Two11 104 Treatment of advanced Renal Cell Carcinoma

  1. 10 year survival of metastatic RCC?
    < 5%
  2. Risk stratification of advanced RCC?
    • MSKCC 1999 
    • • Karnofsky performance score < 80%
    • • Elevated lactate dehydrogenase (>1.5 times upper limit of normal)
    • • Low hemoglobin (<lower limit of normal)
    • • Elevated corrected calcium (>10 mg/dL)
    • • Absence of prior nephrectomy

    • Good risk - 0
    • Intermediate risk - 1-2
    • Poor risk - 3-5

    [@ KCL HeN - Karnofsky, Calcium (>10 g/dl), LDH (>1.5), Hemoglobin, Absence of Prior Nephrectomy] 

    • IMDC 2013 -
    • • Karnofsky performance score <80%
    • • Neutrophilia (>upper limit of normal)
    • • Low hemoglobin (<lower limit of normal)
    • • Elevated corrected calcium (>upper limit of normal)
    • • Thrombocytosis (>upper limit of normal)
    • • <1 yr from diagnosis to VEGF-targeted therapy

    • Good - 0
    • Intermediate - 1-2
    • Poor - 3-6

    [@  The KCT HeN]
  3. Management of metastatic RCC?
    Surgical management - cytoreductive nephrectomy, resection of mets, palliative surgery 

    Immunological approach - IFN, IL-2, Allognenic hematopoetic stem cell transplantation, CPI 

    Targeted approach - Bevacizumab, sorafenib, sunitinib, pazopanib, axitinib, mTOR inhibitors
  4. Time scale of drugs for metastatic RCC?
    Image Upload 1
  5. What are the recent developments in the treatment of metastatic renal cell carcinoma? (TU 69,75-10)

    Management of metastatic RCC
    For clear cell carcinoma - EAU 2020

    Image Upload 2

    • NCCN 2021 - Preferred regimen
    • - Favorable risk - Axitinib+Pembrolizumab, Pazopanib, Sunitib
    • - Intermediate risk/Poor risk - Ipilimumab+ Nivolumab, Axitinib+Pembrolizumab, Cabozatinib 

    • EAU 2021 - First line treatment 
    • - IMDC favourable risk - Nivolumab+Cabozatinib, Pembrolizumab + axitinib 
    • - IMDC Intermediate /Poor risk - Nivolumab+Cabozatinib, Pembrolizumab + axitinib, Nivolumab + Ipilimumab

    From 2005-2019, Sunitinib or Pazopanib  was the first-line therapy for favourable risk (TKI Era). [@ सुनिता पानि  भर्न गइ, प्रेम ब्रो tAXI मा, INtermediate - Ipi/Nivo ]

    Offer sunitinib or pazopanib to treatmentnaïve patients with IMDC favourable-, intermediate-, and poor-risk cc-mRCC who cannot receive (cost issue like in India/Nepal) or tolerate immune checkpoint inhibition.

    Non Clear Cell - Temsirolimus (NCCN)

    Cytotoxic drugs can be used in collecting duct carcinoma
  6. What is cytoreductive nephrectomy?
    Tumour nephrectomy is curative only if all tumour deposits are excised. This includes patients with the primary tumour in place and single- or oligometastatic resectable disease. For most patients with metastatic disease, cytoreductive nephrectomy (CN) is palliative and systemic treatments are necessary
  7. The evidence prior to CARMENA and SURTIME?
    In the past, CN was performed in patients with single- or oligometastatic disease, either in combination with complete metastasectomy or to observe metastatic sites which very rarely disappeared after nephrectomy of the tumour-bearing kidney.

    The oligometastatic state is usually defined as the presence of five or fewer metastatic or recurrent lesions in a case of solid malignancy.
  8. Carmena trial 2018?
    A total of 576 patients with metastatic clear cell RCC were randomized equally to one of two arms: cytoreductive nephrectomy followed by sunitinib or sunitinib alone

    Sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic renal cell carcinoma who were classified as having intermediate or poor-risk disease.
  9. Updated CARMENA trial 2019?
    1.CN might be beneficial for patients with only one IMDC risk factor, especially if they have only one metastatic site.

    2.The number of metastatic sites per se does not help define appropriate candidates for surgery

    3.Delayed nephrectomy after initial systemic treatment in good responders, is associated with longer overall survival, supporting this approach as a beneficial therapeutic strategy
  10. Surtime trial 2018?
    Patients with mRCC were randomized into either immediate CN followed by sunitinib versus three cycles sunitinib followed by CN and sunitinib.

    Sunitinib upfront had better overall survival. [@ Sur-Time Shuffle the Time - N then S or S then N] 

    Deferred CN did not improve the 28-week PFR. With the deferred approach, more patients received sunitinib and OS results were higher. Pretreatment with sunitinib may identify patients with inherent resistance to systemic therapy before planned CN. 

    • These two trial showed that, we should not be doing cytoreductive nephrectommy any more. 
    • Problem with these trials is that, they used MSKCC rather than IMDC criteria that we use routinely.   

    • Cytoreductive in very selective 
    • - In oligometastasis - 
    • - Symptomatic tumor with hematuria, thrombus with risk of embolism

    The findings of the SURTIME trial helped to confirm the results of the CARMENA phase 3 trial. However, we cannot completely rely in this trial, because it was not properly reccruited.
  11. What is the role of cytoreductive nephrectomy in the era of newer targeted therapy? (TU 75,3)

    Cytoreductive nephrectomy guidelines?
    NCCN 2019 - Recommend CN before systemic therapy based on patient selection criteria including potentially resectable tumor,  good prognostic factors, and good performance status.  Systemic therapy in Clear cell RCC with poor risk features.

    EAU 2020

    • Do not perform cytoreductive nephrectomy (CN) in MSKCC poor-risk patients. Strong
    • Do not perform immediate CN in MSKCC intermediate-risk patients who have an asymptomatic synchronous primary tumour and require systemic therapy with vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitor (TKI). Weak
    • Start systemic therapy without CN in MSKCC intermediate-risk patients who have an asymptomatic synchronous primary tumour and require systemic therapy with VEGFR-TKI. Weak
    • Discuss delayed CN in MSKCC intermediaterisk patients under VEGFR-TKI therapy who derive long-term sustained benefit and/or minimal residual metastatic burden. Weak
    • Perform immediate CN in patients with good performance who do not require systemic therapy. Weak
    • Perform immediate CN in patients with oligometastases when complete local treatment of the metastases can be achieved. Weak

    • [Good risk - CN
    • Intermediate risk - sunitinib and if improvement, CN 
    • Poor risk - Sunitinib] 
  12. Better outcomes for resection of metastasis?
    • Presence of solitary metastatic lesions
    • Age younger than 60 years
    • Smaller tumor size (<4cm) 
    • Presence of pulmonary metastases
    • Development of metachronous metastatic disease
  13. Describe the principles of immunomodulators and its role in the management of advanced renal cell carcinoma. (TU 76-10)

    Immunotherapy in RCC?
    Interferon α -  was agent of choice before VEGF era 

    IL-2 - High dose IL-2 induce complete response in some patients, only used if patient does not respond to targeted therapy.

    Allogenic hematopoietic stem cell transplantation - replacement of patients immune and hematopoietic system with healthy HLA compatible donor, generation of GVHD, Conditioning agents - cyclophosphamide + Fludarabine, GVHD prophylaxis - cyclosporine

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  14. Agents targeting which of the following signalling pathways in clear cell RCC have significant antitumor effects in patients with metastatic disease?

    C. VEGF and mammalian target of rapamycin (mTOR).

    Several clinical trials indicate that agents targeting VEGF signalling, including sunitinib, sorafenib, axitinib, pazopanib, levantanib, caboxantinib, and mTOR pathway signalling, including temsirolimus and everolimus, demonstrate substantial tumor responses or significant improvement in progression-free or overall survival
  15. Interleukin 2 in advanced RCC?
    The efficacy of IL-2 has not been adequately evaluated in patients with non–clear cell histologies, and the use of this agent is largely restricted to clear cell RCC patients. 

    Complete responses are seen in 7% to 9% of metastatic clear cell RCC patients receiving high-dose IL-2, with the majority of these remaining disease-free for more than 15 years.

    The combination of IL-2 and interferon leads to higher overall response rates than either agent alone.

    The addition of Lymphokine-activated killer (LAK) cells cells to cytokine therapy does not appear to improve outcome.
  16. Side effects of Interleukin-2?
    • Vascular leak syndrome - hypotension 
    • Third space fluid retention 
    • respiratory compromise 
    • MODS
  17. Graft versus host disease?
    GvHD is a condition that might occur after an allogeneic transplant. In GvHD, the donated bone marrow or peripheral blood stem cells view the recipient's body as foreign, and the donated cells/bone marrow attack the body.
  18. Tyrosine kinase inhibitors?
    BCR-ABL TKI - Imatinib, Dasatinib, nilotinib

    EGFR - TKI - Erlotinib, Gefitinib 

    VEGF - TKI - Sorafenib, Sunitinib, Pazopanib
  19. Side effects of TKI?
    GI events - diarrhoea, rash, hand and foot syndrome, fatigue, asthenia, hypertension, bone marrow suppression, hypothyroidism

    Hepatotoxicity in Pazopanib [@ Pani (water) induced Hepatitis A]
  20. Targeted therapy in RCC
    Bevacizumab - monoclonal antibody against VEGF, not used as single agent, can be used as combination therapy who fail to VEGFR antagonists 

    Sorafenib - PDGF, VEGFR-2 inhibitors, infrequently used as first line therapy 

    sunitinib- PDGF, VEGFR-2 inhibitors

    Pazopanib - selective against VEGFR, retains activity against PDGFR

    Axitinib - highly selective against VEGFR [@ Axi - apex - first - only one - highly selective] 


    Mechanistic target of rapamycin (mTOR) inhibitors - temsirolimus, everolimus - regulate stability of HIF 1α
  21. Sequence of management of metastatic RCC?
    • Risk stratification 
    • Biopsy

    Use of VEGFR followed by mTOR agent upon disease progression results in better outcomes than using mTOR agent first
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Two11 104 Treatment of advanced Renal Cell Carcinoma