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Lung cancer -6- Treatment of stage 4


(All the articles published in past are available at

Question: Thank you Chiragbhai for explaining treatment of stage 3, especially role of PET-CT in proper staging, change of wet 3 B to stage 4 in new staging system, limited role for surgery. It was important to note that most patients are treated by chemotherapy and radiation combination, and that results are as good as surgery with much less morbidity and risk of death. Preferably such patients should be evaluated by a multidisciplinary tumor board or at least a group of doctors, as there are some specific variations of stage 3, which are treated differently. Let us now discuss most common stage, i.e. stage 4, since majority patients present in stage 4.
Ans: Yes, stage 4 is where most patients present, and there have been huge changes in treatment of this stage. Stage 4 is what most people think of as “nothing can be done”. Go home and “seva karo”. For decades, there was nothing major that could be done, hence this negative thinking. However in last about 10 years, especially last 5 years or so has seen approval of so many new medicines, that it is difficult to keep up even for us. But that is good news for patients. Survival has more than doubled compared to 10 years ago. And many more drugs are in advance stages of development.
Que: Can you tell us more about these developments?
Ans: Sure. Earlier we did not even bother much about details of diagnosis, as there was very little to do. We only needed to know small cell versus non small cell histology. Now we have so many tests, since we need to know right target to use the right medicine.
1. Advances started with knowing that there were minor but important differences in response to different chemotherapy agents, for different histology. Currently it is preferable to use Cis or carboplatin plus gemcitabine for squamous cell carcinoma. Whereas cis or carbo plus pemetrexed is preferred for adenocarcinoma.
2. Then came role of maintenance chemotherapy, after initial 4 to 6 cycles of combination chemotherapy. For adenocarcinoma, pemetrexed maintenance has been useful as it is tolerable in long term as well. Similarly, for squamous cell carcinoma, gemcitabine has been tolerated well in long term. Docetaxel has also been used for squamous cell carcinoma, known as switch maintenance, but is well tolerated in fewer patients.
3. First breakthrough in targeted therapy use came with EGFR inhibitors, gefitinib or erlotinib. They work in patients with EGFR mutations, and about 20-40% of adenocarcinoma patients have this mutation (in different studies), more common in women and non smokers (or former smokers). These are oral tablets, very convenient (once a day), and very well tolerated. Only significant side effects are mild diarrhea and acne like rash. Since these are mild, almost always drug can be continued, and with time it improves. Also, rash severity actually correlated with response rate and survival. Hence, more the rash, better it is. Other side effects are rare, and generally not severe, such as asymptomatic rise in SGPT, fatigue, anorexia. These drugs clearly showed in head to head comparison, in several trials, that these tablets were better than chemotherapy in improving survival and in side effect profile, and of course convenience. A new drug in this category is Afatinib, which is a stronger, irreversible, and wider (pan egfr inhibitor) inhibitor of EGFR, with possibly better results, however associated with more side effects (oral mucosits, diarrhea etc) requiring dose reduction in many patients. Our personal experience is also the same.
4. Unfortunately, none of the treatments in stage 4 are curative, and patients invariably develop resistance, sooner or later. Every oncologist however has seen patients who beat the statistics on either side. Average duration of response for EGFR inhibitors is about 8-16 months in different studies, but there are patients who have very short responses or responses lasting 4-5 years or longer. We have also had few such patients, on just gefitinib tablet with excellent disease control for several years, without any chemotherapy. Cost of these medicines is also now reduced to only about 4000-12,000 for different brands, per month. It was about Rs 1 lac plus originally.
5. Now we know how most tumors develop resistance to above agents, i.e. through T790M mutation. And there is a drug which works in such patients in about 80% cases, known as Osimertinib. Test for this mutation is now commercially available, including in India. This is a very recent development. Drug is expensive now, but with time costs come down.

August 9th 2016.

Dr. Chirag A. Shah; M.D. Oncology/Hematology (USA), 079 26754001. Diplomate American Board of Oncology and Hematology. Ahmedabad. Shyam Hem-Onc Clinic. 402 Galaxy, Near Shivranjani, Opp Jhansi ki Rani BRTS, Ahmedabad.

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