months, 21 months,

and 8 months for the favorable, intermediate, and poor risk

C) TREATMENT LOCALIZED / LOCALLY ADVANCED/ ADJUVANT

- Bottom Line General Approach: Surgery - surgical resection) via total or partial nephrectomy for Stage I-III

o if not a candidate for surgery and small renal mass (often just observed. This is a separate topic), radiofrequency ablation/ cryotherapy can be considered. Observation can also be considered.

o No role for adjuvant therapy post resection. Multiple negative trials, see below. - Surveillance: labs and imaging q 6months initially then less frequently for up to 6 years. Canadian

and US guidelines available (see references


Adjuvant therapy trials: Adjuvant Immunotherapy

• Although immunotherapy has had a response in advanced RCC, IFN-alpha and IL-2 have not had a survival benefit in adjuvant setting.

• Awaiting data on checkpoint inhibitors

Adjuvant Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal cell carcinoma: an

Eastern Cooperative Oncology Group/Intergroup trial. Messing et al. J Clin Oncol. 2003; 21(7): 1214-22

Regimen ● Interferon-alfa-NL x 12 cycles vs. observation Mechanism of Action of Experimental Drug

● Pleotrophic protein that has antiviral, immunomodulatory and antiproliferative activities

Primary Endpoint ● OS ● Secondary endpoint: recurrence free survival

Inclusion/Exclusion Criteria

● pT3-pT4a and/or node positive disease post nephrectomy and lymphandectomy

Size (N) ● 283 Results ● Median OS: 7.4 years vs. 10.4 years p=0.09

● Median DFS: 2.2 years vs 3 years p=0.33 Toxicity ● Severe (grade 4) toxicities including neutropenia, myalgia, fatigue,

depression, and other neurologic toxicities occurred in 11.4% of those randomly assigned to interferon treatment

Conclusion ● No benefit to adjuvant interferon on overall survival or on recurrence free survival

Anti-angiogenic or targeted therapy

• Three trials thus far. Two negative, one marginally positive. o ASSURE - 1 year of Sunitinib or Sorafenib vs placebo (no difference in DFS or OS) o S-TRAC – 1 year of sunitinib or placebo (improvement in DFS) o PROTECT – 1 year of pazopanib (pending, likely negative)

ASSURE Trial

Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial Lancet 2016

Regimen ● Sunitinib vs. Sorafenib vs Placebo Mechanism of Action of Experimental Drug

● Inhibition of vascular endothelial growth factor receptor, platelet derived growth factor, c-kit and other kinases

● Shown to be effective in metastatic disease Primary Endpoint ● DFS Inclusion/Exclusion Criteria

● Clear or non-clear RCC, Int Risk (pT1b-T3aN0) High risk (pT3a-pT4N or pTany N+)

Size (N) ● 1322 patients Results ● Median DFS: 5.8, 6.1, 6.6 (placebo) year. No difference in DFS

● Quality of Life: not reported Toxicity ● Higher rates of grade 3/4 hypertension, hand/foot, rash, fatigue with

sunitinib and sorafenib Conclusion ● No benefit to adjuvant sunitinib or sorafenib in locally advanced high

risk renal cell carcinoma


S-TRAC Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy

Ravaud et al NEJM Dec 2016

Regimen ● Sunitinib 50mg/d 4 on/2off vs. placebo Mechanism of Action of Experimental Drug

● Inhibition of vascular endothelial growth factor receptor, platelet derived growth factor, c-kit and other kinases

● Shown to be effective in metastatic disease Primary Endpoint ● DFS (independent and investigator review) Inclusion/Exclusion Criteria

● predominant clear cell RCC, high risk by UCLA Integrated Staging System (based on T stage, Fuhrman nuclear grade and ECOG)

Size (N) ● 615 patients Results ● Median DFS: 6.8 years vs 5.6 years (HR 0.76, p=0.03) (only for independent

review; investigator review was not significant) * OS pending

Toxicity ● Higher rates of grade 3/4 hypertension, hand/foot, rash, fatigue with sunitinib and sorafenib

Conclusion ● Patients with high risk for recurrence, DFS was improved with Sunitinib for independent review, not investigator). Why? It’s likely the DFS is on the cusp of significance and few changes pushes it the other way.

Other Comments ● Bottom Line – 1 year of sunitinib is high risk = 1 year of DFS for high risk patients.

Why difference between ASSURE and S-TRAC regarding sunitinib in adjuvant setting? • Patient characteristics

o Stage - ASSURE allowed pT1b, S-TRAC only allowed pT1b if node +. 33% of ASSURE patients had Stage I or II disease, 0% in S-TRAC. S-TRAC stratified to look at high risk patients (pT3/4 or node+)

o Pathology - S-TRAC required clear pathology, ASSURE did not (20% were not clear cell). o Dose – all S-TRAC started at 50mg dose, 70% at 50mg dose in ASSURE. Also S-TRAC had 88%

relative dose intensity throughout trial, only 40% in ASSURE

PROTECT Trial • Ongoing trial of pazopanib vs placebo post nephrectomy (ASCO 2017) • But media has stated this likely be negative.

Neoadjuvant Therapy

Is it safe? Yes, TKI ? Bev Does it downsize RCC reliably? Not to the extent of changing operability No role in general care of good PS patients. Can be used on poor performance pts or pts with extensive mets to do upfront systemic treatment. Then avoid Sx if not responding.


METASTATIC DISEASE • Bottom Line General Approach:

o Cytoreductive nephrectomy +/- metastasectomy (if solitary): o Retrospective analysis of large database of patients who received VEGF or mTOR inhibitor drugs

suggest a longer surgical with cytoreductive nephrectomy vs no sugery (17.1 vs 7.7 mo) (JCO Sept 2016)

o Current Phase III studies in the era of targeted therapy are ongoing (SURTIME and CARMENA pending). Need to carefully select patients. Typically if good PS, good-int risk and ccRCC typically undergo upfront nephrectomy

o Role of metastasectomy § Retrospective data has found survival benefit. Ideal candidates are single site of disease

>1 year after initial nephrectomy o If resect all disease (primary and met), can observe until relapse. If Stage IV or relapsed: o First line:

§ Sunitinib or Pazopanib for good/ intermediate risk patients. (preferred tx) § Bevacizumab +IFN (Bev not approved in Canada) § Temsirolimus (for poor prognosis patients) § Axitinib

o Second line: § Nivolumab (PD1 antibody) (>Everolimus) (preferred tx) § Cabozantinib (> Everolimus). (preferred tx) § Axitinib § Everolimus

o Third line and beyond: Everolimus if not previously used - Prognosis: median OS 8-24+ months based on risk factors (see Heng criteria above

Historical Treatment High dose IL-2 – reported to have achieved a complete response in 5% of met RCC patients. However, associated with severe cardiotoxicity and only used in specialized hospital with an ICU to manage the serious side effects

Patient Status Therapy (Level 1 evidence) Other Options (>= Level 2)

1st line Good or intermediate risk

Sunitinib Bevacizumab/IFN Pazopanib

High dose IL-2 Sorafenib Observation or CT

Poor risk Temsirolimus Sunitinib or CT

2nd line Post-TKI Nivolumab Cabozantinib Axitinib

Sunitinib Bevacizumab Axitinib CT

3rd line

Post-2 TKIs Nivolumab Cabozantinib Everolimus

Post TKI and mTOR Sorafenib

Post TKI and Nivolumab Axitinib ? Everolimus ?

If patient is poor prognosis, consider temsirolimus over sunitinib

• Poor prognosis defined if at least 3 out of 6 risk factors are present (minimum of 3 poor-risk features required):


From NEJM Review Jan 2017 Systemic Therapy for Metastatic Renal-Cell Carcinoma

Increased expression of MET and AXL has been implicated in the development of resistance to VEGFR inhibitors in preclinical models of renal-cell carcinoma. Hence the development of cabazantinib.

First Line Trials RR PFS (mo) mOS (mo) Sunitinib IFN (Motzer NEJM

31% 6%

11 5 HR=0.42 p<0.05

26.4 21.8 HR =082, p=0.05

Sunitinib Pazopanib (Motzer NEJM

25% 31%

9.5 8.4 NS

29.1 28.3 NS

Bev+IFN IFN AVOREN Trial

26% 13%

8.5 5.2 HR=0.71, p<0.05

18.3 17.4 NS

Bev+IFN IFN CALGB90206

31% 13%

10.2 5.4 HR=0.62, p<0.05

23.3 21.3 NS

Temsirolimus Temsirolimus+IFN IFN Hudes NEJM 2007

8.6 8.1 4.8

5.5 4.7 3.1 HR=0.66 (T), p<0.05

10.9 8.4 7.3 HR 0.73, p<0.05


Important Phase III Clinical Trials: 1st line trials:

(1) Sunitinib (Sutent) • Dose – 50mg daily for 4 weeks with 2 weeks rest, or 37.5mg daily continuously. Reduce to 37.5 or 25 mg • A/E- low antiemetic protocol • Hepatically cleared, cytochrome p450 3A4 • S/E – myelosuppression, cardiac toxicity, hepatic and renal dysfunction, sunitib-induce hypothyroidism,

HTN, hand and foot syndrome, • Monitor – With b/w, also TSH every cycle. ECHO at start.

Sunitinib vs Interferon Alpha in Metastatic Renal Cell Carcinoma

Motzer et al. N Eng J Med. 2007; 356; 2. 115-24

Regimen ● Sunitinib 50mg daily x 4 weeks (then 2 weeks off) vs. interferon alpha

9MU SC 3x/week Mechanism of Action

● Multikinase inhibitor targeting several tyrosine kinases (PDGFR, VEGFR, c-KIT, FLT-3, RET)

Primary Endpoint ● PFS Inclusion/Exclusion Criteria

● Treatment naïve metastatic renal cell carcinoma (90% had nephrectomy) ● No brain metastases ● No evidence of uncontrolled hypertension ● ECOG 0/1

Size (N) ● 750 patients Results ● PFS: 11 months (Sunitinib) vs. 5 months (IFN) HR 0.42, p<0.001

● Response Rate: 31% vs 6%, p<0.001 ● OS: updated trend towards - 26.4 months vs. 21.81 months, P = .051 However, there was cross over. When subgroup reviewed who did not cross over difference on mOS was 28 mo vs 14 mo. ● Quality of Life: Much better with sunitinib vs. interferon alpha based on

FACT-G and FKSI questionnaires. Toxicity ● Higher grade 3/4 fatigue in interferon group ● Higher rates of grade 3 diarrhea, vomiting, hypertension, and

hand-foot syndrome on sunitinib ● Higher rates of leucopenia, neutropenia, thrombocytopenia in sunitinib

group Conclusion ● Significant improvement in PFS and QoL with Sunitinib vs.

Interferon-Alpha for treatment naïve metastatic renal cell carcinoma Notes on Sutent:

• Probability of tumor response increases with daily sunitinib exposure (also associated with longer median TTP and OS) = one size dose not fit all.

• 4w on 2 off may not be suitable for all. It’s too toxic for many patients, steady state and max AUC is by day 10-14. Therefore, can consider shorter duration (max activity by day 7-14) and shorter break (rebound after 2 weeks off)

• Bjarnason et al Urol Oncology 2014 – Individualized treatment – “Treat to G2 Toxicity” o Single center retrospective review across 5 years o Start 50mg/2 4wON/2wOFF, o DL-1: Patients than cannot take 50 mg for 28 days:

§ 50 mg/d individualized # of days / 7 days off o DL-2: Patients than cannot take 50 mg for at least 7 days:

§ 37.5 mg/d individualized # of days / 7 days off o DL-3: Patients than cannot take 37,5 mg for at least 7 days:

§ 25 mg/d individualized # of days / 7 days off o The dose schedule modified groups had mPFS 10.9-11.9 mo and OS 23.4-24.5 mo that was

significantly better than the PFS 5.3 mo; P<0.001 and OS 14.4 mo; P = 0.03)


(2) Pazopanib (Votrient) • Dose – 800mg daily (empty stomach) continuous q4w. Reduce to 400/200mg. • A/E- low antiemetic protocol • Hepatically cleared, cytochrome p450 3A4 • S/E – myelosuppression, cardiac toxicity, hepatic and renal dysfunction, pazopanib-induce

hypothyroidism, HTN, hair color changes, fatigue • Monitor – With b/w, also TSH every cycle. ECHO at start. • Comparison of TKI – Sutent inhibits broader TKI and strong against c-KIT and Flt-3. Soreafenib had

modest activity against both. Pazopanib less activity against Flt-3, thus less myelosuppression. (Recall – FLT3 gene is frequently mutated in AML). Pazo has lower IC50 for VEGFR when compared to sorafenib and sunitinib.

COMPARZ Trial (non-inferiority trial)

Pazopanib versus Sunitinib in Metastatic Renal-Cell Carcinoma Motzer et al. N Eng J Med. 2014; 369: 722-731

* Final overall survival data published as correspondance in N Eng J Med. 2014; 370: 1769-1770

Regimen ● Pazopanib 800 mg once daily vs Sunitinib 50 mg daily x 4 weeks (then 2 weeks off)

Mechanism of Action of Experimental Drug

● Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptors (VEGFR)-1/-2/-3, plateletderived growth factor receptors (PDGFR)-a/-b and stem cell factor receptor c-Kit

● Comparison of efficacy across trials suggested similar progression-free survival benefits with pazopanib and sunitinib.7 Comparison of safety suggested that pazopanib was associated with a lower incidence of fatigue, the hand–foot syndrome, stomatitis, and myelosuppression and with a higher incidence of liver-function abnormalities than was sunitinib

Primary Endpoint ● PFS (non-inferiority) ● Secondary endpoints: OS, ORR, QoL medical resource utilization


● Advanced and/or metastatic RCC with a clear cell component ● No previous systemic treatment ● KPS >=70% ● No brain mets, no poorly controlled hypertension ● Adequate organ function

Size (N) ● 1110 Results ● Median PFS – 8.4 vs 9.5 months, HR=1.05 (Similar amongst all

subgroups) ● ORR: 31% vs 25%, p=0.03 ● mOS: 28.3 months vs. 29.1 months, HR=0.92, p=0.24 ● Median duration of treatment: 8.0 months vs. 7.6 months ● QoL – Fatigue and treatment related side effects were better with

pazopanib compared to sunitinib Toxicity ● More hand–foot syndrome, mucosal inflammation, stomatitis,

hypothyroidism, dysgeusia, dyspepsia, epistaxis, and fatigue with sunitinib

● More changes in hair color, weight loss, and alopecia with pazopanib Conclusion ● First line pazopanib and sunitinib are non-inferior – similar PFS, OS, but

better ORR ● Less fatigue, H&F syndrome and thrombocytopenia with Pazo, but more

transaminitis.

Other Comments ● These data may not apply in countries that do not use the Sutent 4/2 schedule as is true for most centers in Canada. Because of this the uptake of Pazopanib in Canada has been much lower than in most other countries.


Results of the COMPARZ trial, are supported by a smaller Phase II trial (PISCES JCO May 2014) PISCES trial randomized patients to Pazopanib 800mg daily for 10 weeks on, then two week break (placebo) then Sunitinib 50mg for 10 weeks (4 ON/2 OFF) or vise versa. Primary endpoint was patient preference at 22 weeks. Results

• 70% patients preferred pazopanib due to improvements in QOL, 22% preferred sunitib, 8% had no preference. Also reported less fatigue and dysguesia with pazopanib.

(3) Bevacizumab + IFN a. AVOREN Trial – improves mPFS 5.4 to 10.2 mo b. CALGB 90206 - improves mPFS 5.2 to 8.5 months

Note: OS was numerically superior but was not significant for both trials. Bev+IFN was approved for advanced RCC in 2009

AVOREN Trial

Phase III Trial of Bevacizumab Plus Interferon Alfa Versus Interferon Alfa Monotherapy in Patients With Metastatic Renal Cell Carcinoma: Final Results of CALGB 90206

Rini et al. J Clin Oncol 2010; 28: 2137

Regimen ● Bevacizumab 10mg/kg q 2weeks and Interferon-2a 9MU SC 3x/ week vs.placebo plus Interferon-2a 9MU SC 3x/week

Mechanism of Action

● Humanized monocolonal antibody towards VEGF ● Shown in phase 2 studies to be beneficial in metastatic RCC

Primary Endpoint ● OS ● Secondary endpoints: PFS, ORR and safety


● Metastatic renal cell ca with predominant clear cell component (>=50%)

● Undergone partial or full nephrectomy ● No prior systemic treatment ● No brain metastasis, adequate hepatic and renal function ● KPS >=70%

Size (N) ● 649 Results ● OS: 23.3 months vs. 21.3 months, HR=0.91, p=0.3360

● PFS: 10.2 months vs. 5.4 months, HR 0.63, p=0.001 ● OS adjusted for independent factors predictive of survival – HR 0.78,

p=0.02 ● ORR: 70% vs. 39%

Toxicity ● Higher rates of grade 3 + fatigue, asthenia, proteinuria, hypertension with bevacizumab + interferon

● 4 cases of GI perforation (1%) and 4 cases of arterial thrombotic events (1%) with bevacizumab + interferon

Conclusion ● Bevacizumab + interferon did not show a statistically significant benefit in OS compared to placebo + interferon

● PFS was improved with bevicizumab + interferon compared to placebo + interferon

Other Comments ● Several confounding factors may have led to no statistically significant OS benefit – extensive use of TKI treatment post progression, cross over of 13 patients from placebo to bevacizumab arm upon progression

● Bevacizumab is not approved for the treatment of RCC in Canada


The US did a similar trial, the CALGB 90206:

Bevacizumab plus interferon Alfa-2a for treatment of metastatic renal cell carcinoma: a randomized, double-blind phase III trial

Escudier et al. Lancet 2007; 370: 2103-11

Regimen

● Bevacizumab 10mg/kg q 2weeks and Interferon-2a 9MU SC 3x/

week vs. placebo and interferon-2a 9MU SC 3x/week


● Humanized monocolonal antibody towards VEGF ● Shown in phase 2 studies to be beneficial in metastatic RCC

Primary Endpoint

● OS ● Secondary endpoints: PFS, ORR and safety


● Metastatic renal cell ca with a clear cell component ● No prior systemic treatment ● No brain metastasis, adequate hepatic and renal function ● KPS >=70% ● BP <160/90

Size (N)

● 732

Results

● OS: 18.3 months vs. 17.4 months, HR=0.86, p=0.069 ● PFS: 8.5 vs 5.2 mo ● mOS was better in patients who received subsequent TKI

Toxicity

● Higher rates of grade 3 + hypertension, anorexia, fatigue and

proteinuria in bevacizumab arm

Conclusion ● Bevacizumab + interferon did not show a statistically significant

benefit in OS compared to Interferon alone

Other Comments ● In a retrospective analysis, PFS, ORR and OS was statistically

improved in patients who developed grade >=2 hypertension

(4) Temsirolimus • Dose: 25mg IV over 30 min qweekly. Dose reduce to 20, 15mg. Premeds – diphenhydramine 25-50mg IV

prior • A/E- low antiemetic protocol • Hepatically cleared, cytochrome p450 3A4 • S/E – myelosuppression, cardiac toxicity, hepatic and renal dysfunction, lung dysfunction (pneumonitis).

CXR prior to start. • Why use with poor performance patients? Because well tolerated and side-effects are mainly metabolic

with minimal impact on QOL (compared with oral TKIs). Main effects are hyperglycemia (26%), hypercholesterolemia (24%) and hyperlipidemia (27%)

NEJM 2007 - Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma

• 626 pts randomized in first line with untreated poor prognosis met RCC to 25mg IV temsirolimus q3w, 3M units of IFN-alpha SQ q3w or combination of 15mg of temsirolimus and 6M U q3w.

• Results o Temsirolimus alone had improved OS and PFS. Median overall survival times in the interferon

group, the temsirolimus group, and the combination-therapy group were 7.3, 10.9, and 8.4 months


Resistance to VEGF and and mTOR treatments will occur in nearly all patients. On strateguy has been to combine treatments. This has shown no change in PFS or OS but simply more toxicity.

INTORACT Trial

Randomized Phase III Trial of Temsirolimus and Bevacizumab Versus Interferon Alfa and Bevacizumab in Metastatic Renal Cell Carcinoma:

Rini et al. J Clin Oncol. 2014; 32: 752-59

Regimen ● Temsirolimus 25mg IV weekly plus bevacizumab 10mg/kg IV q2weeks vs.

Interferon 9MU SC 3x/week + bevacizumab 10mg/kg IV q2weeks


● Temsirolimus is a highly specific inhibitor of mTOR, the signaling pathway of

which is altered in RCC with clear cell histology, of advanced stage, or with poor prognostic features. mTOR regulates micronutrients, cell growth, apoptosis, and angiogenesis by its downstream effects on a variety of proteins

● Bevacizumab is an inhibitor of VEGR, which is highly expressed ● The combination of temsirolimus and bevacizumab has the potential to further

improve efficacy and possibly overcome or delay resistance to bevacizumab by concomitantly blocking alternative signaling pathways

Primary Endpoint

● PFS ● Secondary endpoints: OS, ORR and safety


● Advanced renal cell ca with a clear cell component ● No prior systemic treatment ● No brain metastasis ● Adequate hepatic and renal function ● KPS >=70% ● No history of thrombotic events in past 6 weeks ● No inadequately controlled BP >=150/100

Size (N)

● 732

Results

● Median PFS: 9.1 months vs. 9.3 months, HR 1.1, p=0.8 ● ORR: 27.0% vs 27.4% ● Median OS: 25.8 vs. 25.5, HR =1.0, p=0.6 ● QOL – No statistically significant difference

Toxicity

● More grade >=3 hypercholesteremia, mucosal inflammation, stomatitis,

hyperglycemia with temsiromlimus/ bevicizumab ● More grade >= 3 neutropenia and myalgia with interferon/ bevicizumab arm

Conclusion

● No differences were observed for PFS, OS, or ORR between the combination

regimens of temsirolimus/bevacizumab and IFN/bevacizumab when administered as first-line treatment in patients with advanced RCC.

(4) Axitinib (Inlyta) • Dose – 5mg PO daily and may escalate to 10mg PO BID or reduce to 2/4mg daily. Cycle 4 weeks. • A/E – low emetogenic protocol • S/E - diarrhea, hepatic dysfunction, drug interactions (cyto 3a4), HTN, dyspepsia, dyspnea • Mechanism – inhibits VEGFR 1-3, c-KIT, PDGFR, thus angiogenis. But also might induce autophagy

(like sorafenib) and also binds to BCR-ABL fusion protein, specifically inhibiting the drug-resistant T315I mutant isoform in CML.


Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial

Hutson et al. Lancet. 2014; 14, 1287-94

Regimen

● Axitinib 5mg mg twice daily vs sorafenib 400 mg twice daily

Mechanism of Action

● Axitinib is a potent and selective second-generation VEGFR inhibitor

Primary Endpoint

● PFS (non-inferiority) ● Secondary endpoints: OS, ORR, response duration, patient reported

outcomes, safety


● Metastatic RCC with a clear cell component ● ECOG 0 or 1 ● No previous systemic treatment ● No brain mets or CNS involvement ● Adequate organ function ● No uncontrolled hypertension, no MI/CVA/TIA within the past 12 months

Size (N)

● 288

Results

● mPFS – 10.1 months vs 6.5 months, HR=0.77, 95% CI 0.56-1.05 p=0.038 ● ORR: 32% vs 15%, p=0.0006 ● Median duration of response: 14.7 vs. 14.3 months ● Patient reported outcomes: No significant difference between treatment arms

Toxicity

● More diarrhoea, hypertension, weight decrease, decreased appetite,

dysphonia, hypothyroidism and upper abdominal pain with axitinib ● More palmar-plantar erythrodysaesthesia, rash, alopecia and erythema with

sorafenib

Conclusion ● Although median progression-free survival was numerically longer with axitinib

than with sorafenib, the difference was not significant ● Median PFS was statistically significant in ECOG 0 patients

Other Comments

● Trial had an ambitious prediction of improved PFS of 4.3 months over

sorafenib which is why it did not meet it’s primary endpoint and did not get FDA approval in the first line even tough Axitinib was clearly better.

Cabozantinib

• CABOSUN Trial (Chouleri JCO 2017) o Phase 2 157 pts with mRCC clear cell component, first line treatment randomized to cabozantinib

60mg daily vs sunitinib 50mg daily 4/2. Patient were intermediate or poor risk by IMRCC criterion. Primary endpoint was PFS. OS secondary.

o Results § PFS – 8.2 vs 5.6 months (HR 0.69 p=0.012) § ORR – 46% vs 18% § OS – 30.3 vs 21.8 months (HR= 0.8 (not significant)

o Conclusions § Cabo is active, but we need Phase 3 trial § No dose/schedule individualization for sunitinib § Unlikely to be approved.


2nd line trials: Typical sequencing can be VEGF-VEGF-mTOR or the sandwich VEGF-mTOR-VEGF. At this time would do pazopanib, then axitnib then everolimus.

Patient Status Therapy (Level 1 evidence) Other Options (>= Level 2)

1st line Good or intermediate risk

Sunitinib Bevacizumab/IFN Pazopanib

High dose IL-2 Sorafenib Observation or CT

Poor risk Temsirolimus Sunitinib or CT

2nd line Post-TKI Nivolumab Cabozantinib Axitinib

Sunitinib Bevacizumab Axitinib CT

3rd line

Post-2 TKIs Nivolumab cabozantinib Everolimus

Post TKI and mTOR Sorafenib

Post TKI and Nivolumab Axitinib? Everolimus?

MET and AXL seem to be associated with tumor progression, also causes resistance to VEGFR inhibitors like sunitinib. Therefore, cabazantinib may be more effective.

• What makes you decide? o Toxicity

§ Against EVE – poor pulmonary function or diabetes § Against Axitinib – refractory HTN

o Efficacy § Against EVE – Axitinib more likely to elicit a response in symptomatic pts. Also two

trials (INTROSEC and METEOR) have shown TKI to TKI better than TKI to mTOR. o Local factors

§ funding

(1) Nivolumab • Indicated after failure of first line TKI or second line after failure of 2 TKI • Dose: 3mg/kg (max 240mg total) over 1 hr in 100cc NS q2w. Continue until progression, but note should

continue if suspect pseudoprogression . If so continue for another 6 weeks and if scans show an additional 10% increase in volume or new lesions, then progression

CheckMate 025

Nivolumab vs. Everolimus in Advanced Renal-Cell Carcinoma Motzer et al. N Engl J Med 2015;373:1803-13

Regimen ● Nivolumab 3mg/kg IV q2weeks vs Everolimus 10mg OD Mechanism of Action of Experimental Drug

● Nivolumab is a fully human IgG4 PD-1 inhibitor that selectively blocks the interaction between PD-1 (expressed on activated t-cells) and PD-L1 and 2 which are expressed on tumor cells. It has been hypothesized that blocking this interaction leads to restored antitumor immunity

Primary Endpoint ● OS ● Secondary endpoints: ORR and safety



● Advanced or metastatic RCC with a clear cell component and measurable disease

● Received 1 or 2 previous regimens of antiangiogenic therapy ● No more than 3 previous total regimens of systemic therapy ● KPS of at least 70% ● Exclusion – no CNS metastases, no previous treatment with an mTOR

inhibitor, no condition requiring glucocorticoids >10mg or prednisone per day

Size (N) ● 821 Results • OS: 25.0 months for nivolumab vs 19.6 months for everolimus,

HR 0.73, p=0.002. OS benefit was seen regardless of PD-L1 expression • ORR: 25% with nivolumab vs 5% with everolimus, Odds ratio 5.98,

p<0.001 • PFS: nivolumab 4.6 months vs. everolimus 4.4 months, HR 0.88, • p=0.11 • Quality of Life: Improved in the nivolumab arm and significantly

different from the everolimus arm

Toxicity ● Grade 3/4 adverse events: 19% with nivolumab and 37% with everolimus

● Most common grade 3/4 toxicity with nivolumab was fatigue and with everolimus was anemia

Conclusion ● Nivolumab was associated with longer overall survival and fewer grade 3/4 adverse events compared to everolims in patients with previously treated advanced renal cell carcinoma

● Treat beyond progression? - nivolumab treatment beyond first progression was associated with reduced tumor burden in approximately 50% of patients with advanced RCC and 14% achieved greater than or equal to 30% reduction in tumor burden

(2) Cabozantinib (Cabometyx) • METEOR trial showed improved OS and PFS vs everolimus in second line. Similar OS benefit as

Nivolumab – approximately 5 months. • Not yet available in Canada

METEOR Trial Cabozitinib vs Everolimus in Advanced Renal Cell Carcinoma

Choueiri et al. N Engl J Med 2015; 373:1814-23

Regimen ● Cabozitinib 60mg OD vs Everolimus 10mg OD Mechanism of Action of Experimental Drug

● Cabozitinib is an oral small-molecule tyrosine kinase inhibitor that targets VEGFR as well as MET and AXL, each of which has been implicated in the pathogenesis of metastatic RCC or in the resistance to antiangiogenic drugs.

Primary Endpoint ● PFS ● Secondary endpoints: OS, ORR


● Advanced or metastatic RCC with a clear cell component and measurable disease ● Previous treatment with at least 1 VEGFR-targeting TKI with radiologic

progression during treatment or within 6 months after the most recent dose ● KPS at least 70% ● No previous therapy with an mTOR inhibitor or with cabozitinib

Size (N) ● 658


Results ● PFS: 7.4 months with cabozitinib vs 3.8 months with everolimus, HR 0.58, p<0.001

● ORR: 21% with cabozitinib vs 5% with everolimus, p<0.001 ● OS: (final analysis) – mOS 21.4 vs 16.5 mo (HR 0.66, P=0.00026) ● PFS and ORR were higher in patients on cabozitinib who only had

sunitinib as previous therapy (post-hoc analysis)

Toxicity ● Grade 3/4 toxicity occurred in 68% of patients on cabozitinib vs. 58% of patients on everolimus

● Cabozitinib grade 3/4 toxicities included hypertension, diarrhea and fatigue

● Everolimus grade 3/4 toxicities included anemia, fatigue and hyperglycemia

Conclusion ● Cabozitinib was associated with a higher PFS in patients with advanced RCC who had progressed on previous VEGF targeted therapy

(3) Sorafenib • A oral bioavailable small molecule inhibitor of VEGFR, PDGFR and Raf • TARGET trial shows improvement in PFS 5.5 vs 2.8 months who failed prior thearpy

TARGET

Sorafenib for Treatment of Renal Cell Carcinoma: Final Efficacy and Safety Results of the Phase III Treatment Approaches in Renal Cancer Global Evaluation Trial Escudier et al. N Engl J Med

2007;356:125-34. and J Clin Oncol. 2009; 27:3312-3318.

Regimen ● Sorafenib 400mg bid vs placebo Mechanism of Action of Experimental Drug

● Orally active multikinase inhibitor that blocks VEGFR-2, VEGFR-3, and PDGF receptor (PDGFR-), as well as RAF-1, Flt-3, and c-KIT

Primary Endpoint ● OS ● Secondary endpoints: PFS, RR and patient reported outcomes


● Unresectable or metastatic RCC who had undergone 1 prior systemic treatment with IL-2 and/or interferon

Size (N) ● 903 Results ● PFS - 5.5 months vs. 2,8 months, HR 0.44, p>0.001

● Overall Survival: 17.8 months vs. 15.2 months, HR 0.88, p=0.146 (cross-over was however allowed)

● OS (with crossover patients censored) – 17.8 months vs. 14.3 months, HR 0.78, p=0.287

● Correlation with VEGF levels – both high and low levels of VEGF responded to Sorafenib

Toxicity ● Higher rates of grade 3 /4 hypertension, hand-foot syndrome, rash/desquamation, diarrhea and fatigue in sorafenib groups

Conclusion ● Sorafenib is effective as 2nd line treatment for advanced/ metastatic renal cell carcinoma after 1st line immunotherapy (INT or IL-2). Since these immunotherapies are never given 1st line Sorafenib is not used 2nd line in Canada.


INTORSECT Trial

Randomized Phase III Trial of Temsirolimus Versus Sorafenib As Second-Line Therapy After Sunitinib in Patients With Metastatic Renal Cell Carcinoma

Hutson et al. J Clin Oncol. 2014; 32: 760-767

Regimen ● Temsirolimus 25mg IV weekly vs. Sorafenib 400 mg bid Mechanism of Action of Experimental Drug

• Temsirolimus is a highly specific inhibitor of mTOR, the signaling pathway of which is altered in RCC with clear cell histology, of advanced stage, or with poor prognostic features.

• Has shown activity in phase 2 studies in pre-treated patients with advanced RCC

Primary Endpoint ● PFS ● Secondary endpoints: OS, ORR and safety


● Any histology mRCC ● Progressive disease after sunitinib ● ECOG 0 or 1 ● No brain metastases ● Adequate hepatic, renal and cardiac function

Size (N) ● 512 Results ● Median PFS: 4.3 vs. 3.9 months HR=0.87, p=0.89

● ORR: 8% in both arms ● Median OS: 12.3 vs. 16.6 months, HR =1.31, p=0.01 P (oddly sorafenib arm had better OS)

Toxicity ● More grade >=3 anemia and hyperglycemia with temsirolimus ● More grade >=3 palmar-plantar erythrodysesthesia with sorafenib

Conclusion • No differences were observed for PFS or ORR between temsirolimus vs. sorafenib in the 2nd line setting

• OS was significantly improved with sorafenib compared to temsirolimus in the 2nd line setting

Other Comments ● A TKI to TKI sequence may be better than a TKI to mTOR sequence?


(4) Axitinib • Dose – 5mg PO BID and may escalate to 10mg PO BID. • Low emetogenic. S/E – diarrhea, hepatic dysfunction, HTN

AXIS Trial

Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial

Rini et al. Lancet. 2011; 378, 1931-39

Regimen ● Axitinib 5mg mg twice daily vs sorafenib 400 mg twice daily Mechanism of Action of Experimental Drug

Axitinib is a potent, selective, second-generation inhibitor of VEGFR 1, 2, and 3 that blocks VEGFRs at sub-nanomolar drug concentrations. Relative potency of axitinib is 50–450 times greater than that of the first-generation VEGFR inhibitors. Additionally, first-generation inhibitors block other targets, such as platelet-derived growth factor receptors (PDGFR), b-RAF, KIT, and FLT-3, which are not substantially inhibited by axitinib.These off-target activities might contribute to the adverse effects of the first-generation inhibitors, suggesting that more specific inhibitors of VEGFR such as axitinib might have an enhanced therapeutic window.

Primary Endpoint ● PFS (non-inferiority) ● Secondary endpoints: OS, ORR, duration of response, time to deterioration


● Advanced/ metastatic RCC with a clear cell component ● ECOG 0 or 1 ● Progressive disease after 1 line of previous systemic treatment ● No brain mets or CNS involvement ● Adequate organ function ● No present use or anticipated need for cytochrome P450

(CYP)3A4-inhibiting, CYP3A4-inducing, or CYP1A2-inducing drugs; ● No known HIV or acquired immunodeficiency syndrome-related disease ● No uncontrolled hypertension, no MI/CVA/TIA within the past 12 months ● No DVE/ PE within the past 6 months Size (N) ● 723

Results ● Median PFS – 6.7 months vs 4.7 months, HR=0.665, p<0.001 ● Median PFS for patients who had previously received cytokines– 12.1 vs

6.5 months, HR=0.464, p<0.001 ● Median PFS for patients previously treated with sunitinib – 4.8 vs

3.4 months, HR=0.741, p=0.01 ● ORR: 19% vs 9%, p=0.0001 ● Median duration of response: 11 vs. 10.6 months ● Time to deterioration: 17% risk reduction with axitinib ● mOS – 20.1 vs 19.2 mo HR 0.969

Toxicity ● Most common grade 3+ adverse events with axitinib: hypertension, diarrhea and fatigue

● Most common grade 3+ adverse events with sorafenib: palmar-plantar erythrodysaesthesia, hypophosphataemia, lipase elevation, and hypertension

Conclusion ● Axitinib led to a statistically significant and clinically meaningful increase in the primary efficacy endpoint of PFS compared with sorafenib

● Time to deterioration was also improved with axitinib ● The tolerability of axitinib was similar to that of sorafenib and other VEGFR

inhibitors, with some exceptions

Other Comments ● This study was not a blinded trial, although all efficacy endpoints were adjudicated by masked independent radiology review

● Patients on axitinib could increase their dosages while patients on sorafenib were not – this may have led to increase efficacy of axitinib

Patients who developed dHTN (>90 mmHg) on trial had improvement in both arms than those who remained normotensive.


2nd line and beyond: EVEROLIMUS

RECORD1 Trial Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomized, placebo-controlled phase

III trial Motzer et al. Lancet. 2008; 372: 449-56

Regimen ● Everolimus 10 mg once daily vs placebo Mechanism of Action of Experimental Drug

● Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR), a component of an intracellular signalling pathway that regulates cellular metabolism, growth, proliferation, and angiogenesis. Everolimus, a derivative of rapamycin, binds to an intracellular protein, FKBP-12, forming a complex that inhibits the mTOR serine-threonine kinase

Primary Endpoint ● PFS ● Secondary endpoints: OS, ORR, safety, QoL, disease related symptoms


● mRCC with a clear cell component ● Progressed on or within 6 months of being on sunitinib or sorafenib ● No previous exposure to mTOR inhibitor ● KPS >=70% ● No untreated brain metastases ● Adequate hepatic, renal and bone marrow function

Size (N) ● 410 Results ● Median PFS: 4.0 vs. 1.9 months HR=0.30, p <0.001

● ORR: 1% vs 0% ● Median OS: Not reached vs. 8.8 months, HR 0.83, p=0.23 ● QoL – No significant difference between treatment arms

Toxicity ● More grade 3/4 stomatitis, infections, non-infectious pnuemonitis, lymphopenia, hyperglycemia, hypophosphotemia, hypercholesterolemia in everolimus group

Conclusion ● Everolimus was associated with a reduction in the risk of progression or death compared with placebo in patients with metastatic renal cell carcinoma whose disease had progressed after treatment with VEGF-targeted therapies

● Increased risk of toxicity with everolimus vs. placebo

Other Comments ● OS likely not significant due to cross over ● In this study leading to the approval for Everolimus 2nd line, 269 pts

received Everolimus. However, most were heavily pretreated and received Everolimus 2nd line (89 pts), 3rd line (141 pts), 4th line (104 pts) and 5th line (82 pts)


A randomized, double-blind phase III study of pazopanib in patients with advanced and/or

metastatic renal cell carcinoma: Final overall survival results and safety update Sternberg et al. European Journal of Cancer. 2013; 49: 1287-1296

Regimen ● Pazopanib 800 mg once daily vs placebo Mechanism of Action of Experimental Drug

● Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptors (VEGFR)-1/-2/-3, plateletderived growth factor receptors (PDGFR)-a/-b and stem cell factor receptor c-Kit

Primary Endpoint ● PFS ● Secondary endpoints: OS, ORR, QoL duration of response


● Advanced and/or metastatic RCC ● Clear cell or predominately clear cell ● Treatment naïve or patients who had progressed on 1 line of previous

cytokine therapy ● ECOG 0 or 1 ● No brain metastases or leptomeningeal disease ● Adequate hepatic, renal and bone marrow function

Size (N) ● 435 (233 treatment naïve, 202 pretreated) Results ● Median PFS – entire population: 9.2 vs 4.2 months HR=0.46, p

<0.001 ● Median PFS – treatment naïve: 11.1 vs. 2.8 months, HR=0.4, p<0.001 ● Median PFS – cytokine pretreated: 7.4 vs. 4.2 months, HR=0.54,

p<0.001 ● ORR: 30% vs 3% ● Median OS: 22.9 months vs. 20.5 months, HR=0.91, p=0.224 ● QoL – No significant difference between treatment arms

Toxicity ● Higher rates of grade 3/4 adverse events with pazopanib – 33% vs 7% ● Most common grade 3/4 adverse events with pazopanib were

hypertension and diarrhea ● 3% arterial thrombotic events on pazopanib ● 13% all grades of hemorrhagic events on pazopanib

Conclusion ● Pazopanib demonstrated a statistically significant and clinically meaningful improvement in PFS compared with placebo in treatment-naive and cytokine-pretreated patients with advanced RCC.

● Pazopanib did not show a statistically significant effect on OS in the final ITT analysis

Other Comments ● OS likely not significant due to cross over and post progression therapy (66% of patients in the placebo arm)

Other Pathology Types: (1) Non-Clear Cell RCC • Limited data, but can use Sunitinib. In ASPEN trial – showed improved PFS and OS vs everolimus Sarcomatoid (5% of RCC) features indicates poor prognosis. mPFS 5.3 mo and mOS 11.7 mos with VEGF inhibitors


• Blockage of VEGFR or delpletion will cause HTN, fatigue, proteinuria and increased risk of bleeding and thrombotic events. All of the anti-VEGF will cause these side effects to varying degrees

• Soreafenib, sutininib and pazopanib also inhibit PDGF, Flt3 and other TKI thus cause H&F syndrome, diarrhea, and dysgusia.

• Sutent is particular prone at inducing hypothyroidism and CHF (~2-3%) • mTOR inhibitors uniquely cuase hypertriglyceridemia, hyperglycemia and non-infectious pneumonitis.


Documents

Renal Cell Carcinoma · Renal Cell Carcinoma STAGE 5 yr overall survival Stage I – T1N0 80-95% Stage II – T2N0 80% Stage III – T3N0 or N+ 60% Stage IV – T4 or M1 10-30% (improved