My paternal grandfather died of rectal cancer, Since family history is among the several risk factors for such kinds of cancer, it was with great interest that I read the exciting report on the complete cure of rectal cancer in 18 patients who received a monoclonal antibody called dostarlimab. The study, conducted in the Memorial Sloan Kettering Cancer Center in New York and published in the New England Journal of Medicine, has given great hope that this form of cancer can be completely cured.
Luis Diaz Jr who conducted the study claimed that this was the first instance of a 100 per cent cure in treated patients with any cancer, with the complete disappearance of the cancerous tumours. There were no complications in any patient. The patients were spared debilitating chemotherapy, radiotherapy and surgery, while emerging cancer-free. While this result was widely welcomed, some experts have called for confirmatory studies on a larger number of patients.
Dostarlimab belongs to a group of monoclonal antibodies called “checkpoint inhibitors”. These are synthetic antibodies which block the proteins that cancer cells produce to prevent the body’s immune system from attacking them. It is a game of blocking the blocker, so that the native immune system which has recognized the cancer threat is not impeded in launching its attack on the malignant cells. This form of immunotherapy does not attack the cancer cells directly but unshackles the body’s own able defenders.
Checkpoint inhibitors are named according to the type of protein they block — CTLA-4 inhibitors, PD-1 inhibitors and PD-L1 inhibitors. Dostarlimab is an inhibitor of the Programmed Cell Death Protein (PD-1). Other checkpoint inhibitors have been used for treating patients with melanoma (skin cancer), Hodgkin lymphoma and non-small cell lung cancer. However, none of them has provided the levels of relief and safety demonstrated by the Sloan Kettering study. This explains the excitement about this study.
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Among the key components of the human immune system are T cells. On their surface lie checkpoint proteins; some of which switch on the immune response to fight infections and cancers, while others switch off the immune response when it threatens to become hyperactive and damage the body’s own tissues. While the body tries to maintain a fine balance between these switches, cancer cells may attempt to subvert the process by blocking the action of the proteins that regulate the immune system’s response to a recognized danger. The checkpoint inhibitors can call cancer’s bluff.
Takasu Honjo of Kyoto University in Japan brought the PD-1 gene to global attention, winning the Nobel Prize in 2018 for that contribution. Nils Lonberg in the Silicon Valley in the US has imparted impetus to monoclonal antibody therapeutics. Apart from enabling high volume production of specific antibodies, this inspired a change of strategy from attacking the cancer cells directly with drugs or radiation to helping the body battle and beat cancer with its own troops. This sparked a series of trials against different cancers.
In his book An Elegant Defense (2019), Pulitzer Prize winner Matt Richtel presents an inspiring vision of this strategy: “If it worked, this would unleash the immune system to operate the way it was intended to work. The theory is a marvel. Within days or weeks, the body’s own defenses could destroy a tumor that toxic chemotherapy couldn’t kill over months or years. The locks would be taken off the T cell guns, the cannons unshackled, cancer’s magic trick exposed.” But others are worried about serious adverse effects if an unhinged immune system goes rogue and causes self-harm.
The recent report provided results from a Phase 2 clinical trial, involving patients whose cancer was confined to the rectum, with dostarlimab therapy proposed as an early stage intervention. Long-term duration of protection from recurrence is not yet known and the trial is continuing. Apart from a long follow-up, more patients will need to be recruited into the ongoing study to properly estimate the level of protection and also study any delayed adverse effects. Other researchers too should be able to replicate such results in independent studies.
Why is a larger study needed, when a 100 per cent recovery has been reported in a lethal disease? Small numbers can be misleading while estimating statistical significance. Small numbers in a non-random, purposive sample follow a “Poisson distribution”. In 1983, health scientists JA Hanley and A Lippman-Hand published an article, “If nothing goes wrong, is everything alright”, in the Journal of The American Medical Association. They showed how with a small sample size, a 3/n formula (where n is the sample size) provides an upper estimate of negative outcomes that can possibly occur even where zero failures were actually observed. Going by the Hanley Lipppman-Hand thesis, the zero failure rate reported in the dostarlimab study is statistically compatible with a possible 16.6 per cent rate of treatment failure, because of the small sample size of 18. A larger study would help to shrink the estimate of possible failure.
Despite these caveats, the recent study offers great hope. JBS Haldane, the famous British biologist and statistician, who chose to become an Indian citizen in the latter part of his life and worked at the Indian Statistical Institute, died of rectal cancer. Before his death, he penned a humorous poem that was published in the New Statesman under the title “Cancer’s A Funny Thing.” With dark humor he wrote, “My rectum is a serious loss to me. But I’ve a very neat colostomy”. If dostarlimab continues to demonstrate a high level of success in providing a complete “cure” for rectal cancer, future patients may not know what colostomy is.
The writer is President Public Health Foundation of India. Views are personal