COVER STORY

NET concern

Doctors help decode the rare disease actor Irrfan Khan is diagnosed with

INDIA-ENTERTAINMENT-BOLLYWOOD

There is nothing you can’t do Sir Irrfan Khan #Blackmail. Twisted and terrific,” tweeted director Meghna Gulzar. Filmmaker Soumik Sen wrote, “The genius of Irrfan Khan in complex shades of dark.” “Blackmail... a brilliant screenplay, unique story, exemplary performances... from Irrfan Khan... so happy to see such creativity,” commented an ecstatic Amitabh Bachchan. Three days before the release of Blackmail, a dark comedy directed by Abhinay Deo, a group of filmmakers, including Rajkumar Hirani, Amol Gupte, Ashutosh Gowariker, Tanuja Chandra and Pradeep Sarkar, attended a special screening and couldn't stop raving about the film. They were doing their best to promote the film, filling the shoes of its lead actor, Irrfan Khan, who missed the promotion tours.

For all you know a patient might be carrying the tumour for long, before he gets diagnosed with it. - Dr (Prof) V.S. Mehta Paras Hospitals, Gurugram
NETs are most commonly seen in the intestines and liver. - Dr P. Jagannath chairman, department of surgical oncology, Lilavati Hospital, Mumbai

Irrfan, 51, had been looking forward to the release of Blackmail, his “most loved film”, even as he was trying to complete the upcoming American film Puzzle—his next Hollywood venture after Inferno, Jurassic World and Life of Pi. But, his hectic life ground to a halt when he was diagnosed with a rare disease—neuroendocrine tumour. He, along with wife Sutapa Sikdar and sons, Babil and Ayaan, rushed to the United Kingdom for treatment.

It all began in early March when Irrfan—known for his stellar performances in films such as Paan Singh Tomar, Lunchbox, Hindi Medium, Piku and Qarib Qarib Singlle—tweeted, “Sometimes you wake up with a jolt with life shaking you up.... Little had I known that my search for rare stories would make me find a rare disease....” It took 11 days for conclusive diagnosis to come by, and on March 16, he announced, on Twitter, that he had been diagnosed with neuroendocrine tumour. Wishes for a speedy recovery poured in from thousands within a few hours. Over 11 days, there were wild speculations about his health, with some people saying he had brain cancer and others pointing to a brain disease. Perhaps, that is why Irrfan clarified in his tweet that “neuro is not always about the brain”. While the disease did come as a jolt to Irrfan, the fighter in him has come to the fore. Said Sutapa, who was his batchmate at the National School of Drama, “My best friend and my partner is a warrior. He is fighting every obstacle with tremendous grace and beauty. I am grateful to my partner for making me a warrior, too. I am, at present, focused on the strategies of the battlefield, which I have to conquer.”

Dr (Prof) V.S. Mehta Dr (Prof) V.S. Mehta

Neuroendocrine tumours or NETs have a tendency to throw surprises at their victims, said Dr (Prof) V.S. Mehta, who served as the chief of Neurosciences Centre and head of neurology at the All India Institute of Medical Sciences (AIIMS), New Delhi, and is now associated with Paras Hospitals in Gurugram. “For all you know a patient might be carrying the tumour for long, before he gets diagnosed with it. He may be going about his routine life, when one day, all of a sudden, the symptoms start showing,” he said.

NETs grow in the endocrine cells of the vast endocrine system, which makes hormones in the body such as insulin, prolactin and oxytocin, and hence can be found anywhere in the body, including pancreas, stomach, intestines, liver and lungs. “But they are most commonly seen in the intestines and liver,” said Dr P. Jagannath, chairman, department of surgical oncology at Lilavati Hospital in Mumbai. While some NETs are metastatic (the ability to spread to other parts of the body), others are “kind of dormant, which means they don't move from their original spot and don't do much harm to the person living with them,” explained Jagannath, also managing trustee of Crusade Against Cancer Foundation. He cited the example of a 27-year-old NET patient whom he met about a year and a half ago. “A tumour was detected in her small intestine during a routine checkup, and she was referred to us. But the NET in her posed no threat to her active life,” he said, adding that the patient still has the tumour but is living her life as any normal woman would.

Dr P. Jagannath Dr P. Jagannath

Most neuroendocrine tumours grow slowly—over years, not months— compared to other types of tumours. But when they do multiply, they put the life of the patient at risk. Vineeta Motiani, 60, was diagnosed with NET at multiple sites in her body—liver, pancreas and ovaries—ten years ago. “Hers is a peculiar case. We ultimately removed the tumours from her pancreas and the liver, but her ovaries are still carrying NET,” said Jagannath. “As NETs specifically arise from hormone-making endocrine cells, many such tumours are known to make hormones themselves. In Motiani's case, the NET in her pancreas was producing insulin-like substance, which would plunge her sugar levels drastically. That is why she had severe fainting spells.” Her liver tumour was removed surgically, and the one in the pancreas was dealt with a new technique called transarterial radio emulsification, wherein radio isotopes are injected into the artery that destroy the tumour, said Jagannath. “Then, we gave her Everolimus, a new drug that controls the tumour for a long time. Her tumours were grade II throughout,” he said.

Motiani said doctors first thought that she had a problem in the brain. They realised it was a rare tumour after further investigations. She said the tumour in her ovaries, which is grade I, is not bothering her as of now. “When there are symptoms, then we will see,” she said. Jagannath said until the symptoms show, they will not touch the tumour. “These patients can survive 15 to 20 years without any problem,” he said.

But Teena Hiramani (name changed) had severe abdominal pain, which was later diagnosed as NET in the rectum. “Pus had collected inside my abdomen. When the doctors were preparing to drain the pus, they found a tumour lower down behind the rectum,” said the 37-year-old Pune resident. “They took a biopsy, which suggested NET.” The tumour was removed, and since then she has been “feeling quite normal”.

Periodic update courses are conducted for general physicians and gastroenterologists to sensitise them about the spectrum of NET. - Dr Avinash Supe, dean of KEM Hospital, Mumbai
It is impossible to attribute a cause to NET. There are no causes, there are no community preventive strategies. - Dr Sanjay Surase, superintendent, J.J. Hospital, Mumbai

Successful treatment of NETs has been possible only recently, said experts. “We now have the support of technology. Our armoury to treat these types of tumours has improved vastly, of late,” said Dr Ramakrishna Prabhu, gastroenterologist, KEM hospital in Mumbai. Innovations include the PRRT (Peptide receptor radionuclide therapy), a radioisotope therapy used to treat NETs especially in the pancreas. “The best part is that there is an isotope that destroys the cell and there is a carrier. And when this combination is injected into the blood stream, it acts like a magic bullet and destroys the cell without destroying the surrounding area,” said Prabhu. “It is the latest technological innovation, which comes at a fraction of the cost, and is available at select hospitals in India. Earlier, patients would have to go to the Netherlands.” Another innovation is the DOTA-NOC scanning method, which is highly sensitive and specific, for detecting gastroenteropancreatic NETs.”

Dr Avinash Supe Dr Avinash Supe

Moreover, said Jagannath, we are way ahead of the United States in terms of technology, and are in line with Europe, which is ten years ahead of the US. “India has very close links with Europe in the area of NET, and we are also following the ENET (European Neuroendocrine Tumor) Society closely,” he said. “The US has very strict regulations, which have kept it from bringing in the latest advancements and drugs for NET—one reason why Steve Jobs succumbed to it.”

Steve Jobs's NET was not detected on time, said Jagannath. “Jobs was wrongly informed that he had a benign NET. It was only after his death [in 2011] that the medical fraternity learnt that there is nothing called a benign NET tumour,” he said. “There are ones that have metastatic potential and ones that are low grade, but none benign in nature. Moreover, Everolimus was not available when Steve Jobs was suffering from NET. It entered the market during the last stages of his disease.” The US Food and Drug Administration, he said, did permit the import of the drug on humanitarian grounds, but it was too late by then.

Dr Sanjay Surase Dr Sanjay Surase

Jobs's ignorance and complacency, too, cost him his life, said Dr Avinash Supe, dean of KEM Hospital. “In early 2000s when a CT scan had revealed that he had a cancerous tumour in his pancreas and he was advised to get it removed, he put it off, thinking alternative therapies and a vegan diet would make it vanish. By the time he actually got serious, the tumour had grown and spread to his liver. It was not a low grade I tumour.”

But now, things have started to change because of increased awareness, said Jagannath, who also founded the India chapter of Asia Pacific Neuroendocrine Tumour Society. The society maintains a registry of patients with NET in India. Thanks to the registry, doctors realised that the actual number of NET cases was more than what was initially assumed. “Earlier, we did not have a database. So, we thought it was as rare as 2.5 to 5 cases per 1,00,000. Diagnosis often got missed,” said Jagannath. He cited the example of a celebrity who was repeatedly misdiagnosed. “She was treated as a psychiatric patient because she used to get these dizzy spells,” he said.

According to a paper submitted by Jagannath in the Indian Journal of Gastroenterology, he and his team collated data of 407 gastroenteropancreatic NET cases diagnosed from 2001 to 2016, and found that a majority of them were symptomatic. Only 98 patients (24 per cent) were asymptomatic. The most common presentation of non-functional tumours was abdominal pain (42.4 per cent), while functional tumours presented most commonly with carcinoid syndrome (symptoms include skin flushing, facial skin lesions and diarrhoea). Use of DOTA-PET, introduced in 2011, has increased evaluation in 33.3 per cent patients. The most common primary site for NET was the pancreas. Histopathological grading was obtained in 230 patients—118 patients were diagnosed with grade I tumour, 74 with grade II and 36 with grade III NET.

We treat NETs only if the patient comes to us with strong symptoms. If the disease is static, it is better not to touch it. - Dr Prachi Patil oncologist, Tata Memorial Hospital, Mumbai

With better investigating modalities, increasing awareness among both patients and clinicians and an increased utilisation of appropriate and improved diagnostic techniques in imaging and biological tests, the number of [reported] NET patients has gone up,” said Dr Prasad, resident doctor, Lilavati Hospital, and assistant to Jagannath. But as the numbers grew, every field involved in the treatment, including gastroenterology, nuclear medicine, radiology, surgery, neurology and pathology came together to treat NET. Supe said that even now the disease remains under-diagnosed, and that periodic update courses are conducted for general physicians and gastroenterologists to sensitise them about the spectrum of the disease.

The first in the diagnosis line are family physicians and pathologists, who take the immunohistochemistry—identification and diagnosis of NETs through biopsy—and also grade the tumours. “Pathology helps us identify the location of the tumour, its grade, and then we decide the method of treatment. But we treat NETs only if the patient comes to us with strong symptoms. If the disease is static, it is better not to touch it,” said Dr Prachi Patil, oncologist at Tata Memorial Hospital in Mumbai.

The thing about NET, like most cancers, is that you never know when it would rear its ugly head again. Jagannath recounted the case of a patient who was diagnosed with NET in the pancreas with liver metastasis just a few months before his wedding. “Although he responded well to the treatment initially, we tried to convince his fiancée to consider her options. But she was determined to marry him and would hear none of it. That was the only wedding I attended of a patient,” he said. Two years later, his health suddenly took a dip. His suffered from a liver dysfunction. “He was brave enough to ask his wife to separate and remarry,” said Jagannath. “He, along with a supportive family, continued his fight against NET for a good two years after which he died. As it was high-grade tumour we could not do surgery, and used chemotherapy instead.”

Experts agreed that there is no particular cause for NETs. “It is impossible to attribute a cause to NET. There are no causes, no community preventive strategies. You cannot be doing CT scans every time. But symptomatic patients must definitely get a CT scan. And, symptoms must not be neglected. For instance, drastic weight loss cannot be ignored. That's a big red flag,” said Dr Sanjay Surase, superintendent, J.J. Hospital, Mumbai. Also, doctors said it was quite impossible to trace a tumour's timeline, or to point to its start date with precision. “Because growth patterns of tumours are different at different periods of time,” explained Prabhu. Low-grade NETs coexist with the body, and do not destroy their host unless at later stages. But, the high-grade ones are parasitic.

On March 20, with a photo of his reflection, Irrfan shared a poem by Rainer Maria Rilke on Instagram: “Let everything happen to you: beauty and terror. Just keep going. No feeling is final....” Godspeed, Irrfan.