Living Longer with Advanced/ Stage 4 Renal Cell Cancer ~ 1st Line Treatment (Treatment Naive/ No Previous Treatment)

Brief

In Malaysia, renal cell cancer or kidney cancer present at stage 4 in 50% of cases.

Cases are detected incidentally during imaging (USG, CT scans), more than those who present with the classical triad of flank pain, gross hematuria and palpable abdominal mass.

Histologically, 80% are of clear cell type and if one is to get renal cell cancer, this is the histology you want because almost all studies and medications for RCC are indicated for clear cell type.

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Renal cell carcinoma (RCC)

For stage 1, 2 and 3 renal cell cancer, there treatment is just radical nephrectomy and nothing more besides close surveillance. There is no proven treatment that had shown benefits in adjuvant setting.

For stage 4 or MRCC, the treatment are mainly targeting at VEGF pathway. Chemotherapy plays no role whatsoever in treatment of MRCC.

VEGF is a regulator of tumor angiogenesis. VEGF stands for ‘vascular endothelial growth factor’. VEGF stimulates vascular endothelial cell growth, survival, and proliferation.

Start

Once patient is diagnosed as advanced/ stage 4 renal cell cancer, what is the next step?

The first step is to determine the patient’s IMDC risk groupings, which will become more important soon to decide on best treatment.

Currently, the common practice is to start patients on either pazopanib or sunitinib no matter which risk group the patient belongs to, even in poor risk group.

Patient will be asked some questions in history taking to determine patient performance status (is there restriction in any physical strenuous activity?).

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Karnofsky scale, ECOG scale and its associated physical activities.

Also, time from initial diagnosis (including original localized disease) to treatment for advanced renal cell cancer is determined to see if it’s more or less than 1 year. (Poorer prognosis and more aggressive cancer if it’s less than 1 year)

Finally, four laboratory investigations; haemoglobin, platelet, neutrophil and calcium levels are needed. (Prepare your full blood count (FBC) and calcium/ albumin investigation report).

International Metastatic RCC Database Consortium (IMDC) score, consists of 6 risk factors and each carry 1 point:

  • Karnofsky performance status (PS) <80%
  • Haemoglobin <lower limit of normal
  • Time from diagnosis to treatment of < 1 year
  • Corrected calcium > upper limit of normal
  • Platelets > upper limit of normal
  • Neutrophils > upper limit of normal

Different IMDC risk groups will results in different median overall survival and also different suitable treatments.

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Still, if one presented with stage 4 renal cell cancer but the metastatic foci is limited and BOTH the primary and metastatic foci can be resected, cure is still possible by surgical resection and no further treatment is needed after that.

Treatments

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Approved treatments for metastatic renal cell cancer (MRCC). VEGF inhibitors and reemergence of immunotherapy (long hiatus, more than 10 years, after interferon treatment in early 1990s).

The main treatment for advanced/ stage 4 renal cell cancer are VEGF inhibitors; pazopanib and sunitinib.

In the past when there are not much difference in progression free survival (PFS) or median overall survival (OS) for VEGF inhibitors, much attention was given over which VEGF inhibitors (monotherapy) had the lowest side effects profile.

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Approved VEGF inhibitors used in first-line setting.

However, with the plethora of positive results reported this year using immunotherapy in advanced renal cell cancer, some international guidelines had already updated their first line treatment for advanced/ stage 4 renal cell cancer to include immunotherapy as not only first line but also first option; as in the case of nivolumab + ipilimumab for intermediate and poor-risk group patients.

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Above are summaries of first line immunotherapy treatment (approved and in the pipeline) for advanced/ stage 4 renal cell cancer. Immunotherapy combinations (with another immunotherapy or with VEGF inhibitor) had generally lower grade 3-5 adverse side effects, longer median overall survival (as seen in nivolumab+ipilimumab) and doubling of progression free survival and high overall response rate (as seen in pembrolizumab + axitinib).

It’s definitely going to be more exciting in coming years as we’d just seen in early phase 2 trial (pembrolizumab + axitinib), which reported doubling of PFS, high overall response rate (73%) and rarely seen 7.7% of patients achieving complete response!

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Synergistic effects postulated by combining both immunotherapy with VEGF inhibitors.

Phase 3 KEYNOTE-426 trial is in progress to confirm the results but, I doubt anyone who can afford this treatment will want to wait or can wait for so long.

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