The SIRTEX Trial, Part 2

Why Sirtex needs a new direction

In the ten years that Mr Gilman Wong has been CEO of Sirtex, he has steered the Healthcare company to incredible success to the delight of shareholders. The share-price recently touched a high of $40 from about $1.40 when he took over.

Good times never last forever, so wisely he is looking at ways of prolonging the Sirtex success story into the months and years to come.

Although SIR-Spheres has proved to be a wonderful product, Sirtex is vulnerable to a decline in profitability, without other products to support its revenue . Some negative considerations:

  • The product is costly. It slows progress without curing the cancer. A cost cutting government might reduce subsidies for treatment. Rising costs might make treatment for some unaffordable.
  • Other products could come on the market with superior results, or other advantages, stealing market share.
  • SIRT  (Selective Internal Radiation Therapy) execution is exacting. It requires high standards of knowledge, careful clinical assessments, and technical expertise. Doctor sentiment may be adversely affected should untoward complications and side effects alter the reward:risk ratio of treatment.
  • The share-price looks expensive, at present levels over $25, and there could be a downwards correction.

The clinical picture

At surgical removal of the primary cancer, in all likelihood some cancer cells will have already spread outside the field of resection. Although after the surgery, the patient may be completely free of symptoms, and cancer clinically dormant, the cells continue to multiply wherever they may be to sooner or later give rise to secondary tumour deposits, most obviously in the liver but by then tumour dissemination is likely to be so widespread that the condition is incurable. The cancer may recur in the colon/rectum. in the many nearby lymph nodes, in nodules through the peritoneal cavity of the abdomen, in the lungs, and in other distant organs and tissues.

Present Clinical Management

Treatment is then directed toward reducing total tumour mass, and to treating those secondary tumours most likely to adversely affect the patient prognosis. In most cases this means focusing on the liver deposits.

At present the first-line (preferred) treatment policy for metastatic colorectal cancer (mCRC) is surgical removal of the liver deposits when feasible, followed by a chemotherapy regime. Plan B using SIRT is implemented when the liver deposits are inoperable. Both liver and the extra-hepatic deposits (EHD) are then also managed with the chemotherapy.

The SIRFLOX Study to establish a basis for up-grading SIRT to first choice treatment regime for mCRC.

The company hopes to continue to grow the number of patients being treated with SIRT by upgrading this form of radiotherapy to the treatment of choice in association with chemotherapy. To this end they have wisely chosen to study the benefits and risks of radio-embolism in a large (530 patients in over 100 hospitals around the world) randomised controlled clinical trial.

The SIRFLOX (SIRT + FOLFLOX6 chemotherapy) trial was designed to see how effective and safe it was to add a course of Folfox chemotherapy ± bev to treatment with SIRT radioembolisation as first-line treatment of patients with liver metastases from mCRC. It has extended over a 7 year period from October 2006 to April 2013. Median follow-up was 36.1 months. The patients chosen would have qualified for SIRT treatment anyway, having non-resectable liver, or liver dominant mCRC.

The Study group was divided into two groups:

  1. Group A of 263 patients was treated with Chemotherapy alone.
  2. Group B with 267 patients received Chemotherapy + SIRT

How has the study compared the relative effectiveness of treatment in the two groups?

The most meaningful comparison would be by using Overall Survival (OS) data. Does the treatment extend the life of the patients  being treated? This trial does not do this because the numbers are insufficient to be statistically significant. However it is planned to address this question when the data of two other current trials (Foxfire and Foxfire Global) become available and boost patient numbers to over 1000, probably 1H CY17.

Instead the trial has measured the size of the tumour deposits in the liver on CT (Computerised Tomography) or MRI (Magnetic Resonance Imaging) at regular intervals complying with the criteria for RECIST  (Response Evaluation Criteria in Solid Tumours).

One might think that a treatment regime would be required to show all tumours becoming smaller during the period of observation. Some tumours may shrink; but it is enough to show a period in which  overall the cancer deposits fail to grow in the liver in this case.

PFS (Progression Free Survival) is the Primary Endpoint  or the main treatment outcome of the trial to be measured. 

The trial also measured Secondary Endpoints or other significant treatment outcomes such as:

  1. The Treatment Response Rate (RR) or the Hepatic Response Rate when it is in  the liver. This measures the percentage of patients experiencing either a complete (CR) when all tumours disappear, or a partial (PR) “shrinkage” of tumours. The latter requires at least a 30% shrinkage in the longest diameter of the target lesions.
  2. The Liver Resection Rate, the percentage of patients who needed to have a surgical resection of liver deposits during the trial.

Study Results with respect to the Primary Endpoint

I / The Primary End-Point or median overall Progression Free Survival

Group A: 10.2 months

Group B:  10.7 months

The patients in Group B receiving SIR-Spheres in addition to chemotherapy thus on average  had two weeks longer without tumour progression but the difference was not statistically significant.   p = 0.428. Thus the addition of SIRT to standard chemotherapy did not improve the overall PFS.

The Hazard Ratio (HR) measures the ratio of Group B patients compared with Group A, who failed to respond, and continued to progress.  It was 0.93 indicating that addition of SIR-Spheres has only a 7% lower risk of tumour progression. Not very significant.

II/ If the median PFS values in the liver were used in the calculations, the benefit conferred by SIR-Sphere was significantly improved.

Group A: 12.6 Months

Group B: 20.5 months

This confirms the effectiveness of SIR-Spheres in arresting the progression of mCRC in the liver. This is not unexpected given the difficulty of treating EHD (Extra-Hepatic Deposits) with the radioembolisation technique. There is an improvement of 7.9 months over the chemotherapy only group. This is statistically significant with p = 0.002.

The HD ratio was 0.69 indicating that there was a 31% improvement in the risk of tumour progression in the liver in Group B receiving SIR-Spheres.

The conclusion is that while  SIR-Spheres is effective in arresting tumour progression in the liver over chemotherapy alone, it does not significantly improve the overall outcome of treating m CRC.

Study Results with respect to the Secondary Endpoint, Tumour Response Rate (RR)

I)  Overall Tumour Response Rate (RR).

Group A: 68.8%;

Group B: 76.4%

p  = 0.113 (not statistically significant)

     Hepatic Response Rate

Group A: 68.8%

Group B: 78.7%

p = 0.042 (statistically significant)

   Complete Response Rate

Group A: 1.9%

Group B: 6.0%

p = 0.02 (statistically significant)

This is a threefold increase in the incidence of complete disappearance of all lesions.

This is a very favourable outcome for patients treated with SIR-Spheres. and a strong argument to keep using SIR-Spheres.

    Liver Resection Rate

With Group A  having a 13.7% incidence, and Group B 14.2%, there was no statistically significance. p = 0.857.

 

Conclusions

Radioembolism continues to be an effective treatment for liver cancer and in 6% of treated patents, may induced shrinkage of all metastases. This would suggest continuing growth in its use. Observers however will need to wait until 2017 to evaluate whether treatment confers a significant extension of survival.

Since on present evidence,  patients with significant extra-hepatic metastases may receive little benefit from adding  SIR-Spheres treatment regime.

I believe that there is a strong case for Sirtex to diversify to additional biotech products.

 



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