KF (S-364) is a 40-year old Indonesian lady. In 2011, she had coughs for more than a year. There was no blood in her phlegm. She took cough syrup but was not effective. In January 2013, she became breathless and found it difficult to climb the stairs. Her problem became more serious and she went to a private hospital in Tangerang. There was fluid in her lungs. Pleural tapping was performed once. But this procedure did not help her much. She was still breathless. Another tapping was done but there was no fluid.

A CT scan was performed and the doctor said there was a tumour. She was referred to a lung surgeon who told her that surgery was not indicated because her lungs could be filled with fluid and there was “not enough preparation” for him to proceed with the surgery.

Not satisfied, KF went to another lung specialist in a Jakarta hospital. Another CT scan was done, specimens were collected, etc., but the specialist could not determine the cause of her problem. The lung specialist suggested that KF’s problem could be due to “jamur” or parasites! KF was prescribed antibiotics. KF was also asked to do a biopsy, which she declined.

KF came to a private hospital in Penang in April 2013. She consulted a lung specialist. A CT done on 5 April 2013 showed:

• Extensive circumferential heterogeneously enhanced lobulated masse in the left hemithorax.
• There is a central fluid / necrotic area seen
• Compression of the left hilar vessels and bronchi
• There is infiltration into mediastinum
• Trachea, oesophagus and heart are displaced to the right side
• Suspicious left pericardial invasion seen
• A faint hypodense nodule seen in segment 8 of the liver measuring 15 mm in diameter.
• Impression:  Large circumferential left hemithorax mass with liver metastasis and suspicious left pericardial invasion. Differential diagnosis: 1. Mesothelioma  2. Bronchogenic carcinoma. 

A biopsy of the left chest tumour indicated poorly differentiated adenocarcinoma infiltrating the chest wall.

Immunohistology report of 20 April 2013 indicated the cells are positive for CK7 only and negative for CK20 and TTF-1.

The lung specialist referred her to a surgeon who told her surgery was not indicated for her case. KF was then referred to an oncologist. KF was prescribed 5 type of medication and one of which was Iressa. KF was asked to go home and try the Iressa and see what happen. If Iressa was not effective, KF would have to undergo chemotherapy.

A week in the private hospital cost RM 21,000. In addition she paid RM 7,000 for the medication inclusive of a month’s supply of Iressa.

KF was told Iressa would cause side effects. And she was not willing to take it. Someone living in the same apartment as she, told her about CA Care. She came to seek our help on 25 April 2013. She presented with the following:

• Difficulty sleeping
• No appetite
• Tiredness and lack of energy
• Difficulty breathing
• Cough throughout the night with white phlegm.

We prescribed KF Capsule A, B, C, D and E. In addition she has to take many teas: Lung 1 and 2, Lung Phlegm, Liver 1 and 2. She was given Cough 5 for her coughs (white phlegm).

What had gone wrong?

1. She went to the hospital in Tangerang. Fluid was tapped out but she did not improve much. The doctor could not say if it was cancer or not. Not satisfied she went to another hospital in Jakarta. Here again there was not much help. One doctor even suggested that the problem could be due to “jamur” or parasites. I wonder how the lung expert could ever give such a suggestion! Anyway the anti-jamur medication did not work for her. 
2. The patient came to a hospital in Penang. After a week stay she was discharged and was still not satisfied. She came to CA Care for help.
3. A week’s stay in the hospital cost her RM 21,000. Did she get any better? The lung specialist could not help. She was referred to a surgeon who could not solve her problem either. The next obvious stop was the oncologist. The oncologist offered five medications one of which was Iressa. The total cost of the medication was RM 7,000. She was told to try out Iressa for a month and see if this could help her!  But she was not keen on Iressa because of the possible side effects. We felt sorry for KF – having made to pay for such an expensive medication which she was not willing to take.
4. Was Iressa prescribed based on “scientific” fact or on a trial and error basis? Immunohistology showed that cells were only positive for CK7 and negative for CK20 and TTF-1. Is this the kind of cancer that would respond to Iressa?  I also do get patients who told me that she/he was asked to take Iressa in spite of the fact that test showed that the cells were negative for Iressa. But the justification given was that even for such “negative” cases Iressa seemed to work on some patients. Looks like we have to throw science out of the window!

Notes on The Epidermal Growth Factor Receptor (EGFR)

According to Kakiuchi et all, Gefitinib (Iressa), has shown potent anti-tumor effects and improved symptoms and quality-of-life of a subset of patients with advanced non-small cell lung cancer (NSCLC). However, a large portion of the patients showed no effect to this agent.  http://www.ncbi.nlm.nih.gov/pubmed/15496427

Lung adenocarcinomas with mutated epidermal growth factor receptor have significant responses to tyrosine kinase inhibitors, although for unselected patients it does not appear to have a survival benefit. Both EGFR mutation and gene amplification status may be important in determining which tumors will respond to tyrosine kinase inhibitors. http://www.jthoracdis.com/article/view/87/152

The tumors that responded to the EGFR TK inhibitors (TKIs) gefitinib and erlotinib contain somatic mutations in the EGFR TK domain. The two most common EGFR mutations are short in-frame deletions of exon 19 and a point mutation (CTG to CGG) in exon 21 at nucleotide 2573. Together, these two types of mutations account for ~90% of all EGFR mutations in NSCLC. Other recurrent but far less common EGFR mutations known to be associated with sensitivity to EGFR TKIs include mutations in exon 18 and in exon 21. Screening for common EGFR mutations in patients with lung adenocarcinomas can now be performed in clinical molecular diagnostic laboratories to predict which patients will respond to EGFR TKIs. It can be performed on archival material as well as on fine-needle biopsies. http://www.nature.com/modpathol/journal/v21/n2s/full/3801018a.html

Predicting Sensitivity to Iressa and Tarceva

Iressa (gefitinib) and Tarceva (erlotinib) were being tested in large numbers of patients with advanced non-small cell lung cancer.  Iressa did not improve overall survival compared to placebo treatment in previously treated NSCLC  patients.

However, about 10% of Western patients treated with either of these drugs had dramatic and sometimes long-lasting responses. Investigators at the Dana Farber Cancer Institute, Massachusetts General Hospital in  Boston, and also at Memorial Sloan Kettering Cancer Center in NYC published results showing that most of these “dramatic responders” had recurring mutations in the tyrosine kinase (TK) domain of the EGFR gene.

In the NSCLC patients who have mutations in the TK domain of the EGFR. This makes the cancer cell exquisitely sensitive to dying when the switch is turned off by a drug like Iressa or Tarceva, and explains why some patients can do so well on these drugs. Although there can be mutations anywhere in the TK domain, only some of them confer sensitivity to the TKIs.

About 45% of sensitizing mutations are what are called in frame deletions in exon 19, making them the most common EGFR mutations. About 40-45% of the sensitizing mutations are point mutations in exon 21. Most of the remaining mutations don’t cause the EGFR to be sensitive to EGFR TKIs.

A point mutation in exon 20 resulting seems to allow the EGFR TK to work much better than normal. Mutations in exon 20 have also been associated with resistance.

Mutations can be detected using sequencing to identify every mutation in the tyrosine kinase domain, whether predictive of responsiveness to TKIs or not. Another method is something called allele-specific polymerase chain reaction (PCR) which can then be detected by a machine. This method only detects 28 of the most common EGFR mutations, but generally requires smaller amounts of tissue than sequencing and has a slightly faster turnaround time. There is also evidence that this method may be more sensitive than direct sequencing.

Quoted from: http://cancergrace.org/lung/2010/10/10/overview-of-molecular-markers-in-lung-cancer/

Read more:  Practical Management of Patients With Non–Small-Cell Lung Cancer Treated With Gefitinib  http://jco.ascopubs.org/content/23/1/165.full