Explained | Why some people suddenly stop responding to chemotherapy

If one puts 10 patients with same type of cancer on the same chemotherapy sessions, 6 would respond to it and four won’t for externally no obvious reason, said an oncologist.

It is easier to imagine cancer as cell pirates hiding in the folds of tissues and escaping the arrows of powerful medicines by a few inches. Scientists are waking up to a new reality where cancer cells are not so helpless and targetable. Though metabolically unstable, they are always on the lookout for more notorious strategies that can disarm the drugs aimed at killing them.

Among the first lines of treatment for most types of cancers are – chemotherapy, radiation therapy and surgery. For some, it could be a combination of all three, depending on the site of the cancerous growth, the stage of disease and if it has spread to other parts of the body. 

Chemotherapy is a powerful group of medicines targeted to kill cancer cells. They are either administered in an oral form or through intravenous fluids. The treatment is planned to destroy the rapidly dividing cancerous cells and if not, shrink them to smaller sizes.

Since these drugs have to invade into the cellular body and target the division, they are inherently aggressive and are associated with DNA damage and inflammation in the healthy cells, an article published in the Nature publications has stated.

As per experts, a lot starts to happen when a person starts with chemotherapy, all healthy cells which divide rapidly like the diseased cancer cells also get a hard hit. 

Some common toxicity symptoms associated with chemotherapy are – hemoglobin drops, platelets fall, hairline recedes, gut lining gets a blow and the body’s natural ability to absorb nutrients and protect itself is largely impaired. The effects of these medicines also accumulate in the internal organs like heart, liver and kidneys.

Some people still respond well to chemotherapy where the medicine is able to get through the cell and interfere in the progression of the disease.

However, for some the cancer starts to become unresponsive to chemotherapy.

Speaking to DH, Dr. Mandeep Singh Malhotra, an oncologist and founder at the Art of Healing Cancer said: “If I put 10 patients with same type of cancer on the same chemotherapy sessions, my safe bet would be that 6 will respond to it and four won’t for externally no obvious reason.”

For years doctors have accepted it but the growing science around cancer has shown them the answer lies in the heart of the cell.

Does chemotherapy have favourites?

Same type of cancer, same stage of the disease and similar treatment protocol but different clinical outcomes - a common problem every oncologist faces on one of their days at the duty.

As per a study, in some patients, particularly ones with advanced forms,  the treatment toxicity is enough to delay the chemotherapy session or having the dosage changed by the attending specialist.

As per cancer experts, a diseased cell is not waiting to be killed but has a mind of its own which is self protective.

Multiple studies have documented how cancer cells can disguise themselves, adapt or resist the incoming medicines. In fact, over years this survival machinery has become even more sophisticated.

There are multiple ways with which a cancer cell can manipulate the attack on them into self preservation.

In some cancer patients, the cancer cells can have special proteins that can flush off the medicine.

“Cancer cells can express proteins on their surface like MDR1 and MRP which can act as pumps. These pumps literally push the chemotherapy drug out of the cell before it can do its job. In this case, the drug is not wrong but it never got a chance to work,” said Dr. Malhotra.

Even if the medicine is able to seep into the diseased cell, the battle is not over yet. Sometimes, the cancer cell can increase the production and activity of certain cellular components that can bind to these medicines and turn them totally ineffective.

“Cancer cells can upregulate an enzyme called GST (glutathione S-transferase). This enzyme binds to the chemotherapy drug inside the cell and neutralises it. The drug reaches the cancer cell, stays inside, but gets chemically inactivated before it can damage the DNA. The cell survives. From the outside, it looks like the chemo isn't working. In reality, the cancer is detoxifying the drug,” the expert explained.

Also, the cancer medicines primarily target the center-seated DNA, comparable to a switch that has to be turned off for the faulty machine to stop working. Studies show some cancer types have efficient DNA repair systems that can undo all the damage done by the anti-cancer treatments and in no time.

For instance, a repair mechanism called ERCC1 (Excision Repair Cross-Complementation Group 1) can fix the bulky DNA damage caused by chemotherapy drugs like cisplatin, a study has stated.

Because the battle is seemingly invisible and happens inside a cell, it can leave both doctors and patients in a state of guesswork and in a limbo about how to proceed.

It is safe to assume that ironically cancer, which is a time sensitive disease, involves a treatment pathway with many U-turns. 

Breathless cells, no symphony 

In an interesting observation, cancer cells outgrow their blood supply and stop depending on oxygen for metabolism. This causes the center of the tumour to become hypoxic (oxygen deprived) and this ‘no oxygen zone’ might suffocate the medicines that need oxygen to function.

“Many chemotherapy drugs need oxygen to generate the reactive species that kill cancer cells. In a hypoxic environment, the drug is simply less effective. These conditions are also known to make the cancer cell more aggressive and resistant. The very cells that are hardest to reach with blood supply are also the hardest to kill with drugs,” said Dr. Malhotra. 

Chemotherapy is designed to kill the rapidly dividing cells, however, not all cancer cells are in the same phase of growth. 

“Some are in highly active states, some in moderate, others are dormant. Chemotherapy can cross right over the dormant cells and they fail to come under its radar. Who knows when the lion wakes up, right? It could be right after the chemo sessions are over. So, speed inconsistency is another problem that is less spoken about,” said Dr. Malhotra.

While doctors can’t say with certainty if a person would respond well to chemotherapy, there are signs as listed by Healthline that could show if the treatment is not working on a patient, including the tumour isn’t shrinking in size, new tumours are emerging, cancer is spreading to other parts of the body or there are other worsening symptoms. 

As per cancer specialists, despite its odds, chemotherapy remains an integral and irreplaceable part of cancer treatment and continues to save lives of many. 

*Disclaimer: Life saving treatments like chemotherapy and radiation therapy are not replaceable and must not be stopped without the instructions of the treating doctor*