Lung cancer is one of the most common cancers in the world, and one of the hardest to survive. To date, it remains the number-one cancer-killer in the US, with a five-year survival rate of just 15%. Because development is often advanced at the time of diagnosis, many are classified as inoperable.

While certain patients do show improvements under an aggressive chemotherapy and radiotherapy regime, it is notoriously difficult to identify these patients. Likewise, it is hard to tell which patients have more aggressive tumours and could benefit from further treatment.

It therefore came as a welcome development when, in October 2013, a new study in the Journal of Clinical Oncology showed that fluorodeoxyglucose positron emission tomography (FDG-PET) scans were a reliable predictor of prognosis. This study, a multisite trial funded by the National Cancer Institute, was led by the American College of Radiology Imaging Network (ACRIN) in collaboration with the Radiation Therapy Oncology Group (RTOG). It took place at 60 cancer centres across the US, and enlisted 250 patients with non-small-cell lung carcinoma.

The study used PET scans to assess the patients’ tumours before and after a combined treatment of chemotherapy and radiation. Unlike CT scans, which merely show the anatomy of an area, a PET scan displays changes in metabolic activity caused by growing cancer cells. A radioactive sugar molecule, FDG, was administered, causing areas of activity to light up on the scan and helping to pinpoint the disease.

"The use of PET scans is increasing, especially for lung cancer, but it’s also used for other types of cancers following radiation or chemo therapy."

Rather than simply assessing the scans by eye, the research team used a metric known as standardised uptake value (SUV) to determine how much FDG had been absorbed. While this metric is controversial, in this study it strongly correlated with patients’ survival rates: the higher the SUV, the greater the risk of the cancer recurring. As the benefits of PET scans become clearer, they are also fast becoming the go-to option in oncological imaging. Dr Mitchell Machtay of the University Hospitals Seidman Cancer Center, Ohio, US, was able to expand on the subject.

Medical Imaging Technology: Could you provide some background? What was your rationale for conducting the trial?

Dr Mitchell Machtay: Following radiation therapy to the chest, there are a lot of changes to the lung tissue that make it difficult to tell whether the radiation worked. The standard way of evaluating patients following radiation is a CT scan, but the results are always extremely abnormal with a lot of inflammatory effects and fibrosis. We call this radiation pneumonitis, radiation lung injury or radiation pneumonopathy.

We hypothesised that using a PET scan would be able to tell us which patients following radiation treatment still had active malignant growing tumours in the area we had treated. It would be a prognostic hallmark that would tell us reasonably early on if there was a chance of that patient becoming a long-term survivor.

These are patients with stage III inoperable lung cancer, but we still consider them potentially curable. With this aggressive combination of radiation and chemotherapy, about 20% of patients who are fit enough to undergo therapy will survive over five years.

What were you exploring in the study?

Well, what’s different about our study is that we wanted to go beyond having the radiologists look at the PET scans qualitatively. We were trying to analyse whether a more scientific, mathematical way of assessing the PET scans would be prognostic, and that’s called the standardised uptake value [see ‘Standardised uptake value’, below]. Essentially, it is a numerical scale of how hot the particular lesion appears on a PET scan.

It’s controversial – some people have used the term ‘silly useless value’ for SUV, because it is prone to technical variations depending on what type of PET scan is used, and what time the injection of radioactive tracer is given relative to the imaging. The patient’s glucose levels can affect the SUV, along with quite a few other things. So we wanted to explore this method in the study – can the SUV as found on a PET scan following chemo radiation be associated with survival?

What did you find?

We found that there is an association: the higher the SUV, the lower the survival. And so it was statistically significant. On the other hand, we were not very successful in identifying the useful cut-off for the SUV. So, from the point of view of the critical usefulness of calculating SUV following treatment, there’s still uncertainty.

We did do a secondary, exploratory analysis looking at some cut-offs, and some of our work suggested that if you use a cut-off of 5.0 or 7.0 then that may be a useful marker for predicting survival. But we’re not convinced yet that those values are robust enough that you can say with certainty whether somebody is going to have a bad outcome. It’s suggestive but not conclusive.

What was interesting about the study from a technical perspective?

We think it is quite interesting to use SUV as opposed to a qualitative review of the PET scans. We showed that many centres are perfectly capable of doing SUV measurements and, for the most part, the local institution assessments of SUV were confirmed by a central review.

"Functional imaging studies such as PET scans are the future of distinguishing active tumours from post-radiation changes and injury."

We are doing some exploratory work since we have all these three-dimensional data sets exploring some other potential imaging biomarkers. An example of that would be metabolic tumour volume, which takes into account how hot the lesion is on a PET scan and the volume of the lesion based on the PET scan.

We think that might be a better prognostic factor, but that work is still in progress using a retrospective view of the data. The way we used it in this study, SUV is just a single snapshot, and it might not be robust enough alone to give us all the information about the lesion.

What are the advantages of using PET as opposed to CT scans to evaluate patients?

CT scans are purely anatomic imaging. Following aggressive radiation, a CT scan shows a large area of abnormal signal that looks like a mass. And that certainly could be active growing malignant tumour, but it could also be a large area of radiation injury to normal tissue. There’s really no way to distinguish that by CT scan because it does not take into account any of the physiology of the region of interest.

So, functional imaging studies such as PET scans, in my view, are the future of distinguishing active tumours from post-radiation changes and injury. The use of PET scans is increasing, especially for lung cancer, but it is also used for other types of cancers following radiation or chemo radiation. In my own practice, we use it quite a bit in head and neck cancer, for example.

What sort of follow-up studies might be useful?

Even though we showed this strong statistical correlation between SUV and survival, we were not successful in defining a true cut-off point, above which you can say with complete confidence that it’s a tumour and below which you can say with confidence it’s not a tumour. So there’s still a lot of work to be done in order to make this more clinically valuable.

But, at this point, I think the findings on an SUV result on a PET scan can be useful in helping the clinician understand whether the patient has a better or worse prognosis. We’re working on it in a number of different ways; one is to go back and do retrospective analyses on this particular database, to see if there are other parameters that we can develop that might be more prognostic than SUV. And an example of that is metabolic tumour volume.

We have also developed a follow-up study. It is a collaboration between the RTOG and the ACRIN, also looking at patients with inoperable lung cancer, and it is novel.

We’re doing the PET scans not just after the radiation and chemo is completed, but also about halfway through the course of radiation. So it is an early look at the metabolism and physiology of the tumour during the fourth week of radiation and chemo. We believe that patients who have a rapid response to shrinkage of the metabolic volume, a decrease in the SUV, will have a better outcome than patients whose tumours haven’t changed much during that fourth week.

We’re also taking this a step beyond, and not just using it as a prognostic biomarker. We are trying to focus the radiation beams more intensely on the area of the scan that is still hot. And that area will get what we call a boost dose of radiation, which we think will have a better chance of sterilising the cancer.

In addition to standard PET scans, a subset of patients is going to get another type of PET scan using a radioactive tracer that identifies regions of tumour hypoxia. We believe this is a marker of tumour resistance to radiation and chemotherapy, and also a marker of a more aggressive cancer.

What are the implications for patients with inoperable lung cancer?

I believe there’s value in doing PET scans following chemo or radiation, and I’m not just basing that on this particular study, but on other investigator studies and my own clinical experience. And the PET scan following radiation can help in counselling patients, it can help in advising patients whether to undergo another biopsy, and, in some cases, it can help determine if the patient needs to go on to another treatment.