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

Brief

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

More cases are detected incidentally during imaging (USG, CT scans) 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 almost all studies and medications for RCC are indicated for clear cell type.

Renal cell carcinoma (RCC)

For stage 1, 2 and 3 RCC, 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 metastatic RCC (mRCC), the treatment are mainly targeting at VEGF pathway.

Chemotherapy plays no role whatsoever in treatment of metastatic RCC.

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 / metastatic renal cell cancer (mRCC), what is the next step?

The first step is to determine the patient’s IMDC risk groupings, which help to decide suitable treatment and informed treatment outcomes.

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 < 1 year
• Corrected calcium > upper limit of normal
• Platelets > upper limit of normal
• Neutrophils > upper limit of normal

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

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).

IMDC risk groups for metastatic renal cell cancer (mRCC) and its corresponding median overall survival in first-line and second-line treatments.

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

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

1. VEGF Inhibitors

The main treatment for mRCC are VEGF inhibitors; pazopanib and sunitinib.

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 due to availability and tolerability…

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.

Summary of approved VEGF inhibitors used in first-line setting.

2. Immunotherapy

There were plethora of positive results reported this year using immunotherapy in advanced renal cell cancer/ mRCC.

Some international guidelines had already updated their first line treatment for mRCC 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.

Above are summaries of first line immunotherapy treatment (approved and in the pipeline) for mRCC.  Two immunotherapy combinations; nivolumab + ipilimumab and pembrolizumab + axitinib showed very promising results here.

As seen in nivolumab and ipilimumab combination for intermediate and poor-risk mRCC, there was lower grade 3-5 adverse side effects reported and longer median overall survival (OS) also.

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

• Phase 3 KEYNOTE-426 trial is in progress to confirm the results

Synergistic effects postulated by combining both immunotherapy with VEGF inhibitors.

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