Reference No: Author(s) Approval date: June Committee. Operational Date: July Review:

Transcription

1 Reference No: Title: Author(s) Systemic anti-cancer therapy (SACT) guidelines for renal cell cancer Dr Alison Clayton Consultant Medical Oncologist & Dr Jane Hurwitz Consultant Medical Oncologist, Cancer Centre, Belfast City Hospital Ownership: Approval by: Operational Date: NICaN NICaN Drugs & Therapeutics Committee July 2016 Version No. 2.0 Supercedes 1.0 Links to other policies Version control for drafts: NICaN Renal SACT protocols Approval date: Next Review: June 2016 July 2018 Date Version Author Comments 2012 V1.0 A Clayton June 2016 V2.0 A Clayton Nivolumab included Other supportive therapies Denosumab added SACT for Renal Cell Cancer 2016 v2.0 Page 1 of 20

2 Authorisation of Systemic Anti-Cancer Therapy (SACT) Guidelines for Renal Cell Cancer These SACT guidelines are being submitted by the authors on behalf of the renal oncologists. SACT for Renal Cell Cancer 2016 v2.0 Page 2 of 20

3 1.0 INTRODUCTION / PURPOSE OF POLICY 1.1 Background These guidelines describe the agreed management for patients with renal cell cancer. They include staging and prognostic scores, the role of surgery and systemic anti-cancer therapy (SACT). 1.2 Purpose To ensure management for patients with renal cell cancer. 2.0 SCOPE OF THE POLICY This document is aimed at all clinical staff involved in the management of patients with renal cell cancer. 3.0 ROLES/RESPONSIBILITIES It is the responsibility of all clinical staff involved in the management of patients with renal cell cancer to familiarise themselves with these guidelines. 4.0 KEY POLICY PRINCIPLES 4.1 Histological sub-types and staging conventional = clear cell papillary chromophobe collecting duct medullary unclassified Sarcomatoid change may be seen with all types SACT for Renal Cell Cancer 2016 v2.0 Page 3 of 20

4 TNM STAGING T1 T2 T3 T1a < 4cm T1b > 4cm < 7 cm limited to the kidney > 7 cm limited to the kidney T2a < 10 cm T2b > 10cm Tumor extends into major veins or invades adrenal gland or perinephric tissues but not beyond Gerota fascia T3a Invades adrenal gland or peri-nephric tissues but not beyond Gerota fascia T3b Extends into renal vein or its segmental (muscle- containing) branches, or vena cava below the diaphragm T3c Extends into IVC above diaphragm or invades the wall of the vena cava T4 N0 N1 N2 M0 M1 Invades beyond Gerota fascia No nodes Single regional node (renal hilar, paraaortic, paracaval) >1 regional node No distant metastases Distant metastases SACT for Renal Cell Cancer 2016 v2.0 Page 4 of 20

5 STAGE GROUPING (1997) STAGE 5yr OS (%) GUINAN 1995 TSUI 2000 I T1, NO, MO II T2, NO, MO III T1-2, N1, MO T3, NO-1, MO IV T1-4, N2, MO T4, NO-2, M0-1 T1-4, N0-1, M1 (N=2473) (N=643) AJCC STAGE 2010 (7TH ED) STAGE I II III IV TNM T1, NO, MO T2, NO, MO T1-2, N1, MO T3, NO-1, MO T4, Any N, M0 Any T, Any N, M1 4.2 Management of localised disease Treatment options for localised disease include radical nephrectomy with or without lymph node dissection, partial nephrectomy, and non- surgical techniques (such as radiofrequency ablation) for selected patients with small, generally T1a tumours. Surgery is indicated for patients with clinical stage III disease (i.e. patients who have a tumour involving the renal vein or vena cava). Patients with minimal regional adenopathy may also be considered for SACT for Renal Cell Cancer 2016 v2.0 Page 5 of 20

6 surgery, as lymph nodes suspicious for disease on CT may be hyperplastic and may not be involved with the tumour Prognosis following nephrectomy UCLA Integrated Staging System (UISS) 1 UISS 1997 Grade ECOG 2yr survival 5yr survival TNM stage I I 1,2 0 96% 94% II I 1,2 >1 89% 67% I 3,4 Any II Any Any III Any 0 III 1 >1 III III 2-4 >1 66% 39% IV 1,2 0 IV IV 3,4 0 42% 23% 1-3 >1 V IV 4 >1 9% 0% SACT for Renal Cell Cancer 2016 v2.0 Page 6 of 20

7 Liebovich score 2 Feature Pathological T category of primary tumour (TNM 2002) Score pt1a 0 pt1b 2 pt2 3 pt3a-4 4 Regional lymph node status pnx or pn0 0 pn1 or pn2 2 Tumour size < 10cm 0 > 10cm 1 Nuclear grade 1 or Histological tumour necrosis No 0 Yes 1 Score Group 0 2 Low risk 3 5 Intermediate risk 6 or more High risk SACT for Renal Cell Cancer 2016 v2.0 Page 7 of 20

8 4.2.2 Adjuvant therapy There is currently no convincing data to support the use of either adjuvant radiotherapy or adjuvant systemic therapy as standard practice. Adjuvant therapy should only be given as part of a clinical trial. 4.3 Metastatic renal cancer Prognostic scores MSK score The prognostic scores developed at the Memorial Sloane Kettering hospital are widely used as reported by Motzer (developed when immunotherapy was the mainstay of treatment) based on 670 patients with advanced RCC 3 Score (1 for each): No nephrectomy KPS < 80 Hb < LLN Ca > 2.5 LDH > 1.5 X ULN SACT for Renal Cell Cancer 2016 v2.0 Page 8 of 20

9 Score 0 1 or Median survival (mnths) follow-up analysis, based on 463 patients with advanced RCC who have undergone nephrectomy 4 Score (1 for each): Time from diagnosis to interferon < 1yr KPS < 80 Hb < LLN Ca > 2.5 LDH > 1.5 X ULN Score 0 1 or Median survival (mnths) HENG score 5 - based on analysis of outcomes of 645 patients treated with anti-vegf therapy. Score (1 for each): Time from diagnosis to treatment < 1yr KPS < 80 HB < LLN CA > 2.5 Neutrophils > ULN Plt> ULN Score 0 1 or Median survival (mnths) NR year OS (%) SACT for Renal Cell Cancer 2016 v2.0 Page 9 of 20

10 4.3.2 Role of surgery Nephrectomy Nephrectomy should be considered for all patients with metastatic renal cell cancer (RCC) with a good performance status (ECOG PS < 1). Two randomised controlled trials have demonstrated a survival benefit for patients with metastatic RCC undergoing nephrectomy followed by interferon compared with interferon alone, with a median overall survival of 11.1 vs 8.1 months (p= 0.05) 6 and 17 vs 7 months (p= 0.03) 7. A combined analysis of these studies showed a median overall survival of 13.6 vs. 7.8 months 8. The role of nephrectomy for patients receiving anti-vegf / TKI therapy is being re-appraised in two randomised phase III trials (CARMENA / EORTC). Retrospective data in patients treated with anti-vegf/tki therapy still suggests patients benefit from nephrectomy and this should therefore still be considered pending results of phase III studies Metastasectomy Selected patients with stage IV RCC with a solitary metastasis should be considered for resection of the metastasis 9. Data suggest this is more likely to be of benefit in patients with metachronous rather than synchronous metastases, particularly if there is a disease free interval of > 12 months. Sites of solitary metastases that are amenable to this approach include the lung, bone, brain, and other selected sites. Both the primary tumour and the metastasis may be resected during the same operation or at different times. Although the majority of patients who undergo resection of a solitary will relapse, long- term survival has been observed in some patients. Radiotherapy should be considered following resection of bone or brain metastases Renal embolisation Renal embolisation may be considered for patients with metastatic RCC who are not suitable for nephrectomy and who are symptomatic from their primary tumour 10, 11. SACT for Renal Cell Cancer 2016 v2.0 Page 10 of 20

11 4.3.3 Systemic therapy First line therapy Background Sunitinib or Pazopanib are currently standard first line therapy options for metastatic renal cell carcinoma with good performance status (ECOG 0-1). The benefits of sunitinib were demonstrated a large phase III trial in patients with clear cell histology, predominantly post-nephrectomy. Patients with nonclear cell histology may also receive a trial of sunitinib therapy (as per NICE guidance). There are no dedicated trials to guide therapy in this smaller group. However, there is some evidence of activity of sunitinib in patients with non-clear cell histology from the expanded access study and reports in small numbers of patients. Benefits in this group are however less certain in view of the lower quality of evidence. Interferon may be considered for patients with PS 2, or for patients with a contra-indication or intolerance to sunitinib and pazopanib. Patients who have small volume asymptomatic disease may be monitored initially prior to commencing systemic therapy as some patients may have very indolent disease which may remain relatively stable without intervention sometimes for long periods of time. Baseline investigations All patients; Biopsy (mandatory to establish histological diagnosis in patients not undergoing cytoreductive nephrectomy) FBC Oncology profile CT thorax, abdomen and pelvis Isotope bone scan Patients being considered for sunitinib therapy; ECG Echocardiogram Thyroid function Dental review SACT for Renal Cell Cancer 2016 v2.0 Page 11 of 20

12 Monitoring response to therapy Patients receiving systemic therapy for metastatic disease should have restaging investigations repeated every 3-4 months on therapy to assess response Anti-VEGFR TKI therapy Sunitinib Sunitinib maleate is an oral multi-targeted receptor tyrosine kinase inhibitor which has demonstrated both anti-tumour and anti-angiogenic effects. Sunitinib maleate selectively inhibits PDGFR, VEGFR 1-3, c-kit and FLT-3- receptors. Sunitinib is licenced as first line therapy for locally advanced or metastatic renal cell carcinoma. In the pivotal phase III trial, 750 patients with metastatic renal cell carcinoma (clear cell type) who had not received prior systemic therapy for MRCC and were of good performance status (PS 0-1) were randomised to receive sunitinib or IFN-α 12. Sunitinib treatment was associated with a clinically and statistically significant improvement in median PFS compared to IFN- (11 vs 5 months; hazard ratio [HR] =0.415; p ) and overall survival (overall analysis vs 21.8 months, p=0.051 ; crossover patients censored 26.4 vs 20 months, p=0.036 ; patients not receiving second line therapy 28.1 vs 14.1 months, p=0.0033). The ORR was 37 vs 9%. Regimen 50mg OD PO days 1-28, followed by 14 days without treatment (6 week cycle). For dose modifications, see individual protocol. Pazopanib Pazopanib is an orally administered, potent multi-target tyrosine kinase inhibitor of VEGFR 1-3, PDGFR-α and β, and stem cell factor receptor (c- KIT). In a phase III RCT 435 patients with locally advanced or metastatic RCC (treatment naive and cytokine pre-treated) received pazopanib or placebo 13. This demonstrated improved PFS (9.2 vs 4.2 months, HR 0.46, p < ) response rate (30 vs 3%, p < 0.001) for pazopanib. SACT for Renal Cell Cancer 2016 v2.0 Page 12 of 20

13 Pazopanib has been compared to sunitinib in 1110 patients with locally advanced and/or metastatic RCC who had not received prior systemic therapy 14. There was no significant difference in PFS (8.4 vs 9.5 months) or OS (28.4 vs 29.3 months) in the two groups. The trial achieved its primary endpoint of non-inferiority in PFS compared to sunitinib. The QOL/toxicity data favoured pazopnib, however assessments were performed at the end of the 4th week on sunitinib when toxicity on that arm would be maximal, and response assessments were performed at the end of the sixth week and so trial design was not optimal. Incidence of hand/foot syndrome, rash, peripheral oedema, stomatitis, fatigue and myelosuppression were lower in the pazopanib arm, but incidence of liver toxicity, alopecia and weight loss was higher. Regimen 800mg OD PO continuously. For dose modifications, see individual protocol m-tor inhibitors Temsirolimus Temsirolimus is not funded Northern Ireland Temsirolimus acts by inhibiting the mammalian target of rapamycin (mtor) kinase. Temsirolimus is licenced for the first line treatment of patients with RCC who have at least three of six prognostic factors denoting poor risk as indicated below; 1. LDH > 1.5 x upper limit of normal 2. Haemoglobin < lower limit of normal 3. Corrected calcium > 10mg/dL (> 2.5mM) 4. Time from diagnosis to first treatment 1 year 5. Karnofsky Performance Status Multiple (2 or more) sites of metastasis In the pivotal phase III study, 626 patients with advanced RCC and at least 3 of the above prognostic factors, were randomised to INF-α only, temsirolimus only, or temsirolimus plus IFN-α.Temsirolimus as a single agent significantly improved OS and PFS compared to IFN-α alone (10.9 vs. 7.3 months; p=0.008 and 3.8 vs. 1.9 months; p<0.00). This was not improved with the combination of temsirolimus and IFN 15. SACT for Renal Cell Cancer 2016 v2.0 Page 13 of 20

14 Choice of initial therapy The majority of patients commence sunitinib therapy; unless there are particular aspects of side effect profile which favour the use of pazopanib in particular patients. Patients responding to sunitinib who experience toxicity problems which are likely to be less with pazopanib should be considered for a change of treatment to pazopanib. Patients with small volume, asymptomatic indolent disease may have a period of active surveillance without treatment for a time prior to commencing active therapy as there is no evidence that this has an adverse impact on prognosis Immunotherapy High dose IL-2 Selected patients may be considered for supra-regional referral to the Christie hospital for assessment for suitability for high dose interleukin-2 treatment Interferon- α. IFN α may be considered for patients with PS 2, or for patients with a contraindication or intolerance to anti-vegfr TKI agents. In the MRC RE-01 trial patients were randomised to IFN α or megace. There was an improved ORR (14 vs 2%), I year survival (43 vs 31%) and OS (8.5 vs 6 months) for IFN α compared to megace. Other studies have shown similar results, with response rates of % and median OS of 8-13 months There is no convincing evidence that combination immuno/chemotherapy is superior to interferon alone One RCT demonstrated a survival advantage for the use of the atzpodien regimen over interferon and vinblastine, but this was not confirmed in the MRC RE-04 study. Regimen IFN α 5 MU subcutaneous 3 X weekly for 1 week then increasing to 10 MU 3 X weekly. For less fit patients consider starting dose of 3MU, increasing to 5 MU if tolerated. SACT for Renal Cell Cancer 2016 v2.0 Page 14 of 20

15 Second line therapy Following prior cytokine therapy Sunitinib Results are available from two independent, single arm, multicentre, phase II trials of sunitinib 24, 25. The trials include a total of 168 patients receiving sunitinib for the treatment of metastatic renal cell carcinoma following failure of prior cytokine therapy. ORR was 42%, and 24% achieved SD was > 3 months. Sorafenib 26 and pazopanib 27 are also licensed for this indication however in this centre we would use sunitinib. Following prior anti-vegfr TKI therapy Axitinib Axitinib is currently the standard second line therapy for patients retaining a good performance status (ECOG 0-1) whose disease has progressed on sunitinib in line with NICE guidance (TA333) Axitinib is a potent and selective tyrosine kinase inhibitor of (VEGFR-1, VEGFR-2 and VEGFR-3. It is licenced for the treatment of adult patients with advanced renal cell carcinoma after failure of prior treatment with sunitinib or a cytokine. The AXIS trial was a phase III study in which 723 patients with advanced RCC whose disease had progressed on or after treatment with one prior systemic therapy were randomised to receive axitinib or sorafenib patients (53.8%) had received one prior sunitinib-based therapy and 251 patients (34.7%) had received one prior cytokine-based therapy (IL-2 or INFα). Median PFS and OS were 6.8 vs 4.7 months (p<0.0001) and 20/1 vs 19.2 months (NS), for axitinib and sorafinib respectively. ORR was 19.4 vs 9.4% (p<0.0001). In patients who had received prior sunitinib, the median PFS and OS were 4.8 vs 3.4 months (p<0.0063) and 15.2 vs 16.5 months (NS). Regimen 5mg PO BD continuously with dose adjustment (escalation or reduction) according to toxicity as per SPC SACT for Renal Cell Cancer 2016 v2.0 Page 15 of 20

16 Everolimus Everolimus is not currently funded routinely in Northern Ireland Individual funding requests for second line everolimus may be considered for patients felt unsuitable for treatment with axitinib Everolimus is an oral mtor inhibitor that is licensed for use following failure of an anti-vegf agent. The RECORD 1 phase III trial randomised 410 patients who had received at least one prior anti VEGF therapy, to everolimus or placebo. PFS was improved in the treatment arm (4.9 vs 1.9 monts; p<0.001). Median OS was 14.8 vs 14.4 months (p=0.162), although this may be confounded by cross0over (80% patients crossed over to receive everolimus) 28. Regimen 10mg OD PO continuously Nivolumab Nivolumab is not currently funded routinely in Northern Ireland Individual funding requests for second line nivolumab may be considered for patients felt unsuitable for treatment with axitinib Nivolumab is a PD-1 checkpoint inhibitor, licensed for treatment of metastatic renal carcinoma following failure of TKI therapy. The data to support the benefits of nivolumab comes from the CHECKMATE 2015 study 29. This study included 821 patients with advanced clear cell renal cell carcinoma who had received up to 2 previous regimens of anti angiogenic therapy. The patients were randomised to receive nivolumab or everolimus. There was a significant improvement in median OS for the nivolumab group (25 compared to 19.6 months). The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P = 0.002). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). Regimen 3mg/kg IV over 60 mins 2 weekly Immunotherapy Patients retaining good performance status following progression on first line anti-vegfr TKI therapy may be considered for treatment with INF-α. These patients could also be considered for referral for consideration of high dose IL- 2 or a clinical trial. SACT for Renal Cell Cancer 2016 v2.0 Page 16 of 20

17 4.3.4 Other supportive therapies Bisphosphonates Zolendronic acid 4 mg IV monthly or alternatively oral bondronat may be considered for patients with bone metastases. Denosumab may be considered as an alternative to bisphosphonate for patients with bony metastatic disease 5.0 IMPLEMENTATION OF POLICY 5.1 Dissemination This policy will be agreed by all consultant oncologists treating patients with SACT for breast cancer. The guideline will form the basis for development of the SACT regimen specific protocols. It will be available on the intranet for use by all doctors, nurses and pharmacists involved in all stages of SACT assessment and delivery in patients with breast cancer. 6.0 MONITORING Use of these guidelines will be monitored using audit. SACT for Renal Cell Cancer 2016 v2.0 Page 17 of 20

18 7.0 EVIDENCE BASE / REFERENCES 1. Zisman A, et al. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. Clin Oncol. 2002;20(23): Leibovich BC, et al. Scoring algorithm to predict survival after nephrectomy and immunotherapy in patients with metastatic renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer Dec 15;98(12): Motzer RJ, et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol Aug;17(8): Motzer RJ, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol Feb 1;22(3): Heng DY, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol Dec 1;27(34): doi: /JCO Epub 2009 Oct Flanigan RC, et al. Nephrectomy followed by interferon alfa-2b compared with Interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001;345: Mickisch GHJ, et al. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 2001; 358: Flanigan RC, et al. Cytoreductive nephrectomy in patients with metastatic renal cancer. A combinedanalysis. J.Urology 2004; 171: Kavolius JP, et al. Resection of metastatic renal cell carcinoma. J Clin Oncol 1998; 16: Munro NP, et al. The role of transarterial embolization in the treatment of renal cell carcinoma. BJU Int Aug;92(3): Kalman D, Varenhorst E. The role of arterial embolization in renal cell carcinoma. Scand J Urol Nephrol Jun;33(3): Motzer RJ et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med Jan 11;356(2): Sternberg CN, et al. Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma:Results of a Randomized Phase III Trial. J Clin Oncol 28(2010) Motzer RJ, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med Aug 22;369(8): Hudes G, et al. Temsirolimus, Interferon Alfa, or Both for Advanced Renal- Cell Carcinoma. N Eng J Med 2007;356: SACT for Renal Cell Cancer 2016 v2.0 Page 18 of 20

19 16. Medical Research Council Renal Cancer Collaborators. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet Jan 2;353(9146): Pyrhonen S, et al. Prospective Randomized Trial of Interferon Alfa-2a Plus Vinblastine Versus Vinblastine Alone in Patients With Advanced Renal Cell Cancer. J Clin Oncol : Motzer RJ, et al. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20(1): Minasian LM, et al. Interferon alfa-2a in advanced renal cell carcinoma: treatment results and survival in 159 patients with long-term follow-up. J Clin Oncol. 1993;11(7): Negrier S, et al. Recombinant human interleukin-2, recombinant human interferon alfa- 2a, or both in metastatic renal-cell carcinoma. Groupe Français d'immunothérapie. N Engl J Med. 1998;338(18): Atzpodien J, et al. Interleukin-2 and Interferon Alfa-2a Based Immunochemotherapy in Advanced Renal Cell Carcinoma: A Prospectively Randomized Trial of thegerman Cooperative Renal Carcinom Chemoimmunotherapy Group (DGCIN).J Clin Oncol : Gore ME, et al. Interferon-α (IFN), interleukin-2 (IL2) and 5-fluorouracil (5FU) vs IFN alone in patients with metastatic renal cell carcinoma (mrcc): results of the randomised MRC/EORTC RE04 trial. J Clin Oncol 26: 2008 (May 20 suppl; abstr 5039) 23. Negrier S, et al. Treatment of patients with metastatic renal carcinoma with a combination of subcutaneous interleukin-2 and interferon alfa with or without fluorouracil. J Clin Oncol Dec 15;18(24): Motzer R, et al. Activity of SU11248, a Multitargeted Inhibitor of Vascular Endothelial Growth Factor Receptor and Platelet-Derived Growth Factor Receptor, in Patients With Metastatic Renal Cell Carcinoma. J Clin Oncol Jan 1;24(1): Motzer RJ, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA Escudier B, et al. Sorafenib for Treatment of Renal Cell Carcinoma: Final Efficacy and Safety Results of the Phase III Treatment Approaches in Renal Cancer Global Evaluation Trial. J Clin Oncol July 2009 vol. 27 no Sternberg CN, et al. Randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer Apr;49(6): Motzer RJ, et al. Efficacy of everolimus in advanced renal cell carcinoma: a doubleblind, randomised, placebo-controlled phase III trial. Lancet 2008;372(9637): Motzer et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. New Engl J of Medicine 2015, Volume 273 No. 19. SACT for Renal Cell Cancer 2016 v2.0 Page 19 of 20

20 30. Rini B, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet Dec 3;378(9807): CONSULTATION PROCESS Northern Ireland renal oncologists 9.0 EQUALITY STATEMENT In line with duties under the equality legislation (Section 75 of the Northern Ireland Act 1998), Targeting Social Need Initiative, Disability discrimination and the Human Rights Act 1998, an initial screening exercise to ascertain if this policy should be subject to a full impact assessment has been carried out. The outcome of the Equality screening for this policy is: Major impact Minor impact No impact. SACT for Renal Cell Cancer 2016 v2.0 Page 20 of 20