A matter of buying time
Diagnosed with stage-four lung cancer three years ago, the prognosis for Ms Sin didn't look good. With cancer cells that had spread from her lungs to her brain, bones and liver, Sin (full name withheld for patient confidentiality reasons) was given three to four months to live.
But a treatment combination of chemotherapy and a relatively new drug that prevents angiogenesis - the formation of new blood vessels - managed to control the disease, relieve pain, and extend her life by more than two years. Sin, who was in her 50s, lived for 26 months before succumbing to the cancer.
The drug that helped her is bevacizumab (beh-vah-SIH-zoo-mab), which is sold under the brand name Avastin and made by Genentech, an arm of the Swiss drug maker Roche. It's designed to bind to and inhibit a protein that plays a critical role in tumour angiogenesis, and hence stop the growth and spread of cancer cells.
Large-scale clinical trials confirming the efficacy and safety of the drug in patients with advanced or recurrent non-small-cell lung cancer (NSCLC) date to 2005. But two sub-studies on only Asian patients, published last year and revealed to local media a fortnight ago, give new hope for late-stage lung cancer patients in Hong Kong, where lung cancer is the biggest cancer killer.
The sub-studies reveal that the treatment combination of bevacizumab and chemotherapy increases the median survival time of late-stage Asian lung cancer patients to two years or more. More importantly, for reasons not yet known to scientists, Asians seem to respond better to the drug.
'We can see that bevacizumab enhanced the survival rate of Asian patients, with its efficacy on Asians perhaps outperforming that on other ethnicities,' says Dr Daniel Chua Tsin-tien, a clinical oncologist and an investigator in one of the studies.
Data for the two sub-studies was each taken from two international Roche-sponsored studies, Avastin in Lung Cancer (AVAiL) and Safety of Avastin in Lung Cancer (SAiL).
AVAiL involved 1,043 patients recruited from 150 centres in 20 countries across Europe, Eastern Asia, Australia, Central and South America, and Canada between February 2005 and August 2006. Of these, 105 were Asian - from Taiwan, Hong Kong and Thailand. They were randomised into three groups: one received 7.5mg of bevacizumab per kilogram of bodyweight and chemotherapy; another received double that drug dose and chemotherapy; and the last group received a placebo and chemotherapy.
Results showed the combination of lower-dose bevacizumab and chemotherapy was most effective at extending median overall survival to 28 months (compared with 17.4 months in the placebo group) and increased the response rate to 48.5 per cent (compared with 10.3 per cent in the placebo group). At this dose, progression-free survival was also raised to 8.2 months (compared with 6.1 months in the placebo group).
'The actions of bevacizumab and chemotherapy are synergistic,' says Chua.
Dr Kenneth Tsang Wah-tak, a specialist in respiratory medicine who was part of the AVAiL sub-study with Chua, explains the lower dose was more effective than the higher dose perhaps because of a 'saturation issue'. 'When there's too much of the drug, the side effects exceed efficacy. A low dose also makes the drug cheaper for patients,' he says.
The other study, SAiL, was designed to further confirm the safety and efficiency of bevacizumab by involving a broader, 'real world' patient population. It enrolled 2,212 patients with untreated, locally advanced, metastatic or recurrent non-squamous NSCLC - including many who were excluded from AVAiL, such as the elderly (aged over 65) and those with poor performance status.
Of the study patients, 314 were Asian - from the mainland, Hong Kong and Taiwan - of an average age of 55.5 years and recruited between August 2006 and June 2008. They received either 7.5 or 15mg of bevacizumab per kilogram bodyweight every three weeks plus chemotherapy for up to six cycles, followed by only bevacizumab until disease progression.
Adverse events were reported in 75 per cent of the patients, the most common being proteinuria (an excess of serum proteins in urine), hypertension and bleeding. Most of these were manageable and required no termination of treatment. In addition, 84 per cent saw their disease stabilise, or the tumour shrank or disappeared.
'The conclusion of both AVAiL and SAiL has reflected that anti-angiogenesis targeted drug bevacizumab can safely ameliorate the patients' condition without sacrificing their health,' says Tsang.
Lung cancer claimed 3,696 lives in Hong Kong in 2010, accounting for 28.3 per cent of all cancer deaths. The disease is the most common cancer in men and No3 among women after breast cancer and colorectal cancer. In 2009, the incidence rate was 55 per 100,000 men and 25 per 100,000 women.
Smoking is the most important cause of lung cancer, though non-smokers are not spared - which was the case with Sin. In fact, the SAiL study authors note that 'never smokers with NSCLC are found disproportionately high in Asian patients, particularly females with adenocarcinoma'.
There are two types of lung cancer: NSCLC accounts for 80 per cent of all cases, and small cell lung cancer (almost always caused by smoking) the remainder. NSCLC can be further sub-categorised: adenocarcinoma, found in the glands of the lungs that produce mucus, constitutes 60 per cent of NSCLC cases among Asians.
Because adenocarcinoma tends to develop in the periphery of the lungs, its early symptoms are often non-specific - chest pains, prolonged coughing, shortness of breath and coughing up blood. Hence, Tsang says most patients are diagnosed when the cancer is at stage three or four. 'Until you're in trouble, you don't know,' he says.
Adenocarcinoma shows some response to chemotherapy. But because of side effects and the resistance that cancer cells develop to the treatment, the chemotherapy often can't be sustained. But for about 60 per cent of adenocarcinoma patients who lack a certain epidermal growth factor receptor (EGFR) gene mutation - and therefore not suited to EGFR-specific targeted therapy - chemotherapy was the only choice until bevacizumab came along.
'For patients without EGFR gene mutation, if an aggressive first-line therapeutic approach is employed, such as chemotherapy with bevacizumab, the survival of patients is more likely to be lengthened and their quality of life guaranteed,' says Chua.
The treatment combination is approved by the US Food and Drug Administration and European Medicines Agency for first-line treatment of late-stage NSCLC patients. In Hong Kong, bevacizumab is approved but not government-subsidised, costing HK$15,000 to HK$20,000 per shot. Chemotherapy costs HK$15,000 to HK$25,000 per course.
Bevacizumab is also used to treat other forms of cancer in the colon, pancreas, breast and kidney cells.