Lung cancer chemotherapy - Iressa is back.

Iressa / Gefitinib was the great white hope on the lung cancer scene about 6 years ago, then faded into obscurity for a while. The problem was that the ISEL study did not demonstrate that this oral chemotherapeutic agent ( a tyrosine kinase inhibitor) was better than placebo in terms of survival benefit. There was, however, evidence of tumour response. That is, tumours seemed to get smaller, but people didn't live longer.

Further studies have demonstrated benefit in more select patient groups - much to the relief, I am sure, of AztraZeneca. The drug has recently been licensed in Australia for use in patients with locally advanced or metastatic non-small cell lung cancer if their tumours express activating mutations of the epidermal growth factor (EGFR) tyrosine kinase.

The IPASS trial, conducted in Asia, demonstrated that, in patients with a previous light smoking or non-smoking history, who had mutations of the EGFR tyrosine kinase and who had not received previous chemotherapy, Iressa was superior to a combination of carboplatin/paclitaxel in terms of disease free survival (9.5 vs 6.3 months). The INTEREST trial demonstrated equivalency of Iressa when compared with docetaxal in patients with locally advanced or metastatic NSCLC who had previously received platinum-based chemotherapy.

It's noteworthy that Iressa is now indicated as a first line chemotherapy in appropriately selected patients (ie those meeting the above criteria). Tarceva/Erlotinib, another EGFR tyrosine kinase inhibitor, is still only licensed for patients whose NSCLC has progressed in spite of first-line platinum based chemotherapy (ie second line). As far as I am aware.

It is bound to become more clear, over the next few months / years, exactly which patients do benefit from these medications - and others like them. Perhaps this will even give us a clearer indication of prognosis in patients with lung cancer.

Andrew

Does lung cancer cause bad breath?

An interesting Oral Presentation given to us at the TSANZ & ANZSRS Annual Scientific Meeting held in Brisbane in March was a presentation called “Exhaled Breath Analysis Characterises Lung Cancer”. This was a study carried out by the Prince Charles Hospital in Brisbane and the University of Queensland.

They used an electronic nose (Cyranose 320) to measure volatile organic compounds (VOCs) in the exhaled breath of three groups of subjects; those who had lung cancer, smokers with a history of >30 pack years, and healthy non-smokers.

Their aim was to identify an exhaled breath VOC profile (‘smellprint’) in lung cancer subjects that discriminates from healthy non-smokers and smokers, aged 60-74 years.

Subjects performed two exhaled vital capacities (10 minutes apart) into a Tedlar sample bag after breathing tidally through an inspiratory port VOC filter for 5 minutes. The samples were analysed using a Cyranose 320.

Their results were that smellprints from lung cancer (n=8) and smoking subjects (n=13) were separated from normal subjects (n=21) with cross validated accuracy (CVV) of 75.9% (p = 0.006) and 97.1% (p <>

They concluded that VOC profiling of exhaled breath using an eNose distinguished healthy subjects from lung cancer and smoking subjects, and between the lung cancer and smoker group, and therefore that the eNose has the potential to be a diagnostic and screening tool for lung cancer.

Previous studies to support this idea have included Gordon (1985) who identified in the exhaled air of lung cancer patients several volatile organic compounds that appeared to be associated with the disease.

Phillips (2003) found that compared to healthy volunteers, patients with primary lung cancer had abnormal breath test findings that were consistent with the accelerated catabolism of alkanes and monomethylated alkanes. He found that a predictive model employing nine of these VOCs exhibited sufficient sensitivity and specificity to be considered as a screen for lung cancer in a high-risk population such as adult smokers.

Machado (2005) concluded that the exhaled breath of patients with lung cancer has distinct characteristics that can be identified with an electronic nose, and that his results provided feasibility to the concept of using the electronic nose for managing and detecting lung cancer.

Testing with an eNose would be a novel, simple, and non-invasive technique to diagnose lung cancer. I look forward to the results of further research.

Heather

PET scanning, in lung cancer and in Ballarat

Professor Alex Pitman from Lake Imaging , at St John of God Hospital in Ballarat, graced us with his presence in Hamilton last night, and provided us with an engaging and informative outline of PET scanning.

PET stands for Positron Emission Tomography. This mode of whole-body scanning is very useful in cancer medicine, having a role in the diagnosis and staging of a wide ranger of tumours. For our purposes, it is an indispensable part of the management of almost all lung cancer.

How does PET scanning work? Now I am no expert in this field. However…. a PET scan is a nuclear-medicine test. It involves the injection of a ‘tracer’ into the patient. In Australia, this tracer is universally F-18 fluoro deoxy glucose, or FDG. Essentially this is F-18 fluorine attached onto a glucose molecule. FDG tracks around the body in the same way as glucose; ie, it is taken up by organs to be metabolized. Tumours take up lots of glucose, but metabolize it pretty poorly – so FDG tracer hangs around in them. The F-18 fluorine bit of FDG is radioactive, and emits positrons, which collide with and annihilate electrons, releasing photons. After the contrast injection, and a bit of a rest, a patient goes throught the PET scanner. The photons are detected by the PET scanner, allowing mapping of the tumour (and the body in general). A PET scan is combined with a CT scan, which allows better visual localization of the tumour within the body.

When do we use it?

1. PET scanning is used in combination with CT scanning and anatomical biopsy for the evaluation of solitary pulmonary nodules. If a nodule is too difficult to biopsy without considerable risk to the patient, a PET scan is a useful way of ‘ruling in’ a malignant diagnosis. In Australia, if a nodule is ‘hot’ on PET scan then there is over 90% likelihood of it being a cancer. (In other countries, fungal infections and TB in particular also often turn up and are hot on PET scan. I have seen a patient with a fungal infection in Australia also undergo surgery because a lesion was ‘hot’ on PET scan, so we need to be a bit careful).

2. PET scanning is also used for staging non-small cell lung cancer prior to surgery. In a patient with lung cancer a PET scan is useful if combined with CT and mediastinal biopsy procedures to evaluate the possibility of malignant involvement of mediastinal lymph nodes prior to surgical treatment. Indeed, a recently published small study has suggested that PET combined with diagnostic CT scan, without mediastinal biopsy sampling, has a very high negative predictive value (NPV) (ie if PET/CT is clearly negative then there is not going to be cancer, NPV in this study 97%) for mediastinal spread, They suggest that PET/CT should be relied on to indicate if a patient with NSCLC is anatomically suitable for surgical resection without the patient needing an invasive mediastinoscopy or endobronchial ultrasound biopsy. However, a study published a couple of weeks earlier suggested that there is considerable risk of false negative and false positive results if PET is relied on alone to evaluate the likelihood of malignant involvement of the mediastinal nodes.

The PET scan operators would very much like us to use PET to re-stage cancer after therapy, and to monitor disease in lung cancer. Medicare will not reimburse PET in those situations (but will for the evaluation of a solitary nodule or for the staging of cancer prior to treatment). The clinical reality is, however, that the benefit of treating recurrent non-small cell lung cancer with radiotherapy and chemotherapy is not sufficient that it can clearly be regarded as a good thing to diagnose recurrent disease early and treat it. That is to say, even if a PET scan picks up recurrent disease, we don’t necessarily know what to do about it. There are some new chemotherapeutic agents that may change the playing field in that regard, but are yet to have their early promise confirmed. If and when they do, the indication for PET scan will become even more broad. For the time being I think that the use of restage lung cancer after treatment routinely would be expensive and indulgent.

Undoubtedly PET scanning has an important, and increasing, role in management of patients with lung cancer. It is terrific for us that there is now a PET scanner in Ballarat. The service they have provided us to date has been excellent. For the benefit of our patients, however, evaluation of the PET/CT in lung cancer still needs to occur in a multidisciplinary environment, with radiologist, nuclear medicine specialist, pathologist, oncologist, thoracic surgeon, respiratory physician, radiation oncologist all present and all able to discuss the patient’s situation. It is difficult to assemble such a team outside of the major metropolitan areas. The team at St Vincent’s Hospital / Peter Macallum in Melbourne have provided a great service for our Victorian patients to date, and continue to do so.

Andrew

Biases that make screening programs look good

Too often lung cancers are diagnosed at a late, untreatable stage, as was the cancer in the CT above. An effective lung cancer screening tool would be great!


Last week I described a recent trial that disappointed, failing to prove that lung cancer screening with low-dose CT (LDCT) saves lives. The designers of this trial are to be applauded for their trial design. They have understood, and tried to avoid, three forms of bias which can make a screening program looks like it is working - when it isn't. These biases have had an impact in the field of prostate and breast cancer screening also - where recent evidence suggests that benefits of screening in some populations (for example women aged 40-50) may have been overstated.

Imagine two people with very small, slow growing, early lung cancers attend different hospitals with indigestion, and are seen by different doctors who manage them independently. One doctor, on the barest provocation, arranges a CT chest for his patient and a small tumour is seen. The other patient does not undergo CT chest. After a run of investigations the first patient has his cancer removed and is followed up for 5 years before being declared free of disease. The second patient is discharged home, but 5 years later presents to his doctor coughing up blood - and a large lung cancer is found on chest xray. He too is treated surgically. Two years later, both patients present to their independent doctors with weight loss and abdominal pain. They are found to have distant spread of cancer and both die 6 months later. The first patient, it seems, survived 7.5 years from the time of diagnosis, the second only 2.5 years. Increasing survival from diagnosis for a lung cancer looks like a good thing, but in this instance survival may not really have been increased; both had cancer at time zero, but only one was diagnosed. This lead to an appearance of increased survival when the cancer was just diagnosed earlier. We call this lead time bias.

The second form of bias is like it. Suppose that a screening program only picks up slow-growing tumours. Suppose aggressive tumours generally make their presence felt clinically within about 6 months and are picked up clinically, and therefore not on screening CT. If a trial predominantly picks up slow-growing tumours then it is possible that a trial will seem to indicate increased survival time in patients undergoing screening only because they are the ones with all the slow-growing tumours. this is called 'length bias'.


Finally, lung cancer prevalence increases with age. It is likely that a number of older people die with lung cancer, rather than from it. This was certainly the finding in the recent Dante trial, the subject of the previous blog. A trial of LDCT screening may pick up, and 'cure', a number of indolent tumours that were never going to make their presence felt anyway. This is 'overdiagnosis bias'.

To overcome these biases it is very important that trials of screening programs are run in a randomised and controlled way. There must be a control group managed in 'usual' fashion. The results of a screening program cannot be compared to historical controls/cancer survival data. And they must be run over an adequate number of years to demonstrate if there really is an overall survival benefit. After all, a screening program that doesn't result in less people really dying from lung cancer, while it may serve to employ lots of people in medical jobs, is in essence a waste of time.

Andrew

Lung cancer screening

Why are we not screening for lung cancer?

So began an editorial in a recent edition of 'The Blue Journal'. In this particular edition, an Italian group was reporting on the DANTE trial, which investigated - in a randomised and controlled structure - the use of low dose CT scanning (LDCT) as a screening tool for lung cancer.

Now, although - as previously blogged - lung cancer is the leading cause of cancer death in our community, discussions about lung cancer screening don't rate a mention in the mainstream news. (Contrast this with prostate, breast, cervical and bowel cancer for example).

Efforts to determine whether our new, super-duper, multi-camera CT scanners can be utilised to screen for lung cancer have - to date - fallen over at the first hurdle. While they have demonstrated, repeatedly, that if you perform CT scans on lots of middle-aged smokers you identify lots of asymptomatic, early, curable tumours they have not yet proven that taking out these tumours saves lives.

The recent study has struggled at the same point.

What did they do? A total of 2,472 men aged 60 to 75 years, with at least a 20 pkt year smoking history (a packet a day for 20 years equivalent) were randomised to either a baseline LDCT scan and annual LDCT scans over 5 years, or else a baseline chest xray with annual clinical review. The current data cover follow up over a mean of 33 months (ie not a very long time yet).

What did they find? They found 60 patients (4.70%) with lung cancer in the LDCT group (63 cancers in total - some patients had more than one). Twenty-eight cancers were found in the initial scan ( ie over 2% of these people had cancers they didn't know about to begin with ), 25 were found on subsequent scans and ten were found because people developed symptoms between their annual scans. In the control group, they found 36 cancers in 34 patients; 8 at basline, 3 at routine review and the others because patients developed symptoms.

What did they do next? Lots of intervention! Thirty-nine of the 60 patients in the LDCT arm with cancer had resections, and of these 36 were complete resection. In the control group it was 18 of 34 resected, 17 completely. In the LDCT group there were 96 invasive procedures, vs 36 in the control group. As the investigators put it ''we performed three times as many invasive procedures and found twice as many lung cancer cases with LDCT than without it, ...(but) .. the absolute numbers of advanced and lethal lung cancer cases were unfortunately identical in the two arms.....moreover a significant proportion of major surgical procedures (13%) were performed for pulmonary lesions that ultimately turned out to be benign..."

What happened next after all that intervention? Mortality rates in the groups are identical to date. Put in plain English, the same number of people died in each arm of the study.

So, LDCT screening for lung cancer in asymptomatic patients with no history of cancer detects nearly twice as many cancers as a 'chest xray and annual specialist review' approach, leads to a raft of invasive and expensive interventions, and has not been proven to save any lives. Yet.

Andrew

Lung cancer news

Lung cancer is a terrible disease, with a significant impact on our community. The attached graph demonstrates mortality rates from lung cancer in Australia over the 94 years to 2004, per 100 000 people. Notice how the peak in deaths from lung cancer amongst men seems to be falling, where amongst women it has risen and -perhaps - plateaued. The late rise amongst women probably represents women taking up the right to smoke in the years around WWII.

In Australian women, lung cancer passed breast cancer as the most common cause of cancer deaths amongst woment - back in 2005. More than 50 Australian women die each week from lung cancer.

If picked up early, there is an 80% chance of being able to cure most lung cancer (Non-small cell lung cancers - NSCLC). However, most lung cancer is not picked up early. If not picked up early, the chance of a cure rapidly falls to below 20%. Generally a cure is only possible if the cancer, and any involved lymph nodes, can be surgically resected.

There has been some noise this week about a new-ish oral chemotherapy agent, Erlotinib (Tarceva). (Erlotinib is an inhibitor of epidermal growth factor (EGFR) tyrosine kinase). Presentations at the 13th World Conference on lung cancer have reported increased disease - free survival if this agent is used immediately following the standard accepted (platinum based) chemotherapy regimens for advanced non-small cell lung cancer. These studies looked at patients who received chemotherapy for NSCLC and did not demonstrate progression of tumour while receiving chemo. This does seem to be progress.

Erlotinib was initially licensed for use in patients who had failed first line chemotherapy (tumours got bigger on chemo) Trials indicated that in this patient group it increased median survival from 4.7 to 6.7 months, and 12 month survival from 21% to 31% of patients. Those numbers don't really float my boat, and are difficult to explain to patients. The recent Saturn trial, however, seems to demonstrate somewhat more impressive results. As always, it's hard to translate chemo / cancer trial results into real life. This trial, however, showed a 41% increase in disease free survival, and a 23% improvement in overall survival (the latter in patients without EGFR mutations - who constitute the bulk of patients with NSCLC but who are considered to respond less well to this sort of EGFR inhibitors). Precisely what these numbers mean in terms of years / months lived and numbers of people surviving is less clear. It is likely, however, that the numbers are more meaningful clinically than the results from the earlier trials, which applied to cancers that progressed on initial chemotherapy.

Erlotinib seems to cause generally tolerable side effects (rash and diarrhoea mainly), and is taken as a tablet once a day. It is likely to be most beneficial in patients with EGFR mutations, and the benefit in those patients has not yet been reported. However, tumours probably become resistant over time. In spite of that misgiving, and the cost - $3300 in Australia per month at present - it is starting to look as if Erlotinib is going to have a continued place in the treatment of advanced non-small cell lung cancer. Hopefully that will be good news for cancer patients.

It certainly seems to be creating a bit of buzz for Roche shareholders.

Andrew