Interview with Dr Choo Su Pin to shed light on a new generation of therapies that could improve the prognosis of liver cancer patients.
Liver cancer is the sixth most common cancer worldwide, which was the cause of 782,000 cancer deaths in 2018. It more significantly affects males and is found to be prevalent in East Asia. Current first-line therapies have found to be no longer effective and the lack of a second-line adds on to the devastating numbers. There is hope however, in recent advancements, with immunotherapy and targeted therapies to improve the prognosis of liver cancer patients, especially those at advance stages.
To elucidate on these new generation therapies is Dr Choo Su Pin, President of Singapore Society of Oncology.
1. What are the contributing risk factors to the high percentage of liver cancer cases in Asia?
Chronic hepatitis B and hepatitis C, non-alcoholic fatty liver disease, alcoholic liver cirrhosis, non-alcoholic causes of cirrhosis, Non-alcoholic Steatohepatitis (NASH) an advanced form of non-alcoholic fatty liver disease, tobacco smoking, obesity, and diabetes. Worldwide hepatitis infection is responsible for 65 percent of HCC cases but in Asia it is more like 80% while in Europe and the United States the majority of cases are due to lifestyle risk factors such as alcohol drinking, obesity, smoking, and hepatitis C infection from shared drug paraphernalia. Use of anabolic steroids is also a risk factor.
When we can reduce the hepatitis infection rates, especially hepatitis B, we start to see a decline in the number of HCC cases. Taiwan has reported a decrease in the number of HCC cases in recent years due to the fall in Hepatitis B rates since they began vaccinating new born babies in the 1980s.
Singapore also introduced vaccination for babies in the 1980s and the benefits are already becoming apparent. It will take another generation or even two to really get it under control but already we are seeing fewer cases of HCC in young people under 40. Babies being infected by their mothers is the most common cause of Hepatitis B infection, so screening at birth and vaccination is the best way to reduce rates.
Thirty years ago, hepatitis B was responsible for 80 percent of the HCC in Singapore just like in the rest of Asia. Today it is only responsible for about 50 percent of the cases here. In Singapore we have seen a decline in the number of HCC cases; especially the hepatitis B-related cases but unfortunately, we are now seeing an increase in the number of cases related to lifestyle such as non-alcoholic fatty liver disease and NASH-related cases due to increasing numbers of overweight and obese people. Fatty liver disease is now the second most common cause of HCC in Singapore which is responsible for far more cases than Hepatitis C and alcoholic cirrhosis put together.
Even people who are not visibly obese can develop fatty liver disease because it is related to the amount of visceral fat, the fat stored around the internal organs rather than the subcutaneous fat stored just beneath the skin. Indicators of high levels of visceral fat are the apple body shape or having a pronounced and quite firm pot belly. Subcutaneous fat is what causes fleshy thighs, love handles and other pinchable inches.
2. What are the current treatment options for hepatocellular carcinoma (HCC) patients?
If detected early; for example, at stage I or II before it has metastasized, we can perform a resection, called a partial hepatectomy, to remove the tumour. With successful curative surgery, the chance of survival beyond five years is more than 40 percent. Sometimes, a liver transplant is recommended as it both removes the cancer as well as the underlying diseased liver. Five-year survival after transplant can be as high as 70 percent.
Unfortunately, the majority of patients are not suitable for surgery as their cancer is too far advanced by the time it is discovered. The problem is that in its early stages HCC is largely asymptomatic, people simply do not show any signs of illness such as fever, pain or swelling in the early stages. HCC is very often only picked up by chance when patients are being treated and examined for something else.
If the cancer is detected too late for a curative resection or transplant to be feasible, then there are various treatment options to try and control the cancer and prolong survival.
For more advanced stage II and III cancers which are still localised to the liver, we offer loco-regional therapies like radiofrequency ablation (using heat to destroy the cancer), chemotherapy directed into the liver (TACE) or radiation directed into the liver (radiation beads released directly into the liver tumour).
For many years we had no treatment options for more advanced stage IV liver cancer or when loco-regional therapies mentioned above were no longer feasible. It was not until the early 2000s that a kinase inhibitor drug was developed that was effective for HCC. Tyrosine kinase inhibitor (TKIs) drugs - also called molecular-targeted drugs or targeted therapy, because they target and inhibit particular pathways that promote cancer growth - have been used to treat other types of cancer since the 1980s but for decades none had worked for HCC. In 2007 oral sorafenib, a multi-kinase targeted therapy, which had been shown to prolong patients’ survival in HCC was released in Singapore, and we finally had a palliative treatment to offer late-stage HCC patients.
For a decade there was no second-line drug to offer if patients failed to respond to sorafenib or stopped responding to it after a few months. During that time many companies were trying to find an alternative first-line drug to sorafenib. There were 70 other drugs evaluated for patients with advanced HCC in all phases of clinical trials but these drugs were shown to have no additional success over sorafenib, compelling a necessary reassessment of this complex cancer.
Fortunately, in the last two or three years we have started to see significant advances in the treatment of late stage HCC. These include immunotherapy drugs which stimulate the patient’s immune system to recognise the cancer cells and attack them as well as several new TKI drugs.
A combination of immunotherapy drugs or an immunotherapy combined with a TKI is becoming the accepted first-line treatment for stage IV HCC. After a drought of more than a decade with no new drugs, in the last couple of years we seem to have something new coming out every six months. I have been fortunate enough to have participated in the trials of several of them including the CELESTIAL trial for cabozantinib, the latest TKI to be approved in Singapore as a second-line therapy.
3. Particularly for advanced stage HCC patients what challenges are there in relation to the treatment options.
For advanced stage HCC patients, the main challenge today is that we can only offer palliative care to try and control the cancer and prolong survival. For early stage HCC patients where resection or transplant is still viable, we can hope for curative treatment but a curative option for advanced stage patients is not even on the horizon yet.
4. Based on the results of the CELESTIAL trial, cabozantinib was approved by the US FDA as a second-line treatment for advanced stage HCC; how will patients benefit from it?
The data from the CELESTIAL trial led to the approval of cabozantinib by FDA and EMA as a second-line therapy for patients with advanced liver cancer. For the group that it works on, which is a selected group of patients who meet the inclusion criteria for the trial there is significant survival benefit.
The median survival time for advanced liver cancer before we had a second-line therapy was less than a year and for Asians around six months. Now, with a second-line therapy we can expect two years or more, quite a significant improvement for this group of patients. The addition of cabozantinib to our pharmacology has increased the treatment options for HCC, and combination treatment with immunotherapy may soon improve the prognosis of patients with HCC.
Combinations of immune checkpoint inhibitors and molecular-targeted drugs or molecular-targeted drugs and established locoregional therapies are particularly likely to produce a paradigm shift in the treatment of HCC in the coming years. It is possible that the treatment landscape for HCC will soon undergo major changes as systemic therapy is integrated into the treatment for all stages, from early to intermediate to advanced, which could significantly improve the prognosis of patients with HCC.
5. Why is a second-line treatment essential for advanced stage HCC patients who have been previously treated?
A second-line therapy is like a second-line of defence if the patient does not respond to first-line therapy.
Treating HCC is much like defending a medieval castle from being attacked. Think of the concentric walls of a medieval castle. The first-line of defence is the moat; once the enemy manages to cross the moat, the second-line of defence is the outer-curtain wall with all the turrets and battlements. If the enemy scale that wall or smash a hole in it, the defenders fall back to the third-line of defence which is the inner wall, and after that the final line of defence is the castle keep.
When a patient presents with late stage IV HCC, we give them a first-line therapy to stop the progression of the cancer, but we know that at some point it will stop being effective and the cancer will begin to progress or grow and spread again.
That’s when we fall back to the second-line therapy. As yet we don’t have a drug that has been specifically approved as third-line therapy but we do now have a lot more immunotherapy and targeted therapy options to try and there is a lot of ongoing research, especially in using different combinations of drugs that may offer further options in the near future.
Cancers and patients are not all the same. Some drugs work well on some cancers but not others, and some cancers respond to one drug but not another. Some patients tolerate drug A reasonably well but have severe side effects with drug B, and for other patients it might be the other way around. That is why every therapeutic addition to our arsenal is important as it provides us with more options to try and find the best match for each patient.
6. How is a second-line treatment different from combination therapies?
A second-line treatment is simply the treatment we try once the first-line treatment is no longer effective. Some drugs, like cabozantinib, might be approved by the FDA or HSA specifically as a second-line treatment.
Combination therapies are just that, therapies that combine an immunotherapy and a targeted therapy, or two immunotherapies or maybe in the future a targeted therapy and something else.
Today we might use a targeted TKI therapy alone as the first-line or we might use a combination of TKI and an immunotherapy drugs as the first-line, and we might us a single drug or a combination as a second-line or even a third-line. As I said all cancers and all patients are different and with late- stage IV HCC our options are only palliative so when one option fails, we will try another.
7. How will a second-line treatment benefit unresectable HCC patients?
Unresectable HCC patients have tumours that are too extensive for surgical removal. These are then treated with either loco-regional therapies like radiofrequency ablation, TACE etc as I mentioned before or for more advanced disease, systemic therapies like a targeted TKI or immunotherapy drug.
Drugs like sorafenib and cabozantinib are referred to as first-line and second-line therapies respectively, for patients newly diagnosed with late stage IV HCC. These are patients in which the cancer was not diagnosed until it had already reached stage IV, or were too advanced for loco-regional therapies to be effective. So, their first-line therapy will be some form of systemic drug therapy such as sorafenib and when that is no longer effective, they may be switched to a second-line therapy like cabozantinib.
Patients who have earlier stage disease but whose cancer cannot be removed by surgery may eventually end up on these systemic drugs too after one or two loco-regional therapies. The intent of treatment would be the same, i.e. controlling the cancer and prolonging survival for as long as possible.
About the Interviewee
Dr Choo Su Pin
President of Singapore Society of Oncology, Senior Medical Oncologist at Curie Oncology, Mount Elizabeth Novena