Life-saving drug for liver cancer.....gimmicks or reality

Woke up on New Year morning to read an article in the Hindu about a hospital in Coimbatore distributing a 'life saving' drug for kidney and liver cancer in conjunction with a pharmaceutical company.

The Hindu : Cities / Coimbatore : A life-saving New Year gift for cancer patients

The drug in question 'Sorafenib' has been much in the news in India mainly due to controversy regarding its high costs that has prompted the government of India to allow compulsory licensing to manufacture the drug at lower costs to generic manufacturers in India.

While I may be accused of being a cynic staring a hobby horse in the mouth, I would like to know why such largesse is not extended to other molecules that are effective in much more prevalent cancers in this country. Much larger numbers of patients in this country fall prey to oral, cervical, breast, hematologic and gastrointestinal cancers than kidney or liver cancers. However no such largesse or benevolence seems to be in view with regard to those drugs.

 I hold no brief for the original manufacturers of sorafenib, but it does seem a witch-hunt to single out this molecule for compulsory licensing in order to control costs. One cannot but suspect vested interests behind the move. If such efforts are applied across the board to all cancer drugs, I will be one of the first to welcome and applaud it.

Sorafenib is a drug that inhibits an enzyme that controls intracellular signalling pathways in liver and kidney cells and has been shown to have some effect on patients with primary liver cancer. In the only large trial (SHARP) testing the efficacy of sorafenib in primary liver cancers, patients on sorafenib had their life prolonged by a few months over those that did not receive sorafenib. So to indeed call the drug 'life-saving' is a bit exaggerated based on current evidence. Of course prolongation of life by a few months can be a great deal of comfort for the patient with advanced liver cancer but it must be clearly understood that current evidence does not support the use of drug as a curative measure....hence as the best available evidence stands today the drug is a 'life-prolonging' and not 'life-saving' drug.

The drug once started has to be continued life-long. It is not clear whether this free dole promised to patients will be continued for their life or whether after sometime patients will have to purchase the drug. The article seems silent on this.

The drug no doubt could have potential in combination with other potentially curative treatments like resection or transplantation but this potential has not yet been proven in published literature. The use in these circumstances is investigational and success based on anecdotal reports or single centre studies.

Therefore gimmickry and misplaced populism seems to be the order of the day in such events. 

I wish better sense will prevail among those planning such doles and those clamouring for them. 

Brouhaha over intestinal transplantation......scattering the chaff

There has been a lost of discussion regarding intestinal transplantation in the context of the victim of the brutal gang-rape in New Delhi recently. Irate protestors, politicians, armchair philosophers and all the usual suspects have been clamouring for 'severe punishment' read 'mutilation', 'torture' and 'death' for the perpetrators of this heinous crime. Some members of the medical fraternity have shockingly and appallingly joined voice with their irresponsible and impulsive suggestions for painless 'mutilation' of the accused forgetting that as professionals they are sworn not to do anything to harm a human being.

Media and medical fraternity have been fairly verbose and prosaic in describing the medical condition of the victim with frequent and graphic updates regarding her condition with the need for intestinal transplantation being thrown-in fairly frequently for good measure. There have also been 'ill-disguised' attempts at garnering fifteen minutes of fame and scoring brownie points in certain quarters provoking comments like 'harvesting the rapists intestines to help the victim' among the less informed and emotional public. There have also been sane and sage voices of reason appearing as well but these have been largely drowned out by the raucous cacophony on part of the rabble-rousers. The medical-media circus has culminated in the shifting the ill-fated victim outside the country to an institution that has 'multi-organ transplant facilities' and 'infrastructure' to help the victim recover despite contradicting reports regarding her condition varying between 'repeated cardiac arrests' to 'extremely critical' and critical but stable' depending on which version you choose to believe. The government itself has contradicted itself on the current condition of 'Nirbhaya', 'Amanat' or 'Jane Doe' depending on what you choose to call her .... (why they could not use her first name however boggles my imagination).

As a responsible medical professional privileged to understand the facts, I feel beholden to try and scatter the chaff regarding intestinal transplantation to provide some scientific perspective to the muddled situation created by contradicting and confusing inconsistent statements.

Intestinal failure occurs when there is insufficient surface area of small intestine to digest and absorb nutrients to meet the demands of the body entirely through enteral route. This usually occurs when large parts of the intestine are lost due to massive removal at one sitting or repeated removals. Traumatic injury is a rare cause of intestinal failure. Patients with intestinal failure have massive diarrhoea, dehydration and nutritional deficiencies due to inability to absorb water, fat, protein and vitamins all of which have to be supplemented through the intravenous route (parenteral) for survival. Parenteral nutrition needs to be delivered through large central veins using indwelling catheters.

The intestine has significant but not infinite potential to compensate for loss of length by increasing absorptive mechanisms and allow nutritional independence through a series of intrinsic changes called 'intestinal adaptation'. Extent of adaptation depends on various factors including the residual length, which part has been resected, presence of large intestine, blood supply as well as general health and age of the patient. It is generally believed that the ileum has higher potential to adapt than the jejunum. Most authorities agree than when less than 50cm small intestine is left behind, it is extremely unlikely that the patient will ever be able to be free for parenteral nutrition.

Long term parenteral nutrition has several consequences including line infections, clotting of veins, nutritional deficiencies, fluid overload, hyperglycaemia and development of progressive liver dysfunction any or all of which are life threatening. More importantly this severely impacts the quality of life of the patient and imposes significant costs. Successful transition to home-based and night time parenteral nutrition is not possible in all cases.

Intestinal transplantation is offered to those who fail all attempts at rehabilitation or develop complications of parenteral infections like repeated line infections, fungal infections or who develop extensive clotting of veins precluding continuation of parenteral nutrition or severe liver dysfunction. In the latter case combined liver and intestinal transplantation can also be necessitated.

INTESTINAL TRANSPLANTATION IS NEVER AN EMERGENCY!
Somehow this fact though mentioned in the current context has been drowned out.
What a patient with massive loss of intestine acutely needs is to be kept free from infection and provided optimal fluid volume, electrolytes and nutrients to compensate for loss of intestinal function. It is important that dehydration, electrolyte disturbances and hypotension be avoided as these can further compromise the ability of the residual intestine or even be fatal. Unless the status of the patient can be optimised and rehabilitation on parenteral nutrition achieved there is no question of performing an intestinal transplant in the future.

Intestinal transplant like any transplant requires a donor organ. This may be a deceased (brain-dead or cadaver) donor or a live donor. The former is preferred due to the ability to provide larger length and inherently larger vessels to join. It is not possible to transplant just anyone's intestine. The donor should be 30-50% of the patient's size ( to allow intestine to fit), be of same or compatible blood group and ideally should be HLA matched. SO ASKING FOR HARVESTING THE RAPIST'S INTESTINES MAY NOT BE OF ANY HELP TO THE VICTIM.

Results of intestinal transplant have been improving but are not yet as good as liver or kidney transplant. This is because the intestine is a hollow organ loaded with bacteria and has much larger population of immune cells (lymphocytes ) in its wall than other organs that make it prone to infection and more likely to incite an immune response (rejection) when transplanted. Intestinal transplant is much more resource intensive in the intermediate to long term rather than solid organ transplant. Despite improvement in critical care, infection control and anti-rejection therapy results of intestinal transplantation are 50-65% at 1 year on average ( 70-80% at the best centres) and at 3 years between 40-50% (55-60% at best centers).  THEREFORE UNLESS THEY ARE WILLING TO PROVIDE LIFELONG FREE CARE, A POPULIST OFFER TO FUND AN INTESTINAL TRANSPLANT FOR THE VICTIM IS ONLY WINDOW-DRESSING.

I have the greatest sympathy for the victim's plight and empathise with the outrage it has generated. However while we condemn the incident in the strongest terms and our heart goes out to the victim, it will do us no favour or credit to lose sight of the medical facts!

Will the trickle become a flood

Man donates organs of son knocked down by railway pole - The Times of India on Mobile

After their death, these Kerala villagers want others to live - Hindustan Times

After their death, these Kerala villagers want others to live - Hindustan Times

What a great gesture!

While this fantastic move is inspirational, it may remain at best symbolic.

Head injuries account for about 10-30% of deaths from road traffic accidents. Most of these fatalities are in the age group of 15-45 years, where organ damage from disease is unlikely.Poor infrastructure, trauma and ambulance services mean that only a small fraction of these individuals would reach a hospital in time or in a condition for their organs to be usable.

Unless parallel attempts are made to improve trauma and ambulance services across the country, such salutary initiatives are unlikely to make a dent in the dismal organ donation scenario.

Caveat lector.....Not everything in the papers is fact....Journalist heal thyself!

To manage organ donation well, a course in transplant coordination - Hindustan Times

The accompanying graphic (Hindustan times Delhi 24th September) totally misrepresents the situation regarding organ donation in the city of Delhi. I wish the reporter had taken the trouble to verify the numbers she was getting from her 'sources'. Caveat lector (reader beware) would be my advice. I am sure the reporter meant well, but the figures mentioned could lull the readers into some utopian fantasy and complacency.

If the numbers were true, particularly those at AIIMS, all transplant surgeons and physicians would be clapping their hands in a rapturous delight. These numbers while still far below what is needed, would herald a happy change in the embarrassingly depressing 'real' situation in India.

It is a welcome development that Delhi doctors are being trained in transplant coordination by experts from Barcelona. The province of Catalunya in Spain, where Barcelona lies, has the distinction of the highest organ donation in the world about 35 per million ( It is 25 per million in US and only 0.04 in India). The province of Catalunya is a torchbearer in the field of organ donation and whatever we can imbibe from their protocols will be welcome to shed our title of being a 'selfish nation'. However blindly aping their system is unlikely to work because they have a great penetration of socialised medicine paid for by state insurance while India is struggling with social medicine even in primary care. We will have to take inspiration from them and find locally applicable solutions to shed this dubious distinction.

The plan being worked out indicates that the powers that be have taken initiative to a felt need in the society, but this alone is unlikely to yield dividends. The strategy has to be multi-pronged and should simultaneously target education, legislation, professional training and societal change. A good staring point would be to take measures to restore faith of society in initiatives of the powers that be in looking after their welfare. Unless this faith is restored, we will be hard pressed to change the status quo no matter what rosy hyperbole is presented in the press.

Special 'mirror image' donor saves two in death

Recently a brain dead 49 year old donated his kidneys that could end up saving two precious lives. The supreme gesture should be saluted like every such noble gesture for community benefit. This donor had an anatomical anomaly called situs inversus totalis.

Situs inversus is an anomaly where the organs are placed in mirror image position from their typical orientation (situs solitus). Situs inversus may occur in various levels with total inversion being called situs inversus totalis the more common form is right sided heart (dextrocardia) with situs solitus.

Situs inversus totalis is usually a benign condition though about 20% are associated with Kartegener's syndrome ( infertility, respiratory disease and situs inversus).

Situs inversus being rare causes an unfamiliar surgical environment for the surgeons who may have never encountered such anatomy during their training. When an deceased organ donor has situs inversus it may pose minor problems and the surgeon has to constantly be aware of the altered anatomy to avoid inadvertent injury to vital structures.

When a living donor has situs inversus it can be problematic to position the graft particularly the right lobe which has to be placed in the left side of recipient. This can lead to angulation of the graft that can compromise its outflow by causing kinking. There are few such reports in literature requiring innovative methods like placement of tissue expanders to prevent angulation.

Cadaveric whole liver may need to be rotated 180 degrees to facilitate tension free vascular anastomosis.

Surgeons in the history of liver transplantation have had to innovate frequently to successfully use scarce donor organs successfully.

Ganesha Chathurti.... celebrate the God of Transplantation

According to Hindu mythology, the elephant headed son of Shiva and Parvati is the first recipient of a transplant although it was a xenotransplant ( from non identical species).

According to the story, Ganesha was asked by his mother Parvati not to allow anyone to enter the house while she bathed. When Shiva, Parvati's husband and father of Ganesha, sought to enter the house he was prevented from doing so by Ganesha siting his mother's orders. The enraged Shiva sent several of his minions to force Ganesha to allow him entry but all these were sent packing by the obedient Ganesha. Blinded by rage, Shiva attacked Ganesha and beheaded him for his impertinence. Seeing this Parvati was livid and threatened to curse the Gods for causing the death of her son. In order to placate Parvati, the celestial physician asked the Gods to fetch the head of the first animal they came across which turned out to be an elephant. The elephant head was transplanted onto Ganesha's body and he was given an elixir to drink which may have been a potent immunosuppressant to prevent rejection of the xenograft.

The iconic depiction of Ganesha is the head of an elephant on a pot bellied body which some have likened to the fat deposition resultant from steroid induced immunosuppression.

Ganesha's vehicle the mouse 'Mooshak' has been compared by some to the importance of mouse models in transplant related research.

Although all these could well be considered myths or a figment of a fertile imagination by agnostics and disbelievers, hindu literature is replete with such miracles that today are considered achievable by modern medicine.

In a lighter vein, one of my fellow transplant surgeons commented that Ganesha did not receive the head of an elephant but an elephant received the body of a human being! This made Ganesha the first human organ donor and not transplant recipient!!