Three revolutions in cancer therapy

My work as a medical oncologist has both professional and personal meaning. I have family members who battled cancer. Some survived and lived to a ripe old age, while others were taken before their time.

In Singapore, one in three deaths is caused by cancer. If we include survivors and their families, the number of lives affected by cancer is even more.

Within each field of medicine, every generation of clinicians and researchers tries to innovate. Millions of women have been saved from cervical cancer by the Pap smear. The Hepatitis B vaccine, by preventing chronic Hepatitis B infection, lowers the risk of liver cancer.

But no prevention regime is 100 per cent effective. There will always be an ongoing need for better therapies. The development of cancer drugs has broadly followed an arc of three revolutions in innovation: Chemotherapy, targeted therapy and immunotherapy.

CHEMOTHERAPY: THE FIRST REVOLUTION

Chemotherapy attacks fast-growing cells, including cancer cells. It has side effects, but is a major advancement in cancer treatment when it was first invented.

For example, in the early 20th century, leukaemia (cancer of the white cells in the blood) was even more feared than it is today. Surgeons were at a loss to treat a cancer that obeyed no boundaries or margins, and permeated every drop of blood and every corner of the bone marrow. Only corticosteroids could provide brief relief.

Sidney Farber, a Boston physician, tested a new drug called aminopterin on 16 seriously ill children with leukaemia. Ten of the 16 went into temporary remission with the chemotherapy. In later years, the Dana-Farber Cancer Institute, a principal teaching hospital in the Harvard Medical School extended campus, would be named after him.

Over the years, chemotherapy revolutionised the treatment of many cancers. Vincent DeVita at the National Cancer Institute (NCI) in the United States developed a four-drug combination that increased the cure rate of patients with advanced Hodgkin Lymphoma from nearly zero to almost 70 per cent, a figure that was surpassed by later work in Stanford and Germany.

Innovations in supportive care helped, too: Better drugs to prevent vomiting; newer antibiotics to treat infections better; and booster injections to help maintain the immune system so that chemotherapy did not weaken it too much.

But the paradigm of combining ever more drugs (with ever more side effects) faced diminishing returns. Many tumours of solid organs like breast, colon-rectum and lung responded to chemotherapy, but not as dramatically as cancers arising from blood, lymph or testicular cells. Patients, understandably, sought to balance their quality of life against the side effects of treatment.

Today, there are still new chemotherapy drugs being developed, either for situations where no good options yet exist, or to minimise side effects so that patients can tolerate treatment better.

TARGETED THERAPY: THE SECOND REVOLUTION

Starting from the mid-20th century, scientists deciphered the structure of DNA, and the secrets of how the DNA alphabet encoded a genetic blueprint to guide each cell – whether in single-celled bacteria or complex multi-cellular life such as plants, animals and humans.

The DNA code tells our cells how to produce proteins and other microscopic machinery. Some proteins help the cell decide when to grow and multiply. Others become receptors – an “antenna” on the cell surface – to receive and interpret messages sent via the bloodstream from other organs.

With knowledge of the normal blueprint, researchers began to understand how DNA mutations could turn cells to cancerous behaviour. In some cases, these cancer-related genes and their ensuing proteins can be targeted either with a drug that hopes to restore normal cell behaviour or an antibody against the cancer cells. Other targeted therapies affect the blood vessels that supply nutrients to the tumour. These include drugs such as bevacizumab (Avastin).

These research findings have been translated into real-world benefits for patients.

Thirty years ago, advanced adenocarcinoma of the lung was a dismal diagnosis with average survival measured in a few months. Today, for lung cancers with a targetable mutation, many patients can expect to live beyond two years despite advanced disease. Tablets like gefitinib (Iressa), erlotinib (Tarceva) and afatinib (Gliotrif) have made a major difference in EGFR-mutated lung cancer. Likewise with crizotinib (Xalkori), ceretinib (Zykadia) and alectinib (Alecensa) for ALK-mutated lung cancer.

Targeted therapies have also improved the chance of cure in early-stage cancers. Breast cancer that is positive for the Her2 marker responds much better when chemotherapy is combined with Her2-targeted therapy such as trastuzumab (Herceptin) and pertuzumab (Perjeta). For locally advanced breast cancers (no distant spread but far too big for immediate surgery), it can make the difference to whether the patient has a chance of surgery, and the potential for cure.

For patients with colorectal cancer that has spread, but only to the liver, there is chance of long-term survival if the liver metastasis can be completely removed. Shrinking the metastasis can make surgery feasible. If the tumour has the right molecular profile, combining chemotherapy with targeted therapy such as cetuximab (Erbitux) or panitumumab (Vectibix) can improve the chances of tumour shrinkage.

In many instances, choosing the right drug requires the medical team to know what targets are available. In recent years, doctors have increasingly recognised that it is no longer sufficient to identify the organ from which a cancer arose. Genetic and molecular sub-typing of the cancer should also be done to guide treatment.

But even with chemotherapy and targeted therapy, the cancer can adapt and become resistant to treatment. We need adaptive treatments that can keep pace with the cancer. Hence, the ongoing interest in immunotherapy.

IMMUNOTHERAPY: THE COMING THIRD REVOLUTION

Some cancers are associated with weakened immunity. For example, solid organ transplant recipients, who take immuno-suppressive drugs to prevent rejection of the donated organ, are at higher risk of cancers, including skin cancer, cervical cancer and lymphoma.

Much research has been done over the years to try and direct the patient’s own immune system to attack their cancer. In principle, it seems logical as cancer cells are abnormal and different from normal cells. The immune system fights disease throughout the body and can adapt to a changing opponent.

In practice, the results of immunotherapy have been mixed and depend on the type of cancer. Traditionally, the best results have been with melanoma. In advanced melanoma, a very small proportion of patients have lasting remission after therapy with high-dose interleukin-2, which hyper-stimulates the immune system. However, the side effects are not easily tolerated.

More recently, agents such as ipilimumab (Yervoy) and pembrolizumab (Keytruda) have shown benefit in patients with advanced melanoma. These work as “checkpoint inhibitors” by lifting the brakes on the immune system. Interestingly, a small proportion of patients have a very durable response and their cancer remains well controlled for a long time after

Immunotherapy is also transforming the management of lung cancer. For example, in non-small cell lung cancer that has relapsed after first-line chemotherapy, the immunotherapy drug nivolumab (Opdivo) elicited better responses and helped patients live longer compared to traditional second-line chemotherapy.

Research is ongoing to see how these drugs can help patients with other types of cancer. There are already encouraging results for gastro-intestinal, bladder, head and neck, and breast cancers.

This is a hopeful time for patients and the doctors who care for them.I look forward to the day when cancer can be better prevented and when all patients on therapy can have excellent outcomes without the burden of side effects.

Dr Tan Wu Meng is a specialist in medical oncology at Parkway Cancer Centre.